Matthew P.

Lungren
Michael R.B. Evans

Contemporary
Editors

Dental Medicine
Clinical
Pharmacology
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Subtitle for
Evidence-Based Considerations
Clinical
Arthur H.Medicine
Jeske Covers T3_HB
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Contemporary Dental Pharmacology
Arthur H. Jeske
Editor

Contemporary Dental
Pharmacology
Evidence-Based Considerations

Second Edition
Editor
Arthur H. Jeske
UTHealth School of Dentistry
Houston, TX, USA

ISBN 978-3-031-53953-4    ISBN 978-3-031-53954-1 (eBook)

https://doi.org/10.1007/978-3-031-53954-1

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Preface

Up-to-date clinical-scientific information remains an absolute requirement

for the healthcare practitioner, and dental education is now undergoing a
transformation that reflects this. In dental schools around the world, the pro-
fession is moving academically from a discipline based ontradition and expe-
rience to one that still requires the practitioner’s psychomotor skills and
judgment and the needs and preferences of the patient, and which also must
integrate new research findings and scientific validation of procedures, mate-
rials, and patient management.
And perhaps no other component of dental education requires more fre-
quent scientific revision of information than pharmacology. The basic array
of medications used in dentistry has changed little in the past 100 years—
local anesthetics, analgesics, and antibiotics comprise the majority of drugs
administered to and prescribed for dental patients. However, practitioners
who graduated from dental school just 10 years ago must now revise their
prescribing patterns to reflect an ever-growing list of new classes of medical
drugs and new information on optimal effectiveness.
There are four major objectives of this book:

1. Update the advanced dental practitioner on current, high-level scientific

information regarding traditionally prescribed dental drugs.
2. Provide the advanced dental practitioner with important information on
selected classes of medically prescribed drugs for cardiovascular disease
(e.g., novel oral anticoagulants) and neurologic conditions, with special
emphasis on incorporating this information into safe and effective patient
management.
3. Identify the most important sources of information on the dental and med-
ical drugs covered, in order to enable the advanced dental practitioner to
periodically assesses new scientific information.
4. Summarize the state of current scientific evidence for the use of basic
dental drugs, including the level(s) of evidence for their applications and
the strength of recommendation taxonomies (SORT), when those are
available.

This second addition focuses on the medications most frequently pre-

scribed in dentistry, as well as important classes of agents which often dictate
changes in both regular dental treatments and dental pharmacotherapy, such
as anticoagulant/antiplatelet agents and drugs for neurologic disorders, and

v
vi Preface

we are pleased to present a new chapter on biologic drugs. We are pleased to

add two new chapters to the book, with up-to-date information on pediatric
considerations and biologic agents. Rather than serving as a comprehensive
pharmacology textbook, this book is designed to provide the practitioner with
scientific evidence and assess the current evidence-based indications, contra-
indications, etc. for the drugs included. Finally, it is hoped that the reader will
utilize the internet-based resources found in Chap. 11 to build upon the infor-
mation presented in the book and continue to consult the scientific literature
in the future management of patients.

Houston, TX, USA Arthur H. Jeske

Contents

Introduction to Contemporary Dental Pharmacology

and Special Topics������������������������������������������������������������������������������������   1
Arthur H. Jeske
Local Anesthetics��������������������������������������������������������������������������������������   9
Arthur H. Jeske

Non-opioid Analgesics in Dental Practice���������������������������������������������� 25
Arthur H. Jeske

Opioid Analgesics, Benzodiazepines, and Other Controlled
Substances������������������������������������������������������������������������������������������������ 33
Arthur H. Jeske
Antibiotics and Antibiotic Prophylaxis�������������������������������������������������� 43
Arthur H. Jeske

Pharmacologic Management of Patients with Drug-Related
Coagulopathies ���������������������������������������������������������������������������������������� 53
Issa A. Hanna, Alfredo R. Arribas, Amir All-­Atabakhsh,
and John A. Valenza

Pharmacology of Psychiatric and Neurologic Drugs���������������������������� 79
Miriam R. Robbins

Endocrine Drugs of Significance in Dentistry �������������������������������������� 95
Arthur H. Jeske
Pharmacologic Treatment of Common Oral Mucosal
Inflammatory and Ulcerative Diseases�������������������������������������������������� 103
Nadarajah Vigneswaran and Susan Muller

Pediatric Considerations in Clinical Pharmacology ���������������������������� 123
Cristiane S. Fonteles
Biologic Agents ���������������������������������������������������������������������������������������� 145
Katherine France
Basic Emergency Drugs and Non-­intravenous Routes of
Administration ���������������������������������������������������������������������������������������� 157
Arthur H. Jeske

Internet Resources for Dental Pharmacology �������������������������������������� 165
Arthur H. Jeske
vii
About the Author

Arthur H. Jeske is a professor (tenured) in the Department of General

Practice and Dental Public Health at the University of Texas School of
Dentistry at Houston, where he is also Associate Dean for Strategic Planning
and Continuing Dental Education. He is Fellow of the International College
of Dentists, the American College of Dentists, the Academy of Dentistry
International, and the Pierre Fauchard Academy. Dr. Jeske is a Consultant to
the American Dental Association’s Council on Scientific Affairs and has
served as an Evidence Reviewer for the American Dental Association
Center for E­ vidence-­Based Dentistry. He is the Pharmacology Section Editor
for The Journal of Craniomandibular & Sleep Practice and has served as
­Editor-in-Chief for the 8th through 14th editions of Mosby’s Dental Drug
Reference. Dr. Jeske is also a general dentist with over 40 years of clinical
experience.

ix
 Introduction to Contemporary
Dental Pharmacology and Special
Topics

Arthur H. Jeske

 he US Food and Drug

T form requires additional preparation (e.g., recon-
Administration Drug Approval stitution into a suspension), that information is
Process also found in this section.
Clinical Pharmacology. All of the pharmaco-
The dental profession is able to incorporate kinetic information about the drug is found here
evidence-­based information into the use of drugs (e.g., peak blood levels, maximum serum con-
owing to the considerable scientific data gener- centrations), as well as routes of metabolism and
ated by the US government’s Food and Drug excretion. The specific actions of the drug are
Administration Drug Approval Process (www. also found in this section (e.g., bacterial suscepti-
f d a . g ov / D r u g s / D eve l o p m e n t R e s o u r c e s / bility data for antibiotics).
Labeling/ucm425415) as illustrated in Fig. 1. Indications and Usage. This section lists the
Monographs produced as labelling informa- various conditions for which the drug has been
tion for drugs approved for the US pharmaceuti- approved for therapeutic use, including indica-
cal market contain detailed information about all tions for its use in combination with other
FDA-approved agents and .pdf versions of the approved drugs. Uses not included in this list
entire document can be easily accessed using the would be considered as “off label,” meaning that
following internet search term: the drug was not specifically approved by the
fda prescribing information [drug name] FDA for such a use.
Contraindications. The conditions under
These documents are organized in the follow- which the drug should not be used are described
ing format: in this section, such as allergy, and known dis-
Description. The official chemical name of eases which may be worsened by administration
the drug and its structural formula are found here, of the drug.
along with detailed descriptions of all of the Warnings. Serious outcomes (e.g., potentially
ingredients found in all of various dose forms of fatal), which can occur as a result of administra-
the drug. Additionally, the dose forms and their tion of the drug, are listed in this section, along
imprinted information are described. If the dose with a description of the emergency measures
which must be undertaken to manage the adverse
outcome(s). Signs and symptoms of the develop-
A. H. Jeske (*) ment of these serious outcomes may also be
UTHealth School of Dentistry, Houston, TX, USA
e-mail: [email protected]
included in this section.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 1

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_1
2 A. H. Jeske

Fig. 1 Biopharmaceutical Research and Development http://phrma-­d ocs.phrma.org/industryprofile/2018/

Process. (Reproduced with permission, Pharmaceutical pdfs/2018_IndustryProfile_DynamicResearchand
Research and Manufacturers of America (PhRMA. The DevEcosystem.pdf
Complex Biopharmaceutical R&D Process. July 2018.

Precautions. This section is comprised of a system, and special notes about adverse reactions
detailed list of preexisting conditions that may observed when the drug is used in combination
limit or preclude the use of the drug, recommen- with other agents are included.
dations for laboratory tests that may be indicated Overdosage. Instructions for managing over-
to monitor the development of adverse outcomes, dose are generally provided in the first part of this
drug interactions, drug-laboratory test interac- section, and specific outcomes from various levels
tions, possible carcinogenic and mutagenic effects of intoxication are described. Also included is
of the drug, and effects of the drug on fertility. information on the ability of the drug to be removed
This is also where the “Pregnancy Category” of by appropriate measures, for example, hemodialy-
the drug is found. Possible adverse outcomes sis and the use of antidotal (reversal agents).
result from the use of drug during labor and deliv- Dosage and administration. Doses for adults
ery, and nursing is also described here, and pre- and special populations for the drug’s
cautions required for special populations indication(s) are listed here, both in gross dosage
(pediatric, geriatric) are described. Finally, units (e.g., adults 500 mg) or weight-adjusted
“Information for Patients” is provided here, dosage (e.g., mg/kg/day for children >3 months).
including dose intervals, duration of therapy, and Recommendations for variations in dosage are
the need for compliance with dosing instructions. described in this section, including recommenda-
Adverse reactions. All of the possible untow- tion for patients with impaired renal and/or
ard reactions to the drug are listed here, along hepatic function, hemodialysis patients, and, if
with their incidence derived from clinical trials. appropriate, instructions for mixing products that
These adverse reactions are organized by organ require reconstitution.
Introduction to Contemporary Dental Pharmacology and Special Topics 3

How supplied. This section describes all of When interpreting various types of scientific
various dose forms and strengths of the drug, evidence, it is important to keep in mind the defi-
with their respective NDC code numbers, and nitions of various types of studies and evidence,
recommendations for storage conditions. as follows.
Clinical studies. The outcomes from signifi- Meta-Analysis. A statistical analysis that
cant clinical studies used to develop specific dos- combines or integrates the results of multiple
ing recommendations, combination uses, etc. are independent clinical trials considered by the
included in this section. These data are very analyst(s) to “combinable” to the level of re-­
detailed, statistical format to inform practitioners analyzing the original data in a single data pool,
about the evidence for use of the drug for these an approach also referred to as quantitative
conditions. synthesis.
References. List of references for laboratory Systematic Review. A review of a body of
standards, special uses, etc. is found here. data that utilizes explicit methods to locate the
Trademark/copyright date information. relevant, primary studies applicable to a specific
research question and explicit criteria to assess
their quality (including risk of bias, etc.).
Evidence-Based Dentistry Randomized Controlled Trials (RCTs).
Studies in which individual participants (subjects)
The current definition of evidence-based den- are allocated to a control group and an experimen-
tistry, as promulgated by the American Dental tal group who receive a specific intervention
Association, is: (treatment). The two groups are otherwise identi-
an approach to oral healthcare that requires the cal for any significant variables. The groups are
judicious integration of systematic assessments of followed (assessed) for specific therapeutic end-
clinically relevant scientific evidence, relating to points used to measure the efficacy of a given
the patient’s oral and medical condition and his- treatment when compared to the controls.
tory, with the dentist’s clinical expertise and the
patient’s treatment needs and preferences. Cohort Studies. In these studies, groups of
people are selected on the basis of their exposure
Various types of evidence are generally pre- to a particular agent or condition and followed
sented as a pyramid, with the lowest (weakest) for specific outcomes at various intervals.
levels of evidence at or near the base of the pyra- Case Control Studies. Individual patients
mid and the highest (strongest) levels at the apex (cases) with a specific condition are matched
of the pyramid, as shown in Fig. 2. with controls (without the condition), and a retro-
spective analysis is used to evaluate difference
between the two groups of cases.
Case Study. A report based on a single patient
(case) with a specific condition and having had a
specific intervention or having been followed
over a specific period of time. Multiple cases may
be reported in a single publication as a short
series of cases.
Expert Opinion, Anecdotal Evidence.
Evidence generated as an opinion from a thought
leader or expert in a given field of study, typically
based on the expert’s clinical experiences in a
variety of individual patient cases which were not
standardized or controlled. Stronger expert opin-
Fig. 2 Evidence pyramid showing hierarchical relation-
ships between various levels of evidence (strongest evi- ion is based upon groups of experts achieving
dence with lowest bias at apex). (From (Higgins 2011) consensus through rigorous discussion of avail-
4 A. H. Jeske

able case and treatment information, frequently priately. Hyposalivation is a common exam-
under the auspices of a respected professional ple of this, and the patient and/or the patient’s
organization. primary caretakers must be alerted to this con-
As noted above, this textbook was developed sideration and should play a role in minimiz-
to present current or very recent, high-level sci- ing the impact of these conditions, primarily
entific evidence about the use of drugs in den- through effective oral hygiene.
tistry, and about specific types of medical drugs 5. References should be consulted to obtain
which may impact the use of dentally-useful detailed information about the management
therapies. As such, it represents a synthesis of of patients with special needs (Wasserman
high-level scientific evidence by experts and not 2009).
opinions of experts.

Medication-Related Osteonecrosis
Special Considerations of the Jaw
in the Administration
and Prescription of Medications In 2014, the American Association of Oral and
in Dental Patients Maxillofacial Surgeons (AAOMS) updated its
Position Paper on Medication-Related
There are several critical factors which the den- Osteonecrosis of the Jaw (MRONJ), formerly
tist must take into consideration prior to the termed “bisphosphonate-related osteonecrosis
administration or prescription of a drug. These of the jaw (BRONJ) (American Association of
include (Jeske 2017): Oral and Maxillofacial Surgeons 2022). This
update expanded the list of drugs known to be
1. Use of a medical drug(s) by the patient. The associated with an increased risk for MRONJ,
use of a drug prescribed by a physician indi- including antiangiogenic drugs (e.g., deno-
cates the presence of a systemic medical sumab, Prolia®) and corticosteroids. The
condition that may predispose the patient to updated document provides estimates of risk for
serious adverse drug-drug interactions and MRONJ, comparisons of the risks and benefits
may limit the patient’s ability to tolerate of medications related to osteonecrosis, and
dental appointments, particularly stress. The guidance for clinicians on the differential diag-
prescribing physician(s) should be involved nosis of MRONJ and prevention measures, as
in the determination of the patient’s ability well as management strategies for patients with
to tolerate specific dental procedures, par- disease-stage MRONJ.
ticularly those categorized as American According to the AAOMS document, risk for
Society of Anesthesiologists’ Physical MRONJ is increased in cancer patients who have
Status Classification III or IV. been treated with zoledronate (Reclast®,
2. Any changes to a patient’s medical drug ther- Zometa®) and anti-angiogenic monoclonal anti-
apy must be done by the prescribing physi- bodies (e.g., denosumab) and tyrosine kinas
cian, especially as this relates to drugs for inhibitors (e.g., sunitinib, Sutent®), although the
serious neurologic and cardiovascular dis- incidence is lower in patients treated with the
eases, such as elevated risk of thromboembo- same drugs for osteoporosis.
lism if antiplatelet or anticoagulant therapy is Local risk factors for MRONJ include opera-
modified. tive treatment (e.g., tooth extraction), anatomic
3. Vital signs and other appropriate physical features (e.g., mandibular bone supporting a com-
assessments should be made at any dental plete denture), and concomitant oral disease (e.g.,
visit in which a drug will be administered. inflammatory dental diseases, periodontitis).
4. The adverse effects of medically prescribed The AAOMS position paper provides addi-
drugs must be monitored and managed appro- tional information on genetic, demographic, and
Introduction to Contemporary Dental Pharmacology and Special Topics 5

systemic factors in MRONJ and a summary of mation on the management of patients with
dental management strategies for patients at-risk established MRONJ.
of MRONJ, including the following:

• Extraction of non-restorable teeth and those Biologic Therapies

with a poor prognosis prior to initiation of
antiresorptive/antiangiogenic therapy More detailed coverage of biologic therapies,
• Elimination of mucosal trauma caused by such as monoclonal antibodies, can be found in a
removable prostheses separate chapter of this book. Monoclonal anti-
• Consultation with the patient’s physician(s) in bodies, anti-TNF agents, and other preparations
order to follow patient-specific MRONJ-­ are now in widespread use and account for a rela-
prevention protocols tively high proportion of drug sales in the United
• Maintenance of good oral hygiene and dental States. While limitations on their use frequently
care include the need for injection, they have had a
• Avoidance of dental implant placement in significant impact on the management of several
oncology patients receiving intravenous anti- important disorders, particularly rheumatoid
resorptive or antiangiogenic medications arthritis and Crohn’s disease. They are generally
large proteins that can be manufactured via
For patients taking oral bisphosphonates (e.g., recombinant DNA methodologies. As the num-
alendronate, Fosamax®), specific guidance for ber of these agents increases, their impact on
cases based on length of medication use includes dental care and dental drug therapy will become
the following: clearer. At this time, the reader is provided with a
current list of examples of these in Table 1 agents
• For individuals who have taken an oral to call attention to the very serious diseases for
bisphosphonate for less than 4 years and have which biologic therapies are indicated. The types
no clinical risk factors, no alteration or delay of agents may be recognized generally by the suf-
in planned oral surgery is necessary (this fixes of their official (“generic”) names, for
includes any and all procedures common to examples, “-mab” indicates “monoclonal anti-
oral and maxillofacial procedures, periodon- body,” “-ib” indicates “inhibitor,” etc.
tists, and other dental providers). Biologic agents can be classified as follows,
• For those patients who have taken an oral based on their specific targets:
bisphosphonate for less than 4 years and have
also taken corticosteroids or antiangiogenic 1. T-cell modulators (e.g., abatacept, Orencia®)
medications concomitantly, the prescribing 2. B-cell cytotoxic agents (e.g., rituximab, Rituxan®)
physician should be contacted to consider dis- 3. IL-1 (interleukin) blockers (e.g., anakinra,
continuation of the oral bisphosphonate (“drug Kineret®)
holiday”) for at least 2 months prior to oral 4. Anti-IL-6 receptor antibody (e.g., tocili-
surgery, if systemic conditions permit. zumab, Actemra®)
• For those patients who have taken an oral 5. JAK (Janus kinase) inhibitors (e.g., tofaci-
bisphosphonate for more than 4 years with or tinib, Xeljanz®)
without any concomitant medical therapy, the 6. TNF (tumor necrosis factor)-alpha blockers
prescribing physician should be contacted to (e.g., adalimumab, Humira®)
consider discontinuation of the antiresorptive
medication for 2 months prior to oral surgery, For dental patients taking biologic therapies,
if systemic conditions permit. the following guidelines should be followed:

The complete position paper should be con- • The prescribing physician(s) should be con-
sulted for detailed information, including infor- sulted to assess the status of the patient’s dis-
6 A. H. Jeske

Table 1 Examples of monoclonal antibodies approved for use in the United States (Jeske 2017)
Official name Tradename Indication(s)
Abciximab ReoPro® Adjunct for prevention of thromboembolism
Adalimumab Humira® Rheumatoid arthritis
Alemtuzumab Campath® Chronic lymphocytic leukemia
Basiliximab Simulect® Anti-rejection (renal transplant)
Bevacizumab Avastin® Metastatic colorectal and other cancers
Canakinumab Ilaris® Cryopyrin-Associated Periodic Syndrome
Certolizumab Cimzia® Rheumatoid arthritis
Cetuximab Erbitux® Squamous cell carcinoma
Daclizumab Zenapax® Anti-rejection (renal transplant)
Denosumab Prolia® Osteoporosis (high fracture risk)
Eculizumab Soliris® Nocturnal hemoglobinuria
Guselkumab Tremfya® Plaque psoriasis
Golimumab Simponi® Rheumatoid arthritis
Ibritumomab Zevalin® Non-Hodgkin’s lymphoma
Infliximab Remicade® Rheumatoid arthritis
Ipilimumab Yervoy® Unresectable metastatic melanoma
Muromonab Orthoclone® Anti-rejection (renal transplant)
Natalizumab Tysabri® Multiple sclerosis
Crohn’s disease
Ofatumumab Arzerra® Chronic lymphocytic leukemia
Omalizumab Xolair® Allergic asthma
Palivizumab Synagis® Respiratory syncytial virus
Panitumumab Vectibix® Metastatic colorectal cancer
Ranibizumab Lucentis® Macular degeneration
Rituximab Rituxan® Non-Hodgkin’s lymphoma
Tocilizumab Actemra® Rheumatoid arthritis
Trastuzumab Herceptin® Breast and gastroesophageal cancers
Ustekinumab Stelara® Plaque psoriasis
Vedolizumab Entyvio® Ulcerative colitis, Crohn’s disease

ease and the ability of the patient to tolerate biologic agents in pregnancy, including risks of
dental procedures. exposure to pregnant and lactating females,
• Immunosuppression is associated with bio- review of the data supporting these risks, and
logic therapies and may predispose the patient other information to assist practitioners and
to a higher incidence and severity of oral and patients in making informed decisions about med-
systemic infections (e.g., tuberculosis), includ- ication use during pregnancy and lactation
ing fungal infections. (U.S. Food and Drug Administration 2015;
• Because the biologic agent must be injected, Watkins and Archambault 2016; Katzung and
injection site discomfort and acute symptoms Trevor 2021). These new labeling requirements
may accompany administration (e.g., nausea, mandated that manufacturers replace the old preg-
diarrhea). nancy risk categories (A, B, C, D, and X) with the
updated information within 3 years [FDA].
Various sections of the new labeling information
 DA Pregnancy and Lactation Drug
F are illustrated in Table 2.
Labeling Additionally, the FDA now requires manufac-
turers to list pregnancy registry information (a
In 2015, the US Food and Drug Administration pregnancy registry being an ongoing, systematic,
(FDA) required major changes in the labeling and epidemiologic study that collects and assesses
information for the use of prescription drugs and data on a mother’s, fetus’ or infant’s adverse
Introduction to Contemporary Dental Pharmacology and Special Topics 7

Table 2 FDA labeling information for pregnant and lac- drugs) in medicine. The FDA approval process
tating patients
generates a tremendous amount of information
Pregnancy that is foundational to the evidence-based use of
 • Pregnancy exposure summary
drugs in dental practice. When new drugs are
 • Risk summary
approved, it is incumbent upon the prudent den-
 • Clinical considerations
   – Disease-associated maternal and/or embryo/fetal tist to determine not only what adverse drug
risk interactions may occur between the new medical
   – Dose adjustments during pregnancy and drug and existing dental drugs, but to ascertain
postpartum the implications that the new drug has for the
   – Maternal adverse reactions
comprehensive management of the patient’s den-
   – Fetal/neonatal adverse reactions
   – Labor or delivery
tal treatment.
 • Data
   – Human
   – Animal References
Lactation
 • Risk summary American Association of Oral and Maxillofacial
 • Clinical considerations Surgeons. Position paper on medication-related osteo-
 • Data necrosis of the jaw. 2022. https://www.aaoms.org/
Females and males of reproductive potential docs/govt_affairs//sponsorship_white_papers/mronj_
 • Pregnancy testing position_papers/mronj_position_paper.pdf.
Higgins JPT. In: Green S, editor. Cochrane handbook
 • Contraception
for systematic reviews of interventions. Version
 • Infertility
5.1.0 (updated March 2011). London: The Cochrane
Collaboration; 2011.
Jeske AH, editor. Mosby’s dental drug reference. 12th ed.
reactions to medications, biologic agents and St. Louis: Elsevier; 2017.
Katzung BS, Trevor AJ, editors. Basic and clinical
vaccines) (www.fda.gov/). pharmacology. 15th ed. New York: McGraw-Hill
Education; 2021.
U.S. Food and Drug Administration. Outline of section
Conclusion 8.1-8.3 on drug labeling. 2015.
Wasserman BS. The special care dental patient. Dent Clin
N Am. 2009;53:2.
Dental drug therapy typically follows and evolves Watkins EJ, Archambault M. Understanding the new
from the development of new drug entities (or pregnancy and lactation drug labeling. J Am Acad
improvements in or new indications for existing Phys Asst. 2016;29(2):50–2.
 Local Anesthetics

Arthur H. Jeske

 echanism of Action and Clinical

M eral and central neurons and the pacemaker and
Implications conducting tissues of the heart, accounting for
the typical signs and symptoms of systemic tox-
Unlike most other pharmaceuticals, local anes- icity observed at elevated blood levels (see sec-
thetics begin their therapeutic action immediately tion “Comparative Efficacy of Injectable Local
upon application to a target tissue, usually via Anesthetics”).
injection into an anatomic space adjacent to a Under pathologic conditions (e.g., nerve
nerve trunk (e.g., nerve block) or nerve endings trauma), neurons can become phenotypically
(e.g., infiltration). This requirement results from altered, and there can be expression of channels
the need to abolish pain impulses in small areas that are pharmacologically characterized as
of the body, and the poor oral bioavailability “tetrodotoxin resistant,” indicating extreme resis-
obviates any utility of these drugs for systemic tance to block, including local anesthetic block
effects. (Alexander et al. 2017; Waxman and Zamponi
Beginning with the pioneering work of Ritchie 2014). This is one possible explanation for the
and Greengard, which established the active form difficulty encountered by clinicians in attempting
of conventional local anesthetic drugs and the to anesthetize teeth, which have been chronically
influence of pH on their clinical behavior, work infected and inflamed due to caries, trauma, etc.
over the last three decades of the twentieth cen- Nerve block caused by local anesthetics
tury has led to an understanding of the principal begins to occur immediately following injection
site of action as the voltage gated sodium channel of the drug near the nerve. Following equilibra-
(Ritchie and Greengard 1966). A folding diagram tion of the local anesthetic solution with the
of the channel is illustrated in Fig. 1. extracellular fluid, the uncharged species of the
Voltage-gated sodium channels are ubiquitous anesthetic penetrates the nerve membrane and
in nature and are designated by the symbol Nav, enters the intraneuronal space. There, the anes-
followed by a number 1.1 to 1.9, representing thetic once again equilibrates into positively
isoforms found in various tissues (Alexander charged and uncharged forms, according to the
et al. 2017). They underlie the functioning of all Henderson-Hasselbalch equation:
electrically excitable tissues, including periph- pKa = pH − log [ base] / [ conjugate acid ]

When the nerve membrane is depolarized,

A. H. Jeske (*)
UTHealth School of Dentistry, Houston, TX, USA voltage sensors alter the conformation of the
e-mail: [email protected] channel, the sodium channels open, and local

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 9

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_2
10 A. H. Jeske

Fig. 1 Folding diagram of the mammalian voltage gated vation (modulated by the inactivation gate) and closing of
sodium channel. The alpha subunit is comprised of four the channel during a depolarization. Local anesthetic bind-
domains of six alpha-helically coiled amino acid ing occurs at the sixth transmembrane helix, at a site near
sequences. These groups span the nerve membrane and the internal opening of the channel (indicated by “drugs”).
surround and form the ion “pore.” A voltage-sensing Reprinted from Neuron Volume 26, No. 1, Catterall WA,
sequence of positively charged amino acids in each domain From Ionic Currents to Molecular Mechanisms: The
responds to changes in polarity of the adjacent nerve mem- Structure and Function of Voltage-­Gated Sodium Channels,
brane, resulting in a transient opening, followed by inacti- pp. 13–25, 2000, with permission from Elsevier

anesthetic molecules can access and bind to their anesthetic that only exists in an uncharged
active site, which lies within the channel, near the form (Catterall 2012; Lirk et al. 2014).
inner opening, at the sixth transmembrane helices 2. Entry of charged anesthetic molecules into the
of domains 1, 3, and 4 of the channel’s alpha sub- neuron via large-pore vanilloid-1 (TRPV-1)
unit (Catterall 2012). Local anesthetic binding channels. This pathway, also known as the
stabilizes the channel in the inactivated form, “hydrophilic pathway,” explains the ability of
which cannot conduct Na+ ions. Accumulation investigational fixed-charge anesthetics to
of a sufficient number of inactivated channels induce nerve blockade when these channels
prevents subsequent conduction of nerve are activated by acute applications of
impulses, effecting a state of nerve block, or local capsaicin.
anesthesia.
Two additional mechanisms of local anes- Local anesthetics may also act via secondary
thetic action have been proposed, including the targets, including potassium and calcium chan-
following: nels, and G protein-coupled and N-methyl-D-­
aspartate (NMDA) receptors (Reader et al. 2017),
1. Direct access to the anesthetic binding site although it is unlikely that these targets play a
from within the lipid core of the neuronal major role in the blockade of peripheral nerve
membrane. This mechanism, also known as fibers (Salinas et al. 2004).
the “hydrophobic pathway,” explains the Rapidly firing neurons are blocked earlier than
nerve-blocking actions of benzocaine, an those with lower firing rates, and smaller neurons
Local Anesthetics 11

are generally blocked before larger ones. In the Physicochemical Characteristics

case of rapidly firing neurons, the rapid opening
of the voltage-gated sodium channels increases Injectable dental local anesthetics are relatively
the likelihood that local anesthetic molecules can small molecular structures (molecular weights
access their binding sites within the channel, in a ranging from 234 to 321 Da These values and
phenomenon known as “frequency dependence” their other physicochemical properties are pre-
(Drasner 2015). sented in Table 1.
Neuronal diameter and other intrinsic traits Relatively high lipid solubility and protein
may alter the susceptibility of nerves to local binding for bupivacaine and tetracaine are the
anesthetic block. For example, for nerves with basis for their relatively long duration of action,
similar cross-sectional area, those with myelin that is, they possess high affinity for the proteo-
would tend to be blocker sooner than those that lipid complex structure of the neuronal cell mem-
lack myelin, as the myelin may serve as a “reser- brane. Lipid affinity is also the basis for the use
voir” for uncharged local anesthetic. of lipid emulsion for treating systemic toxicity of
Theoretically, larger diameter fibers are blocked local anesthetics (see section “Comparative
later than smaller ones because the distance over Efficacy of Injectable Local Anesthetics”).
which the larger fibers can passively propagate an Chemically, conventional local anesthetics are
electrical impulse is greater. Generally, the order classified as amides or esters, based upon the
of blockade of sensory fibers is described as linkage of the aromatic (lipophilic) moiety at one
(Drasner 2015): end of the molecule to the intermediate, aliphatic
Temperature > pain > light touch > pressure > chain. Amides are metabolized primarily via
proprioception. hepatic microsomal oxidation, while esters, with
a relatively weak intermediate bond, are rapidly
Motor fibers are not blocked by dental local hydrolyzed by plasma cholinesterases (Reader
anesthetics unless the anesthetic is placed into et al. 2017). Their relatively small molecular size
close proximity to a motor nerve, for example, limits their allergenicity, although metabolic
cranial nerve VII, as occurs when the parotid products of ester-type agents can be allergenic by
gland is accidentally entered during mandibu- token of their molecular similarity to para-amino
lar block techniques, resulting in temporary benzoic acid (PABA). Recently, sensitization to
facial nerve paralysis. Motor nerve block is a amide local anesthetics has been noted to occur
much more important consideration when local in connection with the application of large
anesthetics are used in the setting of epidural amounts of topical preparations to skin to reduce
and spinal anesthesia (Drasner 2015; Neal pain associated with cosmetic enhancements of
et al. 2018). the body (hair removal, etc.) (To et al. 2014).

Table 1 Physicochemical characteristics of common local anesthetics

Drug Lipid partition coeff. Protein binding (%) Mol. wt. (Da) Concentration in dental cartridges (%)
Articaine 17 70 321 4
Bupivacaine 346 95 288 0.5
Lidocaine 2.4 64 234 2
Mepivacaine 21 77 246 2–3
Prilocaine 25 55 220 4
12 A. H. Jeske

Effect of pH and pK/Buffering may experience a burning sensation during the

injection. This consideration, along with a theo-
Dental local anesthetic drugs are weak bases and retical advantage that increasing the relative pro-
possess a tertiary amine terminus, which can be portion of anesthetic molecules in the uncharged
protonated (except for benzocaine). This highly form can accelerate the onset of the local anes-
polar group confers water solubility upon the thetic effect, has led to the development of
drugs, although the positively charged form (pro- ­ buffering systems for dental local anesthetic
tonated) of the anesthetic apparently is also cartridges.
essential for the binding of the anesthetic to its The potential benefits of buffering local anes-
active site in the voltage-gated sodium channel. thetic solutions (to raise their pH) theoretically
Similarly, the aromatic ring at the opposite end of include faster onset and greater efficacy (owing
the local anesthetic molecule confers lipid solu- to a larger fraction of uncharged anesthetic avail-
bility upon the drug, allowing it to traverse the able to diffuse into the nerve), as well as a reduc-
cell membrane. Diffusion into the nerve does not tion in injection pain associated with acidic
occur via ion pores but through passive diffusion solutions. Reduced pH is also believed to play a
through the neuronal membrane by the uncharged role in the failure of local anesthetic to block
form of the anesthetic. Thus, the higher the pKa nerves when their tissues of innervation are
of the anesthetic, the greater the ionization of the inflamed and the pH of the extracellular fluid
drug in the extracellular fluid and the lower the may drop by as much as 0.5 pH units (Lirk et al.
fraction of uncharged form (Table 2). For the 2014).
long-acting agents bupivacaine and tetracaine, Recent studies on the effect of bicarbonate
with relatively high pKa, their potency derives buffering of the local anesthetic solution prior to
from their high lipid solubility and protein-­ injection have produced equivocal results. For
binding affinity (Table 1), a critical factor that example, Saatchi et al. (2015) studied the effect
explains not only their higher potency, that is, of buffering 2% lidocaine with 1:80,000 epineph-
their nerve-blocking concentration, but also their rine for the success rate of the inferior alveolar
long duration (Drasner 2015). nerve block (IANB) in patients with symptom-
When considering the values presented in atic irreversible pulpitis. Comparing the adminis-
Table 1, the reader should consider the fact that tration of two cartridges of the non-buffered
these numbers apply to plain solutions. For prep- anesthetics with the same dose buffered with
arations with epinephrine, the pH of the solution 0.18 ml of 8.4% sodium bicarbonate solution, the
is adjusted downward, and such solutions may investigators achieved success rates of 62.5% for
have pH values as low as 3.3, with correspond- the buffered solution versus 47.5% for the non-­
ingly greater proportions of charged versus buffered one, without achieving statistical signif-
uncharged molecules. However, once injected icance. Similar outcomes were obtained in a
into body tissues, the pH quickly equilibrates to study of the effect of 2.8 ml buffered 4% lido-
normal tissue fluid pH. This re-equilibration is caine for the IANB (versus the same protocol
not immediate, with the result that some patients without buffering) and showed no significant dif-
ference for success in patients with symptomatic
irreversible pulpitis (32% and 40%, respectively),
Table 2 Relationship between local anesthetic pKa and
fraction of unionized drug at pH 7.4 nor were the ratings of pain during the injection
different (Schellenberg et al. 2015).
Drug pKa % Drug uncharged
Articaine 7.8 28
Interestingly, one study has demonstrated that
Bupivacaine 8.1 15 injection of sodium bicarbonate in a 2% lido-
Lidocaine 7.9 25 caine solution via buccal infiltration of irrevers-
Mepivacaine 7.6 37 ibly inflamed lower first molars followed by a
Prilocaine 7.9 24 conventional IANB block with 2% lidocaine with
Tetracaine 8.6 7 epinephrine produced significantly better success
Local Anesthetics 13

rates versus infiltration of lidocaine with distilled concluded that buffering may reduce pain and
water (78% vs 44%) (Saatchi et al. 2016). The accelerate onset of anesthesia associated with the
mechanism by which this difference occurred inferior alveolar nerve block in children but that
may have been due simply to the additional buff- sample sizes and number of randomized con-
ered lidocaine at the tooth site, with improved trolled trials are needed (Tirupathi and Rajasekhar
diffusion from neutralization of inflamed extra- 2020).
cellular fluid, and it is tempting to speculate that At this time, practitioners who adopt buffer-
alteration of the function of acid-sensing ion ing as part of their IANB local anesthetic proto-
channels may also have played a role. In oral sur- cols for routine dental procedures can expect
gery, the effect of buffering 2% lidocaine with some reductions in onset time and injection pain
epinephrine on various clinical parameters has but little advantage for overall pulpal anesthesia
been investigated, including the impact on blood success rates. The impact of buffering on the
levels of the local anesthetic. success rates for other types of injections will
It has been shown that the buffered prepara- require additional scientific studies. While the
tion resulted in significantly lower blood levels buffering of local anesthetics is considered to be
after IANB, and subjects reported lower injection-­ a standard of care in medicine to minimize the
pain scores and shorter time to lip numbness with discomfort of intradermal local anesthetic injec-
the buffered solution (Phero et al. 2017). tions, the literature in dentistry suggests that it is
Theoretically, the buffered solutions would con- not a standard of care for intraoral injections at
tain smaller fractions of charged local anesthetic this time.
molecules, which are hydrophilic and would be
expected to be absorbed by blood more exten-
sively than the uncharged, less polar forms. This Structure-Activity Relationships
could become a significant factor when large
amounts of local anesthetic are required for sur- Structural modifications to the basic local anes-
gical procedures or for postoperative pain con- thetic molecule that increase lipid solubility have
trol, for example, intercostal block. a marked impact on potency, protein binding
Recently, a meta-analysis of the efficacy of affinity, and duration of action. An example is
sodium bicarbonate buffered versus non-buffered that of bupivacaine, in which substitution of the
lidocaine with epinephrine for the IANB was methyl group of mepivacaine with a butyl group
conducted, and the outcomes of the analysis were results in a significant increase in potency and
based on 11 included studies (Guo et al. 2018). duration of action, the latter effect owing to the
While this report found that buffering signifi- increased binding affinity of the drug for the neu-
cantly decreased time of onset of anesthesia (48 s ronal membrane. In the case of bupivacaine, two
shorter) and injection pain (five-point reduction additional considerations arise from the increase
on the 0–100 VAS), there was no significant dif- proteolipid affinity—first, bupivacaine possesses
ference for anesthetic success rate or the inci- an inherently higher cardiotoxicity than other
dence of painless injections. The investigators local anesthetics, and second, bupivacaine can be
cautioned that the quality of evidence was low to produced in a liposomal delivery formulation, in
moderate due to statistical heterogeneity and low which slow release from liposomes introduced
sample sizes. into a surgical site produce prolonged postopera-
Shurtz et al. evaluated buffered 4% articaine tive pain relief.
for infiltration of the mandibular first molar and Articaine is distinguished from other amide
observed no differences in pain of injection or local anesthetics by two unique structure fea-
onset of anesthesia when compared with unbuf- tures—first, it possesses a sulfur-containing thio-
fered 4% articaine (Shurtz et al. 2015). Most phene ring, which apparently contributes to its
recently, a systematic review of buffered versus ability to diffuse through both soft and hard tis-
unbuffered local anesthetic solutions in children sues more readily than other conventional local
14 A. H. Jeske

speed of onset and duration of local anesthesia

and local and systemic adverse effects. A com-
mon secondary measure is the global assessment
of subjects’ satisfaction with the pain control dur-
ing a procedure.
For success of anesthesia, it now appears that
4% articaine with 1:100,000 epinephrine is supe-
Fig. 2 Structural formula of articaine
rior to 2% lidocaine with 1:100,000 epinephrine
for posterior teeth, which present with symptom-
anesthetics (Fig. 2). It also possesses an ester side atic irreversible pulpitis (31% vs 49% incidence
chain, which, because it is quickly hydrolyzed by of successful anesthesia, RR* 1.60, 95% CI*
non-hepatic esterases, results in more rapid inac- 1.10 to 2.32) (George et al. 2018).
tivation after it leaves its therapeutic site of For studies of soft- and hard-tissue (e.g., tooth
action, contributing to a relatively short (23 min) extraction) procedures, clear evidence favoring
plasma half-life. Since the resulting hydrolysis one particular local anesthetic is lacking (George
product articainic acid is not pharmacologically et al. 2018), and variations in volume of injected
active, systemic toxicity is reduced relatively rap- anesthetic (one versus two cartridges for the
idly, as opposed to the prototype amide lidocaine, inferior alveolar nerve block) did not reveal any
whose initial oxidative metabolite (monoethyl significant differences for success between lido-
glycine xylidide) is an active intermediate than caine and articaine, although in the most recent
may prolong systemic toxicity. systematic review specifically of the inferior
alveolar nerve block, an additional benefit of
supplementary buccal infiltration was evident
 omparative Efficacy of Injectable
C (Corbella et al. 2017). There is moderate quality
Local Anesthetics evidence that for surgical and periodontal proce-
dures, 2% lidocaine with 1:100,000 epinephrine
Beginning in 2009, there have been several sys- was superior to 4% prilocaine plain, although
tematic reviews focusing on the comparative effi- comparisons for 4% prilocaine with 1:200,000
cacy of articaine, lidocaine, and some other local epinephrine are not available, and comparative
anesthetic preparations. Among the most infor- results for surgical outcomes using 0.5% bupiva-
mative, of course, are those which performed and caine with 1:200,000 epinephrine versus other
reported the outcomes of meta-analyses (Corbella anesthetic agents are reported as “uncertain”
et al. 2017; Katyal 2010; Kung et al. 2015; Paxton (George et al. 2018).
and Thomas 2010; George et al. 2018; Zhang Earlier systematic reviews (Katyal 2010;
et al. 2018). Particular interest in the comparative Kung et al. 2015) clearly demonstrated a sig-
efficacy of articaine versus lidocaine arose from nificant contribution of greater anesthetic
the increasingly widespread use of articaine and ­success for 4% articaine with 1:100,000 epi-
its availability, beginning in 1999, in the US den- nephrine for buccal infiltration compared with
tal marketplace. 2% lidocaine with 1:100,000 epinephrine to
The primary outcome measure used to com- the overall estimated success rate for articaine.
pare efficacy among injectable local anesthetics For example, Brandt et al. determined that the
is complete pulpal anesthesia, as assessed by a odds ratio (OR) for the overall success rate for
lack of response of test teeth to electric pulp test- 4% articaine versus 2% lidocaine was 2.44
ing or ability to perform endodontic treatment on (95% CI 1.59–3.76, p < 0.0001), while when
teeth presenting with symptomatic irreversible only buccal infiltration was considered, the
pulpitis with no or only mild procedural discom- advantage for articaine increased to OR 3.81
fort. A variety of additional outcome measures (95% CI 2.71–5.3, p < 0.00001) (Brandt et al.
have been reported, most frequently including 2011).
Local Anesthetics 15

More recently, the anesthetic effectiveness of Local Anesthetic-Related

articaine and lidocaine were compared in a sys- Nerve Injury
tematic review and meta-analysis of trials involv-
ing children <14 years old, and while articaine Interest in local anesthetic-related nerve injury
proved to superior to lidocaine, the differences peaked in the 1990s, at a time when the use of 4%
were small based on outcomes for Facial Pain articaine solutions had become widespread, both
Scores (Taneja et al. 2020). In studies involving in Europe and Canada, following retrospective
the extraction of mandibular third molars, a sys- estimation of the incidence of paresthesias in the
tematic review and meta-analysis comparing dental patient population versus the estimated
articaine versus lidocaine concluded that for frequency of use of various types of dental anes-
articaine, the success rate, subjective onset time, thetics (Haas and Lennon 1995). These concerns
and duration of anesthesia were somewhat supe- have persisted into the twenty-first century
rior, although intraoperative pain scores and (Garisto et al. 2010), although limited scientific
objectively measured onset times were not sig- evidence now suggests that the initial assess-
nificantly different (Zhang et al. 2018). In 2020, ments of neuronal toxicity may have been
an umbrella review and a systematic review and overestimated.
meta-analysis of the comparative efficacy of In fact, a second formulation of 4% articaine
articaine versus lidocaine in cases of symptom- (with 1:200,000 epinephrine) was subsequently
atic irreversible pulpitis both found significantly approved by the US Food and Drug
higher pulpal anesthesia success rates for artic- Administration.
aine (Larocca de Geus et al. 2020; Nagendrababu It is generally accepted that local anesthetics
et al. 2020). can be neurotoxic when relatively concentrated
For virtually all studies of local anesthetics, solutions, for example, 2–4%, are placed in close
adverse events are rare, and differences in pain on proximity to small nerves or in tissues with lim-
injection do not appear to be significant when ited or depleted buffering capability (e.g., cere-
comparing 4% articaine to 2% lidocaine prepara- brospinal fluid). Cauda equina syndrome is well
tions (George et al. 2018). The practitioner has known in medicine as a complication of spinal
several options for local anesthetic preparations, anesthesia (Drasner 2015). In dentistry, local
and based on current scientific evidence, one anesthetic administration is among five proce-
practical approach is to stock both 2% lidocaine dures associated with the majority of cases of
with 1:100,000 epinephrine (for blocks and max- nerve injury, including implant placement, end-
illary buccal infiltrations), 4% articaine with epi- odontic treatment, bone grafting, and dentoalveo-
nephrine (for mandibular buccal infiltration lar surgery (particularly lower third molar
anesthesia), and a plain solution, to be used in removal) (Pogrel 2017). Mechanisms that under-
cases in which epinephrine is absolutely contra- lie these injuries include induction of apoptosis at
indicated (e.g., 3% mepivacaine plain, 4% prilo- lower concentrations and late apoptotic or
caine plain). necrotic cell death at higher ones (Verlinde et al.
A 0.5% bupivacaine does not produce reliably 2016; Werdehausen et al. 2009). In a neuroblas-
long-acting anesthesia in the maxilla, and it is not toma cell line, all conventional local anesthetics
recommended for use in children. Supplementary were shown to induce apoptosis and neurotoxic-
anesthetic techniques (e.g., intraosseous injec- ity in direct relationship to the anesthetic concen-
tions) can also be employed successfully to help tration and appears to be related to the fat
overcome failures of block and or infiltration solubility and potency of the drug, with no sig-
anesthesia and to limit the total dose of anes- nificant differences between amide- and ester-­
thetic, if necessary. A 2% lidocaine with type anesthetics (Werdehausen et al. 2009).
1:100,000 epinephrine or 3% mepivacaine plain A recent literature review of local anesthetic-­
is recommended for use with these techniques induced neurotoxicity identified multiple risk
(Reader et al. 2017). factors for nerve damage, including the block
16 A. H. Jeske

technique used, patient risk factors (e.g., preex- port a beneficial effect of vitamin and other
isting neuropathy or neurological diseases), and dietary supplements. Attempts at surgical correc-
surgical factors (e.g., inadvertent nerve compres- tion of dysesthesias have not been successful, and
sion). Cellular mechanisms that may be associ- the surgery has typically not revealed macro-
ated with neurotoxicity include effects of local scopic damage to the nerves.
anesthetics on the intrinsic caspase pathway, At this time, there appears to be no known
PI3k-pathway, and MAPK-pathways. For periph- method of preventing local anesthetic-related
eral nerve blocks, this review estimated the inci- nerve injury (Pogrel et al. 2011; Pogrel and
dence of local anesthetic-related neurological Thamby 1999; Pogrel 2007, 2002).
complications as less than 3% and concluded that The medicolegal considerations involving iat-
most are “transient sensory deficits” (Verlinde rogenic lingual nerve damage have recently been
et al. 2016). addressed (Pippi et al. 2018) and highlight the
In the United States, the Department of Oral difficulties encountered when attempting to
and Maxillofacial Surgery at the University of establish the etiology of the injury, that is, dif-
California San Francisco has perhaps the longest-­ ferentiation of anesthetic, mechanical, chemical,
running case series of patients with iatrogenic and even thermal mechanisms.
injuries to the maxillofacial area (Pogrel and It is also noteworthy that clinical tests aimed
Thamby 2000). This case series now includes at assessing lingual nerve sensory function have
324 patients whose nerve injuries could only be low sensitivity and only moderate specificity.
the result of local anesthetic injections, and the Experts have concluded that the patient must be
following are reported as consistent features in warned of the possibility of nerve injury during
these cases (Pogrel 2017): the informed consent process, regardless of the
relatively low frequency of local anesthetic-­
• The lingual nerve is the most frequently related injury. Unfortunately, there are no good
affected nerve (twice the rate as the inferior alternatives to local anesthetic injection for pain
alveolar nerve. control for routine, outpatient dental procedures.
• 33% of the patients experience dysesthesia as
a result of the injury.
• Recovery, if it occurs, does so in three months,  ocal Anesthetic Systemic Toxicity
L
and later recoveries are rare. (LAST) and Management
• Virtually, all cases involved the inferior alveo-
lar nerve block, and among permanent injuries, Local anesthetic systemic toxicity (LAST) is a
the vast majority involved this block injection. serious and potentially life-threatening reaction
typically associated with high doses and/or mul-
There is considerable variation in the esti- tiple injections of local anesthetics in a relatively
mates of the actual incidence of these injuries, short period of time. Occasionally, inadvertent
now ranging from 1 in 6000 for temporary neural intravenous or intraarterial injection can occur, in
deficits with the IANB to 1 in 30,000 for perma- which case even relatively small amounts of local
nent injuries (Pogrel and Thamby 2000). anesthetics may precipitate systemic toxicity.
Contrary to some expert opinion, this type of There are several mechanisms that play a role in
nerve damage is not associated with a specific the development of this scenario, which can
anesthetic drug, although it does appear to pre- result in the clinical presentation of the reaction
dominantly affect the lingual nerve. There being atypical (El-Boghdadly and Jinn Chinn
appears to be no established relationship to the 2016). The current literature suggests that LAST
volume of anesthetic injected, and there is no is relatively rare (2.0–2.8 cases per 10,000
beneficial treatment known, despite unfounded peripheral nerve blocks) and is even less likely
suggestions that corticosteroids may improve the for infiltration anesthesia utilized in routine den-
long-term prognosis, nor is there evidence to sup- tal procedures (Barrington and Kluger 2013).
Local Anesthetics 17

Factors related to the occurrence of LAST ing amide local anesthetics (see section “Local
include the following (El-Boghdadly and Jinn Anesthetic-Related Nerve Injury”).
Chinn 2016): • In one case, some classes of histamine H-2
receptor antagonists, for example, cimetidine,
• Patient factors. In elderly patients with inhibit the metabolic disposition of lidocaine
reduced hepatic and renal clearance of drugs, by the hepatic cytochrome P450 CYP 3A4.
even though plasma protein binding and peak Propranolol (Inderal®) and halogenated hydro-
plasma concentration of anesthetics may not carbon anesthetics may reduce cardiac output
differ from those seen in younger adults. Other and hepatic perfusion sufficiently to reduce
patient conditions that may contribute to the clearance of amide local anesthetics. In
LAST include cardiac disease (which reduces both of these cases, a careful medical history
blood flow to vital organs and, therefore, and avoidance of potentially interactive agents
reduces drug clearance), liver disease (a con- is warranted (Moore 1999).
sideration when doses are repeated or local • Anesthetic technique. Certain intraoral block
anesthetic is continuously infused), and preg- injections, particularly the posterior superior
nancy (e.g., increased cardiac output begin- alveolar and inferior alveolar nerve block,
ning in the second trimester of pregnancy may carry a higher probability of penetration of a
increase local anesthetic absorption from blood vessel (based on likelihood of positive
injection sites and increase plasma aspiration). Careful aspiration, slow injection,
concentrations). The well-established rela-
­ and increasing use of buccal infiltration anes-
tionship between bupivacaine-induced LAST thesia for routine, single-tooth dental proce-
and pregnancy dictates extra precautions and dures are important contributions to a
played a role in the development of lipid emul- reduction in LAST in the dental outpatient
sion therapy of LAST, described later in this population.
section.
• Drug doses. Appropriate dosing of local anes- The signs and symptoms of LAST may pres-
thetics, based on patient body weight and sys- ent in temporal variations (Lirk et al. 2014).
temic risk factors, is the single most important “Instant” LAST involves rapid-onset seizures
factor in preventing LAST. Maximum doses and cardiovascular depression and is usually
for common dental local anesthetics are found associated with inadvertent intravascular admin-
in Table 3 (based on manufacturer’s date in istration of relatively high volumes of local anes-
FDA-approved labeling). thetic solution, or smaller amounts injected
• Pharmacokinetics. There are only a few seri- intraarterially. “Slow” LAST typically follows
ous pharmacokinetic drug interactions involv- overdose, rapid absorption of anesthetic by the
circulation, reduced metabolism/hepatic clear-
ance, or reduced plasma protein binding, taking
Table 3 Maximum recommended doses (MRDs) for
conventional dental local anesthetics (manufacturer’s
up to 30 min or longer to manifest.
data) The classical signs and symptoms of impend-
Drug Dose mg/kg Absolute max dose (mg)a ing LAST include sensory disturbances, follow-
Articaine 7 NAb ing by early signs of CNS stimulation attributable
Bupivacaine 2 90 to depression of central inhibitory neurons (mus-
Lidocainec 7 500 cle twitching and fasciculation). As plasma levels
Mepivacaine 6.6 400 increase further, tonic-clonic seizures ensue, cul-
Prilocaine 8 600 minating in post-seizure depression with possible
a
 ose that should not be exceeded in a single
D respiratory arrest. Cardiovascular parameters
appointment
during LAST vary with the stage of toxicity, with
b
The manufacturer of articaine does not specify an abso-
lute maximum dose increases in blood pressure during the phase of
c
Applies to lidocaine preparations with epinephrine CNS excitation, and profound loss of blood pres-
18 A. H. Jeske

sure with severe bradycardia in the terminal followed by a continuous infusion of 1000 ml/h
stage. Exceptions to this cascade may occur, for (Ok et al. 2018).
example, if the patient is being sedated with a To summarize, the management of LAST in
benzodiazepine (which possesses anticonvulsant the dental outpatient setting would include the
activity), CNS stimulation and seizures may be following (El-Boghdadly and Jinn Chinn 2016):
obtunded or not occur at all. LAST is potential
fatal, but the employment of preventive measures • Prevention: Appropriate local anesthetic dos-
reduces the occurrence of cardiac arrest ing, use of less cardiotoxic anesthetics, aspira-
(El-Boghdadly and Jinn Chinn 2016). tion before injection.
The management of LAST involves rapid and, • Detection: Observe for CNS signs (agitation,
depending on the severity of the toxicity, aggres- confusion, seizures, mental depression, sen-
sive rescue measures. Lipid emulsion infusion is sory disturbances) and CVS signs (hyperten-
becoming widely accepted as an interventional sion, tachycardia, hypotension, bradycardia,
measure in LAST, although it does not substitute asystole).
for airway management and ventilation with • Initial Management: Stop injection and den-
100% oxygen. Intravenous infusion of lipid tal procedure, summon help and emergency
emulsion (e.g., 20–30% long-chain triglycerides kit, open and maintain airway, ventilated with
produced from soybean oil) creates a “lipid sink” 100% oxygen, obtain vascular access (i.v. or
in the blood, which allows highly lipophilic local i.o), terminate seizures (administer parenteral
anesthetics such as bupivacaine to partition into benzodiazepine), consider intravenous infu-
the plasma and out of cardiac tissue, thus reduc- sion of lipid emulsion if symptoms persist or
ing the cardiac depression that is characteristics recur.
of this type of anesthetic. Additional mechanisms
that contribute to the beneficial effects of lipid The emergency use of benzodiazepines for sei-
emulsion therapy of LAST-related cardiac zure termination is described in chapter “Pediatric
depression include promotion of mitochondrial Considerations in Clinical Pharmacology” of this
fatty acid metabolism and ATP synthesis and book.
direct increases in cardiac contractility related to
an increased intracellular content of calcium in
myocardial cells (Fettiplace et al. 2014).  eneficial and Adverse Drug
B
Additionally, lipid emulsion can inhibit nitric Interactions Involving Local
oxide release and reverse cardiac sodium channel Anesthetics, Reversal of Soft-Tissue
blockade (Lieblich and Danesi 2017). Anesthesia
A recent systematic review based on case
reports has established the efficacy of intrave- Two beneficial drug-drug interactions involving
nous lipid emulsion therapy for the management dental local anesthetics include the pharmacody-
of local anesthetic-induced cardiotoxicity (Cao namics interaction of epinephrine (a vasocon-
et al. 2015). CNS toxicity is also ameliorated by strictor in the submucosal tissues) and most local
lipid emulsion therapy and has been demon- anesthetics, which are vasodilators. By reducing
strated to be effective not only for LAST due to local blood flow in the vicinity of the site of local
bupivacaine but also for lidocaine and mepiva- anesthetic injection, the vasoconstrictor prolongs
caine. At this time, there is no evidence to con- the duration of action of the anesthetic by reduc-
firm or refute a beneficial effect of adding ing vascular uptake and “washout” (responsible
epinephrine to lipid emulsion. for the offset and termination of the local anes-
An example of a protocol for lipid emulsion thetic effect) and tends to reduce peak plasma
infusion for a patient weighing 70 kg is a bolus levels of local anesthetic as the latter is more
infusion of 100 ml of Intralipid® 20% over 1 min, slowly absorbed.
Local Anesthetics 19

A second beneficial interaction is the direct vention of this dangerous action, in which is the
competitive receptor blockade of alpha adreno- CNS-depressant effect of the sedative may mask
ceptors produced by phentolamine mesylate the signs of CNS excitation seen in the early
(e.g., Oraverse®) to reduce the time to recovery of stages of LAST, a factor that delays recognition
soft-tissue sensation. The therapeutic basis for of the toxicity and effective intervention.
the use of phentolamine is competitive blockade Interactions involving potentiation of the
of epinephrine at alpha-1 adrenoceptors (mediat- CVS-stimulant effects of epinephrine involve the
ing vasoconstriction) and was established in a following (Yagiela 1999):
multicenter, double-blind, randomized Phase II
clinical trial with 122 adult participants (Laviola • Cocaine
et al. 2008). In the study, the participants had • Amphetamines
received one or two cartridges of dental local • Methylphenidate
anesthetics with epinephrine for a dental proce- • Tricyclic antidepressants
dure. Immediately following the procedures, a
cartridge (1.8 ml) with 0.4 mg phentolamine Monoamine oxidase inhibitors do not contra-
mesylate or placebo was injected directly into the indicate the use of epinephrine in local anes-
site previously used for the local anesthetic. thetic. Halogenated hydrocarbon general
Subjects who had received two cartridges of local anesthetics and chloral hydrate sensitize the
anesthetics also received a second cartridge of myocardium to the arrhythmogenic actions of
phentolamine. Adverse events were uncommon, epinephrine. Administration of epinephrine-­
and the injection of the alpha-1 adrenoceptor containing local anesthetics to patients taking
blocker reduced the time to soft-tissue recovery non-cardioselective beta blockers (e.g., propran-
by approximately 50%. Despite this significant olol, Inderal®) can result in clinically significant
reduction in recovery from soft-tissue anesthesia, bradycardia and even cardiac arrest.
Oraverse® has not been widely adopted in dental The mechanism appears to be the elimination
practice in the United States, probably because of of beta-2 receptor-mediated vasodilation ordinar-
the additional expense and the need to perform ily produced by epinephrine, combined with
one or two additional injections. alpha-adrenoceptor-mediate vasoconstriction.
Adverse drug-drug interactions with local Increases in blood pressure resulting from the lat-
anesthetics are rare, although interactions with ter activate the unaffected baroreceptor reflex,
the vasoconstrictor component of dental local causing unopposed, vagally mediated cardiac
anesthetics must be considered as a second cate- depression, since the beta-1 receptors at the heart
gory of interaction. Interactions involving local have also been blocked by the nonselective beta
anesthetic include summation of adverse CNS blocker (Yagiela 1999).
and CVS effects by the co-administration of Less significant drug interactions are also pos-
another local anesthetic or a medically prescribed sible, and the clinician should consult the complete
drug with local anesthetic actions (e.g., a Class I prescribing information for all drugs prescribed.
anti-dysrhythmic drug). These are among the For elderly and medically compromised patients
most potentially dangerous interactions and are with systemic disease that could impact drug
categorized as Significance Rating 1/Potentially metabolism and/or excretion, consultation with the
Life-Threatening (Moore 1999). patient’s physician is recommended.
Another life-threatening interaction is that
which occurs when additive or supra-additive
CNS depression as a result of co-administration Effect of Vasoconstrictors
of local anesthetics with sedatives and/or opioids,
particularly in children with relatively low maxi- In the United States, epinephrine is the most
mal allowable doses of local anesthetic (Moore widely employed vasoconstrictor used in local
1999). An additional factor to consider is the pre- anesthetic preparations in dentistry. Its actions
20 A. H. Jeske

are well known and predictable, and the dose opments—first, an intranasal preparation to
limitations recommended in standard textbooks achieve dental anesthetic for maxillary teeth and
on local anesthetic are generally accepted as safe supporting tissues was recently introduced
for adults, based on the American Society of (Kovanaze®). This product is a combination of a
Anesthesiologists’ Physical Status Classification, lipophilic, long-acting injectable ester local anes-
as follows: thetic (tetracaine 3%) with oxymetazoline 0.05%,
an alpha-1 adrenoceptor agonist commonly avail-
• ASA I: 0.2 mg total dose (equivalent to the able as a vasoconstrictor in nasal decongestants
amount of epinephrine contained in approxi- (e.g., Afrin®). Based on the Phase 2 clinical trial
mately 11 1.8-ml cartridges with a 1:100,000 in 45 adult subjects in need of a single maxillary
concentration) tooth restorative procedures, 83% of subjects
• ASA II: 0.1 mg total dose (equivalent to the receiving the nasal spray anesthetic did not
amount of epinephrine contained in approxi- require rescue local anesthetic injection (Ciancio
mately 5.5 1.8-ml cartridges with a 1:100,000 et al. 2013). A subsequent parallel design study
concentration) comparing the tetracaine/oxymetazoline combi-
• ASA III: 0.04 mg total dose (equivalent to the nation with a tetracaine-only and saline (placebo)
amount of epinephrine contained in approxi- spray, based on need for rescue anesthetic, deter-
mately two 1.8-ml cartridges with a 1:100,000 mined a success rate of 84% for the combination
concentration) preparation, versus 27.3% success rates for both
the tetracaine-only preparation and placebo
Concentrations of epinephrine greater than (Ciancio et al. 2016). In both studies, no serious
1:100,000 do not appear to confer any advantage adverse events were reported.
for dental local anesthesia, either in terms of pro- Initially, these studies were to have included
longation of duration of action or reduction in electric pulp testing as a secondary outcome
peak plasma levels of anesthetic. The initial measure, but those data were not reported, and
physiologic response to intravascular injection of the product’s FDA label indications are limited to
epinephrine is tachycardia, and it has been routine periodontal and restorative and do not
reported that an intravascular dose of 15 ug include endodontic procedures in maxillary pre-
(equivalent to 3 ml of a 1:200,000 concentration) molar and anterior teeth.
will produce a transient increase in heart rate of Intranasal local anesthesia has several advan-
10 beats or more per minute (BPM), with an tages, the most significant being avoidance of
approximate transient increase in systolic pres- needle insertion, ease of administration, and abil-
sure of 15 mmHg or more (El-Boghdadly and ity of dental auxiliaries to administer maxillary
Jinn Chinn 2016). Felypressin, not currently anesthesia in licensing jurisdictions in which
available in dental local anesthetic solutions in topical anesthetic administration is a permitted
the United States, is essentially devoid of the duty. There are, however, several disadvantages
sympathomimetic effects seen with epinephrine, of the product:
as it locally reduces blood flow via a peptidergic
mechanism on venous smooth muscle, and not by • Limited types of teeth that can be effectively
activation of alpha or beta adrenoceptors. anesthetized (maxillary premolars, canines,
and incisors)
• Limited types of procedures that can be accom-
 asally Administered and Topically
N plished under intranasal local anesthesia
Applied Anesthetics • Significantly higher cost than injectable local
anesthetics
In the past decade, attempts to eliminate the need • Significantly longer time for onset of anesthe-
for injections and improve the effectiveness of sia (up to 14 min total for the two sprays
topical agents have resulted in two major devel- required)
Local Anesthetics 21

• Need for refrigeration of the product immediate postoperative period, was introduced
• Lack of approved indication for younger in 1972, but its potential applications in dentistry
children have only recently been investigated. When used
by buccal infiltration in endodontically involved
Intranasal anesthesia can be considered as a teeth, a randomized, double-blind trial of liposo-
viable approach for routing restorative proce- mal bupivacaine versus infiltration of aqueous
dures and periodontal procedures when needle bupivacaine HCl failed to demonstrate signifi-
phobic patients are being treated or when exces- cantly better pain control by the liposomal prepa-
sive soft-tissue anesthesia is to be avoided. ration. In third molar impaction surgery,
The second major development in this area is liposomal bupivacaine provided better postopera-
the widespread availability of combination topi- tive pain control than placebo, with no greater
cal anesthetics, typically produced by compound- incidence of adverse events, although this study
ing pharmacies as extemporaneous preparations could not be considered conclusive due to exten-
made only by prescription from a practitioner. sive protocol violations in the phase 3 placebo-­
These “stronger” topical agents have also been controlled study arm (Lieblich and Danesi 2017).
diverted to non-healthcare setting by the newer Finally, a recent systematic review with 63
cultural emphasis on cosmetic enhancements of included studies concluded that the majority of
the human body, that is, tattoos, piercings, and randomized controlled trials of liposomal bupiva-
hair removal. For years, 5% lidocaine ointment caine for postoperative pain relief versus placebo
and 20% benzocaine have served as the main- or active drugs do not support claims of superior-
stays of topical dental anesthesia, but reports of ity of liposomal bupivacaine (Yisi et al. 2021). At
efficacy of combination topicals for insertion of this time, dental practitioners should carefully
orthodontic intraosseous anchorage devices consider this evidence, as well as the cost of lipo-
(resembling mini implants) have also driven the somal bupivacaine before incorporating it in to
increased use of combination preparations their practices on a regular basis. Dentists should
(Reznik et al. 2009). Typically, these prepara- continue to consider emerging evidence for the
tions combine two topically effective local anes- use of intranasal and combination topical anes-
thetics with a vasoconstrictor (e.g., TAC Alternate thetics for potential applications in general
Gel®, lidocaine + tetracaine + phenylephrine). dentistry.
While effective for obtaining soft-tissue anesthe-
sia for routine procedures, such as SRP and pre-­
injection anesthesia, these combination products Conclusion
do not facilitate invasive dental procedures.
Additionally, the combination of high percent- Conventional dental local anesthetics provide
ages of local anesthetics results in doses as high excellent pain control for routine dental proce-
as 240 mg of anesthetic per ml. One such prepa- dures, and there is little financial incentive for
ration contains lidocaine 12.5%, tetracaine pharmaceutical manufacturers to develop new
12.5%, prilocaine 3%, and phenylephrine 3%, for local anesthetic drug entities for dental indica-
a total of 280 mg of local anesthetic per ml. While tions only. The safe use of these agents must be
brief applications of small amounts of these prep- predicated on the utilization of all appropriate
arations can be tolerated by adults, this quantity measures to prevent LAST, as the management of
of local anesthetic, if swallowed or if allowed to severe systemic toxicity is challenging and may
contact large areas of skin for prolonged periods, require advanced techniques and agents not ordi-
could be disastrous in some settings, particularly narily available in dental offices. Dental practi-
small children or infants who could swallow the tioners should continue to monitor outcomes
anesthetic. from randomized, controlled trials and system-
Exparel®, a liposomal form of bupivacaine atic reviews in order to refine their selection and
designed to provide relief of surgical pain in the use of currently available local anesthetics.
22 A. H. Jeske

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 Non-opioid Analgesics in Dental
Practice

Arthur H. Jeske

Principles of Analgesic Therapy Pharmacologic Characteristics

of NSAID Analgesics for Acute
There are several important principles that must Postoperative Dental Pain
be considered prior to prescribing an analgesic
for a dental patient: There are several chemical classes of NSAIDs,
many of which are used in various medical condi-
1. Analgesics are adjuncts to caries removal and tions, especially osteoarthritis. The most impor-
surgical interventions (tooth extraction, pulp- tant class for the control of pain in dentistry is the
ectomy, incision-and-drainage) and should propionic acid group, which includes ibuprofen
not be used in place of these procedures in the (Advil®), naproxen (Aleve®), and ketoprofen
management of acute dental pain. (Orudis®). These agents possess analgesic, anti-­
2. The selection of an analgesic must be based inflammatory, antipyretic, and antiplatelet thera-
upon the patient’s medical history and current peutic actions and are ideally suited for
disorders and take into account the possibility applications in inflammatory dental conditions
of adverse events and adverse drug/drug (acute apical periodontitis, symptomatic irrevers-
interactions. ible pulpitis). They act by inhibition of cyclooxy-
3. An analgesic regimen should be based upon genase (COX-1 and COX-2), which reduces the
the expected level and duration of pain, taking synthesis of prostaglandins (PGs), and their anal-
into consideration systemic conditions such gesic action is attributable primarily to a reduc-
as cardiovascular, gastrointestinal, and aller- tion of PGE2 and F2α, which are synthesized
gic conditions and defined clinical endpoints rapidly after tissue damage and sensitize nocicep-
(reduction of pain, swelling). tive nerve endings to a wide variety of noxious
4. While no longer recommended as drugs of stimuli. Importantly, inhibition of PG synthesis
first choice for dental pain, the opioids, par- occurs relatively early in painful inflammatory
ticularly those marketed in combination with conditions, so NSAID therapy should commence
acetaminophen, remain important alternatives as early as feasible in pain management.
when NSAIDs are inappropriate due to allergy A recent overview of systematic reviews pro-
and other medical conditions. vides practitioners with a wealth of high-level
evidence for the comparative efficacy of various
A. H. Jeske (*)
oral analgesics, based primarily on the third
UTHealth School of Dentistry, Houston, TX, USA molar impaction surgery model of assessing
e-mail: [email protected] acute postoperative pain (Moore et al. 2015a).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 25

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_3
26 A. H. Jeske

When using this reference, it is helpful to con- Table 1 Selected NNT values for common single-dose
non-opioid oral analgesics used in dentistry, as reported in
sider the number needed to treat (NNT) values
(Jose et al. 2022)
for various analgesics, with values <2 being gen-
Confidence interval
erally considered among the best for single-dose Drug NNT 95%
outcomes. In regard to these values, NNT refers Diclofenac 100 mg 1.9 1.7–2.3
to the number of subjects who need to receive an Diflunisal 1000 mg 2.1 1.8–2.6
intervention in order to see a define beneficial Ibuprofen 200 mg 2.9 2.7–3.2
effect, which in these pain trials is a reduction of Ibuprofen 200 mg + 2.1 1.9–3.1
pain level by at least 50%. Mathematically, NNT 100 mg caffeine
Ibuprofen 400 mg 2.5 2.4–2.6
is defined simply as:
Ibuprofen 200 mg + APAPa 1.6 1.5–1.8
NNT = 1/ ARR 500 mg
Ibuprofen 400 mg + APAP 1.5 1.4–1.7
where ARR is the absolute risk reduction (differ- 1000 mg
ence between active treatment and placebo). Ketoprofen 100 mg 2.1 1.7–2.6
For example, where an active (investigational) Naproxen 500–550 mg 2.7 2.3–3.3
APAP 500 mg 3.5 2.7–4.8
drug produces a 50% or greater reduction in pain
APAP 1000 mg 3.6 3.2–4.1
level in 70% of the subjects and the placebo pro- a
APAP denotes acetaminophen/acetyl para amino phenol
duces a 50% or great reduction in pain in 15% of
the subjects, the NNT is:
NNT = 1 / 0.7 − 0.15, or 1 / 0.55, or 1.8. highlighted in Table 1. This may be based upon
the possibility that higher doses of NSAIDs pro-
In this example, NNT would predict that the vide a greater anti-inflammatory effect, in addi-
active drug would need to be given to only 1.8 tion to their analgesic effect, or the perceived
individual patients (less than 2) to see the defined need for higher dosages may be based upon the
benefit. NNT has both advantages and disadvan- fact that pain of endodontic origin is typically
tages, and an advantage is that it addresses both associated with a much longer duration of preop-
clinical and statistical significance in an easily erative pain, as opposed to the pain of third-molar
understood manner. However, its practical sig- impaction surgery, which is usually exclusively
nificance may vary with the significance of the postoperative and which does not involve the
disease/patient conditions, and it is only useful to prolonged period of bacterial-induced inflamma-
compare NNT values among various interven- tion or invasive dental procedures associated with
tions when the treatments are for the same condi- pulpal disease.
tion, severity, and outcome measure (Schechtman When considering the NNT values presented
2002). It is also important to note that in order for in Table 1, the reader should consider the fact that
a drug or drug combination to have been included these numbers apply to single oral doses of these
in this study, outcomes must be from at least two analgesics, with pain responses assessed over a
randomized, controlled studies with a total of at 4- to 6-h postoperative time interval, and that the
least 200 subjects. The outcomes from subjects in the studies used in the calculations of
(Aminoshariae et al. 2016a) are summarized in these NNT values were fasting.
Table 1. When considering these outcomes, it is
important to note that results from studies of
single-­dose oral analgesics used in the third Acetaminophen
molar-impaction model may differ from the find-
ings of studies done in endodontic patients. High-level scientific evidence from systematic
Typically, studies of relief of postoperative end- reviews of acute postoperative pain in adults
odontic pain have focused on higher (e.g., 600 suggests that, based on number-needed-to-treat
mg) doses of ibuprofen than those from studies (NNT), acetaminophen administered alone is
Non-opioid Analgesics in Dental Practice 27

Table 2 Comparative pharmacologic characteristics of nonsteroidal anti-inflammatory drugs (NSAIDs),a acetamino-

phen and opioid analgesics available in the United States (Jeske 2017)
Characteristic NSAIDs Opioids Acetaminophen Comment
Available OTC Yes No Yes
Tolerance, No Yes No Opioid tolerance and dependence are unlikely to occur
dependence with short-term use (<5 days)
CNS depression No Yes No A sedative effect of opioids may be desirable in some
circumstances
Anti-inflammatory Yes No No Principal advantage of NSAIDs
Anti-pyretic Yes No Yes Beneficial in the presence of infection
Analgesic Yes Yes Yes NSAIDs act primarily peripherally at the site of tissue
injury, while opioids act centrally (CNS). Combinations
are generally superior to single-agent regimens
Antiplatelet agents Yes No No Increased bleeding risk is associated with NSAIDs,
(including aspirin) primarily if taken preoperatively; the effect is reversible
(unlike aspirin, which is irreversible)
GI dysfunction Yes Yes No In addition to nausea and vomiting, opioids are
associated with constipation. NSAID-related GI
irritation is typically seen during prolonged
administration (>5 days)
a
Propionic acid class

not a particularly good analgesic (Moore et al. aminophen, and opioid analgesics is presented in
2015a; Moore et al. 2016). This has been con- Table 2.
firmed in randomized controlled trials of post-
endodontic pain as well (Ciancio 2014).
However, when used in combinations, acet- Prescribing Considerations
aminophen appears to act synergistically with
both NSAIDs and opioid analgesics and the 1. For the management of acute postsurgical
combination of 200–400 mg ibuprofen plus dental pain (including pain of endodontic ori-
500–1000 mg acetaminophen (taken at the gin), in the absence of any significant contra-
same time) results in the best NNT values in indications, therapy should begin with a
the oral surgical pain model (Moore et al. standard dose of a combination, orally admin-
2015a). Additionally, this combination does istered first-choice agents (ibuprofen with
not result in adverse effects greater than those acetaminophen) (Aminoshariae et al. 2016a,
observed in placebo groups when used on a b; Elzaki et al. 2016; Smith et al. 2017).
short-term basis (Moore et al. 2015b). However, 2. For optimal pain relief, the combination of
it should also be noted that the maximum daily 200–400 mg ibuprofen with 500–1000 mg
adult dose of acetaminophen from all sources acetaminophen has been shown to provide
(Rx and OTC) should not exceed 4000 mg pain relief that is superior to virtually all acet-
(Jeske 2017; Moore et al. 2015a). aminophen/opioid combinations and COX-2
Hepatotoxicity may occur from excessive acet- selective NSAIDs (Moore et al. 2015a).
aminophen intake or from interactions with 3. Because peak pain associated with dental
chronic alcohol use. While unusual, allergy to extractions appears to occur within the first
acetaminophen can occur and would absolutely 4–8 h postoperatively and then decline over
contraindicate use of this agent. the next 2–3 days, short-term administration
A summary of the comparative pharmacologic of the ibuprofen/acetaminophen combination
characteristics of propionic acid NSAIDs, acet- can be employed.
28 A. H. Jeske

4. A need for a sedative effect, especially in the bleeding. Short-term use of NSAIDs has been
first 24 h postoperatively, may warrant the shown to be relatively safe when administered
addition of an opioid analgesic in combina- for dental pain (Aminoshariae et al. 2016a).
tion with the NSAID, when the patient’s Furthermore, robust systematic reviews consis-
activities would not be affected by possible tently report s­ ignificantly fewer adverse effects
CNS depression. of NSAIDs when compared to opioids (Chou
5. Warnings with analgesic therapy should be et al. 2020).
issued verbally and in writing on the prescrip- Ingestion of high doses of NSAID analgesics
tion. They should include the possible devel- is associated with nephropathy, and the risk of
opment of allergic reactions, as well as GI this complication increases in elderly patients, as
disturbances, increased bleeding risk, and the well as patients who are dehydrated or have pre-
risk of adverse interactions between acet- existing renal insufficiency, heart failure, or dia-
aminophen and alcohol and acetaminophen betes (Kharasch 2004). It should be noted that
overdose. dehydration could be present in individuals with
6. Whenever possible, analgesics should be symptomatic irreversible pulpitis who have expe-
taken on an empty stomach with a glass of rienced diarrhea and/or nausea and vomiting
water in order to hasten the dissolution of the (possibly induced by self-prescribed antibiotics
dose form and delivery of the drug from the and/or analgesics) and who are not well nour-
stomach to the small intestine. ished/hydrated due to dental pain. This is particu-
7. To extend duration of action to >8 h, a long-­ larly problematic when patients have ingested
acting NSAID at a higher dose (diflunisal over-the-counter NSAIDs or acetaminophen
1000 mg) or an NSAID-acetaminophen com- before receiving dental treatment.
bination at a higher dose (ibuprofen 400 mg + Since renal blood flow and urine formation
acetaminophen 1000 mg) can be employed. are partly regulated by physiologic PGs, blood
8. Caution is advised in patients who are regu- pressure may be elevated by the ingestion of
larly taking NSAIDs for systemic disorders, NSAIDs, and this should be considered when
for example, osteoarthritis, as adding a second designing an analgesic regimen for patients
NSAID to their medication regimens put them with hypertension and other cardiovascular
at risk for serious gastrointestinal irritation disorders.
and possible ulceration, as well as nephritis Bleeding is associated with all NSAIDs, and
and renal failure, and/or severe bleeding. In increased intraoperative and postoperative bleed-
these patients, alternative analgesics (e.g., ing must be anticipated and dealt with effectively,
acetaminophen, opioids) should be consid- including the use of careful surgical technique,
ered and can be added to the patient’s NSAID suturing, and other hemostatic measures (oxi-
regimen if no contraindications exist. dized cellulose packs).
The risk of allergic and adverse respiratory
reactions to NSAIDs should be evaluated through
Adverse Effects a careful medical history, especially in patients
with a prior history of aspirin allergy, asthma,
NSAID analgesics, as prescribed in dentistry, and reactive airway disease.
are generally well tolerated. With the exception Pregnancy constitutes a contraindication to
of allergy, most adverse effects from short-term the use of NSAIDs, particularly in the first and
use of NSAIDs are related to their effects on the third trimesters. Among the commonly used
gastrointestinal tract and platelets. NSAIDs NSAIDs, observed differences in GI irritation
inhibit the formation of gastroprotective PGs, only become manifest after prolonged therapy
and this irritant effect, combined with their anti- (>30 days). Typically, another drug to reduce GI
platelet effect, can result in ulcerations and GI
Non-opioid Analgesics in Dental Practice 29

irritation (e.g., misoprostol) is only prescribed Adverse Drug Interactions

during longer-term administration.
In summary, when used short term for the NSAID analgesics are capable of adversely inter-
management of acute postoperative pain in den- acting with other dental and medical drugs, both
tistry, most NSAIDs and NSAID-acetaminophen through pharmacodynamic and pharmacokinetic
combinations produce no greater incidence or mechanisms. The most significant adverse inter-
severity of adverse effects than placebo. The evi- actions for commonly prescribed NSAID analge-
dence for this is found in the overview of system- sics are listed in Table 3.
atic reviews published by Moore et al. It should
be noted, however, that this same review deter-
mined that some commonly utilized analgesics Corticosteroids
produce significantly more adverse events than
placebo, and these agents include aspirin 1000 In some cases, anti-inflammatory corticosteroids
mg, diflunisal 1000 mg, all opioids, and may be beneficial in providing short-term pain
­fixed-­dose combination products containing opi- relief, particularly in cases of inflammation asso-
oids (Moore et al. 2015b). ciated with apical periodontitis, acute apical
abscess, and third-molar extraction. In a prospec-
tive, triple-blinded, split-mouth randomized trials,
Al-Dajani (Al-Dajani 2017) evaluated single i.m.
doses of dexamethasone versus placebo adminis-
tered preoperatively in patients prior to third

Table 3 Clinically significant drug interactions involving NSAID analgesics used in dentistry (modified from (Ciancio
2014))a
Primary drug Action Interaction (and effect)
Alcohol Enhanced by Increased GI irritation, nausea, GI pain, bleeding
NSAIDs
Diuretics, antihypertensive Antagonized by Increased salt and water retention with increased blood pressure
drugs NSAIDs
Coumarins (including Enhanced by Increased risk of bleeding
warfarin) NSAIDs
Antiplatelet agents (aspirin, Enhanced by Increased risk of bleeding; increased risk of thromboembolism
clopidogrel) NSAIDs (ibuprofen blocks the antiplatelet effect of aspirin when the drugs
are taken concurrently)
Direct oral anticoagulants Enhanced by Increased risk of bleeding
(rivaroxaban, dabigatran) NSAIDs
Potassium-sparing diuretics Enhanced by NSAIDs may increase serum potassium levels
NSAIDs
Potassium supplements Enhanced by NSAIDs may increase serum potassium levels
NSAIDs
Cancer chemotherapeutic Enhanced by Increased risk of GI ulceration
agents NSAIDs
Selective serotonin Reuptake Enhanced by Increased risk of GI ulceration and bleeding
inhibitors (SSRIs) NSAIDs
Corticosteroids Enhanced by Increase salt and water retention; increased risk of GI ulceration
NSAIDs
a
Less significant drug interactions are also possible—the clinician should consult the complete prescribing information
for all drugs prescribed. For elderly and medically compromised patients with systemic disease that could impact drug
metabolism and/or excretion, consultation with the patient’s physician is recommended
30 A. H. Jeske

molar surgery and concluded that this method can pared to take additional hemostatic measures
be safely used to decrease postoperative pain and during the procedure in patients who are under-
improve daily functioning. By implication, corti- going surgical procedures and who have received
costeroids may also spare opioid use, thus avoid- preoperative NSAID medications, and this effect
ing opioid-related issues such as constipation and has also been demonstrated in orthodontic
CNS depression. Based on recent scientific evi- patients following placement of bands or separa-
dence, both methylprednisolone and dexametha- tors. It should be noted that evidence is lacking
sone can be utilized in such situations, although for a similar pre-emptive analgesic effect of acet-
an injection is required (Bane et al. 2016; Chen aminophen when administered preoperatively. In
et al. 2017). A recent systematic review deter- endodontics, a recent systematic review demon-
mined that preoperative administration of cortico- strated that oral preoperative administration of a
steroids (4 or 8 mg oral dexamethasone, 40 mg corticosteroid provides superior postoperative
parenteral dexamethasone) was effective in reduc- pain relief when compared to NSAIDs as oral
ing in post-endodontic pain (Aminoshariae et al. premedication, with the additional benefit of
2016b). Orally administered corticosteroids can improving success rates of local anesthetic nerve
be used to suppress inflammation, both pre- and blocks (Jose et al. 2022).
postoperatively, and this use is commonly Other strategies for pre-emptive analgesia
exploited in third-molar surgery. include administration of long-acting local anes-
In periodontics, for dental implant surgery, thetics (e.g., bupivacaine), a positive effect occur-
postoperative glucocorticoids used as primary ring even when used with general anesthesia for
analgesics can produce pain reduction equiva- extracted of impacted third molar teeth.
lent to NSAIDs used alone (Khouly et al. 2021).
It is important to note in regard to the preemptive
use of corticosteroids that best results are Conclusion
obtained with parenteral (rather than oral)
administration. At this time, the optimal regi- Dentists should continue to consider emerging
mens for these applications have not been estab- evidence for the use of non-opioid analgesics,
lished (Wagner et al. 2022). especially in view of the ever-increasing problem
The characteristics and uses of corticosteroidsof opioid abuse and diversion.
are described in greater detail in chapter Dentists can now confidently prescribe an
“Endocrine Drugs of Significance in Dentistry”. NSAID or recommend OTC (e.g., ibuprofen +
acetaminophen) combinations for excellent relief
of acute dental pain, based on high-level scien-
Pre-emptive Analgesia tific evidence. This evidence is readily accessible
by searching the PubMed database of the US
NSAIDs have been evaluated for use pre-­ National Library of Medicine, and entering the
emptively (preoperative administration to reduce name of a specific drug within the following
postoperative pain). The reader is referred to an search terms:
excellent update on this topic by Lieblich Single dose oral _____ for acute postoperative
(Lieblich 2017). Typically, single-dose ibuprofen pain in adults.
400–600 mg, administered approximately 1 h
before a procedure, is recommended, based on Current evidence supports the use of an NSAID
limited evidence, although there is limited evi- (ibuprofen), in combination with acetaminophen
dence that single NSAID administration, includ- if possible as first-choice therapy for the manage-
ing ibuprofen and ketorolac, is not effective for ment of acute postoperative dental pain in adults.
this use (Aminoshariae et al. 2016b). When used In children, a single NSAID is currently sup-
in this manner, intraoperative bleeding is ported by the American Academy of Pediatric
increased, and the practitioner should be pre- Dentistry’s Guideline on Pain Management as the
Non-opioid Analgesics in Dental Practice 31

first-line agent in the treatment of acute mild to clinical trial of efficiency of nonsteroidal anti-­
inflammatory drugs in the control of post-endodontic
moderate postoperative pain (American Academy pain. J Endod. 2016;42(6):835–42.
of Pediatric Dentistry 2017). Jeske AH, editor. Mosby’s dental drug reference. 12th ed.
St. Louis: Mosby; 2017.
Jose J, Teja KV, Palanivelu A, Khandelwal A, Siddique
R. Analgesic efficacy of corticosteroids and nonste-
References roidal anti-inflammatory drugs through oral route in
the reduction of postendodontic pain: a systematic
Al-Dajani M. Can preoperative intramuscular single-dose review. J Conserv Dent. 2022;25(1):9–19.
dexamethasone improve patient-centered outcomes Kharasch ED. Perioperative COX-2 inhibitors: knowl-
following third molar surgery? J Oral Maxillofac Surg. edge and challenges. Anesth Analg. 2004;98:1–3.
2017;75:1616–26. Khouly I, Braun RS, Ordway M, Alrajhi M, Fatima S,
American Academy of Pediatric Dentistry. Policy on Kiran B, Veitz-Keenan A. Post-operative pain manage-
acute pediatric dental pain management. Chicago: ment in dental implant surgery: a systematic review
AAPD; 2017. and meta-analysis of randomized clinical trials. Clin
Aminoshariae A, Kulild JC, Donaldson M. Short-term use Oral Investig. 2021;25(5):2511–36.
of nonsteroidal anti-inflammatory drugs and adverse Lieblich S. Clinical focus: pre-emptive analgesia. J Oral
effects. An updated systematic review. J Am Dent Maxillofac Surg. 2017;75(2):245–6.
Assoc. 2016a;147(2):98–110. Moore RA, Derry S, Aldington D, Wiffen PJ. Single
Aminoshariae A, Kulild JC, Donaldson M, Hersh dose oral analgesics for acute postoperative pain in
EV. Evidence-based recommendations for analgesic adults—an overview of Cochrane systematic reviews.
efficacy to treat pain of endodontic origin. J Am Dent Cochrane Libr. 2015a;9:CD008659.
Assoc. 2016b;147(10):826–39. Moore RA, Derry S, Aldington D, Wiffen PJ. Adverse
Bane K, Charpentier E, Bronnec F, Descroix V, Gaye-­ events associated with single dose oral analgesics for
Ndiaye F, Kane AW, Toledo R, Machtou P, Azerad acute postoperative pain in adults—an overview of
J. Randomized trial of intraosseous methylpred- Cochrane systematic reviews. Cochrane Database Syst
nisolone injection for acute dental pain. J Endod. Rev. 2015b;10:CD011407.
2016;42(1):2–7. Moore PA, Dionne RA, Cooper SA, Hersh EV. Why
Chen Q, Chen J, Hu B, Feng G, Song J. Submucosal do we prescribe Vicodin? J Am Dent Assoc.
injection of dexamethasone reduces postoperative 2016;147(7):530–3.
discomfort after third-molar extraction. A system- Schechtman E. Odds ratio, relative risk, absolute
atic review and meta-analysis. J Am Dent Assoc. risk reduction, and the number needed to treat—
2017;148(2):81–91. which of these should we use? Value Health.
Chou R, Wagner J, Ahmed AY, Blazina I, Brodt E, 2002;5(5):431–6.
Buckley DL, Cheney TP, Choo E, Dana T, Gordon D, Smith EA, Marshall JG, Selph SS, Barker DR, Sedgley
Khandelwal S, Kantner S, McDonagh MS, Sedgley CM. Nonsteroidal anti-inflammatory drugs for man-
C, Skelly AC. Treatments for acute pain: a systematic aging postoperative pain in patients who present with
review. Agency Healthc Res Qual. 2020;20(21):6. preoperative pain: a systematic review and meta-­
Ciancio SG. Drug interactions: a guide for dentistry. analysis. J Endod. 2017;43(1):7–15.
MetLife Qual. Res. Guide, 4th ed. 2014. http://www. Wagner JC, Johnson TM, Gilbert WA. Should periodon-
metdental.com. tists prescribe postoperative oral corticosteroids to
Elzaki WM, Abubakr NH, Ziada HM, Ibrahim control pain and swelling? A systematic review. Clin
YE. Double-blind randomized placebo-controlled Adv Periodont. 2022;12(2):134–42.
 Opioid Analgesics,
Benzodiazepines, and Other
Controlled Substances

Arthur H. Jeske

Principles of Opioid Prescribing 9. All instructions for patient analgesia and

analgesic prescriptions should be carefully
­
There are several important principles that must documented.
be considered prior to prescribing an opioid anal-
gesic for a dental patient (American Association
of Oral and Maxillofacial Surgeons 2017): Pharmacologic Characteristics
of Oral Opioids for Acute
1. A nonsteroidal anti-inflammatory drug Postoperative Dental Pain
(NSAID) may be used preoperatively to
reduce the severity of postoperative pain. There are three major classes of opioids—natu-
2. Perioperative corticosteroids can used to ral opium derivatives, semisynthetic opioids, and
reduce swelling and other discomfort after synthetic opioid agonists. In dentistry, the most
impaction surgery. important of these is the semisynthetic class,
3. Long-acting local anesthetics may delay the which includes codeine, hydrocodone, and oxy-
severity and onset of postoperative pain. codone. Synthetic agents such as fentanyl and
4. Long-acting, extended release opioids should meperidine are used primarily by the intrave-
not be used for acute pain. nous route and are not covered in this chapter.
5. Unless contraindicated, NSAIDs are first-­ The most commonly used pharmaceutical forms
choice analgesics for acute pain. of opioids for the control of pain in dentistry are
6. NSAIDs and acetaminophen can be used in combinations of the opioid component with
combination to improve analgesic outcomes, acetaminophen (e.g., Vicodin®). All of these
although dosage must be carefully monitored. agents act non-selectively at mu, kappa, and
7. Short-acting opioids may be appropriate for delta opioid receptors and possess analgesic,
acute “breakthrough” pain. antitussive, and sedative therapeutic actions but
8. Practitioners may be required to use lack the beneficial anti-inflammatory and anti-
prescription-­drug monitoring programs, and pyretic therapeutic actions seen with the
these programs can be useful to detect opioid NSAIDs. The addition of acetaminophen to an
misuse or addiction. opioid pain-control regimen gains two specific
advantages—first, the acetaminophen possesses
A. H. Jeske (*) antipyretic activity, and second, acetaminophen
UTHealth School of Dentistry, Houston, TX, USA and opioids appear to act synergistically and
e-mail: [email protected] therefore are capable of producing levels of pain

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 33

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_4
34 A. H. Jeske

relief not achievable with even higher doses of acetaminophen (Moore et al. 2015). These out-
either agent taken alone. comes are particularly relevant to acute postop-
erative dental pain, as the majority of the
randomized controlled trials that comprise
Non-Analgesic Actions and Adverse these systematic reviews and meta-analyses
Effects were conducted using the third-molar impac-
tion surgery pain model. A summary of the
Depending on the dose and the degree of opioid comparative efficacy of various analgesics
tolerance in an individual, the following non-­ based on number-­needed-­to treat values for sin-
analgesic effects are characteristics of most opi- gle doses of various opioids and opioid combi-
oids: dizziness, somnolence, nausea, vomiting nation products suggests that oxycodone, in
(caused by stimulation of the chemoreceptor trig- combination of higher doses of acetaminophen,
ger zone in the brainstem), respiratory depression appears to be worth of consideration when an
(initially caused by reduction of the sensitivity of NSAID cannot be used for acute postoperative
the respiratory center to carbon dioxide), miosis, dental pain (Table 1).
constipation, cardiovascular depression, and, Some caution must be observed when inter-
eventually, loss of consciousness, coma, and preting the NNT values shown in Table 1.
death (usually due to cardiorespiratory arrest). NNT is a relative measure of the reduction of
Virtually, all of these actions are the result of pain level following a single dose of an analgesic
drug binding to the mu opioid receptor, and virtu- and does not quantify the subjective relief of pain
ally, all can be reversed by the administration of that may be produced by drugs with significant
sufficient doses of narcotic antagonists (e.g., CNS depressant effects, such as opioids. While a
naloxone). given opioid analgesic’s NNT (as reported above)
Consideration must be given to the potential may be less favorable, that is, higher than a non-­
for respiratory depression in individuals who opioids, this value alone does not predict the
present with a compromised airway (e.g., entire pain-relieving effect, which varies with the
Mallampati Class III) and those with obstructive opioid’s alteration of the central processing of
sleep apnea (OSA). While there are many factors pain stimuli and the interpretation of the pain.
that determine the potential for postoperative opi-
oid toxicity in patients with OSA, current evi-
dence suggests a need for multimodal Table 1 Number-needed-to-treat (NNT) values for opi-
oid and opioid-acetaminophen combination analgesics
postoperative pain control in these individuals, versus placebo, based on overview of systematic reviews
including local anesthetics and non-opioid anal- and meta-analyses (Gaskell et al. 2009; Moore et al. 2015)
gesics (e.g., NSAIDs) (Maund et al. 2011; Confidence interval
American Society of Anesthesiologists Task Drug NNT 95%
Force 2014). Oxycodone 5 mg + APAP 5.5 na
325 mg
Oxycodone 10 mg + APAP 2.7 2.4–3.1
650 mg
Comparative Efficacy of Opioids Oxycodone 10 mg + APAP 1.8 1.6–2.2
1000 mg
High-level scientific evidence from systematic Oxycodone 15 mg 4.6 2.9–11
reviews of acute postoperative pain in adults Codeine 30 mg + APAP 6.9 4.8–12
suggests that based on number-needed-to-treat 300 mg
Codeine 60 mg + APAP 3.9 2.9–4.5
(NNT) that single opioids and opioid-­ 600–650 mg
acetaminophen combinations are generally Codeine 60 mg + APAP 2.2 1.8–2.9
equivalent to single NSAIDs but are inferior to 800–1000 mg
pain relief outcomes associated with some Codeine 60 mg 12 8.4–18
NSAIDs and the combination of ibuprofen and APAP acetaminophen/acetyl para amino phenol
Opioid Analgesics, Benzodiazepines, and Other Controlled Substances 35

This same phenomenon also makes the quantita- be clinically insignificant (Kinnunen et al. 2019).
tive study of opioid analgesia, based on VAS Oxycodone is principally inactivated metaboli-
instruments and other tests, more challenging. cally by CYP 3A4, and caution must be exercised
Of interest for practitioners in the United if it is to be administered to patients taking induc-
States is the absence of systematic reviews and ers of CYP 3A4 (e.g., corticosteroids) or inhibi-
meta-analyses for pain relief outcomes using tors (e.g., azole antifungal drugs, macrolide
hydrocodone and hydrocodone-acetaminophen antibiotics).
combinations. This is likely due to the fact that
hydrocodone has been banned or is unavailable
in many other countries for some time. It is pos- Prescribing Considerations
sible to glean some moderate-quality evidence
for the combination of hydrocodone and acet- 1. For acute postoperative pain, only short-term
aminophen from a limited number of clinical administration of the analgesic should be
trials. For example, in a comparison of cele- needed.
coxib 400 mg with hydrocodone and 2. A need for a sedative effect, especially in the
hydrocodone-­ acetaminophen in outpatient first 24 h postoperatively, may warrant the use
orthopedic patients, hydrocodone compared of an opioid analgesic in combination with
favorably to placebo and performed equally acetaminophen or an NSAID, when the
well with celecoxib over the first 8 h postopera- patient’s activities would not be affected by
tively but was inferior to celecoxib at subse- possible CNS depression and when no other
quent test intervals, and the hydrocodone contraindications exist.
products produced a significantly higher inci- 3. Warnings with opioid analgesic therapy
dence of adverse effects. Similarly, interna- should be issued verbally and in writing on
tional studies of hydromorphone (Dilaudid®) the prescription. They should include the pro-
are not available in systematic reviews, and this hibition of alcohol intake during opioid treat-
agent, therefore, cannot be recommended as ment, as well as possible interactions with
evidence-­based pain control in dentistry. other CNS depressant drugs and development
Recently, the comparative efficacy of opioid of allergic reactions, as well as possible nau-
analgesics in the management of dental pain has sea and vomiting. The adverse interactions
been further elucidated in two systematic between acetaminophen and alcohol under-
reviews, both of which found that while 5 mg of score the need for warning the patient about
oxycodone alone produced analgesia that was alcohol ingestion.
no better than placebo, it does produce effective 4. Pregnancy constitutes a contraindication to
analgesia when used in combination with acet- the use of NSAIDs, particularly in the first
aminophen (Miroshnychenko et al. 2023; Teoh and third trimesters. Among the commonly
et al. 2022). used NSAIDs, observed differences in GI irri-
Oxycodone, used in combination with effec- tation only become manifest after prolonged
tive doses of acetaminophen, currently appears to therapy>30 days). Typically, another drug to
be the opioid of first choice. In contrast to hydro- reduce GI irritation (e.g., misoprostol) is only
codone, codeine, and tramadol, oxycodone does prescribed during longer-term administration.
not depend on activation by CYP 2D6. A recent 5. Scientific evidence to support the selection of
review of its pharmacokinetic and pharmacody- hydrocodone over another opioid, for exam-
namic properties (Kinnunen et al. 2019) suggests ple, oxycodone, is lacking. While there are a
that while approximately 19% of a dose of oxy- limited number of systematic reviews and
codone is metabolized by CYP 2D6 to oxymor- meta-analyses for oxycodone, this type of evi-
phone, which does not readily cross the blood dence has not been available for hydrocodone,
barrier, and the contribution of active metabolites partly because the drug is not available in
to analgesia produced by oxycodone appears to many countries other than the United States
36 A. H. Jeske

(Moore et al. 2016). For this reason, and

Rx
because oxycodone responses appear to be
less susceptible to CYP-related pharmacoge- Oxycodone 5 mg immediate-release
netic variations, the author recommends the
tabs
use of immediate-­release forms of oxycodone
as an evidence-­based opioid analgesic to be Dispense 6 (six) tabs
used in combination with acetaminophen for
the management of acute postoperative pain Sig: Take 2 (two) tabs with 1,000 mg
in adults. acetaminophen every 8 hours for
6. Systemic diseases must be taken into consid- acute dental pain.
eration when prescribing opioids. Liver dis-
ease can compromise the metabolic Warnings: Do not drive or operate
disposition of opioids, as well as first-pass machinery while taking. Do not drink
elimination during the initial absorption of alcohol or use other CNS depressants
orally administered opioids. In such cases, the
while taking. May be habit forming.
dose should be reduced and the dosage inter-
val increased to reduce the potential for toxic-
ity. In patients with kidney disease, opioids Fig. 1 Sample prescription for acute postoperative dental
with active metabolites (e.g., codeine, meperi- pain using an opioid in combination with over-the-counter
dine, and morphine) should be avoided, as acetaminophen
these metabolites are ordinarily excreted in
the urine (Wie 2017).
7. When prescribing oxycodone, the prescrip-  dverse Drug Interactions, Opioid
A
tion should note that an immediate-release Pharmacogenetics
form, not an extended-release one (e.g.
Oxycontin®) is to be issued to the patient. Opioid analgesics are capable of adversely inter-
acting with other dental and medical drugs, both
An example of an evidence-based prescrip- through pharmacodynamic and pharmacokinetic
tion for an opioid for short-term management of mechanisms (Haas 1999). The most significant
acute postoperative pain in an otherwise healthy adverse interactions for commonly prescribed
adult without contraindications is illustrated in opioids are found in Table 2.
Fig. 1. It should be noted that the rationale for Less significant drug interactions are also pos-
the use of this combination is based upon data sible—the clinician should consult the complete
from the overview analysis of systematic reviews prescribing information for all drugs prescribed.
by Moore et al. (Moore et al. 2015) and is For elderly and medically compromised patients
designed to provide effective reduction in pain with systemic disease that could impact drug
level and to take advantage of the synergistic metabolism and/or excretion, consultation with
actions of opioids combined with acetamino- the patient’s physician is recommended (Haas
phen and the prolongation of effect at the rela- 1999).
tively higher dose of each component. Among the commonly prescribed opioids,
The prescription illustrated here limits the three are prodrugs, that is, they are metabolically
total daily exposure of the patient to 3000 mg (3 converted from an inactive/less active parent
doses of 1000 mg over 24 h), and it limits the form into an active metabolite. These agents
total amount of opioid dispensed to less than ten include codeine (metabolized to morphine),
tablets. If a longer duration of pain control is hydrocodone (metabolized to hydromorphone),
needed, the number of opioid dosage units can be and tramadol (metabolized to the active M-1 opi-
increased proportionately. oid structure). All of these reactions depend on
Opioid Analgesics, Benzodiazepines, and Other Controlled Substances 37

Table 2 Clinically significant drug interactions involving opioid analgesics (Haas 1999)
Significance
Primary drug rating Interaction and effect
Alcohol 2/Moderate Increased CNS depression, dizziness, somnolence
Antihistamines 2/Moderate Increased salt and water retention with increased blood
pressure
MAO inhibitors 1/Severe Increased risk of seizures (meperidine
Selective Serotonin Reuptake 2/Moderate Increased CNS depression; possible reduced analgesic action
Inhibitors (hydrocodone)
Sedative/hypnotic drugs 1/Severe Increased CNS depression, risk of cardiorespiratory
depression/arrest
Muscle relaxants 1/severe

60% extensive metabolizers, 30% intermediate

metabolizers, 3% poor metabolizers, and 7%
ultrarapid metabolizers, and this is typical of the
distribution for the general population of the
United States (Bernard et al. 2006; Stauble et al.
2014).
At present, because of the limited availability
Fig. 2 Oxidative demethylation of hydrocodone to of pharmacogenetic testing (primarily associated
hydromorphone by the action of CYP2D6 enzyme with testing costs), dentists are not able to base
opioid selection on phenotype.
the activity of the cytochrome P450 isoform CYP
2D6. Figure 2 illustrates the oxidation of hydro-
codone by this enzyme. Sedative/Hypnotics
Variations in patient responses to these agents
are based upon four levels of CYP 2D6 activities, In the past 20 years, both the efficacy and the
and patients can be classified as either poor safety of benzodiazepines for routine sedation of
metabolizers, intermediate metabolizers, exten- dental outpatients have been unequivocally
sive metabolizers, or ultrarapid metabolizers established. While there are many benzodiaze-
(Bernard et al. 2006). Based on the relative rates pines on the market, their principal clinical dif-
of this enzymatic drug activation reaction, ultrar- ferences derive primarily from differences in
apid metabolizers would be expected to exhibit pharmacokinetics and their propensity to induce
exaggerated analgesic responses, as well as exag- sleep versus relief of anxiety, that is, their useful-
gerated adverse effects. Stauble et al. (2014) ness as hypnotics for the management of insom-
demonstrated that pain relief from the adminis- nia or antianxiety actions with less impact on
tration of hydrocodone in female patients follow- consciousness. At this time in the United States,
ing Caesarean section was correlated with plasma the benzodiazepines most commonly used in the
concentrations of the hydromorphone metabolite, dental setting include the following:
not the parent molecule hydrocodone, establish-
ing hydrocodone as a prodrug, that is, a drug that • Diazepam (e.g., Valium®)
must be metabolically converted to an active • Lorazepam (e.g., Ativan®))
metabolite to achieve a therapeutic effect. The • Midazolam (e.g., Versed®)
incidence of the variations among these CYP • Triazolam (e.g., Halcion®)
2D6 phenotypes varies with the population stud-
ied. In the study of Stauble et al., the distribution There are very few randomized controlled tri-
of CYP 2D6 among females in the study was als of these drugs for dental outpatient sedation,
38 A. H. Jeske

and none carry an FDA-approved label indication administered 5 mg diazepam and without a pro-
specifically for dental sedation. However, this longed recovery period. Subsequently, the Dental
“off-label” use has become accepted over time Organization for Conscious Sedation (DOCS)
through case studies and retrospective safety protocols were promulgated, with the recommen-
analyses (Dionne et al. 2006; Ehrich et al. 1997). dation that patient responses to the initial seda-
The clinical pharmacologic properties of these tive doses be carefully monitored prior to
representative sedative/hypnotics are found in administration of an additional dose of sedative
Table 3. (Gordon et al. 2007).
Unlike diazepam and lorazepam, midazolam The most significant adverse drug interactions
and triazolam have a rapid onset, even when used involving benzodiazepines involve excessive
orally, a relatively short duration, and are subject CNS depression with possible cardiorespiratory
to a high first-pass effect due to rapid inactivation depression when they are co-administered with
of approximately 25% of the absorbed dose by other CNS depressants, particularly opioids,
hepatic cytochrome P450 enzymes (Becker alcohol, and barbiturates. Additionally, serious
2011). It should be noted that administration of pharmacokinetic interactions may occur, particu-
the oral dose form sublingually effectively larly for benzodiazepines with high oral bioavail-
bypasses initial hepatic degradation and results in ability and, therefore, high susceptibility to
higher peak plasma levels with intensified seda- agents that reduce the “first-pass” effect (hepatic
tive actions (Becker 2011). extraction of the drug as it passes from the gastro-
The safety and efficacy of benzodiazepines intestinal tract to the circulation) (e.g., mid-
and related drugs (e.g., zolpidem) for sedation of azolam and triazolam). Of particular note in
anxious dental patients have been validated over dentistry are the effects of macrolide antibiotics
the past two decades. Following the introduction and azole-type antifungal drugs. According to the
of triazolam (Halcion®) on the US market in 1982 manufacturer’s data for oral midazolam, erythro-
for the short-term management of insomnia, the mycin, administered at doses of 500 mg three
dental profession began to use it for preoperative times daily, increases the Cnax of oral midazolam
sedation of dental outpatients, recognizing that by approximately 170%, while once-daily doses
its short duration of action and absence of active of ketoconazole increase the Cmax by over 300%.
metabolites were favorable when compared with Increases in area under the curve (AUC) for these
longer acting benzodiazepines with active metab- same interactions were 281–341% and 1490%,
olites, such as diazepam. In 1997, its comparative respectively. Obviously, the doses of midazolam
safety and efficacy with diazepam in patients administered to patients taking these antibiotics
with documented anxiety undergoing endodontic and antifungal agents would need to be signifi-
treatment were studied (Ehrich et al. 1997). Oral cantly reduced to avoid excessive sedation. The
doses of 0.25 mg triazolam were found to be emergency antidote for benzodiazepine over-
more effective and equally safe with orally dose, flumazenil, is described in greater detail in
chapter “Pediatric Considerations in Clinical
Table 3 Pharmacologic properties of selected benzodi- Pharmacology”.
azepine sedative/hypnotic agents All benzodiazepines commonly used for den-
Plasma Duration of tal outpatient sedation are Schedule IV controlled
Drug Adult dose half-life action substances in the United States and may produce
Diazepam 5–15 mg 20–70 h 2–3 h tolerance and dependence when used for pro-
Lorazepam 2–4 mg 10–20 h 8–12 h longed periods. The short-term administration of
Midazolama 0.25–0.5 1–5 h 30–45 min
these drugs for dental outpatient sedation is not
mg/kg
Triazolam 0.125– 1–5 h 6–8 h associated with tolerance or dependence. One of
0.5 mg these agents—alprazolam (Xanax®)—is cur-
a
Approved in the United States for oral use only in rently among those drugs being marketed in large
patients under the age of 18 quantities through illicit channels, even in “coun-
Opioid Analgesics, Benzodiazepines, and Other Controlled Substances 39

terfeit” forms. Benzodiazepines are now fre- zodiazepine, including the infusions of high
quently implicated in cases of drug overdose doses of propofol, fentanyl, ketamine, quetiap-
deaths (Lembke et al. 2018). ine, and haloperidol (Vo et al. 2017).

Carisoprodol Prescription Monitoring Programs

Carisoprol (e.g., Soma®) is now classified by the Currently, there are many states in the United
US Drug Enforcement Administration as a States that have now implemented prescription
Schedule IV controlled substance. It is included drug monitoring programs designed to continu-
here because it may be diverted to illicit channels ously assess the prescribing patterns for con-
and co-abused with other addictive substances, trolled substances among health care providers,
including opioids and/or benzodiazepines. including veterinarians, in their jurisdictions.
Carisoprodol is a centrally acting skeletal muscle Frequently operated by state boards of pharmacy,
relaxant whose precise mechanism of action is these programs use electronic databases to track
unknown. It is indicated as an adjunct to rest, all prescriptions for controlled substances issued
physical therapy, analgesics, and other measures in their jurisdictions and can be used by state
for the relief of discomfort of acute, painful mus- regulatory boards and law enforcement agencies
culoskeletal conditions. Adverse effects include a to identify inappropriate patters of prescribing.
high incidence of somnolence and occasional Examples of such inappropriate patterns could
tachycardia, facial flush, dizziness, headache, include the following:
light-headedness, dermatitis, nausea, abdominal
cramps, and dyspnea. Carisoprodol also pos- • One patient receiving prescriptions for a con-
sesses properties of physical and psychological trolled substance from multiple practitioners
dependence, and its frequent co-abuse with opi- within the same time period
oids and benzodiazepines as part of this “Holy • Multiple patients with the same address
Trinity” of co-abused drugs led to its being clas- receiving prescriptions for controlled
sified by US Drug Enforcement administration as substances
a Schedule IV controlled substance in 2012 • Prescriptions for controlled substances that
(Horsfall and Sprague 2017). are not within the scope of practice of a par-
Carisoprodol interacts with benzodiazepines ticular type of practitioner (e.g., an amphet-
in the brain to produce a synergistic increased in amine prescription issued by a dental
dopamine in the nucleus accumbens with respira- provider)
tory depression, increasing the likelihood of
respiratory arrest when co-ingested with opioids Data on controlled substance prescriptions
(Horsfall and Sprague 2017). This reclassifica- issued by dentists over a 2-year period in a US
tion reportedly has resulted in fewer cases of state (South Carolina) were analyzed and pub-
carisoprodol overdose in some states (Sun et al. lished in 2016 (McCauley et al. 2016). That study
2017). These characteristics distinguish the drug determined that 653,650 prescriptions were
from other types of commonly prescribed skele- issued by dentists, and significantly, 113,818
tal muscle relaxants, which are not currently clas- patients had received multiple opioid prescrip-
sified as controlled substances. tions within a 30-day period. These data can be
Withdrawal from sustained abuse of cariso- used to inform the dental profession about the
prodol results in a severe syndrome resembling extent to which prescribing controlled substances
neuroleptic malignant syndrome (Paul et al. is problematic in a given geographic area, and
2016). Management of carisoprodol withdrawal prescription monitoring programs have the capa-
and may require more extreme pharmacologic bility to issue alerts on certain patients who
measures than simply administering an i.v. ben- appear to be engaging in “doctor shopping,” drug
40 A. H. Jeske

diversion, and drug abuse. A survey of members Carisoprodol has few indications in dentistry,
of the US National Dental Practice-Based and based on its recent classification as a
Research Network found that higher levels of Schedule IV controlled substance, the dentist
opioid prescribing were associated with less con- should carefully consider the possibility of abuse
sistent implementation of the use of prescription and diversion associated with it.
drug monitoring programs (McCauley et al.
2018).
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Surgeons. White paper: opioid prescribing: acute and
postoperative pain management. 2017.
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codeine in combination with acetaminophen is tients. J Am Dent Assoc. 2006;137:502–13.
now questionable, based on the possibility that Ehrich DG, Lundgren JP, Dionne RA, Nicoll BK, Hutter
JW. Comparison of triazolam, diazepam and pla-
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2D6 may experience cardiorespiratory arrest patients. J Endod. 1997;23(3):181–4.
when this drug is used. Gaskell H, Derry S, Moore RA, McQuay HJ. Single dose
Practitioners who carefully consider the CNS oral oxycodone and oxycodone plus paracetamol
(acetaminophen) for acute postoperative pain in adults.
depressant properties of opioid analgesics can Cochrane Database Syst Rev. 2009;3:CD002763.
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Haas DA. Adverse drug interactions in dental practice:
with confidence, based upon robust scientific evi- interactions associated with analgesics. J Am Dent
dence. Minimizing the amount of opioid dis- Assoc. 1999;130:397–407.
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monitoring programs where available can help cology of the “Holy Trinity”. Basic Clin Pharmacol
Toxicol. 2017;120(2):115–9.
reduce abuse and diversion of prescription Kinnunen M, Piirainen P, Kokki H, Lammi P, Roki
opioids. M. Updated clinical pharmacokinetics and phar-
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Lembke A, Papac J, Humphreys K. Our other prescription
outpatients, based on known efficacy and safety, drug problem. N Engl J Med. 2018;378(8):693–5.
and relatively low risk of abuse when prescribed Maund E, McDaid C, Rice S. Paracetamol and selective
in very small quantities. However, the practitio- and nonselective nonsteroidal anti-inflammatory drugs
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McCauley JL, Hyer JM, Ramakrishnan VR, Leite R, Moore PA, Dionne RA, Cooper SA, Hersh EV. Why
Melvin CL, Fillingim RB, Frick C, Brady KT. Dental do we prescribe Vicodin? J Am Dent Assoc.
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among dental patients: administrative data from the Paul G, Parshotam GL, Garg R. Carisoprodol with-
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McCauley JL, Leite RS, Gordan VV, Fillingim RB, Pharmacol. 2016;32(3):387–8.
Gilbert GH, Meyerowitz C, Cochran D, Rinda DB, Stauble ME, Moore AW, Langman LJ, Boswell
Brady KT. Opioid prescribing and risk mitiga- MV, Baumgartner R, McGee S, Metry J, Jortani
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 Antibiotics and Antibiotic
Prophylaxis

Arthur H. Jeske

Introduction and Principles p­ ublications have summarized the frequency of

­various antibiotic prescriptions written in the
Antibiotics play an important role in the man- United States (Germak et al. 2017; Roberts
agement of odontogenic infections (primarily et al. 2017) and internationally (Soares et al.
as adjuncts to surgical procedures) and for pre- 2021). The outcomes of these survey-based
vention of systemic infections arising from bac- studies indicate that virtually all of the antibiot-
teremias associated with dental procedures in ics considered to be appropriate for the man-
patients at risk for serious systemic infective agement of odontogenic infections at the end of
complications (e.g., infective endocarditis). the twentieth century remain antibiotics-of-
However, dental professionals must be vigilant choice in contemporary dental practice. An
in the use of these drugs to avoid their overuse exception to this generalization from the inter-
and help address the serious issue of increasing national survey outcomes is the continued
antibiotic resistance (Centers for Disease ­presence of erythromycin as an antibiotic of
Control and Prevention 2013). Since the choice (Segura-Egea et al. 2017).
approval of phenoxymethylpenicillin (penicil- In the United States, the unfavorable charac-
lin V) by the Food and Drug Administration in teristics of erythromycin base and other erythro-
1956, dental infections in outpatients have been mycin salts, including poor pharmacokinetics,
managed successfully with a penicillin or irritancy in the gastrointestinal tract, and rapid
another oral narrow-spectrum antibiotic, which development of bacterial resistance, are docu-
is effective against infections caused by mented sufficiently so that its use in this country
­susceptible gram-positive and anaerobic bacte- has largely been abandoned.
ria. Currently, only a few, selected classes of Tetracyclines, metronidazole, and macro-
antibiotics are indicated for the dental manage- lides may be used in the management of peri-
ment of oral infections, including penicillins, odontitis, particularly refractory cases, where
cephalosporins, lincosamides, and macrolides sub-­ antimicrobial doses of tetracyclines and
(American Association of Endodontists 2012; macrolides appear to be beneficial (Haffajee
American Academy of Pediatric Dentistry et al. 2003; Hirsch et al. 2012). This chapter is
2014; Flynn 2011). Recently, three recent focused on commonly used oral antibiotics,
with an emphasis on high-level scientific evi-
dence. The reader is referred to other sources
A. H. Jeske (*)
UTHealth School of Dentistry, Houston, TX, USA for information on antiviral and antifungal
e-mail: [email protected] agents.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 43

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_5
44 A. H. Jeske

There are several important principles that l­actam aminopenicillin. Aminopenicillins have
must be understood prior to prescribing an antibi- an extended spectrum, which includes some
otic for a dental patient: gram-­negative organisms that are not typically
involved in odontogenic infections. Amoxicillin
1. Antibiotics are adjuncts to debridement and/ is now the most widely prescribed drug in this
or surgical interventions (tooth extraction, class, owing primarily to its pharmacokinetic
pulpectomy, incision-and-drainage) and traits. Because penicillins act by inhibition of
should not be used in place of these proce- bacterial cell wall synthesis, they have little sys-
dures in the management of infections. temic toxicity in mammals (mammalian cells
2. Antibiotics are not effective against viruses or lack a “cell wall”). However, penicillins may
fungal organisms. Their successful use carry a relatively higher risk of allergy than other
depends on an accurate diagnosis, which dental antibiotics. Penicillin VK was formerly
should confirm a bacterial etiology. recommended as the antibiotic of first choice for
3. An antibiotic regimen should be based upon routine dental infections, but amoxicillin has
the signs and symptoms of the bacterial dis- largely replaced it in the United States.
ease. The patient’s responses to an antibiotic
should be monitored using defined clinical Cephalosporins Since the development of
endpoints (reduction of swelling, reduction of cephalexin, considered a first-generation agent in
body temperature). the United States, there are now four generations
4. Prophylactic use of antibiotics in dentistry is of cephalosporins. Each later generation was
limited (see Prescribing Considerations). The synthesized to provide a broader spectrum of
­
practitioner must be familiar with the current activity. While cephalosporins are indicated for
scientific evidence for this use, as well as cur- antibiotic prophylaxis in selected patients, they
rent guidelines established by dental and are generally not preferred as routine agents in
medical professional organizations. cases of odontogenic infections. They are
5. Some antibiotics may carry a high risk of included among alternative agents for antibiotic
allergic reactions and should be used only prophylaxis because of their effectiveness against
after careful consideration of the patient’s gram-positive cocci.
medical and dental history.
6. There are relatively few randomized, con- In patients with allergy to penicillin, first-­
trolled clinical trials of antibiotics in dentistry generation cephalosporins (e.g., cephalexin,
and, therefore, relatively few systematic Keflex®) carry a relatively low rate of cross-­
reviews and meta-analyses on which to base sensitivity of approximately 1%, but this can
therapeutic decisions. vary considerably for other generations of these
7. The prescription of antibiotics is not appropri- agents (Campagna et al. 2012). In cases in
ate as an interim measure when symptoms which a cephalosporin is appropriate for the
warrant immediate physical examination of management of an odontogenic infection, an
the patient, particularly in children (Cherry agent from the second-­generation cephamycin
et al. 2012). subgroup should be selected, as this group pos-
sesses greater antibacterial efficacy against
gram-negative anaerobes than other groups of
 ntibiotics Commonly Used
A cephalosporins (Molavi 1991). Agents in this
in Dentistry subgroup include cefoxitin, cefotetan, and
cefmetazole. Cephalosporins are bactericidal
Penicillins There are many forms of penicillin, and possess a mechanism of action similar to
the most common being amoxicillin, a beta that of the penicillins, that is, inhibition of bac-
Antibiotics and Antibiotic Prophylaxis 45

terial cell wall synthesis by blocking the trans- on its favorable pharmacokinetics, is the pre-
peptidation reaction. ferred representative for dental use of this class
of antibiotic.
Lincosamides Clindamycin is a lincosamide
that is very effective against anaerobic and Nitroimidazoles Metronidazole was originally
mixed aerobic-anaerobic infections. It possesses marketed for use in the treatment of protozoan
favorable pharmacokinetics and has become a infections that also has proven bactericidal ­activity
widely used alternative for dental infections in against anaerobes. Because many oral ­infections
cases of penicillin allergy. Lincosamides were (acute periodontal infections) are predominantly
initially implicated as a major causative agent anaerobic in nature, metronidazole may be useful
for pseudomembranous colitis. It now appears alone or in combination with amoxicillin. It has
that they have a risk for this complication simi- proven to be very effective when tested in vitro
lar to that of the cephalosporins and aminopeni- against periodontal pathogenic organisms.
cillins. Lincosamides may be bactericidal in Because metronidazole is effective only against
some bacterial species, particularly at higher anaerobic organisms, its recommended role is as
dosages, and their mechanism of action involves an adjunct to be used with a penicillin when a
inhibition of bacterial protein synthesis by bind- suboptimal clinical response to the penicillin
­
ing to the same 50s ribosomal subunit as occurs (Bali et al. 2015).
erythromycin.
Tetracyclines Tetracyclines, including doxy-
Macrolides Erythromycin, clarithromycin, and cycline, are broad-spectrum, bacteriostatic
azithromycin are members of this group and agents that inhibit bacterial protein synthesis by
may be bacteriostatic or bactericidal, at higher binding to the 30s ribosomal subunit. They che-
concentrations. Macrolides inhibit protein syn- late calcium ions and thus have a propensity to
thesis by binding to the 50s ribosomal cause fluorescent tooth staining through incor-
RNA. Macrolides possess less favorable charac- poration into the enamel of developing teeth
teristics for use in dentistry than the other antibi- and even into remineralizing enamel of teeth
otic classes. Macrolides also bind to cytochrome that have already erupted (McKenna et al.
P450 hepatic enzymes and can result in numer- 1999). While not typically indicated for routine
ous seriously toxic drug interactions. Macrolides odontogenic infections, tetracyclines at sub-
(azithromycin) are associated with cardiac antimicrobial doses modulate matrix metallo-
arrhythmias, and erythromycin may also stimu- proteinases (collagenases) involved in the
late uncomfortable contractions of GI smooth breakdown of extracellular structures and
muscle because of its similarity to a locally inflammation. They are used in selected cases
released GI pro-motility hormone, motilin. of periodontitis refractory to conventional ther-
Except for use as alternatives for infective endo- apy procedures. Some patients may develop
carditis prophylaxis, they are not preferred as photosensitivity to these drugs, which can be
first-choice or penicillin-­ alternative drugs for severe (Jeske 2017).
routine odontogenic infections. For the manage-
ment of odontogenic infections with agents from The specific names and other characteristics
this class, erythromycin base and its various salts of dentally useful antibiotics are shown in Table 1
are not recommended, and azithromycin, based (Jeske 2017).
46 A. H. Jeske

Table 1 Classification and characteristics of common dental antibiotics for oral administration
Mechanism of Recommended
Antibiotic Class action adult oral dosagea Special considerations
Penicillin VK Beta lactam Bactericidal 500 mg q 4 h Absorption impaired by food
penicillin
Amoxicillin Aminopenicillin Bactericidal 500 mg q 8 h Absorption not impaired by food,
available with beta lactamase inhibitor
Cephalexin Cephalosporin Bactericidal 2 g 30 min to 1 h Risk of cross-allergy with penicillins is
before procedure low; alternative agent for prophylaxis
Clindamycin Lincosamide Bactericidal 300 mg q 6 h Excellent alternative in cases of
penicillin allergy
Azithromycin Macrolide Bacteriostatic 500 mg day 1, then Once daily dosing; Alternative agent
250 mg 1 q day for prophylaxis
Clarithromycin Macrolide Bacteriostatic 500 mg q 12 h Alternative agent for prophylaxis
Metronidazole Nitroimidazole Bactericidal 500 mg q 8 h Disulfiram-like reactions with alcohol;
effective against anaerobes only
Doxycycline Tetracycline Bacteriostatic 20 mg q 12 h prior Adjunct for periodontal therapy;
to meals available in local delivery forms
a
See (American Academy of Pediatric Dentistry 2014) for information regarding pediatric dosages

necessitating doses taken every 4 h. This dose

Prescribing Considerations interval is inconvenient when compared with
the 6- to 8-h dosing intervals that can be used
1. Following the diagnosis of a bacterial infec- with most other dental antibiotics.
tion and removal of the infected tissue (i.e., 2. The typical course of antibiotic therapy for
drainage or extraction or root canal therapy), dental infections runs for 5–7 days, unless
the dental provider can begin antibiotic ther- symptoms persist. The patient should be mon-
apy with a standard dose of an orally admin- itored closely at the beginning of antibiotic
istered first-choice agent (such as amoxicillin therapy. Noticeable improvement should be
500 mg) or an alternative agent. It is appro- expected within 24–48 h.
priate to initiate antibiotic therapy on an 3. Because of reduced absorption in the presence
empirical basis (without obtaining culture of food, penicillin V should be prescribed 1 h
and sensitivity testing). Culture and sensitiv- before meals or 2 h after meals.
ity testing requires additional time and may 4. Penicillins do not appear to be effective for
or may not identify specific etiologic patho- the management of symptomatic irreversible
gens. Culture and sensitivity testing should pulpitis (Keenan et al. 2005). Guidelines for
be considered if initial therapy is not effec- the selection and use of antibiotics in adults
tive. At this time, it appears that penicillin V for endodontic infections have been published
is inferior when taken at 6-hour intervals. by the American Association of Endodontists
This is because of its pharmacokinetic pro- (American Association of Endodontists
file with rapidly peaking serum levels fol- 2012).
lowed by rapid decline. Penicillins are 5. The American Academy of Pediatric Dentistry
among a group of antibiotics that are termed has promulgated guidelines for antibiotic use
“time dependent” for their pharmacody- in children (American Academy of Pediatric
namic action (bactericidal effect) (Craig Dentistry 2014). Note that antibiotic dosages
1998; Klutman 1996). must be adjusted for the child’s body weight.
Put simply, the duration of time that peni- Generally, the same antibiotics routinely used
cillin V exceeds typical bacterial MICs (mini- for odontogenic infections in adults are also
mal inhibitory concentrations) relative to its the preferred agents in the pediatric patient
dosing interval is insufficient at 6-h intervals, population.
Antibiotics and Antibiotic Prophylaxis 47

6. Warnings with antibiotic therapy should be However, when in doubt, the dentist is obli-
issued verbally and in writing on the prescrip- gated to consult with the patient’s physician(s) to
tion. They should include the possible devel- determine the need for antibiotic prophylaxis and
opment of allergic reactions and diarrhea and the appropriateness of the recommended regi-
other GI disturbances. It is recommended that men. Recently, a secular trend analysis of the
refills not be authorized for antibiotic pre- incidence of infective endocarditis in a country in
scriptions so that unnecessary, prolonged which antibiotic prophylaxis for patients at risk
exposure of the patient to the drug is avoided, of infective endocarditis had been abandoned
minimizing the risk of adverse effects, as well suggests that the abandonment of the practice
as development of antibiotic-resistant bacte- may have contributed to a rise in cases of infec-
rial strains. tive endocarditis. Further, it appears that this
7. Recent studies indicate that special consider- increase affected patients previously deemed not
ation should be given to the prescription of have conditions that put them at high risk for
antibiotics in obese patients. The data suggest developing infective endocarditis (Dayer et al.
that pharmacokinetic alterations in obese indi- 2015).
viduals, even following successful bariatric At this time, recent expert analyses of the
surgery, necessitate higher doses of amoxicil- practice of antibiotic prophylaxis to prevent
lin in order to achieve expected therapeutic infective endocarditis have been published with
outcomes (Soares et al. 2021). important major conclusions. Dayer et al.
(Dayer et al. 2018) concluded that while antibi-
otic prophylaxis to prevent infective endocardi-
Antibiotic Prophylaxis tis produces a “marginal gain,” the benefits of
the prophylaxis outweigh the risks, especially in
While there is little scientific evidence to support patients at high-risk for endocarditis, and even
the use of prophylactic antibiotics to prevent for those at moderate risk. This group further
postoperative complications, guidance from suggested that when all evidence is considered,
­professional resources suggests its continued use the possibility that antibiotic prophylaxis has
in patients at highest risk of developing compli- some small impact cannot be discounted.
cations from infective endocarditis (Thornhill Finally, these authors indicated that antibiotic
et al. 2018). Most regimens involve a single, pre- prophylaxis involves very little expense and the
operative dose of a bactericidal agent with activ- dosing regimens currently recommended mini-
ity against Streptococcus viridans. There is mize the risk of development of antibiotic
limited evidence showing that a second dose will resistance.
not enhance outcomes (Lopes et al. 2011). There In a related publication, Thornhill et al.
is also limited evidence that antibiotic prophy- (2018) suggest that patients previously classified
laxis reduces complications following implant as “moderate risk” for infective endocarditis
placement and no strong evidence supporting use might also be considered as high-risk and that
to prevent complications of third-molar surgery current guidelines for stratifying the risks of
(Esposito et al. 2013; Lodi et al. 2012). Antibiotic infective endocarditis related to dental proce-
prophylaxis prior to dental treatment in patients dures may require re-evaluation. This appears to
with total joint arthroplasty (artificial joint) is have been confirmed indirectly in a report of an
controversial, and professional guidance now outbreak of bacterial endocarditis in a US oral
emphasizes good oral hygiene to prevent infec- surgery practice (Ross et al. 2018). In this report
tive complications in these patients. At this time, on 15 patients who developed infective endocar-
there is insufficient scientific evidence on which ditis and who underwent oral surgical proce-
to base the practice (American Academy of dures, ten had predisposing cardiovascular
Orthopedic Surgeons and American Dental conditions, and of these, five had mitral valve
Association 2012). prolapse, a condition for which current guide-
48 A. H. Jeske

lines no longer recommend prophylactic antibi- and cramping. They may also disrupt the normal
otic (Wilson et al. 2007). flora, resulting in diarrhea, or lead to antibiotic-­
Currently, individuals who abuse drugs intra- associated colitis and a potentially life-­
venously are considered to be at high risk of threatening overgrowth of C. difficile.
staphylococcal infective endocarditis, to the Symptoms with most cases of antibiotic-­
extent that these patients are being denied heart associated diarrhea dissipate when the antibiotic
valve replacement surgery owing to the high risk is discontinued. It is imperative that patients be
of failure (Sanaiha et al. 2020). However, at this cautioned against the use of antidiarrheal drugs
time, there are no professionally promulgated and/or probiotics in place of medical diagnosis
guidelines for the use of antibiotic prophylaxis in and management of this rare, but serious, compli-
these types of patients, although dental practitio- cation. The development of any sign or symptom
ners should certainly be aware of this risk and the of an allergic reaction (rash, itching, and/or hives)
potential cardiac complications that may arise. requires that the antibiotic agent be discontinued
In 2021, the American Heart Association pub- immediately and the patient be evaluated medi-
lished a scientific statement on the current status cally (Beacher et al. 2015).
of the prevention of viridans-group infective Penicillins are typically associated with a rate
endocarditis and removed clindamycin from its of allergy that is relatively higher than for other
list of recommended prophylactic antibiotics, classes of antibiotics. These reactions may range
replacing it with doxycycline 100 mg (Wilson from delayed-onset, mild forms (e.g., rash) to
et al. 2021). immediate-onset Type I anaphylaxis.
In 2022, outcomes from a case cross-over Robust guidance on the relative incidence of
analysis and cohort study of over 7 million US serious adverse reactions to oral antibiotics pre-
citizens confirmed that antibiotic prophylaxis scribed by dentists has been published (Thornhill
reduces associations between oral surgical proce- et al. 2019). In this study, outcomes from the
dures and infective endocarditis in individuals at British National Healthcare System were sur-
high risk for infective endocarditis (). veyed over an 8-year period, which included
With regard to antibiotic prophylaxis to pre- nearly 29 million prescriptions for antibiotics
vent infection of prosthetic joints, a recent cohort written by dentists. Among the conclusions of
study performed on a database consisting of the that study, amoxicillin was deemed to be “remark-
entire population of England (55 million), there ably safe,” while clindamycin had the worst
was no significant temporal association between adverse drug reaction profile, with a 30-fold
late prosthetic joint infections and invasive den- higher incidence of fatal reactions. The ranking
tal procedures (Thornhill et al. 2022a). That of the antibiotics in this study from least likely to
group concluded that there is no rationale to most likely to cause an adverse drug reaction was
administer antibiotics to prevent prosthetic joint (1) amoxicillin, (2) cephalosporins, (3) erythro-
infections in patients undergoing invasive dental mycin, (4) tetracyclines, (5) azithromycin, (6)
procedures. metronidazole, (7) amoxicillin with clavulanic
acid, (8) clarithromycin, (9) penicillin V, and (10)
clindamycin.
Adverse Effects

Antibiotics, as prescribed in dentistry, are gener- Adverse Drug Interactions

ally well tolerated. With the exception of allergy,
most adverse effects from antibiotics are related Antibiotics are capable of adversely interacting
to their effects on the gastrointestinal tract. with other dental and medical drugs, both
Virtually, all antibiotics may irritate the stomach through pharmacodynamic and pharmacoki-
or stimulate contractions of gastrointestinal netic mechanisms. The most significant adverse
smooth muscle, resulting in nausea, vomiting, pharmacodynamic interaction for commonly
Antibiotics and Antibiotic Prophylaxis 49

Table 2 Clinically significant drug interactions involving antibiotics used in dentistry (modified from (Ciancio 2011))
Primary drug Action Interaction (and effect)
Alcohol Metabolism Metronidazole (severe nausea, vomiting)
decreased by
Benzodiazepines Enhanced by Erythromycin, clarithromycin (increased CNS depression)
Carbamazepine Enhanced by Erythromycin, clarithromycin (increase carbamazepine toxicity
Coumarins (including Enhanced by Erythromycin, clarithromycin, metronidazole, penicillins,
warfarin) tetracyclines (increased risk of bleeding)
Digoxin Enhanced by Erythromycin, clarithromycin (increased toxicity of digoxin,
including cardiac arrhythmias
Lidocaine Enhanced by Erythromycin, clarithromycin (increased toxicity of lidocaine, CNS
depression)
Penicillins Antagonized by Probenecid, salicylates, coumarin, diphenylhydantoin, griseofulvin
(reduced efficacy against infection)
Statins Enhanced by Erythromycin, clarithromycin (increased statin toxicity, e.g.,
rhabdomyolysis)
Tetracyclines Antagonized by Antacids, iron (reduced absorption of tetracyclines)
Tetracyclines Antagonizes Penicillin (reduced efficacy against infection)
Theophylline Potentiated by Erythromycin, clarithromycin (increase toxicity of theophylline,
possible cardiac arrhythmias)

prescribed antibiotics is the mutual antagonism

that occurs when a bactericidal agent (penicil- Antibiotics for Periodontitis
lins, cephalosporins) is co-administered with a
bacteriostatic agent (tetracycline). The recent Both systemic and locally applied antibiotics
scientific evidence does not support an adverse have been investigated for the management of
interaction between oral contraceptives and periodontal diseases, focused primarily on refrac-
antibiotics used in dentistry (Taylor and tory periodontitis (periodontitis that responds
Pemberton 2012). poorly to conventional therapy).
Conversely, if drugs with similar mechanisms A recent systematic review of this subject
of action are administered together, a beneficial indicates that the scientific evidence for systemic
synergism may result. Combinations of antibiot- antibiotics in the treatment of refractory peri-
ics are not generally recommended in dentistry. odontitis does not support this indication, nor
However, the addition of metronidazole to a peni- does it show that systemic antibiotics add an
cillin regimen may improve outcomes because of incremental benefit to conventional treatment
the selective action of metronidazole on strictly along (e.g., mechanical debridement) (Santos
anaerobic organisms. Among the antibiotics dis- et al. 2016). Until there are more studies with less
cussed here, macrolides are the most likely to heterogeneity and with parallel design, the use of
produce pharmacokinetic drug interactions. systemic antibiotics for periodontal therapy
Serious adverse interactions of various classes of remains controversial.
dental antibiotics are listed in Table 2 (Ciancio
2011).
Less significant drug interactions are also pos- Conclusion
sible—the clinician is urged to consult the com-
plete prescribing information for all drugs Antibiotics continue to play an important, albeit
prescribed adjunctive, role in the management of routine
For medically compromised patients with sys- odontogenic infections. They are safe and effec-
temic disease that could affect drug metabolism tive when prescribed at recommended doses and
and/or excretion, consultation with the patient’s based on the patient’s presenting signs, symp-
physician is recommended toms, and coexisting medical conditions. The
50 A. H. Jeske

number of patients who are candidates for antibi- American Academy of Pediatric Dentistry. Use of anti-
biotic therapy for pediatric dental patients, revised.
otic prophylaxis is relatively small, and prophy- 2014. http://www.aapd.org/Policies_Guidelines/G_
lactic use should be guided by the current AntibioticTherapy.pdf.
recommendations of professional organizations, American Association of Endodontists. Colleagues for
as based on scientific studies. Dentists should excellence newsletter. Winter. 2012. http://www.
aae.org/UploadedFiles/PublicationsandResearch/
continue to consider emerging evidence for the EndodonticsColleaguesforExcellenceNewsletter/win-
use of low dosage antibiotics in cases of refrac- ter12ecfe.pdf.
tory periodontitis and other inflammatory dis- Bali R, Sharma P, Gaba S. Use of metronidazole as part
eases. At present, the topic of dental antibiotics of an empirical antibiotic regimen after incision and
drainage of infections of the odontogenic spaces. Br J
can be summarized as follows: Oral Maxillofac Surg. 2015;53(1):18–22.
Beacher N, Sweeney MP, Bagg J. Dentists, antibiotics
1. Penicillins and aminopenicillins (e.g., amoxi- and Clostridium difficile-associated disease. Br Dent
cillin) remains drugs-of-first-choice for the J. 2015;219(6):275–9.
Campagna JD, Bond MC, Schabelman E, Hayes
management of routine odontogenic infections. BD. The use of cephalosporins in penicillin-aller-
2. Alternative antibiotics to be used in cases in gic patients: a literature review. J Emerg Med.
which penicillins are contraindicated include 2012;42(5):612–20.
clindamycin, azithromycin, metronidazole, Centers for Disease Control and Prevention. Antibiotic
resistance threats in the United States. 2013. http://
and moxifloxacin. www.cdc.gov/drugresistance/threat-­report-­2013.
3. Antibiotic resistance is problematic in medi- Cherry WR, Lee JY, Shugars DA, White RP, Vann
cine but is still of limited significance in the WF. Antibiotic use for treating infections in children:
treatment of odontogenic infections in dental a survey of dentists’ prescribing practices. J Am Dent
Assoc. 2012;143(1):31–8.
outpatients. Ciancio SG. Drug interactions: a guide for dentistry.
4. Based upon the consensus of experts, antibi- MetLife Qual. Res. Guide, 3rd ed. 2011. http://www.
otic prophylaxis remains indicated in limited metdental.com.
groups of patients with specific, high-risk Craig WA. Choosing an antibiotic on the basis of phar-
macodynamics. Ear Nose Throat J. 1998;77(6):7–11.
conditions for cardiac and prosthetic joint Dayer MJ, Jones S, Prendergast B, Baddour LM,
infections. Lockhart PB, Thornhill MH. Incidence of infec-
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scientific evidence that mandates changes in trend, interrupted time-­ series analysis. Lancet.
2015;385(9974):1219–28.
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6. New findings from retrospective case studies Chemother. 2018;24(1):18–24.
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 Pharmacologic Management
of Patients with Drug-Related
Coagulopathies

Issa A. Hanna, Alfredo R. Arribas,

Amir All-­Atabakhsh, and John A. Valenza

 nderstanding Clinical Hemostasis:

U these medicines for congenital coagulopathies,
The Key to Patient Management diseased-induced states (e.g., pregnancy, cancer,
severe trauma or burns, etc.), or effects of medi-
Understanding and applying clinical knowledge cations that are pro-coagulant (e.g., birth con-
of hemostasis is essential in managing patients trol). The authors intend to provide the clinician
undergoing dental procedures who are on “blood-­ with an understanding of the physiology of clot-
thinners.” This requires the clinician to make the ting, associated medication therapies, and, more
distinction between the function of antiplatelet importantly, evidence-based principles and rec-
and anticoagulant medications. Patients utilize ommendations on managing patients on “blood
these medications for primary or secondary pre- thinners.” We will provide an overview of the ele-
vention of thromboembolic complications of vas- ments involved in clotting in response to vascular
cular disease (Palareti and Cosmi 2009). The injury, especially due to dental procedures, which
clinical implications and management will vary will further aid the clinician in making evidence-­
accordingly, and a portion of these patients will based clinical judgments when treating this
be on a combination of multiple antiplatelet or patient population.
antiplatelet and anticoagulants.
The prevalence of antiplatelet and anticoagu-
lant use is increasing due to an aging population Clinical Hemostasis
and increased survival of cardiovascular or cere-
brovascular insults. As a result, clinicians will Hemostasis is a multifactorial and dynamic pro-
regularly encounter this population of patients in cess. After vessel injury, there is an immediate
their practices. This chapter will focus on patients vasoconstriction phase to decrease the flow of
who are using these medications for acquired blood, lasting approximately 20 min (Mingarro-­
medical problems and not on patients who utilize de-­León et al. 2014). Injury to the vessel wall
also leads to exposure of subendothelial collagen
and the progression into the platelet phase of
I. A. Hanna (*) · A. R. Arribas · A. All-Atabakhsh ·
J. A. Valenza hemostasis.
School of Dentistry, University of Texas, Prior to understanding platelet function after
Houston, TX, USA vessel wall injury, the clinician should recognize
e-mail: [email protected]; that the uninjured, vascular endothelium inhibits
[email protected];
[email protected]; platelet function, and this prevents a thrombotic
[email protected] event. When a vessel wall is disrupted, as with

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 53

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_6
54 I. A. Hanna et al.

Fig. 1 Hemostatic
response to vascular
injury

surgical intervention, there is a series of events naturally bound to the subendothelial collagen
that lead to hemostasis. This series of events is and released upon injury (note: additional VWF
described in Fig. 1. is also released by subsequent platelet activation)
(Wilson et al. 2015). This helps form a platelet
clot, which improves hemostasis (Mingarro-de-­
Platelet Phase León et al. 2014). Aggregation of the platelet
plug is then assisted by the activation of platelet
The fundamental cell responsible for the produc- glycoprotein (Gp) IIb/IIIa (αIIbβ3) receptor,
tion of platelets is the megakaryocyte, which is which facilitates the binding of VWF and fibrino-
derived from hematopoietic stem cell precursors. gen to these receptors (Yip et al. 2005). Figure 2
The megakaryocyte produces and releases plate- provides greater detail on the platelet cascade and
lets and is primarily regulated by the enzyme the factors involved in obtaining a platelet plug. It
thrombopoietin (TPO), which is principally pro- is important to note that circulating endogenous
duced in the liver, with some contribution from thrombin, adenosine phosphate (ADP), epineph-
the kidney and bone marrow. The circulating rine, and thromboxane A2 are important in plate-
platelet has a life span of 7–10 days with approxi- let activation and clot formation (Howard et al.
mately 33% of platelets being stored in the spleen 2013). Inhibition of these select proteins has
(Wilson et al. 2015). Normal platelet count is important clinical consequences on the formation
150,000–450,000/uL, and a significant decrease of the platelet plug.
in platelets may also represent risks associated
with postoperative bleeding (Branehög et al.
1975). Coagulation Phase
Once circulating platelets are no longer inhib-
ited from binding to the vessel wall, the promo- Following the platelet phase is the coagulation
tion of adhesion of platelets to the exposed phase (Fig. 3). The binding of coagulation factor
collagen occurs. This is initially mediated by X to receptors on the platelet surface occurs and
exposed von Willebrand Factor (VWF), which is accelerates conversion to factor Xa, which is crit-
Pharmacologic Management of Patients with Drug-Related Coagulopathies 55

Fig. 2 Platelet phase of

hemostasis

Fig. 3 Coagulation
phase of hemostasis

ical in converting prothrombin to thrombin. plasmin, which then lyses the fibrin plug
Thrombin then acts to convert the soluble fibrino- (Mingarro-de-León et al. 2014).
gen clot to a strong, insoluble fibrin plug Antiplatelet therapy targets the initial stages
(Mingarro-de-León et al. 2014). of clotting formation by disrupting platelet aggre-
The coagulation phase terminates when the gation and the formation of a platelet plug, as
damaged vessel wall is repaired and/or the clot is described earlier in the chapter. Anticoagulation
stable. The clot then undergoes fibrinolysis, therapies target the latter stages of clot formation
which is facilitated by the conversion of prekal- by inhibiting the function of clotting factors and
likrein to kallikrein by Factor XII. Kallikrein disrupting the coagulation cascade (Bagot and
then converts inactive plasminogen to active Arya 2008).
56 I. A. Hanna et al.

Knowing the physiology of hemostasis, the physiology of thrombosis. In the 1850s, Virchow
dental clinician can better co-manage the use of described three phenomena that increased the
blood thinners with the physician and plan how likelihood of thrombosis. These concepts have
to approach providing dental care to patients on been further refined over the past decades but are
these medications. summarized as follows:
When treating patients taking medications
that disrupt platelet function, the clinician should • Interrupted blood flow (stasis)
anticipate the likelihood for prolonged intraop- • Irritation of vessel lining (endothelial or ves-
erative and/or immediate postoperative bleeding. sel wall injury)
With patients on anticoagulants, however, the • Blood coagulation (hypercoagulopathy)
­clinician should expect relatively normal intraop- (Bagot and Arya 2008)
erative or immediate postoperative hemostasis,
but the potential for bleeding problems or Antiplatelet therapy is widely used to reduce
­complications hours later when the coagulation the risk of myocardial infarction and in the treat-
cascade occurs. ment of patients with high-risk atherosclerotic
vascular disease, acute coronary syndrome, and
arterial/venous thrombosis. It is also utilized in
Antiplatelet Therapy patients with a history of prior percutaneous coro-
nary interventions, coronary bypass surgery, atrial
Indications for Antiplatelet Therapies fibrillation, and stroke (Dinkova et al. 2013).
Table 1 illustrates these morbidities and how
Understanding antiplatelet and anticoagulant they contribute to an increased likelihood of
therapies is directly tied to the underlying patho- thrombosis.

Table 1 Antiplatelet morbidities and how they contribute to risk of thrombosis (Dinkova et al. 2013)
Pathophysiology Phenomena contributing to thrombosis Adverse outcome
Atherosclerotic vascular Vessel wall injury (due to atheromatous plaques Myocardial infarction and its
disease/acute coronary deposited within the tunica intima) sequelae such as rupture of the
syndrome/myocardial Interrupted blood flow (due to formation of myocardium
infarction atheroma in coronary arteries which disrupts
laminar blood flow)
Venous thrombosis Interrupted blood flow (due to stasis, Superficial or deep vein
immobilization, peripheral vascular disease, etc.) thrombosis, which may lead to
Vessel wall injury (due to trauma, surgery, etc.) an embolism such as a
pulmonary embolism
Arterial thrombosis Interrupted blood flow (due to stasis, aneurysm, Arterial thrombosis which can
vessel wall dissection, etc.) lead to an arterial embolus
Vessel wall injury (due to aneurysm, vessel wall
dissection, etc.)
Percutaneous coronary Vessel wall injury (sclerosis of intravascular walls Thrombosis of coronary
Intervention (i.e., angioplasty requiring widening of vessel diameter or placement vasculature, myocardial
and coronary stents) of an indwelling intravascular stent) ischemia, myocardial
Interrupted blood flow (turbulent blood flow in the infarction
presence of stents)
Coronary bypass surgery Interrupted blood flow (via surgical placement of a Thrombosis of bypass graft
shunt to bypass a coronary artery blockage
Atrial fibrillation Interrupted blood flow (inadequate atrial contraction Stroke (ischemic)
leading to turbulent blood flow, which potentiates
thrombosis)
Transient ischemic activity Interrupted blood flow (due to thrombus formation Cerebral ischemia and
(TIA)/stroke (ischemic) in cerebral arteries or emboli from proximal possible cerebral Infarction
arteries)
Pharmacologic Management of Patients with Drug-Related Coagulopathies 57

Assessing Platelet Function dues of the COX enzymes, which renders the
platelet nonfunctional for the duration of its life
Platelet Function Tests span. In turn, the generation of thromboxane A2,
Historically, bleeding time (BT) has been used to which is a catalyst of platelet aggregation, is
determine platelet functionality. It was initially decreased. This inactivation of COX lasts up to
described in vivo by Duke in 1910. BT was 10 days (i.e., the entire life of the platelet)
regarded as the most useful screening tool for (Malmquist 2011).
platelet function until the early 1990s. However, There are no significant differences in COX
overwhelming literature suggests that prolonged enzyme inhibition between 81 or 325 mg doses.
BT does not translate into increased blood loss The differences are limited to anti-inflammatory
from surgery. Many studies have shown that a and antipyretic activities, which are outside the
low dose of acetylsalicylic acid (aspirin) has an scope of this chapter (Dinkova et al. 2013).
effect on bleeding time but has no clinical signifi-
cance (Dinkova et al. 2013). Clopidogrel/Ticagrelor/Prasugrel/
Other available platelet function tests can be Ticlopidine
subdivided into platelet adherence, aggregation, Clopidogrel (Plavix®) is an antiplatelet agent
or activation studies. These studies are best uti- belonging to the thienopyridine family.
lized for special patient populations, such as in Clopidogrel blocks the P2Y12 receptor on the
individuals with congenital platelet disorders platelet cell membranes, inhibiting ADP-induced
(e.g. light transmission aggregometry [LTA]) or platelet aggregation. It is a pro-drug and needs to
in trauma (e.g., thromboelastogram [TEG]). be metabolized to its active metabolite by several
hepatic cytochrome P450 isoenzymes.
Clopidogrel is indicated for monotherapy
Antiplatelet Medications for the prevention of atherothrombotic events
in patients suffering myocardial infarction,
Multiple mediators precipitate platelet aggrega- ischemic stroke, or peripheral arterial disease.
tion and adhesion. Antiplatelet medications have It is also used in conjunction with aspirin in
been developed to individually target these medi- patients suffering from acute coronary syn-
ators to achieve their desired effects. Examples of drome (ACS) for non-ST segment elevation
these medications are outlined in Table 2. ACS (unstable angina or non-Q-wave myocar-
dial infarction), including patients undergoing
 OX Inhibitors: Aspirin
C percutaneous ­coronary intervention (PCI) with
Acetylsalicylic acid was initially synthesized in stent placement and ST-segment elevation fol-
the 1850s by acetylation of salicylic acid. lowing acute myocardial infarction in medi-
Methods to synthesize acetylsalicylic were fur- cally treated patients eligible for thrombolytic
ther refined over the next few decades. In 1899, therapy.
scientists at Bayer named it “aspirin” and began Platelet inhibition by clopidogrel is both dose-
large-scale distribution (Dinkova et al. 2013). and time-dependent, and patients are usually
Aspirin irreversibly binds with platelets to given a loading dose of 300–600 mg and then
inhibit aggregation by acetylation of serine resi- maintained at 75 mg/day.

Table 2 Classes of antiplatelet medications (Dinkova et al. 2013)

Inhibitors of ADP-mediated Prostaglandin Phosphodiesterase Fibrinogen receptor
COX inhibitors activation of P2Y12 receptors analogues inhibitor antagonist
Acetylsalicylic acid Clopidogrel (Plavix)a Alprostadil Dipyridamole Abciximab
(Aspirin)a Prasugrel (Effient)a Iloprost Tirofiban
Ticagrelor (Brilinta)a
Ticlopidine (Ticlid)a
58 I. A. Hanna et al.

The duration of clopidogrel therapy varies  anagement of Patients on Single

M
according to the indication (Dinkova et al. 2013): and Dual Antiplatelet Therapy

• Myocardial infarction: from a few days to less Antiplatelet therapies are used to manage a mul-
than 35 days titude of medical conditions. Single antiplatelet
• Ischemic stroke: from 7 days to less than six therapy (SAPT) is commonly used to manage
months cerebrovascular accidents (CVA), cerebrovascu-
• Following the insertion of a bare metal stent lar disease, coronary artery bypass grafts
(BMS): 4–12 weeks (CABG), percutaneous coronary intervention
• Following the insertion of a drug-eluting stent (PCI), or as a final treatment modality after a
(DES): 6–12 months period of dual antiplatelet therapy (DAPT). Dual
antiplatelet therapy is typically used for patients
Ticagrelor (Brilinta®) is a new direct inhibi- who have had a recent cardiac stent placed due to
tor of the platelet P2Y12 receptor and therefore coronary artery disease. Though many patients
does not require metabolic activation. Unlike often transition to SAPT after a period of time, a
thienopyridines, ticagrelor binds reversibly to subset of high-risk patients will maintain long-­
the P2Y12 receptor and at a site that is inde- term DAPT. It is also important for the dental cli-
pendent of ADP. However, it still results in nician to confirm the type of stent and date of
suppression of ADP-induced platelet activation placement (patients are given a medical card after
by temporarily “locking” the receptor in an stent placement that specifies the type of stent
inactive state until it dissociates. Ticagrelor inserted). Patients with bare metal stents are typi-
has a significantly faster onset and offset of cally maintained on DAPT for a minimum of 1
antiplatelet activity compared with clopidogrel month and usually maintained on a single anti-
in subjects with stable coronary artery disease platelet therapy after that. Patients with drug-­
or acute coronary syndromes. Ticagrelor is eluting stents are typically maintained on dual
indicated for the prevention of thrombotic antiplatelet therapy for at least 12 months and
events in patients with acute coronary syn- then maintained on a single antiplatelet therapy
drome or myocardial infarction with ST eleva- afterward (Singh et al. 2013). It is important that
tion. The drug is combined with acetylsalicylic DAPT remains uninterrupted in these time frames
acid unless the latter is contraindicated to prevent thromboses and associated morbidity
(Dinkova et al. 2013). (Grines et al. 2007).
Prasugrel (Effient®) is the newest member Providing safe and predictable care to the den-
of the thienopyridine family and also irrevers- tal patient who is on antiplatelet therapy can be
ibly binds to P2Y12-receptor with a rapid onset confusing and, in many instances, without
and stronger inhibitory effect than clopidogrel. evidence-­based direction. Many variables must
It is licensed for use with aspirin for the pre- be considered when making treatment decisions
vention of atherothrombotic events in patients for these patients. These include the patient’s
with acute coronary syndrome (Dinkova et al. overall state of health, the risk of bleeding from
2013). the planned surgical procedure, as well as the
Ticlopidine (Ticlid®) is an ADP receptor risks associated with cessation of any antiplatelet
blocker, preventing the binding of fibrinogen to medications. The dental clinician should always
platelet glycoprotein. It is indicated for use in consult the appropriate managing physician,
patients who cannot tolerate aspirin or with aspi- whether it is a primary care provider (PCP) or a
rin in DAPT (Dinkova et al. 2013). Ticlopidine specialist (ADA 2018). When discussing the
has fallen out of favor because of bone marrow patient’s care with the medical clinician, it is
toxicity (Iqbal et al. 2023). imperative to review the extent of the surgery,
Pharmacologic Management of Patients with Drug-Related Coagulopathies 59

anticipated bleeding and determine a risk assess- ing. Napenas et al. in 2013 published data from a
ment on whether to treat the patient from a medi- literature review of 15 articles and found no clini-
cal standpoint. After reviewing the literature, the cally significant increase in the risk of postopera-
authors’ goal is to provide the dental clinician tive bleeding in patients either on SAPT or DAPT
with evidence-based data that will help them dis- that underwent invasive dental procedures
cuss the decision on managing the patient’s anti- (Napeñas et al. 2013).
platelet medications, whether SAPT or DAPT, In 2015, Dezsi et al. compared postoperative
with the managing physician. bleeding in patients undergoing dental extrac-
When determining the course as it relates to tions who were on SAPT or DAPT. Patients were
antiplatelet therapy and dental surgery, the clini- observed in-office until stable clot formation was
cian must consider that discontinuing therapy noted. Those on SAPT took up to 60 min to form
increases the risk of systemic morbidities. Prior a stable clot, whereas DAPT patients took as long
studies have shown that discontinuing antiplatelet as 130 min. However, clinical outcomes were no
therapy for surgical intervention provides signifi- different in either group, and no morbidity was
cantly increased systemic risks versus the risk of recorded. The authors concluded that dental
bleeding and complications of bleeding if anti- extractions could be safely performed while
platelet therapy is maintained. Maulez et al., in a maintaining single or dual antiplatelet therapy
case-controlled study, looked at 309 patients who (Dézsi et al. 2015). These studies provide clear
were diagnosed with an ischemic stroke or tran- evidence that the risk of maintaining antiplatelet
sient ischemic attack (TIA) undergoing long-­term therapy for invasive dental procedures is low, and
aspirin therapy before their event and 309 patients the systemic risk of discontinuing therapy is high.
with an ischemic stroke (IS) and TIA who did not Treatment decisions must therefore consider the
have aspirin therapy 6 months prior to their event dental clinician’s professional comfort level with
(Maulaz et al. 2005). The results showed that hemostasis control, the complexity and invasive-
aspirin interruption increased the risk of an IS/ ness of the procedure, and the baseline risk of
TIA by 3.4-fold with a 95% confidence interval bleeding, especially with a patient on antiplatelet
(CI). Risks were even greater for patients with a therapy. For complex dental surgery, it may be
prior diagnosis of coronary heart disease (Maulaz prudent for the dental clinician to stage proce-
et al. 2005). When contemplating the cessation of dures to decrease the associated risk of bleeding
aspirin or SAPT for dental procedures, the risk of complications.
an ischemic event and associated morbidities Cardona-Tortajada et al. monitored 155
must be compared to the risk of hemorrhage from patients on varied SAPT who underwent dental
the surgical intervention. The risk of cessation of extractions. Twenty-six patients had minor bleed-
antiplatelet therapy is only one component in ing complications, which were controlled by
making treatment decisions for this patient popu- local hemostatic measures, and one patient had
lation. The clinician must also have valid data to severe bleeding and required an emergency room
determine if patients who remain on antiplatelet visit. The antiplatelet drug had no influence on
therapy have a risk of significant bleeding after postoperative bleeding, yet the number of teeth
dental surgical procedures. extracted was statistically relevant to postopera-
Traditionally, the dental clinician requests that tive bleeding complications. Cardona-Tortajada
the managing physician hold antiplatelet therapy et al. advised not to extract more than three teeth
prior to dental surgical procedures. We now know at a time and that these should either be adjacent
that cessation of antiplatelet therapy can have or correlative and not in different parts of the
significant systemic consequences. In addition, dental arch (Cardona-Tortajada et al. 2009).
many studies have shown that maintaining anti- These recommendations seem to make sense, as
platelet therapy has no significantly increased more extensive and invasive surgeries have an
morbidity associated with postoperative bleed- inherent increased risk of bleeding as a baseline,
60 I. A. Hanna et al.

which will only be amplified for the patient on which include atrial fibrillation, venous thrombo-
antiplatelet therapy. embolisms, and the presence of a mechanical
In summary, the data presented shows that heart valve (Guyatt et al. 2012a,b). Unlike anti-
cessation of antiplatelet therapy, whether SAPT platelet therapies, the efficacy of anticoagulant
or DAPT, has a greater risk of systemic morbidity therapies has been traditionally monitored. We
than the risk of bleeding from dental surgery, will discuss the changing paradigm in the direct
while these therapies are maintained. Other oral anticoagulants section. The severity of the
important factors for the clinician to consider disease state usually dictates more aggressive
when making treatment decisions include patient anticoagulation (usually monitored by the
medical comorbidities, patient medications, inva- patient’s International Normalized Ratio (INR)).
siveness and extent of the procedure, dentist’s Table 3 summarizes the indications for anticoag-
comfort level with hemostasis, and care of the ulant therapies.
medically complex patient, as well as patient’s In these scenarios, the clinician is placed in a
ability to recognize postoperative bleeding issues dilemma. Unplanned cessation of anticoagulant
and having access to after-hours care. Patients on therapy can have devastating effects, such as fatal
antiplatelet therapy may have an increased risk of mechanical heart valve (MHV) thrombosis in
postoperative bleeding, yet this bleeding is usu- 15% of patients, embolic stroke leading to death
ally well controlled with local hemostatic mea- or major disability in 70% of patients, and with
sures and uncommonly associated with morbidity. venous thromboembolism a case-fatality rate of
Additionally, in more invasive and extensive sur- approximately 5–9%. On the other hand, continu-
geries, the clinician should stage the procedure to ing anticoagulant therapy results in a major bleed-
decrease the risk of significant post-op bleeding. ing risk of 2–4%, of which there is a case-­fatality
rate of 8–10% (Spyropoulos and Douketis 2012).
Because of the more severe clinical conse-
Anticoagulation Therapy quences of thrombosis over major bleeding, a
strategy that incurs three to ten more cases of
Indications for Anticoagulation major bleeds to prevent one case of thrombosis or
Therapies stroke would, in theory, be clinically acceptable.
This is based on the devastating consequences of
The dental clinician should be aware of the gen- a stroke as compared with a bleed, which in the
eral indications for the use of anticoagulants, majority of cases, can be surgically controlled.

Table 3 Suggested risk stratification for perioperative thromboembolism (Spyropoulos and Douketis 2012)
Risk category MHV Atrial fibrillation
Venous thromboembolism
High (>10%/year risk of Any mechanical mitral valve CHADS2 score 5 or 6
Recent (<3 months) VTE
ATE or 10%/month risk of Caged-ball or tilting disc Recent (<3 months)
Severe thrombophilia
VTE valve in mitral/aortic position stroke or TIA Deficiency of protein C,
protein S or antithrombin
Recent (<6 months) stroke or Rheumatic Disease Antiphospholipid antibodies
TIA Multiple thrombophilias
Intermediate (4–10%/year Bilateral AVR with major risk CHADS2 score 3 or 4 VTE within past 3–12
risk of ATE or 4–10%/ factors for stroke months
month risk of VTE) Recurrent VTE
Non-severe thrombophilia
Active cancer
Low (<4%/year risk of ATE Bilateral AVR with major risk CHADS2 score 0–2 (and VTE>12 months ago
or <2%/month risk of VTE) factors for stroke no prior stroke or TIA)
TIA transient ischemic attack, AVR aortic valve replacement, ATE atrial thromboembolism, VTE venous thromboembo-
lism, MHV mechanical heart valve
Pharmacologic Management of Patients with Drug-Related Coagulopathies 61

Assessing Coagulation Function with vitamin K metabolism, thereby causing a

syndrome similar to vitamin K deficiency. This
We will briefly review concepts that aid the clini- paved the way for discovering a more potent vari-
cian in managing anticoagulated patients under- ant of coumarins, namely, warfarin, for use as a
going dental surgical procedures. rodenticide. Warfarin is derived from WARF for
Wisconsin Alumni Research Foundation and -arin
Prothrombin Time (PT)/International for its connection to coumarin (Link 1959).
Normalized Ratio (INR) Warfarin interferes with the synthesis of the
The INR was developed to incorporate the inter- vitamin K-dependent clotting factors, which
national sensitivity index (ISI) values and include prothrombin (factor II) and factors VII,
attempt to make prothrombin time (PT) results IX, and X. The synthesis of the vitamin
uniformly usable. The working reference has K-dependent anticoagulant proteins, proteins C
been calibrated against internationally accepted and S, is also reduced by warfarin.
standard reference preparations, which have an
ISI value of 1.0. The ISI value is the exponent in Mechanism of Action
the formula and is, therefore, critical for calcu- All the vitamin K-dependent clotting factors pos-
lating the INR. sess glutamic acid residues at their N-termini. A
posttranslational modification adds a carboxyl
INR = ( patient PT / mean normal PT )
ISI
group to the γ-carbon of these residues to gener-
Consequently, small errors in the ISI assign- ate γ-carboxyglutamic acid.
ment may affect the calculated INR substantially. Warfarin inhibits vitamin K epoxide reductase
An otherwise healthy patient who is not anti-­ (VKOR), thereby blocking the γ-carboxylation
coagulated will have an INR value of 1 process. This results in the synthesis of vitamin
(Al-Mubarak et al. 2007). K-dependent clotting proteins that are only par-
tially γ-carboxylated.
Partial Thromboplastin Time (PTT) Warfarin acts as an anticoagulant because
Partial thromboplastin time (PTT) has been these partially γ-carboxylated proteins have
described as measuring the overall speed of a clot reduced or absent biologic activity. The onset of
formation, correlating with the activity of the action of warfarin is delayed until the newly syn-
intrinsic clotting cascade. PTT must be inter- thesized clotting factors with reduced activity
preted with caution as it doesn’t reflect the in vivo gradually replace their fully active counterparts.
hemostatic response and the interaction between The antithrombotic effect of warfarin depends
the vessel wall, platelets, fibrinogen, and circulat- on a reduction in the functional levels of factor X
ing coagulation factors (WHO 1999). and prothrombin, clotting factors that have half-­
lives of 24 and 72 h, respectively (FDA 2010).

Anticoagulation Medications: Pharmacology

Warfarin Warfarin is a racemic mixture of R and S isomers
and is rapidly and almost completely absorbed
Current oral anticoagulant practice dates back from the gastrointestinal tract. Racemic warfarin
almost 75 years to when vitamin K antagonists has a plasma half-life of 36–42 h, and more than
were discovered as a result of investigations into 97% of circulating warfarin is bound to albumin.
the cause of hemorrhagic disease in cattle. Only the small fraction of unbound warfarin is
Characterized by a decrease in prothrombin lev- biologically active (Wilson et al. 2015).
els, this disorder was caused by the ingestion of Variability of anticoagulation with warfarin
hay containing spoiled sweet clover. in between individuals is significantly dependent
Hydroxycoumarin, a lactone, which was isolated on the expression of a group of cytochrome
from bacterial contaminants in the hay, interferes P-450-2C9 (CYP2C9) enzymes, which is
62 I. A. Hanna et al.

responsible for o­ xidative metabolism (metabolic Anticoagulation Medications:

clearance) of the more active S-enantiomer, and Heparin
the Vitamin K epoxide reductase enzyme
(VKORC1), which reduces the Vitamin K, the Heparin is a proteoglycan that functions as a
cofactor necessary for gamma-carboxylation of cofactor of the naturally occurring anticoagulant,
Vitamin K-dependent clotting factors. This can antithrombin. Because the half-life of heparin is
predispose to overdosage conditions and a higher short (60 min), the therapeutic levels are main-
risk of bleeding. tained by intravenous bolus injections followed
In 2007, the FDA issued a black box warning, by monitored infusion. The therapeutic range is
which updated the product label of warfarin by monitored by prolongation of the partial throm-
advising physicians to consider CYP2C9 and boplastin time (PTT). There are several different
VKORC1 genetic tests to improve their initial types of heparin; notable is low-molecular-­
estimate of warfarin dose (FDA 2010). weight heparin (LMWH) with a longer half-life
and can be delivered subcutaneous once or twice
I nteractions with Other Commonly a day in contrast to unfractionated heparin (FDA
Used Medications 2006). Enoxaparin (Lovenox®) and Dalteparin
The fundamental mechanisms of interaction (Fragmin®) are commonly used LMWHs in clini-
between warfarin and antibiotics are twofold: cal practice.
Patients who have been on long-term therapy
1. Antimicrobial agents disrupt gastrointestinal with heparin do not require laboratory monitor-
flora that synthesizes vitamin K (Onysko et al. ing; however, when monitoring is required (such
2016). as intraoral bony surgery), an anti-Xa assay is
2. Antimicrobials inhibit cytochrome p450 used because the PTT is not predictably pro-
(CYP450) enzymes (primarily CYP2C9 and longed (Malmquist 2011).
3A4), which are responsible for the metabolism Complications associated with heparin are
of warfarin. The antibiotics most likely to limited, the most notable being heparin-induced
­interfere with warfarin are Trimethoprim and thrombocytopenia (HIT). HIT is a rare, life-­
Sulfamethoxazole (TMP/SMX), ciprofloxacin, threatening complication of heparin due to an
levofloxacin, metronidazole, fluconazole, autoimmune response toward Platelet Factor 4
azithromycin, and clarithromycin. Low-risk and heparin complex, which results in thrombo-
agents include clindamycin, cephalexin, and cytopenia and arterial and venous thrombosis.
penicillin G. A 2008 study investigated the anti- The most common manifestations are bleeding
coagulation effects of a 10–20% preemptive and a drop in platelet count. It is typically treated
warfarin dose reduction versus no dosing with immediate cessation of heparin and the use
change in patients taking TMP/SMX or levo- of an alternative, non-heparin-based anticoagu-
floxacin. The investigators found that the pre- lant (Greinacher et al. 2017).
emptive warfarin dose reduction (intervention)
significantly decreased the number of suprath-
erapeutic INR values above 4 when compared Direct Oral Anticoagulants (DOAC)
to controls (two of eight vs eight of nine)
(Onysko et al. 2016). There is no consensus in The direct oral anticoagulants (DOAC) are a
the dental literature to support adjusting warfa- newer class of drugs that act to attenuate coagu-
rin dosing in the presence of TMP/SMX or met- lation by targeting a specific factor in the coagu-
ronidazole in the pre or postoperative setting, lation pathway. Due to the new nature of these
but the clinician should be aware of the drugs, the nomenclature in the literature is
increased risk of bleeding if the patient has been somewhat varied and without absolute consen-
recently prescribed antibiotics, especially TMP/ sus. In 2015, Barnes et al., for the International
SMX or metronidazole (Onysko et al. 2016). Society on Thrombosis and Hemostasis
Pharmacologic Management of Patients with Drug-Related Coagulopathies 63

Subcommittee on the Control of Anticoagulation, aware and informed of the other terms used for
published a discussion of various terms and rec- this class of drugs.
ommendations on nomenclature for these new These drugs either prevent the generation of
drugs. The varied nomenclature discussed by thrombin (Factor IIa) or directly inhibit throm-
Barnes et al. were novel oral anticoagulants bin. The drugs that indirectly inhibit thrombin
(NOAC), target-­ specific oral anticoagulants formation do so by targeting Factor Xa. Inhibition
(TSOAC), and direct acting oral anticoagulants of Factor Xa interferes with the formation of the
(DOAC) (Barnes et al. 2015). The subcommit- fibrin clot by blocking the conversion of fibrino-
tee recognized that the oldest and most com- gen to fibrin. Even more recent agents act by
monly used term was novel oral anticoagulants directly inhibiting thrombin in the clotting cas-
(NOAC). Yet, they also recommend that the cade, inactivating thrombin, and inhibiting
classification term for these drugs be transi- thrombogenesis (Shi and Crowther 2019).
tioned to direct acting oral anticoagulants DOACs that are currently available include fac-
(DOAC) as this better describes their mecha- tor Xa inhibitors Rivaroxaban (Xarelto®),
nism of action (Barnes et al. 2015). For the pur- Apixaban (Eliquis®), Edoxaban (Savaysa®), and
pose of this chapter and to limit confusion in Betrixaban (Bevyxxa®) and direct thrombin inhib-
terminology, the term direct oral anticoagulants itor dabigatran (Pradaxa®) as noted in Table 4
(DOAC) will be used. Yet the reader should be (Thean and Alberghini 2016; Chen et al. 2020).

Table 4 Most commonly used novel oral anticoagulants (Barnes et al. 2015; Chen et al. 2020; Parasrampuria and Truitt
2016)
Brand Generic Target
name name factor Indications (FDA approved) Clearance/metabolism
Pradaxa Dabigatran IIa Stroke prevention in NVAF (Nonvalvular Renal (80%)
Atrial fibrillation)
Treatment of DVT and PE
Prevention of recurrent DVT and PE prevention of
thromboembolism after total hip replacement
Atrial fibrillation
Xarelto Rivaroxaban Xa Stroke prevention in NVAF (nonvalvular atrial Renal, hepatic
fibrillation)
Treatment of DVT and PE
Prevention of recurrent DVT and PE
Prevention of thromboembolism after total knee
replacement and total hip replacement
Prevention of thromboembolism in hospitalized
acutely ill medical patients
Prevention of major cardiovascular events in patients
with chronic CAD/peripheral artery disease
Eliquis Apixaban Xa Stroke prevention in NVAF (Nonvalvular atrial Renal (27%)
fibrillation) GI tract
Prevention of thromboembolism after total knee
replacement and total hip replacement
Treatment of DVT and PE
Prevention of recurrent deep vein thrombosis and
pulmonary embolism
Savaysa Edoxaban Xa Stroke prevention in NVAF (nonvalvular atrial Renal (50%)
fibrillation) Metabolism and biliary
Treatment of DVT and PE secretion (50%)
Bevyxxa Betrixaban Xa Prevention of deep vein thrombosis and pulmonary GI (93–95%)
embolism in adults hospitalized for an acute medical (Renal 5–7%)
illness
64 I. A. Hanna et al.

Dabigatran, rivaroxaban, apixaban, and tain factors II, IX, and X, yet the 4-factor con-
edoxaban are FDA-approved for lowering the centrate also contains factor VII. The 4-factor
risk of stroke and embolism in nonvalvular atrial concentrate, in theory, should be more effective
fibrillation (NVAF) as well as deep vein throm- at correcting INR due to factor VII inclusion.
bosis and pulmonary embolism treatment/pro- The recommended dose of prothrombin complex
phylaxis. Unique indications include betrixaban concentrate (PCC) for reversal of anticoagula-
for prophylaxis of venous thromboembolism tion ranges from 25 to 100 U/kg depending on
(VTE) in hospitalized patients for an acute med- the product used (Joseph et al. 2014; Frontera
ical illness and rivaroxaban in combination with et al. 2014).
aspirin to reduce major cardiovascular events in Irrespective of the blood product adminis-
patients with chronic coronary artery disease tered to reverse warfarin anticoagulation, the
(CAD) or peripheral artery disease (Chen et al. patient should also receive intravenous vitamin
2020). It should be noted that there are also mul- K at a dose of 2.5–5 mg administered over 30
tiple off-­label indications for which these drugs min; otherwise, the INR is unlikely to com-
are being used. pletely correct, and a “rebound coagulopathy”
may develop after the transfused factors are
cleared. Intravenous administration of vitamin K
Reversal Agents for Anticoagulants has a small risk of severe anaphylactoid reaction
and should only be given by slow intravenous
Fresh frozen plasma (FFP) is the most com- infusion (over 20–30 min), and oral vitamin K
monly used method in North America for rapidly should be used whenever possible. Because
reversing warfarin. The usual dose of FFP for more rapid reversal is achieved with intravenous
anticoagulant reversal is 15 mL/kg of body administration, it is preferred in cases when
weight. When urgent reversal of a therapeutic urgent reversal is required, such as life-threaten-
(rather than supratherapeutic) INR is required, a ing bleeding or reversal of the warfarin effect in
lower dose of 5–8 mL/kg may be appropriate. a patient diagnosed with acute HIT (Crowther
FFP rarely completely corrects the INR without and Warkentin 2008).
the use of Vitamin K, irrespective of the FFP Preparation, delivery, and administration of
dose or the INR value. Risks of FFP include fail- FFP, PCC, and IV Vitamin K do not make them
ure to completely reverse coagulopathy, immune- a practical method of reversal of a bleeding
mediated thrombocytopenia, and anaphylactoid patient using anticoagulants in the typical office
reactions, to name a few (Joseph et al. 2014; setting.
Frontera et al. 2014).
These limitations have led to recommenda-  pecific Reversal Agents for DOACs
S
tions that prothrombin complex concentrates Ligand-specific and small molecule reversal
(PCCs) be used in place of FFP for the treatment agents have been more recently utilized, and
of anticoagulant-associated coagulation factor long-term outcomes are still currently under
deficiencies. PCCs reverse coagulopathy labora- investigation. These agents are likely to be pri-
tory markers from warfarin over coagulation marily used in life-threatening bleeding and
more rapidly and effectively than FFP (Joseph emergent surgery (Abed et al. 2017). In addition,
et al. 2014; Frontera et al. 2014). these agents may allow the safer implementation
There are two different PCCs available, the of uninterrupted or minimally interrupted DOAC
3-factor and the 4-factor concentrates. Both con- protocols for elective surgery.
Pharmacologic Management of Patients with Drug-Related Coagulopathies 65

There are currently two DOAC reversal agents The utilization of DOAC reversal agents
approved for use in the United States. Andexanet should be limited to indicated interventions,
alfa is approved for the reversal of apixaban and which usually include life-threatening bleeding
rivaroxaban, and idarucizumab is approved for and bleeding not amendable or responsive to
the reversal of dabigatran (Cuker et al. 2019). other interventions (Cuker et al. 2019).
Idarucizumab (Praxbind®) is a monoclonal A North American panel of anticoagulation
antibody that acts as a noncompetitive irrevers- experts published a clinical guidance review in
ible inhibitor of unbound and thrombin-bound 2019 providing a comprehensive framework for
dabigatran and its active metabolites. The com- DOAC reversal (Cuker et al. 2019).
pound has a high affinity, and it is a specific The panel did recommend that the use of
inhibitor of dabigatran action. The agent has a andexanet alfa be also extended to the off-label
rapid onset mechanism of action and has been reversal of edoxaban and betrixaban (Shi and
demonstrated to be safe and efficacious with a Crowther 2019). The panel’s DOAC reversal
simple dosing regimen. Laboratory evidence of guidelines are well summarized in Fig. 4.
reversal is observed within minutes. Idarucizumab In summary, the dental clinician must review
was approved by the FDA in 2015 and is widely the anticoagulated patient’s overall health and
incorporated into protocols for use in acute bleed- the risk for developing a thrombosis, determine
ing or emergent surgery (Dalal et al. 2016; the potential for major postoperative bleeding,
Andresen et al. 2018). utilize the guidance of the patient’s managing
Andexanet-alfa (Andexxa®) is a recombinant physician to direct anticoagulation management,
modified human factor Xa decoy protein. It binds and plan for intraoperative and postoperative
with high affinity to Factor Xa inhibitors within contingencies in the consultation appointment.
2 min of IV administration, thereby neutralizing In instances where additional resources are
the direct and indirect effects of Factor Xa. A required to safely carry out the surgical plan, the
bolus dose is followed by an infusion with the clinician should consider referral to a hospital-
restoration of thrombotic activity being reflected based provider or an oral and maxillofacial
by the change in thrombin generation and quanti- surgeon.
tative anti-FXa activity. Andexanet-alfa reverses The management of nonmajor bleeding with
the anticoagulant effects of small molecule anti-­ DOACs typically involves holding the anticoagu-
FXa agents (rivaroxaban and apixaban) as well as lant and implementing local control measures.
low molecular weight heparin and fondaparinux DOACs half-lives are approximately 12 hours;
(the latter two being indirect FXa inhibitors). therefore, holding a dose should result in a fast
This was approved by the FDA in May of 2018 decline of the anticoagulant effect (Wigle et al.
(Dalal et al. 2016; Andresen et al. 2018). 2019).
66 I. A. Hanna et al.

Fig. 4 Anticoagulation forum DOAC reversal guidelines summary (Cuker et al. 2019)

Management of Patients planned procedure. Inpatients who have a high

on Anticoagulation Therapy risk of thrombosis, regardless of the complexity
of the case, should undergo an anticoagulation
Given the prevalence of patients on anticoagulation bridging protocol to minimize the duration of not
therapy presenting for oral surgical procedures, the being anticoagulated. Data has shown heparin
clinician will be required to make clinical decisions bridging therapy will reduce the postoperative
to optimize the patient’s outcomes (i.e., minimiz- VTE risk by approximately two-thirds. On the
ing the risk of thrombosis and postoperative bleed- opposite end of the spectrum, in patients with a
ing). These decisions include assessing the need to low risk of thrombosis, regardless of the com-
continue anticoagulation, assessing the likelihood plexity of the case, bridging is not typically indi-
of major bleeding with the planned surgical proce- cated, and a strategy that considers stopping
dure, intraoperative hemostasis strategies, and anticoagulation prior to surgery can be utilized. It
appropriate postoperative surveillance. is in the intermediate-­risk patients where clinical
judgment and experience of the clinician dictate
what approach to bridging is warranted. It would
Warfarin be prudent not to bridge in cases where signifi-
cant bleeding is predicted and therefore consider
The risk of thrombosis and determining the con- cessation of anticoagulation prior to surgery in
tinuation of anticoagulation during surgical inter- concert with the supervising managing physi-
vention always play a role in treatment decisions. cian. In cases with a low risk of bleeding, such as
The 9th edition of the ACCP (American College most dental surgical procedures, it would be in
of Chest Physicians) Antithrombotic Therapy the patient’s overall best interest to continue anti-
and Prevention of Thrombosis Guidelines recom- coagulation by either continuing the patient’s
mends initially stratifying patients based on their typical regimen or utilizing bridging protocols.
risk of thrombosis (low, intermediate, or high) The flowchart below (Fig. 5) is a useful guide to
(Guyatt et al. 2012a, b). Subsequently, the help the clinician with the decision process
clinician should assess the complexity of the
­ (Spyropoulos and Douketis 2012).
Pharmacologic Management of Patients with Drug-Related Coagulopathies 67

Thromboembolic
Risk: NVAF,
MHV, VTE

Low
High Intermediate
Category E

High Bleed Risk: Low Bleed Risk: High Bleed Risk: Low Bleed Risk:
Category A Category B Category C Category D

Consider
Bridging* No Bridging** Bridging** No Bridging

Fig. 5 Suggested periprocedural heparin bridging strategies for patients on chronic VKA therapy based on patient
thromboembolic and procedural bleed risk (Spyropoulos and Douketis 2012) (reprinted with permission)

In scenarios where bridging is warranted, the same-day follow up call and post-op day one
managing physician will guide the dental clini- follow-up appointment or call. Yet for a patient
cian with a strategy that includes the timing of with a concern for higher risk of a bleeding event,
cessation of the patient’s regimen and initiation the prudent clinician may choose to observe the
of the bridging treatment (Spyropoulos and patient for a period of time in the office after the
Douketis 2012). Many bridging protocols have procedure, followed by post-op calls, or an inpa-
been proposed; one such example that a physi- tient observation status when deemed needed.
cian may utilize is illustrated in Table 5. In patients who are at intermediate to high risk
Spyropoulos cited a recent systematic review of thrombosis, an alternative strategy to bridging
of 7169 patients undergoing periprocedural may be to not interrupt their anticoagulation ther-
bridging therapy and found a thromboembolism apy. Wahl showed a 0.95% incidence of severe
rate of 0.9% (95% CI, 0.0–3.4%) and a major thrombosis when warfarin was discontinued for
bleeding rate of 4.3% (95% CI, 2.4–6.2%) pri- tooth extractions, most of which led to patient
marily when LMWH bridging was used death (Wahl 1998). Akopov conducted a retro-
(Spyropoulos and Douketis 2012). The chapter’s spective analysis of 197 patients presenting over a
authors’ professional approach to mitigating 12-month period with nonfatal cardioembolic
bleeding risks in these patients is based on the cerebral infarction, 14 (7.1%) of these patients suf-
determined risk of postoperative bleeding, fered infarcts related to the discontinuation of war-
accounting for the extent of the surgery, and the farin therapy for procedures (Akopov et al. 2005).
assessment of systemic bleeding risks. The Maintaining warfarin anticoagulation in the
patient treated in an outpatient setting who is at perioperative setting requires the clinician to
lower risk of a bleeding event may require a keep a few principles in mind:
68 I. A. Hanna et al.

Table 5 Anticoagulation
bridging protocols
(Spyropoulos and
Douketis 2012)
(reprinted with
permission)
Pharmacologic Management of Patients with Drug-Related Coagulopathies 69

• Patients who are anticoagulated are at an INR ranges of 2.5 to 3.5. As the data reaffirms,
inherently increased risk of a bleeding event. patients with INR ranges of 3.0 or less can be
• Patients who are not in a therapeutic range are safely treated with minimal risk of a significant
at increased risk of thrombosis. postoperative bleed. Accounting for the fact that
• Patients who are at supratherapeutic levels most indications for warfarin therapy call for a
have an even greater risk of significant post-­ therapeutic INR range of 3 or lower, patients can
surgical bleeding. be safely treated while minimizing the risk of
thrombosis. Patients that present with supra-­
The question then lies in patients who are kept therapeutic INR ranges (3 or greater) should be
on warfarin therapy. Are there INR ranges that deferred by the dental clinician for optimization
are safe from a dental surgical standpoint to treat by their physician. It is critical to remember that
with minimal risk of significant postoperative PT/INR lab testing should be performed on the
bleeding while maintaining the thrombosis pre- same day of treatment to ensure an accurate pre-
vention benefits of anticoagulation? Morimoto operative INR.
et al., in a 2011 prospective study, performed 433 If the patient is deemed at low risk of a throm-
extractions on 382 patients with a postoperative boembolic event (as described earlier in this sec-
hemorrhage rate of 3.9%. Greater than 90% of tion), withdrawal of warfarin without bridging is
the cases with postoperative bleeding occurred typically accomplished two to seven days preop-
within six days of extraction, and 60% had an eratively. The variability of the withholding
INR of 3.0 or greater. Bleeding events in patients period depends on other systemic factors, includ-
with an INR of 2.0–3.0 were twofold lower com- ing advanced age, systolic heart failure, and liver
pared with patients with an INR greater than 3.0. function.
The study also noted that surgical factors that In order to help the clinician to determine the
increased the risk of bleeding included acute safety of dental treatment for patients receiving
inflammation and the need for surgical extraction warfarin, we have slightly modified a table
(Morimoto et al. 2011). Weltman et al. performed ­originally published by Herman et al. in 1997,
a systematic review in 2015 of the management as noted in Table 6 (Hermann et al. 1997). We
of patients undergoing dental extractions who have adapted the original recommendations to
were also receiving warfarin therapy. The align better with the current data that has been
authors’ findings determined that patients whose presented. These are recommendations to be
INR was 3.0 or less can safely continue their war- considered by each clinician, who should use
farin regimen prior to dental extraction proce- appropriate judgment when making final treat-
dures without significant risk of bleeding. The ment decisions.
study did also show that gelatin sponge packing Regardless of the choice between stopping
did improve post-op bleeding in this patient pop- warfarin with or without bridging, anticoagula-
ulation (Weltman et al. 2015). tion can be restarted on the evening of the pro-
The clinician must recognize that most medi- cedure if there is minimal concern for bleeding
cal diagnoses treated with warfarin require a ther- at the conclusion of the procedure. With bridg-
apeutic INR range between 2.0 and 3.0 (e.g., ing, the parenteral anticoagulant can be discon-
atrial fibrillation, DVT w/ or w/o PE), with tinued when the INR is within the therapeutic
mechanical heart valve patients requiring higher range.
70 I. A. Hanna et al.

Table 6 The warfarin patient-outpatient dental procedure safety recommendations (Hermann et al. 1997)

Dental Procedure Suboptimal INR Range Normal INR Range Out of

Range
<1.5 1.5 to 2.0 to 2.5 to 3.0 >3.0 to >3.5
<2.0 <2.5 3.5
Mechanical Prosthetic Heart
Valve
Atrial Fibrillation; Venous
Thrombosis; Pulmonary
Embolism
Examination,
Radiographs,
Impressions,
Orthodontics
Simple Restorative
Dentistry,
Supragingival
Prophylaxis
Complex Restorative Probably
Dentistry, Scaling and Safe with
Root Planning, Local
Endodontics Measures
*
Simple Extraction, Local Probably
Biopsy Measures Safe with
* Local
Measures
*
Multiple Extractions, Local Probably
Single Surgical Measures Safe with
Extraction (including * Local
Bony Impaction) Measures
*
Single Dental Implant Local Probably
Placement, Measures Safe with
Gingivectomy, Minor * Local
Periodontal Flap Measures
Procedure *
Full Arch or Full Local Probably
Mouth Extractions Measures Safe with
* Local
Measures
*
Extraction of Multiple Probably
Bony Impactions, Safe with
Placement of Multiple Local
Dental Implants, Measures
Extensive Flap Surgery *
*
Increased need for the use of local measures such as: sutures, Gelfoam®, SURGICEL®, topical thrombin,
tranexamic acid
Pharmacologic Management of Patients with Drug-Related Coagulopathies 71

 anagement of Patients on Direct

M reversing and monitoring these agents; risk of
Oral Anticoagulants (DOACs) thromboembolism, as proposed by the ACCP
(Guyatt et al. 2012a); and patient comorbidities.
Treating patients on direct oral anticoagulants From this review, they concluded that there are
(DOACs) presents additional challenges for the four possible options when treating this patient
dental clinician. With increasing indications of population:
use and market penetration, the number of
patients taking these drugs is large and will con- 1. Continue DOAC
tinue to grow. Soon after the FDA approval of the 2. Perform the procedure as late in the day as
first DOACs, Pradaxa in 2010 and Xarelto in possible
2011 and Firrolo and Hupp in 2012 published a 3. Discontinue use 24 h prior to treatment
clinical manuscript addressing the use of DOACs 4. Discontinue use 48 h prior to treatment
and implications for the management of the den-
tal patient (Firriolo and Hupp 2012). At the time, Their final recommendation was that patients
the authors concluded that the clinical data pres- on DOACs would most likely benefit from
ent to make sound judgments on the management options 1 or 2 (Elad et al. 2016). Elad et al.
of these therapies and dental extractions was developed a suggested treatment algorithm as
lacking and that clinical studies were needed. noted in Fig. 6.
The authors reinforced discussing options, risks, Elad et al. also cautioned the dental clinician
and management with the patient’s physician. in caring for these patients, stating that until there
They concluded as a precaution that in cases is greater evidence about the bleeding risk in
where it is deemed necessary to stop DOACs for patients on DOACs and, referral to a hospital-­
surgery (i.e., risk of major bleeding), the medica- based dental clinic or an oral and maxillofacial
tion should be stopped at least 24 h prior to the surgeon should be considered.
procedure. They also concluded that it should be A dental narrative published in the Australian
restarted only after the risk of bleeding has Dental Journal in 2015 by Thean and Alberghini
become minimal within the first 24–48 h. Elad reaffirms those recommendations provided by
et al., in 2014, attempted to better clarify direc- Elad et al. (Thean and Alberghini 2016; Elad et al.
tive care for this population by performing a 2016). Thean and Alberghini reinforced that the
review of 18 randomized clinical trials (Elad dental clinician must direct care under the guid-
et al. 2016). Elad et al. took into account factors ance of the patient’s physician and not unilaterally
such as the risk of procedural bleeding; issues of withhold anticoagulation therapy for dental treat-

Fig. 6 Suggested
algorithm for
management approach
prior to dental
intervention (Elad et al.
2016) (reprinted with
permission)
72 I. A. Hanna et al.

ment. They recommended DOACs can be contin- recommendations as summarized in Table 7

ued and bleeding controlled with local measures (Spyropoulos and Douketis 2012).
for procedures with low risk of bleeding, such as In 2018, a review article by Lusk et al. evalu-
simple single extractions. These local measures ated the available evidence regarding how to
included the use of Gelfoam® or SURGICEL® safely manage DOAC therapy in patients requir-
packing, mechanical pressure, suturing, and/or ing dental procedures with a low-to-moderate
tranexamic acid mouthwash. For high-risk proce- risk of bleeding. They concluded that among
dures, such as multiple extractions or surgical patients undergoing low-to-moderate risk dental
extractions, they also recommend the dental clini- procedures while receiving DOAC therapy,
cian refer to an oral and maxillofacial surgeon for bleeding rates were low regardless of whether the
care. For patients undergoing more extensive sur- DOAC was held or continued surrounding the
gery, cessation of DOACs may be indicated procedure. Documented bleeding was mild and
(Thean and Alberghini 2016). easily controlled by local hemostatic measures.
In 2012, Spyropoulos discussed the possible Patients can safely continue DOAC therapy sur-
need for 2–3 days of a low-dose LMWH bridging rounding these low-to-moderate risk dental pro-
regimen (e.g., enoxaparin 40 mg once daily) in cedures (Lusk et al. 2018).
postoperative patients who are unable to take oral In their definition, low-risk procedures
medications (Spyropoulos and Douketis 2012). include local anesthetic administration, simple
For patients undergoing cessation of DOAC ther- restorations, supragingival scaling, and single-
apy, Spyropoulos recommends cessation time tooth extraction. Moderate risk procedures
periods based on renal clearance and surgical risk include extractions of two to four teeth and local
of bleeding. He defines simple dental extractions gingival surgery of five or fewer teeth. High-risk
as having a low risk of bleeding (a 2-day risk of procedures include extractions of six or more
major bleed of 0–2%) and multiple tooth extrac- teeth, osseous biopsy, placement of multiple
tions as a high risk for bleeding (2-day risk of a implants, and generalized gingival surgery of six
major bleed of 2–4%). Based on the patient’s or more teeth.
renal function and the risk of procedural bleed- In 2019, a systematic review and meta-­
ing, he then provides preoperative drug cessation analysis by Manfredi et al. evaluated the current

Table 7 Preoperative oral anticoagulant cessation recommendations (Spyropoulos and Douketis 2012) (reprinted with
permission)
Pharmacologic Management of Patients with Drug-Related Coagulopathies 73

literature regarding the importance of discontinu- SURGICEL®

ing or not discontinuing (DOACs) before inva-
sive oral procedures and to establish the frequency Another adjunct that can be used for capillary,
and type of postoperative bleeding events in venous, and small arterial bleeds is SURGICEL®,
patients. They concluded that the studies included which is an oxidized regenerated cellulose agent.
in the review and analysis did not discern any Due to the low pH level, it has acidic properties
important differences in postoperative bleeding and achieves hemostasis via the denaturation of
events in patients who continued versus patients blood proteins, mechanical activation of the clot-
who discontinued DOACs, and no thromboem- ting cascade, and local vasoconstriction. Another
bolic events were recorded (Manfredi et al. distinguishing factor is the antibacterial proper-
2019). However, they cautioned that the results ties of SURGICEL®. It should be used with cau-
should be interpreted with caution because of the tion in areas where there is potential of nerve
low quality of the studies evaluated. exposure (i.e., inferior alveolar nerve, mental
nerve, etc.) due to its acidic nature. Invariably,
SURGICEL® should be retrieved after hemosta-
Local Hemostatic Agents sis is achieved unless its removal poses a signifi-
cant risk of re-bleeding. This is to prevent
What we have discussed so far are all preparations complications such as a giant cell-type of reac-
in anticipation for the planned surgical procedure. tion at the surgical site (Achneck et al. 2010).
In any of the abovementioned scenarios (bridging, Morimoto et al. reported 87 cases receiving
continuation of oral anticoagulant, or cessation of antiplatelet drugs. Teeth were extracted without
anticoagulation), the patient may continue to have reducing antiplatelet therapy, oxidized cellulose
more than expected intraoperative bleeding. was applied, and suturing was performed for
Fortunately, there are agents available, as dis- local hemostasis. They concluded that sufficient
cussed below, that can help control the intraopera- hemostasis can be obtained in most cases of tooth
tive oozing. It should be noted that none of these extraction, and appropriate local hemostatic
measures substitute the first response to any per- methods can be successful when postoperative
sistent bleeding, which is to apply firm pressure hemorrhage occurs (Morimoto et al. 2008).
either manually or with the patient biting on
folded gauze for at least 10 minutes.
Fibrin Glue

Gelfoam® Fibrin glue is effective as a hemostatic agent as it

mimics the final pathway of the coagulation cas-
Gelfoam® is a water-insoluble, porous, pliable cade, where fibrinogen is converted into fibrin
product prepared from purified porcine skin under the action of thrombin, factor XIII, fibro-
capable of absorbing up to 45 times its weight of nectin, and ionized calcium (Brewer and Correa
whole blood. It may be cut without fraying and is 2006). It combines two components: thrombin
able to absorb and hold within its interstices (principally human) and fibrinogen (normally
many times its weight of blood and other fluids. It plasma-derived) (Achneck et al. 2010). Fibrin
is theorized that Gelfoam® promotes coagulation glue is effective in managing bleeding in patients
both by surface area hemostasis and by providing with high risk of prolonged and excessive bleed-
a mechanical framework for coagulation. When ing after surgery. Traditionally, it has been used
used, it must be applied with moderate pressure to manage bleeding in cardiovascular, hepatic,
to the site of bleeding. It should not be used and splenic surgeries. It also has proven itself as
in locations with a risk of infection (i.e., surgical a useful tool in the armamentarium for treating
extraction of an infected tooth), and it typically the dental surgery patient who is at high risk for
resorbs within 6 weeks (Achneck et al. 2010). bleeding during or after surgery (Mankad and
74 I. A. Hanna et al.

Codispoti 2001). Fibrin glue contains human or Conclusion

animal components, leading to hesitation of use
in certain patients (Achneck et al. 2010). The data presented in this chapter demonstrates
that in most clinical cases, the decision can be
made to maintain antiplatelet or anticoagulation
 ranexamic Acid (TXA),
T therapy for routine dental treatment, including
ϵ-aminocaproic Acid (Amicar) “simple” extractions. This is especially true for
patients who are at high medical risk of a throm-
Tranexamic acid (TXA), and ϵ-aminocaproic boembolic event and/or patients requiring minor
acid (Amicar) are antifibrinolytic agents that dental surgical procedures.
block the proteolytic site of plasmin and inhibit Intraoperative hemostatic measures would
plasminogen activator incorporation into the benefit any patient who is on one or more blood
nascent fibrin clot. A 4.8% TXA solution has thinners, irrespective of the treatment algorithm
been proven to be very effective in reducing chosen. However, it is most critical in the patient
bleeding complications (Dinkova et al. 2013). who maintains his/her blood thinner therapy
This solution may be difficult to obtain from a during his/her operative course. Malmquist pro-
pharmacy unless prior arrangements have been vided a list of key hemostatic measures that
made. A recommended regimen is to hold 10 ml should be considered, that include the following
in the mouth for 2 min, 30 min pre-procedure, (Malmquist 2011):
and then repeat every 2 h for six to ten doses as
needed (Carter and Goss 2003). 1. Avoid flap procedures
Carter et al. demonstrated that a 2-day course 2. Limit surgical trauma, for example, limiting
of 4.8% TXA is as efficacious as a 5-day course the number of teeth extracted or the section-
in controlling hemostasis post-dental extractions ing of teeth
in patients anticoagulated with warfarin (Carter 3. Curette-associated socket granulation tissue
and Goss 2003). 4. Obtain primary closure when a flap has been
elevated
5. Use non-resorbable sutures to control the
Topical Thrombin tension on the flap and eliminate the possibil-
ity of premature breakdown of the suture
Thrombin forms the foundation of a fibrin clot by material
promoting the conversion of fibrinogen to fibrin. 6. Use topical hemostatic materials in the surgi-
Thrombin is commonly derived from bovine cal site to reduce bleeding
sources, yet bovine thrombin has been known to 7. Use electrocautery or laser to minimize
cause a significant immune response in some bleeding
patients. As such, new formulations derived from 8. Apply an appropriately placed pressure
human plasma or recombinant human sources are dressing for a sufficient period of time
available and are being formulated (Achneck 9. Use topical rinses, such as tranexamic acid,
et al. 2010). The application of thrombin in con- to inhibit fibrinolysis
trolling hemostasis during dental surgery can be 10. Provide treatment early in the day, allowing
performed by applying thrombin directly to the for observation of bleeding throughout the
surgical site, yet it is best utilized by combining day
thrombin synergistically with a second hemo-
static agent, such as Gelfoam®, as a carrier. This Decisions should always be co-managed
combination can then be packed into the surgical under the guidance of the treating physician and
site for hemostatic control. include the consideration of the following:
Pharmacologic Management of Patients with Drug-Related Coagulopathies 75

• The physiology and sequence of hemostasis Branehög I, Ridell B, Swolin B, Weinfeld

A. Megakaryocyte quantifications in relation to throm-
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Treatment of Hemophilia No 40. World Federation of
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therapies Cardona-Tortajada F, Sainz-Gomez E, Figuerido-­
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 Pharmacology of Psychiatric
and Neurologic Drugs

Miriam R. Robbins

Introduction able interactions of these drugs with drugs

commonly prescribed by dentists. Comprehensive
Psychiatric and neurologic diseases are common in information on the pharmacodynamics and phar-
the general population and therefore are commonly macokinetic of these psychotropic and neurologic
encountered in dental patients. Approximately drugs can be accessed elsewhere.
15% of the worldwide population are affected-a
number that is expected to increase as life expec-
tancy increase (Feigin et al. 2020). Such diseases Psychiatric Disorders
may vary in severity and consequences, but treat-
ment of these chronic conditions generally involves Psychiatric diseases are common in the United
long-term use of multiple pharmacologic agents. States. One in five US adults lives with a mental
Because of the similarity in the underlying patho- illness (57.8 million or 22.8% in 2021). Mental
physiology of the diseases presented, there is over- health surveys carried out in the United States
lap between the medications used. For example, suggest that during any 1-year period, approxi-
anticonvulsant medications are also used to treat mately 26% of the population will have a mental
mood disorders. The majority of patients with disorder, and almost 50% of all people will have
Parkinson’s disease (PD) and Alzheimer’s disease mental illness sometime during their lifetime
(AD) will exhibit neuropsychiatric symptoms (Nimh.nih.gov 2023a). A total of 1.21% of adults
including depression, anxiety, agitation, apathy, in the United States live with schizophrenia
and psychosis at some time during the course of (Nimh.nih.gov 2023b). And 2.6% of adults in the
disease. The focus of this chapter is to summarize United States live with bipolar disorder (Nimh.
potential drug interactions of clinical importance to nih.gov 2023c). Also, 8.4% of adults in the United
the oral health care provider, based on a review of States—21 million—had at least one major
the most current evidence-based literature available depressive episode in the past year. (Nimh.nih.
with an emphasis on systematic reviews (Table 1). gov 2023d) Furthermore, 19.1% of adults in the
Although the information presented on various United States experienced an anxiety disorder
medications used to treat these disorders is pre- such as generalized anxiety, posttraumatic stress
sented here, it is intended to highlight the undesir- disorder, obsessive-compulsive disorder, and pho-
bias (Nimh.nih.gov 2023e). Psychiatric disorders
have high rates of co-occurrence with patients
M. R. Robbins (*)
exhibiting more than one type of symptom (e.g.,
School of Dental Medicine, University of
Pennsylvania, Philadelphia, PA, USA depression and anxiety frequently occur together).
e-mail: [email protected] Additionally, patients may have medical comor-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 79
A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_7
80 M. R. Robbins

Table 1 Dental drug interactions

Dental drugs Interacting drug(s) Details of interaction Recommendations Key references
Aspirin and Lithium NSAIDs inhibit renal Best to use Bauer and Mitchner
NSAIDs clearance of lithium, diflunisal (2004), Hashimoto et al.
potentially resulting in Limit use of (2002), Alda (2015)
lithium toxicity within NSAIDs to 2–3
5–10 days days
Decrease dose of
lithium
SSRIs (fluoxetine, Increased risk of Limit use to 2–3 Serebruany (2006),
sertraline, paroxetine) bleeding (especially days. Avoid in Anglin et al. (2014),
SRI (duloxetine) GI) due to interference patients with Mansour et al. (2006),
Donepezil with platelet function history of GI Loke et al. (2008)
Galantamine bleeding or
Rivastigmine bleeding diathesis
Divalproex sodium Synergistic effect on Avoid Vasudev et al. (2010),
Valproic acid bleeding with aspirin Abdallah (2014), Manu
et al. (2016)
Acetaminophen Carbamazepine Increased potential Avoid concurrent Patsalos and Perucca
Phenytoin hepatotoxicity of use (2003), Perucca (2006)
acetaminophen and Max daily dose of
decrease its acetaminophen <2
pharmacologic effects g
Lamotrigine Reduction in Limit use to 2–3 Patsalos and Perucca
therapeutic levels of days (2003)
lamotrigine
Tramadol Bupropion Increased seizures and/ Avoid Sansone and Sansone
MAOIs or serotonin syndrome (2009)
SSRIs
TCAs
Pramipexole Increased CNS and/or Monitor
respiratory depression
MAOIs Hypertension and Avoid
autonomic reactions
Codeine SSRIs (fluoxetine, Decreased efficacy of Alternative pain Becker (2008),
Hydrocodone sertraline, paroxetine) pain medication due to medications Friedlander and Norman
Oxycodone Bupropion delayed metabolism (2002))
Haloperidol (CYP2P6 inhibitors) of
prodrug to active
morphine derivative
Antipsychotics Increased central CNS Reduce dose of
Benzodiazepines depression narcotics, alternate
TCAs pain medications
Doxycycline Lithium Increased lithium Avoid Hashimoto et al. (2002),
Metronidazole levels; risk of toxicity Alda (2015)
Tetracycline
Metronidazole Antipsychotics Decreased seizure Use with caution, Kennedy et al. (2013),
Carbamazepine threshold reduce dose Ruiz Diaz et al. (2020),
Phenobarbital Patsalos and Perucca
Phenytoin (2003), Perucca (2006)
Primidone
Pharmacology of Psychiatric and Neurologic Drugs 81

Table 1 (continued)
Dental drugs Interacting drug(s) Details of interaction Recommendations Key references
Macrolides Benzodiazepines Inhibition of AED/ Avoid or monitor Gubbins and
Erythromycin (except lorazepam) psychotropic drug AED/psychotropic Heldenbrand (2010),
Clarithromycin Carbamazepine metabolism leading to drug levels Patsalos and Perucca
Phenobarbital increased CNS (2003), Perucca (2006)
Phenytoin depression (CYP450
Valproate inhibition)
Valproate Increased valproate Avoid Vasudev et al. (2010),
concentration Abdallah (2014)
(CYP3A4 inhibition)
Fluoxetine QT prolongation Avoid Kennedy et al. (2013),
Haloperidol Ruiz Diaz et al. (2020)
Pramipexole
Quetiapine
Sertindole
Venlafaxine
Zotepine
Donepezil Decreased hepatic Monitor, consult Defilippi and Crismon
Galantamine metabolism of with physician if (2003), Bentué-Ferrer
cholinesterase extended course is et al. (2003)
inhibitors increasing anticipated
cholinergic activity
Doxycycline Carbamazepine Decreased doxycycline Use alternate Perucca (2006
Phenobarbital half-life by 50% antibiotic
Phenytoin
Fluconazole Carbamazepine Inhibition by antifungal Avoid or monitor Kennedy et al. (2013),
Ketoconazole Clonazepam of metabolism of drug AE/psychotropic Gubbins and
Itraconazole Phenobarbital (CYP450) inhibition) drug levels Heldenbrand (2010),
Phenytoin potentiating Monitor, consult Defilippi and Crismon
Quetiapine psychotropic effects with physician if (2003), Perucca (2006)
Benzodiazepines and possibly toxic extended course is
Donepezil serum levels anticipated
Galantamine Decreased hepatic
metabolism of
cholinesterase
inhibitors increasing
cholinergic activity
Local anesthetics Older generation Blockage of α1- Monitor vital signs Yagiela (1999), Brown
with epinephrine antipsychotics receptors can cause during and after and Rhodus (2005),
(haloperidol and orthostatic hypotension administration. Moodley (2017),
chlorpromazine). Not that rarely can be Limit to two Malamed (2014),
seen with newer worsened by the carpules of Saraghi et al. (2017),
atypical antipsychotics β2-receptor stimulation 1:10,000 Friedlander and Marder
COMT inhibitors by epinephrine epinephrine or less. (2002), Balakrishnan and
Entacapone Delayed metabolism of Aspirate to avoid Ebenezer (2013)
Tolcapone both epinephrine and intravascular
TCAs levonordefrin possibly injection. Avoid use
potentiating of epinephrine
cardiovascular effects impregnated
Possible potentiation of retraction cord.
the sympathetic effects Avoid
of epinephrine or levonordefrin use
levonordefrin with TCAs
(more prevalent with
levonordefrin)
82 M. R. Robbins

bidities, either as direct effect of the underlying dence of side effects (including xerostomia,
pathophysiology or as a side effect of chronic and/ orthostatic hypotension, and cardiac toxicities)
or debilitating disease. More than 50% of patients and more adverse drug interactions. Today, TCAs
with substance abuse disorders have a co-occur- are more commonly used in the management of
ring mental illness (Substance Abuse and Mental chronic pain and insomnia due to their ability to
Health Services Administration 2015). Psychiatric elevate synaptic norepinephrine concentrations
disorders are frequently associated with rates of and sedative properties (Finnerup et al. 2015;
compliance with medical and dental treatment. Catalani et al. 2014).
A mainstay of treatment for psychiatric disor- MAOIs were the first group of drugs used to
ders is psychotropic medications. Patient treat depression but are currently only used to
responses are variable, so the use of combination treat patient resistant to other pharmacologic
therapy is common. Patients may be on several therapies. MAOIs act by inhibiting the activity of
different medications depending on their under- presynaptic monoamine oxidase (MAO; MAO-A
lying symptoms, and there is crossover between and MAO-B), leading to increased epinephrine,
the medications and disorders. Psychotropic norepinephrine, serotonin, and dopamine con-
medications may have short- and long-term centrations in the neuronal cytoplasm (Becker
adverse effects and frequently have drug interac- 2008), leading to downregulation of postsynaptic
tions with clinical implications for medical and receptors (Bhat and Preethishree 2015). They fell
dental providers. Common types of medications out of favor because of serious dietary and drug
include antidepressants, mood stabilizers, anti- restrictions that were needed to avoid life-­
psychotics, and antianxiety drugs (Box 1). threatening hypertensive episodes. These
included dietary restrictions of any foods con-
taining tyramine and any other drugs with an
Antidepressants
effect of serotonin uptake (Rabkin et al. 1984).
While the exact mechanism is not known, it is Tricyclic antidepressants gained popularity in
hypothesized that antidepressant drugs work by the 1960s as the major antidepressant medication
inhibiting the uptake of serotonin and/or norepi- in the United States. In addition to limiting the
nephrine in the synapse. Millions of patients take reuptake of neurotransmitters, TCAs have alpha-1
antidepressant medications in the United States antagonist, anticholinergic and antihistamine
not only to treat depression but also to treat anxi- properties (Baldessarini 2006). Anticholinergic
ety, panic disorders, posttraumatic stress disor- side effects include xerostomia, urinary retention,
der, obsessive-compulsive disorder, and seasonal and constipation, while the alpha-1 blockade
affect disorder. Some antidepressants are pre- causes orthostatic hypotension. Metabolism
scribed off-label to treat problems such as chronic occurs in the liver, via the cytochrome P450 path-
pain, insomnia, ADHD, menstrual symptoms, way. Notable central nervous system effects of
migraines, and tobacco cessation (Fishbain 2000; TCAs include sedation and a reduction in the sei-
Urits et al. 2019). zure threshold. Cardiovascular effects of TCAs
Antidepressant classes are named depending include tachycardia and changes in cardiac con-
on their effect on reuptake or enzyme inhibition. duction possibly leading in some cases to cardiac
Commonly prescribed antidepressants include arrhythmias and causing widening of the QRS
selective serotonin reuptake inhibitors (SSRIs), complex and QT prolongation. TCAs display
serotonin and norepinephrine reuptake inhibitors analgesic properties at doses significantly lower
(SNRIs), and bupropion. Tricyclics (TCAs), tet- than those used to treat depression and are consid-
racyclics, and monoamine oxidase inhibitors ered a first-line drug in the treatment of neuro-
(MAOIs) are older classes of antidepressants that pathic pain, fibromyalgia, back pain, and chronic
are used less frequently because of higher inci- headaches (Fennema et al. 2017).
Pharmacology of Psychiatric and Neurologic Drugs 83

Box 1 Psychiatric Medications

Antidepressants Citalopram (Celexa®) Mood stabilizers Carbamazepine (Tegretol®)
Selective serotonin reuptake Escitalopram, Divalproex (Depakote®)
inhibitors (SSRIs) (Lexapro®) Gabapentin (Neurontin®)
Tricyclics Fluoxetine (Prozac®) Lamotrigine (Lamictal®)
Monoamine oxidase Fluvoxamine (Luvox®) Lithium (Eskalith®,
inhibitors (MAOI) Paroxetine (Paxil®) Lithonate®)
Serotonin norepinephrine Sertraline (Zoloft®) Oxcarbazepine (Trileptal®)
reuptake inhibitor (SNRI) Topiramate (Topamax®)
Serotonin-2 antagonists/ Valproic Acid (Depakene®,
reuptake inhibitor (SARI) Epival®)
Norepinephrine dopamine Amitriptyline (Elavil®) Antipsychotics Typical (first generation)
reuptake inhibitor (NDRI) Clomipramine Chlorpromazine
(Anafranil®) (Thorazine®)
Desipramine Flupenthixol (Fluanxol®)
(Norpramin®) Fluphenazine (Modecate®)
Doxepin (Sinequon®) Haloperidol (Haldol®)
Imipramine (Tofranil®) Loxapine (Loxapac®)
Nortriptyline Mesoridazine (Serentil®)
(Pamelor®) Pericyazine (Neuleptil®)
Protriptyline (Vivactil®) Perphenazine (Trilafon®)
Trimipramine Pimozide (Orap®)
(Surmontil®) Pipotiazine (Piportil®)
Phenelzine (Nardil®) Prochlorperazine (Stemetil®)
Tranylcypromine Thioridazine (Mellaril®)
(Parnate®) Thiothixene (Navane®)
Trifluoperazine (Stelazine®)
Zuclopenthixol (Clopixol®)
Venlafaxine (Effexor®) Atypical (second generation)
Duloxetine (Cymbalta®) Aripiprazole (Abilify®)
Clozapine (Clozaril®)
Lurasidone (Latuda®)
Olanzapine (Zyprexa®)
Quetiapine (Seroquel®)
Risperidone (Risperdal®)
Trazodone (Desyrel®) Anxiolytics Benzodiazepines
Alprazolam (Xanax®)
Bromazepam (Lexotanil®)
Chlordiazepoxide (Librium®)
Clonazepam (Klonopin®)
Clorazepate (Tranxene®)
Diazepam (Valium®)
Flurazepam (Dalmane®)
Lorazepam (Ativan®)
Nitrazepam (Magadon®)
Oxazepam (Serax®)
Temazepam (Restoril®)
Triazolam (Halcion®)
Bupropion Non-benzodiazepine
(Wellbuturin®, Zyban®) Buspirone (BuSpar®)
Hydroxyzine (Vistaril®)
Meprobamate (Miltown®)
Pregabalin (Lyrica®)
Propranolol (Inderal ®)
84 M. R. Robbins

Selective serotonin reuptake inhibitors (SSRI) flexia, muscle rigidity and tremors, agitation,
inhibit the neuronal uptake of serotonin and gen- and confusion (Sansone and Sansone 2009).
erally have the least side effects of all classes of Additional symptoms can include diaphoresis,
antidepressants. They are used to treat mild to tachycardia, hyperthermia, hypertension, visual
moderate depression, obsessive-compulsive syn- hallucinations, and coma. Dental drugs of con-
drome, panic disorder, social phobias, and post- cern include opioid analgesics (especially
traumatic stress disorder. With the exception of meperidine), anesthetic agents including fen-
paroxetine, SSRIs have relatively minimal anti- tanyl, tramadol, and erythromycin and should
cholinergic properties or sedative effects. Unlike be avoided in patients taking serotonergic drugs.
TCAs, SSRIs do not affect the seizure threshold SSRIs and SNRIs increase the risk of bleeding
or cardiac conduction. Common side effects through the reduction of platelet levels of sero-
include nausea, diarrhea, headache, jitteriness tonin that causes decreased platelet aggregation
and agitation, and insomnia. SSRIs (especially and clot formation (Serebruany 2006). Patients
fluoxetine, paroxetine, and sertraline) are also taking SSRIs (especially fluoxetine, paroxetine,
potentially associated with an increase in sleep and sertraline) have an increased risk of upper
bruxism, although the exact etiology is currently gastrointestinal (GI) bleeding, and that this risk
unknown (Garrett and Hawley 2018). may be synergistically increased by concurrent
Other atypical antidepressants include the use of NSAIDs (Anglin et al. 2014). Additionally,
SNRIs represented by venlafaxine and dulox- paroxetine, sertraline, and fluvoxamine inhibit
etine. They resemble the tricyclic antidepressants the enzymes needed to metabolize NSAIDs
in action and have similar side effects including including ibuprofen, naproxen, diclofenac, and
sedations, nausea, insomnia, xerostomia, and celecoxib, further increasing the risk of signifi-
constipation. They can cause elevations and heart cant bleeding (Mansour et al. 2006; Loke et al.
rate and blood pressure because of norepineph- 2008).
rine uptake inhibition. They are also commonly The SSRI antidepressants also can inhibit sev-
used in the treatment of chronic neuropathic pain eral of the cytochrome P-450 enzymes produced
including diabetic neuropathy, fibromyalgia, and in the liver, impacting the biotransformation and
post herpetic neuralgia (Finnerup et al. 2015). clearance of other drugs. This occurs with vary-
ing intensity with fluoxetine and paroxetine
exhibit the greatest degree of inhibition. Of clini-
 ental Pharmacology Implications
D cal relevance is the inhibition of CYP2D6, which
for Patients Medicated is responsible for metabolizing codeine, hydro-
with Antidepressants codone, and oxycodone from a prodrug to an
active morphine metabolite. Patients medicated
Potential drug interactions with antidepressants with these SSRIs may not experience the expected
of dental concern include sedatives, narcotic analgesic effect from codeine or its derivatives
and nonsteroidal anti-inflammatory drugs (Becker 2008; Friedlander and Norman 2002).
(NSAIDs) analgesics, and epinephrine/levonor- A long held and commonly believed drug
defrin. Antidepressants have significant sedative interaction is between MAOIs and local anesthet-
properties, and caution should be taken when ics with vasoconstrictors. It was believed that
­prescribing any other medication with sedative inhibition of MAO could potentiate the activity
side effects. Antidepressants that elevate sero- of epinephrine by delaying its oxidation, leading
tonin levels can precipitate seizures or serotonin to increased and potentially harmful cardiovascu-
syndrome if used in conjunction with other lar reactions. Restriction on using local anes-
medications that increase serotonin levels. thetic with epinephrine or levonordefrin is
Serotonin syndrome is a potentially fatal conse- frequently listed as a contraindication with
quence of excessive central nervous system MAOIs. However, review of the literature shows
serotonergic activity characterized by hyperre- an absence of case reports to support this claim.
Pharmacology of Psychiatric and Neurologic Drugs 85

More recent reviews show no credible evidence daily dosing schedule and careful monitoring of
of a significant interaction between MAOIs and serum lithium levels. Early signs of lithium toxic-
epinephrine or levonordefrin (Yagiela 1999; ity included nausea, vomiting, lethargy or drows-
Brown and Rhodus 2005), and this has been sup- iness, slurred speech, and muscle weakness,
ported by human and animal studies and clinical which quickly progress to ataxia, dysrhythmias,
experience. seizures, renal failure, and coma if serum levels
A similar contraindication for the use of epi- are not lowered. In addition to lithium, the atypi-
nephrine and levonordefrin has been proposed cal antipsychotic olanzapine is also use to treat
for TCAs. Animal models show significant inter- bipolar depression in patients who have refrac-
action between TCAs and adrenergic vasocon- tory disease or are unable to tolerate lithium’s
strictors (Yagiela 1999) including increases in side effects.
systolic blood pressure. However, there are no Several anticonvulsant medications have also
case reports in the English literature that translate proven useful in managing bipolar affective dis-
into clinically adverse events at the doses of local orders in addition to seizure disorders. It is
anesthetic used during most dental procedures, thought that they work by stabilizing the neuro-
especially with epinephrine (Moodley 2017; nal membranes and helping to suppressing the
Malamed 2014; Saraghi et al. 2017). Despite this, spread of impulses to neighboring neuron path-
most anesthesia texts and pharmacology sites ways. Commonly used anticonvulsants include
continue to suggest limiting the use of local anes- carbamazepine, topiramate, lamotrigine, gaba-
thetics with epinephrine to 0.05 mg and avoiding pentin, and valproate (both as divalproex and val-
the use of anesthesia with levonordefrin all proic acid) (Melvin et al. 2008).
together. Additional human research is needed to
determine if therapeutic doses of local anesthetic
with vasoconstrictors are related to negative car-  ental Pharmacology Implications
D
diovascular outcomes in patient taking TCAs. for Patients Medicated with Lithium
and Anticonvulsants

Mood Stabilizers NSAIDs and metronidazole are two dental drugs

that can cause lithium toxicity by reducing renal
Traditionally, mood stabilizers were primarily clearance in a short period of time. Likewise, tet-
antimanic agents, but more recently, the defini- racycline and doxycycline can raise lithium lev-
tion has been expanded to include agents with els through an unknown mechanism causing the
efficacy in treating acute symptoms of manic and potential of toxicity. Macrolides such as erythro-
depressive symptoms as well as in preventing mycin and clarithromycin can lead to increased
these symptoms in bipolar disorder (Bauer and serum levels of carbamazepine and divalproex/
Mitchner 2004). Lithium is the only psychotropic valproic acid leading to toxicity. Alternative anti-
agent that is truly a mood stabilizer, and it is con- biotics and pain medications are recommended.
sidered the first-line drug for the treatment of Valproate (divalproex and valproic acid) can
bipolar disorder. While the mechanism of action cause thrombocytopenia, abnormal platelet func-
is not completely understood, but it is thought to tion, and changes in coagulation factor levels,
somehow stabilize neuronal membranes, thereby leading to an increased risk of bleeding (Vasudev
reducing their rate of discharge and neurotrans- et al. 2010; Abdallah 2014). NSAIDs and aspirin
mitter turnover (Hashimoto et al. 2002; Alda should be avoided in patients taking these drugs.
2015). Lithium is excreted solely by the kidneys Carbamazepine can also cause blood dyscrasias,
and has a number of side effects including car- including anemia, leukopenia, and agranulocyto-
diac dysrhythmias, GI disturbances, and tremors. sis, and so patients taking this drug are usually
It has a very narrow therapeutic ratio and a high carefully monitored via frequent CBCs (Manu
risk of toxicity, necessitating strict adherence to a et al. 2016).
86 M. R. Robbins

Antipsychotics epinephrine in patients taking older antipsy-

chotics like haloperidol and chlorpromazine.
Antipsychotics are psychotropic drugs used to The macrolide antibiotics clarithromycin and
treat psychotic symptoms such as delusions and erythromycin should be used cautiously in
hallucinations seen in schizophrenia, mania, some of the newer atypical antipsychotics (like
delusional disorder, and psychotic depression. quetiapine) because of competing metabolism
They are also frequently used in patients with leading to increased serum levels of the anti-
Alzheimer’s disease who have acute agitation. psychotic. This can lead to QT interval prolon-
They are generally classified as typical (first gen- gation and cardiac arrhythmias (Kennedy et al.
eration) or atypical (second generation). They 2013; Ruiz Diaz et al. 2020).
work as antagonists at dopamine receptors in
various parts of the brain. Blockage of the D2
receptors in the limbic system produces the anti- Benzodiazepines
psychotic result, but most of these drugs lack
specificity for this receptor. Interaction with other Benzodiazepines are most commonly used to
dopamine receptors as well as other receptor sys- treat anxiety and are the drug of choice for gener-
tems, including histaminic, muscarinic, seroto- alized anxiety disorder. They are often used in
nergic, and a-adrenergic receptors produce many combination with other antidepressants to treat
side effects (Miyamoto et al. 2012). These panic disorders and other anxiety states. They
include extrapyramidal symptoms such as akathi- work by indirectly enhancing γ-aminobutyric
sia and tardive dyskinesia (more prevalent with acid (GABA) neurotransmission and receptor
typical antipsychotics), sedation, weight gain, sensitivity. Side effects include depressed respi-
xerostomia, orthostatic hypotension, cognitive ration and cardiovascular tone, sedation, fatigue,
impairment, prolactin effects, and cardiac and dependence (Kyrios 2014).
changes (including QT interval prolongation)
(Kennedy et al. 2013). Development of extrapy-
ramidal symptoms with the typical antipsychotic  ental Pharmacology Implications
D
medications is often treated by the addition of for Patients Medicated
anticholinergic drugs, nonselective beta blockers, with Anxiolytics
or benzodiazepines.
Drug tolerance and dependence are of concern.
Benzodiazepines have a wide therapeutic index,
 ental Pharmacology Implications
D and therefore most dental drug interactions are
for Patients Medicated unlikely to produce significant toxicity (Griffin
with Antipsychotics III et al. 2013). Exceptions include macrolide
antibiotics erythromycin and clarithromycin
Antipsychotic medications may potentiate and the azole antifungals (fluconazole, ketocon-
other central nervous system depressants such azole, and itraconazole) that compete for the
as narcotic analgesics. Caution should be used same hepatic cytochrome P450 enzyme needed
when prescribing to prevent orthostatic hypo- to metabolize all benzodiazepines (except
tension and respiratory depression (Friedlander ­lorazepam). Co-administration can cause ele-
and Marder 2002). Blockage of α1-receptors by vated serum levels and prolonged action, espe-
the typical antipsychotics can cause orthostatic cially with triazolam and midazolam (Gubbins
hypotension that theoretically could be wors- and Heldenbrand 2010). Additionally, caution
ened by the β2-receptor stimulation by epi- should be used with other drugs that have the
nephrine. Local anesthetic with epinephrine potential to enhance CNS and respiratory
should be limited to no more than 0.05 mg of depression.
Pharmacology of Psychiatric and Neurologic Drugs 87

Parkinson’s Disease Neuropsychiatric symptoms are treated using

SSRIs as the first drugs of choice, but tricyclic anti-
Parkinson’s disease is a progressive multisystem depressants, SNRIs, and antipsychotics may all be
and multi-symptomatic degenerative neurologi- used depending on severity of the symptoms and
cal condition believed to be the result of both patient’s response to drugs (Menza et al. 2009;
genetic and environmental factors. It is due to a Bomasang-Layno et al. 2015; Suchowersky et al.
loss of dopaminergic neurons in the substantia 2006; Chen 2012) (Box 2). Common oral side
nigra region of the brain. It is one of the fastest effects of medications used to treat Parkinson’s dis-
growing neurologic disorders worldwide due to ease include orthostatic hypotension, xerostomia,
the aging population. It is estimated that more and bruxism.
than a million people in the United States have
Parkinson disease, with the number expected to
Box 2 Pharmacologic Treatment of
significantly increase in the coming years (Willis
Parkinson’s Disease (Suchowersky et al.
et al. 2022). This number doesn’t account for the
2006; Chen 2012)
thousands of cases that go undetected. Men are
Tremor control Cholinesterase
one and a half times more likely to have Amantadine inhibitors
Parkinson’s than women (Marras et al. 2018). (Symmetrel®) Rivastigmine
Parkinson’s disease ranks among most common Trihexyphenidyl (Exelon®)
late-life neurodegenerative diseases (after (Artane®) Donepezil (Aricept®)
Benztropine (Cogentin®) Galantamine
Alzheimer’s disease) and affects approximately Propranolol (Razadyne®)
1.5–2.0% of people aged 60 years and older (nonselective beta Tacrine (Cognex®)
(Nussbaum and Ellis 2003; Wirdefeldt et al. blocker)
2011; Pringsheim et al. 2014). Dopamine precursor N-methyl D aspartate
Clinical manifestations of Parkinson’s disease Levodopa/Carbidopa antagonist
Sinemet® Memantine
include rigidity and bradykinesia accompanied by a Parcopa® (Namenda®)
resting tremor. Additionally, neuropsychiatric Stalevo® Memantine and
symptoms including cognitive impairment, depres- Rytary® donepezil (Namzaric®)
sion, anxiety, hallucinations, and psychosis are Dopamine agonists Antidepressants
Pramipexole (Mirapex®) Citalopram (Celexa®)
common (Aarsland et al. 1999; Aarsland et al. 2009; Ropinirole (Requip®) Fluoxetine (Prozac®)
Miyasaki et al. 2006). Pharmacologic treatment of Apomorphine Paroxetine (Paxil®)
Parkinson disease can be divided into symptomatic (Apokyn®) Sertraline (Zoloft®)
and neuroprotective (disease-­ modifying) therapy Rotigotine (Neupro®) Trazodone (Desyrel®)
Bromocriptine
aimed at controlling symptoms and maintaining (Parlodel®)
functional independence. Treatment protocols MAO-B inhibitor Anxiolytics
aimed at controlling symptoms focus on increasing Selegiline (Eldepryl®) Lorazepam (Ativan®)
dopamine availability and preventing its breakdown Rasagiline (Azilect®) Oxazepam (Serax®)
Safinamide (Xadago®) Alprazolam (Xanax®)
by inhibiting acetylcholine. This is usually done by
Zydis selegiline HCL Buspirone (BuSpar®)
utilizing levodopa/carbidopa levodopa alone or (Zelapar®)
with the addition of catechol-O-methyltransferase COMT inhibitors Antipsychotics
(COMT) inhibitors. Although levodopa is the most Entacapone (Comtan®) Aripiprazole (Abilify®)
effective medication available for treating the Tolcapone (Tasmar®) Clozapine (Clozaril®)
Opicapone (Ongentys®) Olanzapine (Zyprexa®)
motor symptoms of Parkinson disease, other neu- Anticholinergics Quetiapine (Seroquel®)
roprotective medications such as monoamine oxi- Trihexyphenidyl Risperidone
dase type B inhibitors (MAOBIs), amantadine, (Artane®) (Risperdal®)
anticholinergics, β-blockers, or dopamine agonists Benztropine (Cogentin®) Ziprasidone (Geodon®)
Biperiden (Akineton®)
may be ­ initiated first to avoid levodopa-­ related
motor complications (Connolly and Lang 2014).
88 M. R. Robbins

 ental Pharmacology Implications

D destruction of cortical neurons (Selkoe and
for Patients Medicated Schenk 2003; Walsh and Selkoe 2004; Kumar
for Parkinson’s Disease and Singh 2015). An estimated 5.7 million
Americans are living with Alzheimer’s dementia
Potential drug interactions of concern include in 2018 including an estimated 5.5 million people
COMT inhibitors and local anesthetics with age 65 and older and approximately 200,000
vasopressors. These drugs reversibly block individuals under age 65 who have younger-onset
catechol-­O-methyltransferase inhibiting the Alzheimer’s. Alzheimer’s disease is the sixth-­
inactivation of exogenously administered epi-
­ leading cause of death in the United States and
nephrine and levonordefrin contained in a local the fifth-leading cause of death among those age
anesthetic solution. Tachycardia, hypertension, 65 and older (Alzheimer’s Association 2018).
and arrhythmias have been reported. The rate of progression of the cognitive
Vasoconstrictors should be used with caution. changes of AD is variable from patient to patient,
Vital signs should be monitored during and after but on average, a person with AD lives four to 8
administration of the first carpule, and total dose years after diagnosis. Symptoms often predate a
should be limited to 2 or less carpules of formal diagnosis by several year. Diagnosis is
1:100,000 (0.034 mg) of epinephrine. Care made on the basis of a history of pattern of symp-
should be taken to aspirate to prevent intravascu- toms over time including a clinical history of pro-
lar injection (Malamed 2014; Balakrishnan and gressive dementia and the exclusion of other
Ebenezer 2013). Retraction cord impregnated causes. Along with cognitive changes seen in
with epinephrine should not be used. Most anti- AD, psychiatric and behavioral symptoms are
parkinsonian drugs aimed at increasing the common in patients with AD and contribute sub-
amount of dopamine present cause CNS depres- stantially to the morbidity of the illness. During
sion, and therefore any additional sedative could the early stages, patients may experience person-
have additive effect (Friedlander et al. 2009). ality changes such as irritability, depression and
Other drug reactions with the psychotropic drugs anxiety. In the later stages, symptoms such as
used in Parkinson are covered previously. apathy, psychomotor impairment, and psychosis
become more prevalent. Delusions or hallucina-
tions appear in 30–50% of AD patients, and as
Alzheimer’s Disease high as 80% of patients exhibit agitated or aggres-
sive behavior (Ropacki and Jeste 2005; Lopez
Alzheimer’s disease (AD) is a progressive neuro- et al. 2001).
degenerative condition that accounts for 80% of Pharmacologic treatment of AD is aimed at
all cases of dementia in the United States (Alz. modulating the decline of cognitive, functional,
org 2018). AD is characterized by a progressive and behavioral symptoms by increasing the con-
and irreversible deterioration in cognitive abili- centration of neurotransmitters in the brain (Box
ties including memory and abstract thought and 3) (Kumar and Singh 2015; Casey 2015; Orgeta
functionality that impairs activities of daily living et al. 2017). Most of the current pharmacologic
ultimately leading to death. The exact etiology of treatments available reduce or control some of
AD isn’t known, but it is believed to be multifac- the cognitive and behavioral symptoms and do
torial, involving several genetic, environmental, not alter the progressive pathophysiology of the
and biologic risk factors. The formation of cere- disease or stop the damage and destructions of
bral plaques composed of intracellular neurofi- neurons. There are five FDA-approved drugs for
brillary tangles of tau proteins and extracellular the treatment of AD-three cholinesterase inhibi-
amyloidal protein deposits is a key pathologic tors (donepezil, galantamine, and rivastigmine),
finding. These plaques lead to neuroinflamma- one N-methyl D aspartate (NMDA) antagonist
tion that results in the progressive damage and (memantine) and one combination drug (meman-
Pharmacology of Psychiatric and Neurologic Drugs 89

tine combined with donepezil). Early to moderate recently approved to treat early Alzheimer’s that
stage AD is treated using the cholinesterase are the first to target the fundamental pathophysi-
inhibitors, which prevent the breakdown of ace- ology of the disease. A third drug Donanemab is
tylcholine and can delay worsening of symptoms currently in Phase III clinical trials. These mono-
and improved cognitive function for one to five clonal antibodies bind to soluble amyloid-beta
years for about 50% of the patients that take them protofibrils, reducing amyloid plaque accumula-
(Han et al. 2017). Common side effects include tion resulting in a slowing in cognitive and func-
GI distress (nausea, vomiting, and diarrhea) as tional decline when compared to placebo (Van
well as dizziness and fatigue (Noetzli and Eap Dyck et al. 2023). They are given via intravenous
2013). Memantine either alone or with donepezil infusions. Side effects include infusion-related
is used in more advanced disease and may delay reactions including chills, fever, rash, and body
worsening of symptoms by modulating the aches and amyloid-related imaging abnormalities
glutamate-­induced overactivation of the NMDA with edema (ARIA) and brain bleeds. It is too
receptor that contributes to neuronal damage and early to determine if there are other significant
death (Kishi et al. 2017). long-term side effects associated with this class
of medications.
As AD progresses, behavioral symptoms and
Box 3 Pharmacologic Management of
mood disorders often necessitate the initiation of
Alzheimer’s Disease (Casey 2015; Orgeta
psychotropic medications to modify these effects.
et al. 2017; Van Dyck et al. 2023)
These include all of the major groups of psychi-
First-line Donepezil (Aricept®) atric medications including antidepressants (tri-
medications Galantamine (Razadyne®)
cholinesterase Rivastigmine (Exelon®) cyclic, SSRI, and SNRI) for depression and
inhibitors Memantine (Namenda®) apathy; anxiolytics for anxiety, restlessness, ver-
N-methyl-D- Memantine and donepezil bally disruptive behavior, and resistance; antipsy-
aspartate receptor (Namzaric®) chotic medications for hallucinations, delusions,
antagonists Aducanumab (Aduhelm®)
Combination Lecanemab (Leqembi®) aggression, agitation, hostility, and uncoopera-
Amyloid beta- Citalopram (Celexa®) tiveness; and mood stabilizers for agitation and
directed antibody Fluoxetine (Prozac®) sleeping aids for AD-associated sleep distur-
Adjunctive Paroxetine (Paxil®) bances (Sink et al. 2005; Gauthier et al. 2010).
medications Sertraline (Zoloft®)
Antidepressants Trazodone (Desyrel®) While atypical antipsychotics are generally the
Anxiolytics/ Venlafaxine (Effexor®) first drugs of choice, they have been associated
hypnotics Lorazepam (Ativan®) with increased mortality in patients with demen-
Antipsychotics Alprazolam (Xanax®) tia and behavioral symptoms, and their effective-
Mood stabilizers Zolpidem (Ambien®)
Triazolam (Halcion®) ness is low with no significant difference from
Aripiprazole (Abilify®) placebo. Risperidone and olanzapine in particu-
Clozapine (Clozaril®) lar have been linked to an elevated risk of cere-
Haloperidol (Haldol®) brovascular adverse events (Mulsant et al. 2005;
Quetiapine (Seroquel®)
Carbamazepine Giron et al. 2001; Olin et al. 2002; Schneider
(Tegretol®) et al. 2006; Wang et al. 2015). These drugs all
Divalproex sodium cause some degree of xerostomia, which can
(Depakote®) increase the rate of caries and periodontal dis-
Lamotrigine (Lamictal®)
Levetiracetam (Keppra®) ease. The use of antipsychotic medications (espe-
cially the first-generation neuroleptics) increases
the risk of development of extrapyramidal symp-
toms that can lead to involuntary jaw movements
Aducanumab (Aduhelm™) and lecanemab making it difficult for the patient to eat, speak,
(Leqembi®) are two new immunotherapies and tolerate a removable prosthesis if needed.
90 M. R. Robbins

 ental Pharmacology Implications

D seizure type, age of onset, and clinical manifesta-
for Patients with Alzheimer’s Disease tions. There is frequent overlap of signs and
symptoms, sometimes making the final diagnosis
Increased potential for adverse drug interactions of the type of epilepsy difficult. Many patients
may occur with the AD patient on multiple have more than one type of seizure and the fea-
medications. tures of each type of seizures may change over
Care should be taken before prescribing time (Robbins 2009).
antimicrobials, analgesics, and anxiolytics. The International League Against Epilepsy
Co-administration of galantamine with macro- developed an international classification of epi-
lide antibiotics or azole antifungals may leptic seizures based on clinical and electroen-
decrease the metabolism of the cholinesterase cephalographic features in 1981, which was
inhibitors leading to both peripheral and central revised in 2017 (Fisher et al. 2017). Seizures are
hypercholinergic effects, such as agitation, divided into focal (previously partial) or gener-
excitation, bradycardia, and loss of conscious- alized depending if one or both hemispheres of
ness (Defilippi and Crismon 2003; Bentué- the brain are involved. Subcategories include
Ferrer et al. 2003). Many of the potential drug motor or non-motor onset (for both) and retained
interactions of concern relate to the psychiatric or impaired awareness for focal seizures.
drugs used to treat the behavioral aspect of AD Antiepileptic drugs (AEDs) are the mainstay of
and are covered earlier in the chapter treatment (Box 4) (Glauser et al. 2016; Schmidt
(Pasqualetti et al. 2015). and Schachter 2014). They work by suppressing
seizure occurrence but do not correct the under-
lying pathologic process that produces the sei-
Seizure Disorders zures in the first place. Therefore, patients with
epilepsy frequently need lifelong treatment.
A seizure is the result of spontaneous excessive There are many available AEDs, some of which
electric discharge of cerebral neurons that results are used as monotherapy and others that are
in alteration in level of consciousness, motor used in combination with other medications.
activity, sensory changes, and behavioral abnor- They are categorized as first, second, and third
malities. Approximately 10% of Americans will generation based on when they were introduced
experience a seizure in their lifetime. An isolated for use, with the majority of the older or first-
seizure can be due to many things including a generation AEDs metabolized by the liver.
high fever, drug or alcohol withdrawal, or a met- These first-generation medications (carbamaze-
abolic imbalance and is not classified as pine, ethosuximide, phenobarbital, phenytoin,
epilepsy. primidone, and valproic acid) are still com-
Epilepsy refers to a group of common neuro- monly used but have a higher rate of undesirable
logic disorders characterized by chronic and dose-dependent side effects, including cognitive
recurrent paroxysmal seizure activity (at least and sedating effects. Carbamazepine, ethosuxi-
two unprovoked episodes of unknown etiology) mide, phenobarbital, phenytoin, and primidone
(Epilepsy Foundation 2018). It is the fourth most are potent inducers (valproic acid is an inhibi-
common neurological disorder in the United tor) of drug metabolizing hepatic enzymes lead-
States. In 2015, the Center for Disease Control ing to clinically important adverse drug
estimated that 1.2% of the total US population interactions. Compared to first-generation
(~3.4 million people) had active epilepsy (Zack AEDs, the newer or second-­generation agents
and Kobau 2017). Incidence is highest among generally have wider therapeutic ranges and
young children (<2 years of age and the elderly fewer serious adverse effects (Löscher et al.
(>70 years of age). There are over 30 different 2013; Zhuo et al. 2017). Since fewer of these
types of seizures and over 60 different types of AEDs are metabolized by the liver, protein
epilepsy. Each is defined by such factors as cause, binding and drug interactions are not as prob-
Pharmacology of Psychiatric and Neurologic Drugs 91

 ental Pharmacology Implications

D
Box 4 Antiepileptic (AED) Drugs (Epilepsy for Patients Taking AEDs
Foundation 2018; Zack and Kobau 2017)
Narrow-spectrum AEDs (focal seizures) Anticonvulsants may increase hepatic micro-
somal enzyme activity, which can reduce the
• Carbamazepine (Tegretol®) blood concentration of other drugs metabolized
• Felbamate (Felbatol®) by the same enzyme system. Carbamazepine,
• Gabapentin (Neurontin®) phenytoin, primidone, and phenobarbital are par-
• Lacosamide (Vimpat®) ticularly strong hepatic enzyme inducers leading
• Oxcarbazepine (Trileptal®) to reduced serum concentrations of the co-­
• Phenobarbital (Luminal®) administered drug and reduced pharmacological
• Phenytoin (Dilantin®) effect. Affected drugs of clinical importance in
• Pregabalin (Lyrica®) dentistry include antibiotics (doxycycline, metro-
• Primidone (Mysoline®) nidazole), benzodiazepines (alprazolam, cloba-
• Tiagabine (Gabitril®) zam, clonazepam, diazepam, and midazolam),
• Vigabatrin (Sabril®) and steroids (dexamethasone and prednisone)
(Patsalos and Perucca 2003). Clarithromycin,
Broad-spectrum AEDs (focal and gen- erythromycin fluconazole, ketoconazole, and
eralized seizures) metronidazole all inhibit the metabolism of car-
bamazepine, leading to potentially toxic level
• Clonazepam (Klonopin®) (Perucca 2006). Miconazole and fluconazole can
• Divalproex (Depakote®) substantially increase plasma concentrations of
• Ethosuximide (Zarontin®) phenytoin. Valproate (divalproex and valproic
• Lamotrigine (Lamictal®) acid) can cause thrombocytopenia, abnormal
• Levetiracetam (Keppra®) platelet function, and changes in coagulation fac-
• Rufinamide (Bonze®) tor levels, leading to an increased risk of bleeding
• Topiramate (Topamax®) (Vasudev et al. 2010; Abdallah 2014). NSAIDs
• Valproic acid (Depakene®) and aspirin should be avoided in patients taking
• Zonisamide (Zonegran®) these drugs.

lematic as some of the older medications (Chen Conclusion

et al. 2018).
The second-generation agents are also pre- Neurologic and psychiatric illnesses are esti-
scribed “off-label” for non-seizure disorders, mated to affect as many as 1.5 billion people
such as chronic neuropathic pain (including worldwide. This number is expected to increase
migraine), fibromyalgia, and trigeminal neu- as the population ages—a number that is expected
ralgia. When used to treat pain, these agents to grow as life expectancy increases (Gooch et al.
may be referred to “analgesics.” Their actions 2017). Treatment of these chronic conditions
and use are significantly different from opiates involves long-term use of multiple pharmaco-
or nonsteroidal anti-inflammatory drugs. logic agents, raising the concern of side effects
Carbamazepine, gabapentin, lamotrigine, topi- and possible drug interactions with medications
ramate, and valproate are used as mood stabi- used during the delivery of dental care. With the
lizers in the treatment of bipolar disorder continued introduction of new therapeutic classes
(Melvin et al. 2008). Anticonvulsants have of drugs for these conditions, the potential for
been evaluated in some disorders of impulse adverse drug interactions will continue to grow.
control, such as impulsive aggressiveness Appropriate preoperative assessment of dental
(Brodie et al. 2016). patients should always include obtaining a
92 M. R. Robbins

through medical history that includes a current Brodie MJ, Besag F, Ettinger AB, Mula M, Gobbi G,
Comai S, Aldenkamp AP, Steinhoff BJ. Epilepsy, anti-
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 Endocrine Drugs of Significance
in Dentistry

Arthur H. Jeske

Adrenocorticosteroids strated effectiveness for the reduction of swelling

and trismus, although outcomes for pain reduc-
In dentistry, corticosteroids with anti-­tion are equivocal (Arora et al. 2018; Taylor et al.
inflammatory activity are used in a variety of 2018). Administration of the corticosteroid
inflammatory conditions (e.g., pulpitis) and to achieves greater effectiveness when the paren-
control postoperative morbidity (e.g., oral sur- teral, rather than other, route is utilized and by
gery). Among the most frequently used and stud- administration of the corticosteroid prior to the
ied agents are dexamethasone (e.g., Decadron®), surgical procedure (Al-Dajani 2017; Herrera-­
methylprednisolone, and prednisolone. Briones et al. 2013), and preoperative administra-
In endodontics, evidence from several recent tion is likely more successful because of the
systematic reviews suggests that steroids appear relatively slow onset of action of these agents,
to be effective in cases of irreversible pulpitis associated with their principal action in altering
(Aminoshariae et al. 2016) and, depending on the gene transcription. With regard to dose of syn-
type and dose of agent, can be effective for man- thetic corticosteroids, a recent prospective
agement of postoperative pain of endodontic ­ randomized clinical study demonstrated that
­origin (Shamszadeh et al. 2018). Among beta- there was no difference between 4-mg and 8-mg
methasone, dexamethasone, prednisolone, and doses of dexamethasone in suppression of post-
methylprednisolone, prednisolone appeared to operative edema following third-molar surgery,
produce significantly greater pain reduction at
6 h, possibly associated with its more rapid diffu- Table 1 Summary of anti-inflammatory corticosteroids
sion into cells, where nuclear DNA transcription Anti-­
is affected by these agents (Shamszadeh et al. inflammatory Equivalent
2018). Anti-inflammatory corticosteroids avail- Agent activitya dose (mg)b
able in the United States and their dosages are Hydrocortisone 1 20
summarized in Table 1. Cortisone 0.8 25
Prednisone 4 5
The perioperative use of corticosteroids in
Prednisolone 5 5
oral surgery is well documented, with demon- Methylprednisolone 5 4
Betamethasone 25–40 0.6
A. H. Jeske (*) Dexamethasone 30 0.75
UTHealth School of Dentistry, Houston, TX, USA Relative to hydrocortisone
a

e-mail: [email protected] Dose equivalent to hydrocortisone

b

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 95

A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_8
96 A. H. Jeske

although the same study was unable to detect a Symptoms associated with acute adrenal insuffi-
significant analgesic action of the drug (Arora ciency may occur during stressful dental proce-
et al. 2018). dures, and while rare, they can be life-threatening.
Currently, the American Association of This condition is classified as primary adrenal
Oral and Maxillofacial Surgeons recommends insufficiency (e.g., destruction or atrophy of the
consideration of the use of a perioperative cor- adrenal gland), secondary adrenal insufficiency
ticosteroid (dexamethasone) to limit swelling (e.g., pituitary disorders), Cushing syndrome
and decrease postoperative discomfort after (e.g., long-term corticosteroid use as anti-­
third-­molar extractions as part of its white rejection therapy in organ transplantation), and
paper recommendations on opioid prescribing adrenal crisis. Adrenal crisis is of great concern
and acute and postoperative pain management when managing patients undergoing stressful or
(Arora et al. 2018), without specification of prolonged procedures, such as quadrant surger-
dosage. ies. Clinically, adrenal crisis is due to inadequate
secretion of endogenous corticosteroids during
stress and involves several organ systems, includ-
 anagement of Patient At-Risk
M ing the GI tract (cramping, nausea, vomiting),
of Acute Adrenal Insufficiency with hypotension, weakness, fatigue, headache,
cyanosis, dehydration, and muscle and joint pain.
Prolonged medical therapy with corticosteroids The underlying biochemical changes include
is a common intervention for a wide variety of hyponatremia, eosinophilia, hypoglycemia, and
diseases and conditions, including autoimmune azotemia. Therapy must be immediate and
diseases (e.g., lupus erythematosus, allergic reac- aggressive and usually involves administration of
tions), eye and gastrointestinal diseases, muscu- fluids and electrolytes and infusion of high doses
loskeletal conditions, neurologic disorders, organ of hydrocortisone (Miller et al. 2001). Risk fac-
transplantation, and, of course, replacement of tors for the development of adrenal crisis include
corticosteroids associated with adrenal cortical adrenal insufficiency, pain, infection, invasive
disorders, such as autoimmune Addison’s dis- procedure, general anesthesia, and poor health
ease. Natural adrenocorticosteroids are classified status at the time of the procedure. Fortunately,
as glucocorticoids (with effects on intermediary this condition occurs only rarely, with an esti-
metabolism and immunity, e.g., cortisol), miner- mated risk of less than 1 case per 650,000 with
alocorticoids (having salt-retentive functions, adrenal insufficiency. This is based on a recent
e.g., aldosterone), and androgenic/estrogenic systematic review that identified six documented
hormones (Katzung and Trevor 2015). case reports over a 66-year period (Khalaf et al.
Glucocorticoids have significant suppressive 2013). More recently, a triple-blind, randomized,
effects on inflammatory processes, by affecting controlled trial has determined that in dental
the numbers, distribution, and functions of leuko- patients undergoing minor surgical procedures
cytes and by reducing cytokines and chemokines. with local anesthesia and taking long-term gluco-
They also inhibit macrophage activity and corticoid for conditions other than primary adre-
antigen-­presenting cells and block phospholipase nal insufficiency, “routine blanket” glucocorticoid
A2 with concomitant reduction of prostaglandin supplementation is unnecessary (Ramasamy and
synthesis (Katzung and Trevor 2015). Madhan 2023). With regard to the adverse effects
It is generally held that corticosteroid therapy that may be associated with the perioperative
lasting longer than 2 weeks can result in adrenal administration of dexamethasone, Polderman
cortical suppression due to negative feedback of et al. recently determined that this corticosteroid
the supplemental hormone on the secretory cells probably does not increase the risk of infection
of the adrenal cortex. It is important to note that following surgical procedures, although the evi-
this suppression is also associated inhalational dence for an effect on wound healing remains
use of corticosteroids for chronic asthma. inconclusive, and mild increases in blood sugar
Endocrine Drugs of Significance in Dentistry 97

Table 2 Corticosteroid supplementation for various a large-scale cohort in the United Kingdom indi-
types of dental procedure risk category in patients with
cate that 16.2% of women aged 12–49 years used
adrenal insufficiency (Miller et al. 2001)
a combination oral contraceptive and an addi-
Corticosteroid supplementation for types of dental
procedures by risk category in patients with adrenal
tional 5.6% used a progestogen-only birth control
insufficiency pill (Cea-Soriano et al. 2014). In the United
Negligible risk States, based on estimates from 2018, prescrip-
Nonsurgical dental procedures tions for estrogens, ethinyl estradiol, and various
Supplementation regimen: none required
contraceptive combination products typically
Mild risk
Minor oral surgery (limited number of simple represent several preparations among the most
extractions, biopsies) widely used drugs.
Supplementation regimen: 25 mg For many years, the relationship between the
Hydrocortisone equivalent use of estrogens and periodontal disease and
Day of procedure
postsurgical complications (e.g., acute alveolar
Moderate-to-major risk
Major oral surgery (multiple extractions, quadrant osteitis) has been known and studied in den-
periodontal surgery, impaction surgery, general tistry. Additionally, the increased risk of preg-
anesthesia, procedures >1 h) nancy in female dental patients taking oral
Supplementation regimen: 50–100 mg
contraceptives caused by antibiotic therapy has
Hydrocortisone equivalent day of procedure and for at
least 1 day postoperatively raised medicolegal concerns in the dental
profession.
Antibiotic/Oral Contraceptive Interaction.
can occur, which can be greater in patients with There are three potential mechanisms by which
diabetes mellitus (Polderman et al. 2018). the effectiveness of oral contraceptives may be
In spite of the low incidence of adrenal crisis reduced by antibiotics (Taylor and Pemberton
in patients with adrenal insufficiency who are 2012):
undergoing dental procedures, recommendations
for perioperative corticosteroid supplementation 1. Diarrhea and vomiting. Both vomiting and
persist, despite findings that routine dental proce- persistent diarrhea result in reduce absorption
dures done under local anesthesia are very of combined oral contraceptives (e.g., proges-
unlikely to precipitate adrenal crisis (Miller et al. togen with ethinyl estradiol) and progestogen-­
2001). Dental outcomes notwithstanding the only formulations. In such cases, it is
incidence of clinically significant adrenal insuf- recommended that if vomiting occurs within
ficiency appear to be significantly higher in surgi- 2 h of taking the medication, another dose
cal intensive care unit populations. In one should be taken immediately, and in the case
prospective study of patients seen for trauma, of diarrhea, additional contraceptive measures
general surgery, urology, and gynecologic oncol- should be used until recover is complete.
ogy over a 9-month period, the overall rate of 2. Enzymatic induction by antibiotics.
adrenal insufficiency was 0.66% (Barquist and Rifamycin-­type antibiotics (e.g., rifampicin,
Kirton 1997). On this basis, recommendations rifabutin) can induce hepatic microsomal oxi-
for supplementation have been based upon strati- dase enzymes, which breakdown ethinyl
fied risks, as presented in Table 2. estradiol, and the resultant decrease in circu-
lating ethinyl estradiol levels reduce its con-
traceptive effect. While this interaction has
 ral Contraceptives, Estrogen/
O been scientifically documented to result in
Progestogens alterations to estrogen pharmacokinetics, no
studies to date have evaluated actual preg-
Oral contraceptive drugs are among the most nancy risks associated with the alteration of
widely prescribed pharmaceutical products blood levels of oral contraceptive (Simmons
throughout the world. Recent estimates based on et al. 2018a).
98 A. H. Jeske

3. Disruption of gastrointestinal flora associ- Oral Contraceptives and Risk of

ated with antibiotics. Ethinyl estradiol also Postoperative Localized Alveolitis. The increased
undergoes enterohepatic cycling necessary risk for localized alveolitis in users of oral contra-
for the activation by gut bacteria of the hor- ceptive drugs has been well documented and
mone prior to its being reabsorbed, although known to be positively associated with the dose of
progestogens do not undergo this recycling. estrogen in the contraceptive. It is also documented
Therefore, concerns have been raised about that the risk for this post-­extraction complication
non-rifamycin-type antibiotics, including can be reduced in users of oral contraceptives if
common dentally prescribed agents such as tooth extraction is performed during the 23rd
penicillins, and their potential to reduce the through 28th day of the pill cycle (Catellani et al.
effectiveness of oral contraceptives contain- 1980). Recently, a meta-analysis has provided
ing ethinyl estradiol. However, a recent sys- more robust statistical estimates of the likelihood
tematic review with 29 included studies of alveolar osteitis in oral contraceptive users
indicated that evidence derived from clinical (Bienek and Filliben 2016). In this review that
and pharmacokinetic studies does not sup- included 29 studies, it was found that among
port the existence of drug interactions females, oral contraceptive use nearly doubled the
between hormonal contraception and non- rate of alveolar osteitis (13.9% among users, 7.5%
rifamycin antibiotics (Simmons et al. 2018b). among nonusers). Additionally, this study demon-
Concurrently, another individual study of the strated a greater risk generally for females than
impact of dicloxacillin on pregnancy risk males, and the vast majority of the studies reviewed
among 364 Danish females taking oral con- determined that smokers had a significantly higher
traceptives and using dicloxacillin prior to risk of the complication. Therefore, the current sci-
conception determined an odds ratio for entific evidence suggests a need for additional vigi-
unintended pregnancy of 1.18 (95% CI 0.84– lance in monitoring patients for the development of
1.65), although the risk was slightly higher localized alveolitis following tooth extraction if
for users of progestogen-­only contraceptives they take oral contraceptives.
(OR 1.83, 95% CI 0.63–5.34) (Pottegard
et al. 2018). Interestingly, virtually all
authors of publications related to this subject Thyroid and Anti-Thyroid Agents
advise caution and the recommendation for
supplementary contraceptive measures for The appropriate dental management of patients
some or all conditions in which females are with thyroid disease rests upon understanding the
exposed to antibiotics while taking oral con- physiological effects of the disease, recognition
traceptive agents (Taylor and Pemberton of the signs and symptoms that represent inade-
2012). quate control of the disease, and safely using
dental therapeutic agents, with an emphasis on
Oral Contraceptives and Periodontal avoiding adverse drug interactions and side
Disease. Oral contraceptive use has for quite effects. Worldwide, the prevalence of overt
some time been associated with gingival hyperthyroidism in countries with sufficient
inflammation (Heasman and Hughes 2014), iodine supplementation ranges from 0.2% to
apparently beginning in the early era of oral 1.3% (Preshaw 2000). In the United States, based
contraception in which estrogen dosages were on the 2002 National Health and Nutrition
relatively high. However, the most recent stud- Examination Survey (NHANES III), over hyper-
ies demonstrate that in the era of “modern” thyroidism occurred in 0.5% of the population,
low-dose oral contraceptive formulations, with 0.7% having subclinical hyperthyroidism,
these drugs do not place patients at an increased and there is a significantly higher incidence in
risk for gingivitis or periodontitis (Preshaw females than males (2.7% vs. 0.23%) (Taylor
2000). et al. 2018).
Endocrine Drugs of Significance in Dentistry 99

There are three major classes of agents used to baseline thyroid-stimulating hormone levels and
manage thyroid disease in outpatients (Table 3) complete blood counts. The type of medication(s)
(Katzung and Trevor 2015). used to treat the disease should also be deter-
The major concerns for the dental manage- mined and potential adverse drug interactions
ment of patients with thyroid disease center on evaluated. Baseline vital signs must be assessed
assessment of the stability of the patient’s dis- prior to undertaking dental treatment.
ease, compliance of the patient with thyroid sup- In a small study of subjects with short-term
plementation (in cases of hypothyroidism), hypothyroidism assessing cardiovascular and
physical assessment of the patient at the time of other responses to epinephrine infusion, hypo-
the dental procedure (e.g., vital signs), recogni- thyroid individuals had a normal response to epi-
tion of the signs and symptoms of hypo- and nephrine, in spite of their initially reduced
hyperthyroidism, and planning for potential baseline pulse rates and metabolic parameter
emergencies that might be expected in patients (e.g., blood glucose levels) (Johnson et al. 1995).
with thyroid disease. One of the major concerns The investigators concluded that under physio-
has been related to the potential interaction logical conditions, there did not appear to be any
between thyroid supplementation and vasocon- synergistic relationship between thyroid status
strictors used in local anesthetics. and catecholamines.
In dental patients, in addition to the patient’s During treatment, vital signs should be regu-
medical history, hypothyroidism is associated larly monitored and appointment duration limited
with hypotension, tachycardia, lethargy, cold to the patient’s tolerance. Local anesthetics with
intolerance, myxedema, reduced respiratory rate, epinephrine are not contraindicated when medi-
and weight gain. Significantly, hypothyroidism cal therapy has resulted in a normal (euthyroid)
may also put the patient an increased risk of sei- state. However, one review article suggests that
zures. Hyperthyroidism is associated with summation of the cardiovascular effects of epi-
fatigue, heat intolerance, tachycardia, palpita- nephrine with those of excessive blood levels of
tions, nervousness, proptosis, tremor, warm skin, thyroid hormone can occur, and the interaction
and weight loss. was rated as category 4 (major or minor, with
The most recent guidelines for the manage- “possible,” not established, documentation)
ment of patients with thyroid disease suggest that (Yagiela 1999). Current drug literature databases
it be done in three phases—pretreatment, intraop- (drugs.com, see Chap. “Biologic Agents”) rate
erative, and posttreatment (Pinto and Glick the interactions as “moderate,” with a need for
2002). Prior to dental treatment, the type of thy- monitoring for signs and symptoms of adverse
roid disease should be determined, as well as the effects. A recent case report suggests that rapid
possible presence of comorbid conditions, such intervention in suspected cases of thyroid storm
as cardiovascular disease. In any case in which can result in uneventful recovery, although medi-
thyroid disease is suspected but untreated, elec- cal assistance should be summoned (Lee et al.
tive dental therapy should be postponed until 2016).
medical evaluation and stabilization have been Following treatment, caution should be exer-
completed. It is recommended that medical con- cised in regard to the increased sensitivity of the
trol of the disease be determined by obtaining hypothyroid patient to central nervous system

Table 3 Major classes of drugs used in the treatment of thyroid disease

Drug class Indication Toxicity(ies)
Thyroid preparations (Levothyroxine, Hypothyroidism Symptoms of thyroid excess (text)
Liothyronine)
Antithyroid preparations (Methimazole, Hyperthyroidism GI distress, rash, agranulocytosis, hepatitis,
Propylthiouracil) hypothyroidism
Beta blockers (Propranolol) Hyperthyroidism Asthma, AV block, hypotension, bradycardia
100 A. H. Jeske

depression, for example, with opioid analgesics. dose of 900 international units) require hospital-
In hyperthyroid patients, precautions should be ization (Johansen and Christensen 2018). In such
taken in regard to the use of NSAID analgesics or cases, the median hospital stay was 94 h (range
aspirin, due to the possible presence of cardiovas- 12–721 h), and treatment could have involved IV
cular disease and the reduced binding of thyroxin or IM glucagon, IV or IM octreotide, surgical
(T4) to T4-binding globulin, resulting in increased excision, IV corticosteroids, and oral administra-
levels of free thyroxin and possible thyrotoxico- tion of complex carbohydrates, in addition to IV
sis (Yagiela 1999). glucose administration. Complications of these
overdoses included intermittent cerebral impair-
ment, hypokalemia and other electrolyte anoma-
Insulin lies, cardiac arrhythmias, and liver function.
Accordingly, the management of patients who
Drugs used in the management of blood glucose experience insulin overdose reactions in the den-
for control of diabetes mellitus are in wide use, tal office must be carefully diagnosed and man-
and patient compliance with insulin regimens is aged aggressively, which may include transport
essential in preventing loss of glycemic control and admission to the hospital.
and (significantly for dentistry) acute excesses
(hyperglycemia) and deficiencies (hypoglyce-
mia) in blood glucose that create emergency Conclusion
­situations. While the management of these emer-
gencies is beyond the scope of this chapter, it is The pharmacological management of dental
important to understand the current scientific patients with endocrine disorders varies with the
basis for use of the hormone insulin and its severity of the disease and the type(s) of medica-
implications. tions and/or hormonal supplements prescribed
Currently, two types of insulin delivery are in by physicians managing the endocrine disease.
general use by patients with diabetes mellitus. In patients with endocrine disorders, a careful
Multiple daily injections have been in use for medical history and consultation with patients’
many years, while continuous subcutaneous physicians are necessary not only to safely
insulin infusion device was introduced more administer and prescribe dental drugs but also to
recently. Typically, these insulin delivery tech- assess the patient’s physical status, ability to tol-
niques are based on self-monitoring of blood glu- erate dental procedures, and anticipate emergen-
cose (e.g., glucometer testing of blood samples) cies that might arise in conjunction with dental
or real-time continuous glucose monitoring. treatment.
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 Pharmacologic Treatment
of Common Oral Mucosal
Inflammatory and Ulcerative
Diseases

Nadarajah Vigneswaran and Susan Muller

 ral Mucosal Inflammatory

O buccal mucosa, and gingiva. The blisters
and Ulcerative Diseases quickly breakdown to form painful shallow
of Infectious Origin ulcers surfaced by a yellow to gray pseudo-
membrane with a red halo. The ulcers gener-
 erpes Simplex Virus Type 1 (HSV1)
H ally heal within 2 weeks without scarring.
Infections Other clinical findings may include lymphade-
nopathy, headache, coated tongue and mal-
Description odor, loss of appetite, and hypersalivation.
Primary herpetic gingivostomatitis usually arises in • Differential diagnoses of primary HSV
children and young adults. Primary infection may include herpetiform recurrent aphthous ulcer-
be mild or asymptomatic; however, clinical fea- ations, necrotizing ulcerative gingivitis, infec-
tures can present in up to 30% of patients (Arduino tious mononucleosis, erythema multiforme
and Porter 2006). Infection is almost always asso- minor, Coxsackie virus, and Varicella Zoster
ciated with HSV-1 although primary orofacial Virus infection (Table 1).
HSV-2 infection has been reported in some older
patients due to sexual practices. Recurrent HSV Infection
• Reactivation of the latent HSV can be trig-
Clinical Features gered by many causes or may be spontaneous.
Reported trigger factors include fever, invasive
Primary HSV Infection dental procedures, UV light, emotional stress,
• There is a wide range of signs and symptoms fatigue, immunosuppression, and trauma.
including myalgia or malaise followed in • Recurrent HSV in immunocompetent individu-
1–3 days by mucocutaneous vesicular erup- als typically occurs on the lips and keratinized
tions of the lips, tongue, hard and soft palates, oral mucosa such as hard palate and attached
gingiva. The lesions begin as red macules that
form vesicles, which are highly infectious. The
N. Vigneswaran (*) vesicles break forming scabs or ulcers. In the
Department of Diagnostic and Biomedical Sciences
University of Texas School of Dentistry, Houston, oral cavity, due to masticatory forces, vesicles
TX, USA may not be seen. In addition, rather than a sin-
e-mail: [email protected] gle ulcer, small crops of s­hallow ulcers can
S. Muller occur, chiefly on the palate. The ulcers gener-
Atlanta Oral Pathology, DeKalb Medical, ally heal within 2 weeks.
Decatur, GA, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 103
A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_9
104 N. Vigneswaran and S. Muller

Table 1 Differential diagnoses for oral inflammatory and ulcerative diseases based on clinical presentation and
etiology
Etiology
Type Infectious Immunologic Other
Primary acute Primary herpetic Erythema multiforme Traumatic ulcers
gingivostomatitis
Primary chronic Mucositis: Candidiasis None Oral squamous cell carcinoma
Ulcers: Cytomegalovirus- Necrotizing sialometaplasia
induced oral ulcers Traumatic ulcerative granuloma
Deep fungal infections: with stromal eosinophilia
Oral histoplasmosis and (TUGSE)
blastomycosis Ulcerations with sequestration
Recurrent acute Recurrent oral herpes Recurrent aphthous stomatitis None
simplex and herpes zoster Herpes-associated erythema
virus infections multiforme
Recurrent chronic Chronic herpes simplex Lichen planus None
virus infection Mucous membrane pemphigoid
Pemphigus vulgaris
Paraneoplastic pemphigus/
paraneoplastic autoimmune
multi-organ syndrome (PNP/
PAMS)
Drug-mediated oral reactions

Chronic (Recrudescent) Herpetic Ulcers • Detection of viral DNA of HSV by poly-

• It is associated with immunosuppression, merase chain reaction (PCR) is more sensitive
including solid organ and bone marrow trans- than tissue culture and is not contingent upon
plants, AIDS, and long-term immunosup- the presence of viable virus.
pressive drug therapy. Unlike recurrent • Serological testing of HSV is not always accu-
HSV1 intraoral lesions in immunocompetent rate and may give both false negatives and
individuals, chronic HSV lesions can present false positives, particularly in type-specific
on both keratinized and nonkeratinized antibody tests for HSV-1 and HSV-2.
mucosa and hence may be difficult to distin-
guish from other oral mucosal disorders Therapeutic Guidelines
including recurrent aphthous ulcers. The • Primary HSV1 infection is a self-limiting con-
lesions can last for prolonged periods of time dition in an immunocompetent individual and
and may appear as crateriform ulcers or can needs only symptomatic treatment. It is impor-
exhibit a distinct linear ulceration. The ulcers tant to ensure adequate hydration and nutrition
may be red or have a pseudomembranous (Arduino and Porter 2006). Other topical ther-
cover. apies include ice, lip balms, and over-the-
counter topical anesthetic preparations.
Diagnosis • In immunocompetent individuals, therapy
• Usually, diagnosis of primary and recurrent may be of limited benefit for primary HSV1
HSV infection is based on clinical history and infection. Systemic antiviral therapy has
patient presentation. When the presentation is proven beneficial if the drug is started within
atypical (i.e., chronic herpetic ulcers), confir- 48 h of onset (Magel et al. 2013, Radulescu
matory laboratory testing is required. 2016) (Table 2).
• A Papanicolaou (Pap) test or Tzanck test can • Prophylactic antiviral therapy in immunosup-
show virally altered epithelial cells obtained pressive patients at high risk for chronic HSV
from the lesion. However, false negatives can is usually administered (Table 2). Sunscreen,
occur as the test reportedly detects <60% of especially to the lips, may help in preventing
infections. recurrent HSV infection.
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 105

Table 2 Commonly prescribed pharmacologic therapy for primary and recurrent oral HSV infection
Disease status Acylovir Valacyclovir Famciclovir
Immunocompetent patient
Primary HSV infection 200 mg 5× day for 10 days 1000 mg BID for 10 days 250 mg TID for 10 days
Recurrent HSV infection 200 mg 5× day for 5 days 500 mg BID for 3 days 125 mg BID for 5 days
HSV-prophylaxis/suppressiona 400 mg BID 500 mg QD 250 mg BID
Immunocompromised patient
Primary HSV infection 400 mg 5× day for 10 days N/A N/A
Recurrent HSV infection 400 mg TID for 7–10 days 500 mg BID for 7 days 500 mg BID for 7 days
HSV-prophylaxis/suppressiona 400 mg BID 500 mg BID 500 mg BID
a
Off-label use for suppressive anti-viral therapy for recurrent erythema multiforme. Note: use all systemic HSV medica-
tions with caution when prescribing to patients with impaired renal function and hepatic disease. For use in pre-­
pubescent children use acyclovir

• Both topical (acyclovir 5% ointment and pen- Pseudomembranous Candidiasis

ciclovir 1% cream) and systemic antiviral • It is the most readily recognized form of oral
therapies (acyclovir, famciclovir, and valacy- candidiasis that presents with white/yellow
clovir) are approved for treating primary and curd-like adherent plaques that can be
recurrent oral HSV infections (Table 2). removed with scraping. The underlying
mucosa is erythematous. This form of candi-
diasis can occur anywhere in the oral cavity
 ral Candidiasis and Associated Oral
O although tongue, buccal vestibule, and oro-
Lesions pharynx are typically infected. Patients may
complain of an altered taste and may have
Description mild pain.
Oral candidiasis, a fungal infection, is the most • Pseudomembranous candidiasis may occur
common opportunistic infection affecting the oral as localized infection in the soft palate in
cavity. Candida albicans (C. albicans) is a com- asthmatic patients using inhaled corticoste-
­
mensal organism and is part of the normal oral flora, roids. Oral candidiasis associated with inhaled
found in at least 35% of healthy, asymptomatic corticosteroid use is seen more commonly in
mouths. The organism becomes a pathogen when patients using high potency corticosteroid
the immune system is compromised, or mucosal fluticasone than those treated with low potent
barriers are disrupted causing disease. Local predis- beclomethasone.
posing factors include removable dentures, xerosto-
mia, and local immunosuppression such as topical  trophic (Erythematous) Candidiasis
A
steroid or antibiotic use. Systemic predisposing fac- • It presents as diffuse erythema lacking any of
tors include immunosuppression due to disease the white curd-like pseudomembranes. Acute
including diabetes, HIV infection, B12, or iron defi- erythematous candidiasis results from persis-
ciency anemia and medications such as corticoste- tent pseudomembranous candidiasis.
roids, broad spectrum antibiotics, and chemotherapy. • The palate and dorsal tongue are the most
Most oral infections are caused by C. albicans, but common sites for chronic atrophic candidia-
other species have been isolated including C. tropi- sis. It commonly presents as generalized dif-
calis, C. glabrata, and C. krusei. C. albicans is a fuse erythema with depapillation (atrophic
dimorphic organism and can grow as yeast or in glossitis) of the dorsal surface of the tongue.
hyphal form, which can colonize the superficial lay- Typically, the dorsal tongue appears red and
ers of the oral epithelium. atrophic or bald with loss of the filiform papil-
lae. Affected patients frequently complain of
Clinical Features chronic tongue soreness and burning sensa-
Oral candidiasis has numerous clinical presenta- tion, particularly when eating spicy foods.
tions, and the patient may have more than one • Chronic erythematous candidiasis is the most
presentation at the same time. common type of candidal infection seen in the
106 N. Vigneswaran and S. Muller

elderly and in individuals wearing removable the mucosa of the upper and lower lips over-
complete or partial dentures with acrylic den- lap, creating a constant warm and moist envi-
ture base, commonly known as denture ronment promoting infection.
stomatitis. • Although angular cheilitis can occur alone, it
is often seen with intraoral candidiasis, usu-
Denture Stomatitis ally the atrophic form including denture sto-
• It presents as diffuse erythema under a full or matitis. Patients complain of discomfort
partial acrylic denture and is caused by poor particularly when opening the mouth.
denture hygiene and is most commonly seen Circumoral type of erythematous candidiasis,
in 24-h denture wearers. The maxillary alveo- involving entire upper and lower lips and peri-
lus and hard palate are the most commonly oral skin, is seen in patients who habitually
affected sites. Denture stomatitis can be lick their lips or frequently use petroleum-
­mistaken for a contact allergy as the erythema based lip balms for dry lips.
corresponds to the denture margins. Chronic
irritation from poor fitting dentures and failure  hronic Hyperplastic Candidiasis
C
to remove the dentures while sleeping are the • Presents as isolated thick white plaques that
main causes for the development of chronic do not wipe off. Clinically, it can be confused
candidal infection. with oral leukoplakia. It frequently occurs in
• Candidal adherence to the acrylic denture individuals without any local or systemic pre-
bases occurs directly to the poorly fitting den- disposing factors, involving the retrocommis-
tures with roughened surfaces, and preexisting sural area or lateral surface of the tongue.
bacterial plaque leads to the formation of can- • Hyperplastic candidiasis mimicking leukopla-
didal biofilm. Formation of the candidal bio- kia would resolve completely after a course of
films in denture bases promotes transition from antifungal treatment. In contrast, conventional
blastospores to hyphae, increasing their viru- leukoplakia with dysplasia (premalignant
lence and infectivity. Hence, poorly fitting lesion), which frequently have secondary can-
dentures acting as reservoirs for candidal didal infection/colonization, will not resolve
organisms contribute to recurrence of this form with a course of antifungal treatment.
of candidiasis in long-term denture wearers.
Diagnosis
 edian Rhomboid Glossitis
M • Most forms of oral candidiasis can be diag-
• It presents as a central area of erythema along nosed based on clinical findings, along with
the midline dorsal tongue with atrophic papil- detailed medical and dental history. If the
lae. Steroid inhalers, smoking, and poor oral patients have had a recent history of antibiotic
hygiene are predisposing factors. Occasionally, or steroid use, or if the presentation is an area
a similar lesion can be observed on the palate of bright erythema underneath a denture, the
where the affected tongue comes in contact. diagnosis is often straightforward.
• Median rhomboid glossitis may be asymp- • Chronic hyperplastic candidiasis can mimic
tomatic, or patients may complain of altered oral leukoplakia and may require biopsy to con-
taste or discomfort when eating spicy or acidic firm the infectious nature of the clinical find-
foods. ings. Oral exfoliative cytology can confirm the
presence of candidal hyphae and yeast forms.
Angular Cheilitis • Fungal cultures can also be used, but this is
• It presents as erythematous fissured areas at rarely done except in individuals who are
the corners of the mouth and is a mixed fungal resistant to standard therapy. A culture can
and bacterial infection. Predisposing factors identify the exact species of Candida and their
include loss of vertical dimension, whereby drug sensitivity.
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 107

Therapeutic Guidelines helpful, and in some cases, pilocarpine or cev-

• Determining the predisposing factor(s) caus- imeline, which stimulate salivary flow, can be
ing oral candidiasis is the important first step, prescribed.
as even with appropriate antifungal medica- • Patients with oral candidiasis secondary to
tion, recurrent candidiasis can be an ongoing steroid inhalers should be educated on the
problem. importance of rinsing the mouth thoroughly
• Patients with complete and removable partial after inhaler use or using inhalers with spacer
dentures should remove the dentures while devices.
sleeping. Frequent denture disinfection is rec- • Patients need to be reminded to remove their
ommended to prevent the recurrence of den- dentures when using the topical treatment as
ture stomatitis. This can be accomplished by the medication will not reach the affected
soaking the denture overnight in chlorhexi- area. In addition, denture wearers can line the
dine, which has fungal static properties (Silva inside of the denture with either nystatin or
et al. 2012). clotrimazole cream daily as an appropriate
• Alternative methods for disinfecting acrylic antifungal treatment for the denture.
denture bases include soaking the denture in • Topical nystatin, ketoconazole, and clotrima-
sodium hypochlorite (1%) for 10 min or sub- zole creams are also useful for angular cheilitis
jecting the dentures for microwave irradiation (Table 3). If there is a significant inflammatory
(800 W) immersed in water for 6 min (Silva component, topical antifungal-­ corticosteroid
et al. 2012). combination therapy with either clotrimazole-
• Candidiasis in patients with xerostomia may betamethasone cream or nystatin-triamcino-
benefit from a multipronged approach as lone cream can be used as the steroid will
hyposalivation can have many causes. The quickly reduce the inflammation.
most common cause is drug-induced xerosto- • Topical or systemic antifungal therapies are
mia, but radiation to the head and neck and usually the first line of treatment in oropha-
Sjögren Syndrome are also associated with ryngeal candidiasis, which are listed in Table 3
xerostomia. Patients should be encouraged to (Gupta 2013). Nystatin oral suspension or
maintain good oral hygiene, proper hydration, pastilles and clotrimazole troches used as top-
and frequent rinsing to keep the mouth moist. ical therapy is usually effective in resolving
Over-the-counter saliva substitutes may be oral candidiasis. The patient needs to be

Table 3 Commonly prescribed pharmacologic therapy for oropharyngeal candidiasis and angular cheilitis
Disease Nystatin Clotrimazole Fluconazole Posaconazolea
Oropharyngeal Oral suspension; Troches, 10 mg Tablet, 100 mg, Oral suspension;
candidiasis 100,000 units/mL 5× day for 2-weeks, BID on day 1, then 40 mg/mL
1tsp, 4× daily for 2-weeks, NPO 30 minb 100 mg/day for 13 100 mg (2.5 mL) PO
hold for 3 min, expectorate, daysc BID on day 1, then
no food/liquid/rinsing for 100 mg PO QD for 13
30 minb daysb
Angular cheilitis Cream; 100,000 units/g; Clotrimazole and N/A N/A
apply topically 4× day for betamethasone
2 weeks dipropionate;
1%/0.05%
Apply topically 4×
day for 2 weeks
a
Prophylaxis for invasive candidiasis in severely immunocompromised and allogeneic hematopoietic stem cells trans-
plant (aHSCT) patients and treatment for oropharyngeal candidiasis refractory to fluconazole
b
Note: If the patients wear dentures, these must be removed before rinsing
c
Note: Be aware of possible drug interactions with: warfarin, statins, oral hypoglycemic agents; may need a 4 week
course in selected cases
108 N. Vigneswaran and S. Muller

reminded not to rinse, drink, or eat for at least (Vigneswaran and Rodu 2008; Stoopler and
30 min after using the topical antifungal medi- Sollecito 2014; Vigneswaran and Muller 2020).
cations to prevent the drug from being diluted RAS is the most frequent form of recurrent soli-
or washed away. Topical miconazole, a muco- tary oral ulcers affecting approximately 20% of
adhesive tablet sold under the brand name of the general population with a slight female predi-
Oravig, is applied to the maxillary vestibule lection (Vigneswaran and Rodu 2008; Vigneswaran
near the canine fossa once a day. and Muller 2020). Most RAS patients are healthy
• Systemic medications for oral candidiasis young (age range 10–19 years) individuals with-
include fluconazole, ketoconazole, itracon- out any underlying systemic immune deregulation
azole, posaconazole, voriconazole, and echi- (Vigneswaran and Rodu 2008).
nocandins; however, fluconazole is the
first-line systemic treatment (Gupta 2013) Clinical Findings
(Table 3).
• Fluconazole is effective in oropharyngeal can- Recurrent Aphthous Stomatitis (RAS)
didiasis and in patients who have failed topical • RAS is usually preceded by prodromal symp-
antifungal treatment. Fluconazole is used to toms of burning or tingling for up to 48 h
treat candidiasis in patients with immunosup- before lesion onset. The ulcers generally
pression from HIV infection, cancer therapy, occur on nonkeratinized mucosa and appear
solid organ and marrow transplants, and auto- as an ulcer with a white-yellow pseudomem-
immune disease. Fluconazole can also be used branous covering surrounded by an erythem-
as a preventive agent in this population who atous halo.
are susceptible to recurrent infections. It is • RAS is classified into three forms based on
important to be aware of drug interactions size, site, duration, and the tendency to heal
before prescribing fluconazole, including war- with scarring: minor (MiRAS), major
farin, statins, phenytoin, proton pump inhibi- (MaRAS), and herpetiform (HeRAS) types.
tors, and sulfonylureas. Fluconazole should be • Minor RAS (MiRAS) is the most common
used with caution in patients who have type seen in 80% of RAS patients. The MiRAS
impaired liver function. ulcers are usually less than 1 cm in diameter
• Posaconazole is recommended as prophylaxis and heal within 2 weeks.
for invasive candidiasis in severely immuno- • Major RAS (MaRAS) is a rare and more
compromised and allogenic hematopoietic severe form of RAS, presenting as continu-
stem cells transplant (aHSCT) patients. ously recurring ulcers measuring more than
Posaconazole is the treatment of choice for 1 cm in diameter with a healing time exceed-
oropharyngeal candidiasis refractory to fluco- ing 2–3 weeks. These ulcers tend to heal with
nazole (Gupta 2013) (Table 3). scaring and have predilection to lips and pos-
terior portion of the oral cavity (soft palate and
oropharyngeal fauces).
I mmune-Mediated Oral Mucosal • Herpetiform RAS (HeRAS) is the least common
Inflammatory and Ulcerative form of RAS that appear as numerous small
Diseases ulcers (2–3 mm in diameter) that can affect mul-
tiple intraoral sites. HeRAS tends to occur at a
Recurrent Aphthous Stomatitis later age (> 20 years) than other clinical types
with is more common in females than males.
Description
Recurrent aphthous stomatitis (RAS) commonly Behçet’s Syndrome
known as aphthous ulcers or canker sores is a self- • Behcet’s syndrome is a rare systemic vasculi-
limiting, chronic oral mucosal disease that pres- tis characterized by oral and genital ulcers and
ents as solitary single or multiple painful ulcers ocular lesions, including uveitis. Vascular
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 109

manifestations include venous thrombosis in • Other systemic drugs implicated in oral

up to 30% of cases (Escudier et al. 2006). ulcers include a number of nonsteroidal anti-­
• Arthritis or arthralgia is frequently the pre- inflammatory drugs (i.e., naproxen, flurbi-
senting feature most commonly of the knees profen, piroxicam, and rofecoxib), proton
and ankles along with other systemic mani- pump inhibitor esomeprazole (Nexium), and
festations. The cause is unknown but is immunosuppressive drugs (i.e., sirolimus,
believed to be due to an autoimmune process everolimus, methotrexate) (Madinier et al.
triggered by an environmental or infectious 2000).
agent in a genetically predisposed patient.
HLA-B51 on chromosome 6p is the most Diagnosis
strongly associated risk factor for Behçet’s • In most cases, RAS can be diagnosed based on
syndrome. history and clinical presentation (Table 1).
• Patients presenting with constant recurrence of There is no specific laboratory test for diag-
>3 major aphthous ulcer are diagnosed as nosing RAS. However, it is important to dif-
“complex aphthosis,” which is considered to ferentiate oral ulcers due to local factors,
be a “forme fruste” (attenuated m
­ anifestation) infections, autoimmunity/hypersensitivity,
of Behcet’s syndrome (Jorizzo et al. 1985; and malignancy (Table 1). Microscopic fea-
Letsinger et al. 2005). tures of RAS ulcers are nonspecific and may
appear similar to a traumatic ulcer. If the
Periodic Fever Adenitis Pharyngitis ulcers appear atypical, then a biopsy is recom-
Aphthous Ulcer (PFAPA) Syndrome mended to exclude ulcers of infectious origin
• PFAPA is a recurrent fever syndrome charac- or malignancy.
terized by episodes of fever lasting between 3 • HeRAS can clinically be confused with intra-
and 6 days, associated with at least one addi- oral recurrent HSV-1 infection. Unlike HeRAS,
tional clinical finding: aphthous stomatitis, which arises in nonkeratinized mucosa, recur-
cervical adenitis, and pharyngitis (Wang et al. rent HSV-1 ulcers in an immunocompetent
2021). PFAPA regularly recurs every patient occur on keratinized mucosa.
3–8 weeks. The age of onset varies but usually • The diagnosis of Behçet’s syndrome is by
presents in children and adolescents. clinical presentation and exclusion of other
Treatment options for PFAPA include nonste- diagnoses. No specific laboratory tests exist
roidal anti-inflammatory drugs, corticoste- for Behçet’s syndrome. The International
roids, and tonsillectomy (Wang et al. 2021). Study Group guidelines for diagnosing BD
include frequent recurrence of oral aphtho-
Drug-Induced Aphthous-Like Oral Ulcers sis (mandatory criteria), associated with at
• In rare instances, older patients without a his- least two other criteria among a list of geni-
tory of RAS develop aphthous-like ulcers tal, cutaneous, and ocular manifestations
after starting to take a new drug. Anti-angina (i.e., genital ulcers, erythema nodosum,
drug nicorandil is the most frequently cited uveitis).
drug to cause apthous-like ulcerations • No specific test exists for the diagnosis of
(Vigneswaran and Muller 2020). PFAPA which results in delayed diagnosis.
• Nonsteroidal anti-inflammatory drugs such Response to corticosteroid therapy is often
as diclofenac and flurbiprofen have been used to confirm diagnosis. Laboratory testing
reported to cause oral and genital ulcers. can rule out cyclic neutropenia or one of the
The angiotensin-­converting enzyme (ACE) hereditary periodic fever syndromes.
inhibitor captopril and the angiotensin II • Identifying and discontinuing the offending
receptor blocker losartan may also cause medication with resolution of ulcers without
aphthous-like ulcers (Vigneswaran and recurrence is the diagnostic criteria for drug-­
Muller 2020). induced aphthous-like ulcers.
110 N. Vigneswaran and S. Muller

Therapeutic Guidelines reduction in frequency of recurrence, pain, or

• Although there is no permanent cure for RAS, time to healing. Furthermore, many treatment
recurrence of oral ulcers becomes less fre- recommendations are based on individual
quent and may even resolve completely with case studies without adequate controls and
advancing age. thus are of questionable validity.
• Patients should be advised to avoid trauma that • Categories of aphthous ulcer medications
can arise with braces, dental appliances, and include over-the-counter topical pain prepa-
malposed dentition. Patients should be encour- rations, antimicrobial agents, topical and
aged to use a soft-bristled toothbrush and tooth- intralesional glucocorticoids, systemic glu-
paste without the detergent sodium lauryl sulfate cocorticoids, and systemic immunosuppres-
(SLS). Some patients will report an association sive agents (Table 4). In addition, some
with certain foods such as nuts, chocolate, fruits, reports advocate physical manipulation by
and vegetables, as well as ingredients in some surgery or cauterizing agents.
toothpastes, gums, and hard candies. The culprit • Use of antimicrobial oral rinses (i.e., chlorhex-
is different for different patients, and keeping a idine), topical analgesics, topical occlusive
food diary may help to isolate a specific item pastes, and topical corticosteroid remains the
with an outbreak of aphthous ulcers. first line of treatment for minor RAS.
• For drug-induced aphthous-like ulcer, the • Over-the-counter drugs such as Zilactin-B®
offending medication should be discontinued, adhesive gel (contains 10% benzocaine) and
but symptomatic treatment of the ulcer is sim- Orabase-B® paste (contains 20% benzocaine)
ilar to aphthous ulcers. provide protective coatings with topical anes-
• Drug treatment for RAS is generally based on thetics. For symptomatic relief, apply either of
the severity of disease, the impact on the these drugs topically to the ulcers four times
patient’s quality of life, accompanying sys- day until resolution of the ulcers. Topical
temic medical conditions, and potential application of 5% amlexanox (Aphthasol),
adverse side effects of the therapeutic agent. which is an anti-allergic and anti-­inflammatory
In evaluating the treatment efficacy of drug drug reduces pain and accelerates ulcer heal-
therapy for RAS, it is important to realize that ing and is recommended for patients who
aphthous ulcers heal spontaneously and that develop MiRAS infrequently but have a low
the frequency of recurrence, lesion duration, tolerance to pain.
and degree of pain perception vary among • In North America, topical, intralesional, and
patients. This makes it difficult to critically systemic glucocorticoids are the most com-
evaluate treatment regimens that claim a monly prescribed therapy for RAS depend-

Table 4 Commonly prescribed pharmacologic therapy for recurrent aphthous stomatitis (RAS)
Intralesional
corticosteroid Systemic
Disease Topical corticosteroid injection corticosteroid Pentoxifylline
Minor RAS Clobetasol propionate or N/A N/A N/A
fluocinonide 0.05% gel/cream
BID-TID
Major RAS a
Clobetasol propionate 0.05% N/A N/A N/A
< 3 ulcers gel
Less frequent 4–5× day for 2-weeks
Complex a
Dexamethasone oral solution, Triamcinolone a
Prednisolone 1.0 mg/ 400 mg, tid for
aphthosis and 0.05 mg/5 mL acetonide 10 mg/ kg or 0.16 mg/kg 3–6 months for
Major RAS of 4× daily for 10 days; hold for mL (Kenalog-10); dexamethasone oral maintenance to
Behcet’s 3 min, expectorate, no food/ 0.4 mg/cm2 solution with a rapid prevent or reduce
syndrome liquid or rinsing for 30 min taper for 2–3 weeks recurrences
Prescribe chlorhexidine oral rinse or fluconazole for antifungal prophylaxis
a
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 111

ing on the frequency of the recurrence, type, with minimal or no mucosal involvement; (2)
and number of ulcers (Wolverton 2013) EM major: severe form with generalized
(Table 4). cutaneous lesions with mucosal involvement;
• Corticosteroid-sparing therapies for severe and (3) Stevens-Johnson Syndrome (SJS)
major RAS also known as complex aphthosis and toxic epidermal necrolysis (TEN): most
and major RAS associated with Behcet’s syn- severe form; mucosal lesions are similar to
drome include vasoactive agent pentoxifyl- EM major with different types of cutaneous
line, immunosuppressive drugs such as lesions.
thalidomide, azathioprine, cyclophosphamide, • Infectious agents are the most common cause
methotrexate, and cyclosporine A (Table 4). for precipitating EM in children and young
Severe cases of c­ orticosteroid-­refractory cases adults, whereas EM in adults is triggered by
of major RAS can be treated also with the medications and environmental chemicals.
anti-TNF-α drugs such as Infliximab, • Drugs are the most common cause for trigger-
Etanercept, and Adalimumab and anti-­ ing EM major, Stevens-Johnson syndrome,
interleukin 1 drug Anakinra (Liu et al. 2022). and toxic epidermal necrolysis. The common
These drugs should be reserved for use by der- drugs implicated in precipitating EM are anti-
matologists, internists, and rheumatologists convulsants, antibiotics, and nonsteroidal
because of the serious adverse effects associ- anti-inflammatory drugs.
ated with these drugs. • Almost 50% of EM cases are idiopathic,
occurring without any known triggers.
Subclinical HSV infection is considered the
Erythema Multiforme and Related most likely trigger for idiopathic EM. Frequent
Disorders occurrence of EM (> 6 episodes per year) is
linked in most cases to HSV infections, which
Description is known as recurrent herpes-associated EM
Erythema multiforme (EM) is an acute, self-­ (HAEM).
limiting immune-mediated mucocutaneous dis- • The “target” or “iris” lesions are the hallmark
ease presenting with distinct cutaneous targetoid of EM and appear as fixed, symmetrical,
lesions with or without oral, ocular and genital round lesions with concentric rings and cen-
mucosal lesions (Bagan et al. 2005; Lamoreux tral duskiness, especially on the palms. Skin
et al. 2006). EM is considered a cell-mediated lesions present as itchy dull-red, purpuric
type IV hypersensitivity reaction triggered most macules, or urticarial plaque that may prog-
commonly by infection. Recurrent herpes sim- ress to vesicle or bulla. The Nikolsky sign is
plex virus (HSV) infection is the trigger for 90% negative in the affected skin or mucosa. Oral
EM cases (Sokumbi and Wetter 2012; Yuan and mucosal lesions present as painful diffuse ery-
Woo 2015). thema, with or without hemorrhagic ulcers.
• The oral mucosal involvement in Stevens-­
Clinical Findings Johnson syndrome is more severe and more
• Erythema multiforme is more common extensive than that of EM major. Oral ulcers
among younger males, and it is rare in young of EM major commonly present as solitary
children (<3 years) and older adults ulcers closely resembling aphthous ulcers.
(>50 years) (Farthing et al. 2005).
• EM typically presents with an abrupt onset of EM-Related Conditions
cutaneous eruptions and mucosal ulcerations Reactive infectious mucocutaneous eruptions
without any prodromal symptoms. Based on (RIME): It presents as severe erythematous ero-
the increasing severity, EM is subdivided sive and ulcerative lesions involving oral, genital
into three clinical types: (1) EM minor: less and ocular mucosal surfaces with limited or no
severe form, with localized cutaneous lesions cutaneous involvement (Song et al. 2021; Pan
112 N. Vigneswaran and S. Muller

and Hussain 2023). Encountered commonly • Antimicrobial (Chlorhexidine 0.12%) and

among male children and adolescents with a local anesthetic oral rinses are recommended
mean age of 12 years, RIME is triggered by non-­ to reduce the pain and prevent secondary
HSV respiratory viral infection (Pan and Hussain infection of the oral ulcerations.
2023). • Severe cases of erythema multiforme major,
Mycoplasma pneumoniae-induced rash SJS, and TEN require hospitalization in a burn
and mucositis (MIRM): Mycoplasma pneu- unit for managing complications such as
moniae (MP) is a respiratory pathogen implicated impaired oral intake, dehydration, and sec-
in the community acquired pneumonia. ondary infection.
Approximately 25% of the patients afflicted with • There is no consensus on the use of systemic
Mycoplasma pneumoniae present with extrapul- corticosteroid for treating SJS and TEN
monary manifestations, which includes oral ero- patients. Use of systemic corticosteroid in SJS
sive and ulcerative mucositis with or without and TEN patients with widespread skin
cutaneous rashes. MIRM is frequently diagnosed sloughing (>10% of total body surface) is
during winter months among male children and associated with higher fatality rates due to
adolescents. Patients initially experience prodro- increased risk for infection and sepsis.
mal symptoms including fever, malaise, and • If systemic corticosteroid therapy is indicated
cough followed by oral erosive and ulcerative for SJS and TEN patients, it should be started
mucositis (Lofgren and Lenkeit 2021). early in the disease course with 2–2.5 mg/kg/
daily IV methylprednisolone in divided doses
Diagnosis followed by rapid tapering until new blister
• EM is diagnosed on the clinical findings, and formations cease. Corticosteroid-sparing
there is no specific laboratory test for diagnos- treatments for SJS and TEN patients include
ing erythema multiforme. Laboratory testing cyclosporine (5 mg/kg/daily) and
and cultures may be indicated in recurrent IV-immunoglobulins.
cases of EM to identify the microbial patho- • Severity of oral mucosal involvement in EM
gen precipitating the EM. HSV-PCR can be may vary significantly. Patients with severe
performed in the swab obtained from oral oral mucosal ulcerations may need a short
lesions to confirm the diagnosis. course of prednisolone (40–60/day) tapered
• Oral lesions of RIME and MIRM closely over 2–3 weeks. Patients with minor oral
mimic oral lesions of immunologically medi- ulcerations and erosions can be managed with
ated vesiculobullous diseases. Biopsies of a high-potency topical corticosteroid gel (i.e.,
non-ulcerated mucosa for routine histopatho- Clobetasol 0.05%) or topical corticosteroid
logic and direct immunofluorescent studies oral rinse (Dexamethasone oral solution,
are necessary to confirm the diagnosis of ery- 0.5 mg/5 mL). Therapeutic dose and duration
thema multiforme and to rule out any other are similar to the ones used for treating major
immunologically mediated mucocutaneous RAS (see Table 4).
disease (Pan and Hussain 2023). • The standard of care for patients with
HSV-­ a ssociated recurrent EM and idio-
Therapeutic Guidelines pathic recurrent EM is antiviral prophy-
• Erythema multiforme has an uncomplicated laxis with acyclovir (400 mg PO, bid) or
clinical course in most patients, except in Valacyclovir (500 mg PO, bid) or famci-
patients with an immunocompromised status clovir (250 mg PO, BID) for more than
who are at risk for developing secondary bac- 6 months (Table 2).
terial infections of the skin or the mucosa. The • Recurrent EM unresponsive to antiviral
most important step in the treatment of prophylaxis may need treatment with sys-
patients with EM is identifying and eliminat- temic immune modulating drugs such as
ing the causative drug(s) or agent. azathioprine, dapsone, mycophenolate
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 113

mofetil, and cyclosporine. However, the • Oral LP usually develops in adults over the
effectiveness of these drugs in controlling age of 40 with a strong female predilection.
the recurrence of EM has not been validated The following intraoral sites are, in descend-
in well-controlled clinical trials. Moreover, ing order, the most common sites of involve-
these drugs are ­associated with significant ment for LP: gingiva, buccal mucosa, tongue,
side effects and hence should be used lips, and palate.
cautiously. • Oral LP has several clinical types that include
• Treatments for MIRM include systemic reticular, erosive, and ulcerative variants. The
macrolide antibiotics, intravenous immuno- reticular variant is the most common clinical
globulin, and cyclosporin (Chen and Li type of oral LP and presents as lacy white ker-
2022). atotic striae and patches. These lesions exhibit
• Currently, there is no viral prophylactic ther- symmetrical distributions involving bilateral
apy for RIME because it can be triggered by buccal mucosa, lateral and ventral surface of
several types of respiratory viral pathogens, the tongue, and lips. The reticular variant of
which include adenovirus, enterovirus, sea- LP is asymptomatic and usually detected as an
sonal, and COVID coronavirus. incidental finding during a routine oral
examination.
• Erosive LP presents as painful, diffuse ero-
 ral Lichen Planus and Lichenoid
O sive and ulcerative areas of erythema with
Oral Mucositis white striae and patches at the periphery.
Erosive LP frequently affects the gingiva
Description presenting as desquamative gingivitis.
Lichen planus (LP) is a relatively common immu- Chronic irritation or trauma exacerbates
nologically mediated mucocutaneous inflamma- oral lesions of lichen planus, which is
tory and ulcerative disease affecting known as an isomorphic response, or
approximately 1–5% of the adult population Koebner’s phenomenon. Lichen planus
(Gorouhi et al. 2014). Although LP is suspected involving the gingiva (desquamative gingi-
to be an autoimmune disease, the target antigen is vitis) tends to be more active in areas with
unknown (Didona et al. 2022). Autoantibodies fixed prosthesis (i.e., crown, bridges, and
against Dsg-1 and -3, a pathognomonic feature of dental implants) compared to natural teeth.
pemphigus vulgaris, have been reported to be • Only 15–20% of patients with oral lichen pla-
positive in patients with oral lichen planus nus present with lichen planus affecting the
(Didona and Hertl 2022). However, the patho- skin (Didona et al. 2022). On the other hand,
genic role of these autoantibodies in oral lichen 60% of patients with cutaneous lichen planus
planus is not known. LP affects skin, nails, hair, will have oral mucosal involvement. Genital
and mucosal surface lined by stratified squamous mucosal involvement in seen in 25–30% of
epithelium but does not involve the internal patients with oral lichen planus (Didona et al.
organs (Gorouhi et al. 2014). The prevalence of 2022).
oral LP is higher in patients with chronic hepati-
tis C virus (HCV) infections, and hence, oral LP Diagnosis
is considered one of the extrahepatic manifesta- • The clinical differential diagnoses for oral LP
tions of chronic HCV (Nagao et al. 2016). include a lichenoid reaction to medications,
contact hypersensitivity reaction to local aller-
Clinical Findings gens (i.e., cinnamon flavoring) or amalgam,
• Mucosal LP most commonly involves the oral discoid lupus erythematosus, chronic graft-­
cavity (oral LP) and in rare instances may versus-­host disease (cGVHD), and oral poten-
affect the oropharynx, esophagus, and vulvo- tially malignant disorders (Gillenwater et al.
vaginal mucosa. 2013).
114 N. Vigneswaran and S. Muller

• The most common group of drugs implicated nant disorders such as proliferative verrucous
in triggering oral lichenoid drug reactions are leukoplakia can be misdiagnosed clinically
as follows: and microscopically as oral LP (Muller 2017).
–– Antihypertensive and antiarrhythmic Hence, patients with both symptomatic and
agents (i.e., hydrochlorothiazide, beta asymptomatic oral LP should undergo regular
blockers, angiotensin-converting enzyme periodic follow-up and biopsy of any suspi-
inhibitors, Quinidine). cious lesions.
–– Anticonvulsants (i.e., Carbamazepine). • Although no curative treatments are currently
–– Antimalarial agents. available for treating oral LP, topical or sys-
–– Nonsteroidal anti-inflammatory drugs. temic immunomodulating drugs are used to
–– Drugs used in the treatment of arthritis and control symptomatic oral lesions with inflam-
gout (i.e., Sulfadiazine, Allopurinol, mation, atrophy, and erosion and to aid heal-
Penicillamine, Gold). ing of the ulcerated lesions (Gonzalez-Moles
–– Anti-programmed cell death 1 (PD-1) and et al. 2018).
anti-programmed cell death-ligand 1 (PD-­ • If a lichenoid drug reaction is suspected,
L1) immunotherapy. changing the offending medication may
–– Therapeutic monoclonal antibodies used result in the resolution of the lesions.
for treating chronic immune medicated Lichenoid contact hypersensitivity reaction
inflammatory diseases. to amalgam would resolve when the amal-
• A diagnosis of lichen planus is made on the gam restoration is replaced with composite.
basis of the typical clinical appearance and an If cinnamon-­ induced contact lichenoid
incisional biopsy of the representative and hypersensitivity reaction is suspected,
non-ulcerated lesion. An incisional biopsy for patients should be advised to discontinue the
routine histopathology and direct immunoflu- use of cinnamon flavored oral hygiene prod-
orescence testing is necessary to distinguish ucts, foods, and chewing gums. Elimination
oral LP from oral epithelial dysplasia, lupus of chronic mucosal trauma and dry mouth
erythematosus, and mucous membrane would also help in preventing exacerbation
pemphigoid. of oral LP.
• Clinicopathologic correlation is necessary to • Patients diagnosed with oral LP may need to
distinguish idiopathic oral LP from lichenoid be screened for chronic hepatitis C infection.
mucositis triggered by medications, amalgam, Treatment of chronic hepatitis C infection
local allergens (i.e., cinnamon), chronic using “direct-acting” antiviral medications is
GVHD, and chronic hepatitis C infections. reported to cure the associated oral LP lesions
• Oral potentially malignant disorders with epi- (Scelza et al. 2022).
thelial dysplasia and proliferative verrucous • Corticosteroid remains the first line of therapy
leukoplakias may present with a dense band for oral LP. Localized and less severe oral LP
of lymphocytic infiltrate at the epithelial-­ lesions are best managed by the use of a high-­
connective tissue interface (interface mucosi- potency topical corticosteroid gel or oral solu-
tis) closely mimicking lichen planus resulting tions (Table 5).
in misdiagnosis as lichen planus. • Lichen planus involving the gingiva (desqua-
mative gingivitis) is best managed using a
Therapeutic Guidelines topical high-potency corticosteroid applied
• The treatment of patients with oral LP must be using medication carrier trays. Use of a medi-
individualized based on the severity of symp- cation carrier tray to apply corticosteroid topi-
toms, extent of the oral lesions, and response cally to the affected gingiva not only improves
to treatment (Table 5). Patients presenting the local absorption of the medication but also
with asymptomatic oral LP do not need any prevents the drug dissolving in the saliva and
drug therapy. Evolving oral potentially malig- being swallowed.
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 115

Table 5 Commonly prescribed pharmacologic therapy for oral lichen planus (OLP)
Intralesional
Topical corticosteroid Systemic
Disease corticosteroid injection corticosteroid Tacrolimus Others
Erosive a
Fluocinonide or N/A N/A b
Tacrolimus N/A
OLP-mild Clobetasol ointment; 0.1%,
and localized propionate gel 3–4 times/day for
0.05%; 3–4 times/ 2–3 weeks
day for 3–4 weeks
c
Gingivitis-­ aClobetasol N/A N/A b
Tacrolimus b
Doxycycline 100 mg,
associated propionate gel ointment; 0.1%, QD for 2–6 months
OLP 0.05%; 2–3 times/ 2–3 times/day for
day using 2 weeks using
medication carrier medication carrier
tray for 2–3 weeks tray
Erosive a
Dexamethasone oral N/A N/A b
Tacrolimus N/A
OLP-­ solution, aqueous oral
moderate and 0.05 mg/5 mL rinse; 1 mg/1 L of
widespread 4× daily for water; rinse for
2–3 weeks swish 2 min and spit; 4×
and spit daily for 3 weeks
Severe N/A Localized: a
Widespread: N/A b
Hydroxychloroquine
erosive Triamcinolone Prednisolone (Plaquenil)
ulcerative acetonide 1.0 mg/kg or 200–400 mg/day for
OLP 40 mg/mL 0.16 mg/kg 1–6 months
(Kenalog-40); dexamethasone
0.1–0.2 mL/ oral solution with
cm2 slow tapering for
3–6 weeks
a
Prescribe chlorhexidine oral rinse or fluconazole for antifungal prophylaxis
b
Off-label use; increased risk of visual field defects, morbilliform rash
c
For managing gingivitis associated with lichen planus doxycycline (anti-collagenolytic effect) is used for the initial
2–6 months of treatment and then topical steroids are used for maintenance. Important: remember that doxycycline may
decrease the effectiveness of birth control pills, so those patients will need supplemental birth control. Also, remember
to warn about possible photosensitivity

• Severe generalized erosive and ulcerative oral • Patients with oral LP who are unresponsive to
LP may need treatment with systemic cortico- corticosteroid therapy or develop severe
steroid therapy, either prednisolone (0. 5 mg/ adverse effects can be treated with other topi-
Kg) or equivalent dose of dexamethasone oral cal and systemic immunomodulating drugs,
solution for 4–6 weeks (Table 5). The dosage such as cyclosporine, tacrolimus, mycopheno-
and duration of the treatment vary depending late, methotrexate, and hydroxychloroquine
on the severity and the extent of the lesions. (Plaquenil) (Table 5).
Intralesional injection of triamcinolone ace- • Various types of biological therapies target-
tonide suspension is the preferred choice of ing the underlying immune-dysregulation
treatment for severe localized ulcerative have been used to treat oral LP refractory to
lesions of oral LP, minimizing the adverse conventional treatments. Apremilast is an oral
effects associated with systemic corticosteroid phosphodiesterase type 4 inhibitor that dimin-
treatment (Table 5). ishes the production of pro-inflammatory
• Prophylactic antifungal treatment should be cytokines TNF-alpha, IFN-gamma, IL-2,
co-administered with topical or systemic cor- IL-5, IL-8, and IL-12 implicated in the patho-
ticosteroid treatment for oral LP to prevent the genesis of LP. Potential therapeutic benefits
development of candidiasis secondary to cor- of apremilast for oral LP were initially
ticosteroid treatment (Table 5). reported in case series and recently a multi-
116 N. Vigneswaran and S. Muller

center retrospective study (Didona et al. (Bickle et al. 2002; Bagan et al. 2005; Xu et al.
2022). Other ­ biologicals used for treating 2013; Sultan et al. 2017; Du et al. 2022). The
refractory oral LP include anti-TNF-alpha true incidence of MMP is unknown, but it is a
(i.e., infliximab, ­ etanercept, adalimumab), rare disease compared to oral lichen planus.
anti-IL17 (i.e., Secukinumab), anti-IL12/13 Other muco-cutaneous immunobullous diseases
(i.e., ustekinumab), and anti-IL-23 (i.e., that may reveal similar clinical and microscopic
guselkumab) drugs (Didona et al. 2022). findings to MMP include bullous pemphigoid
Recent studies have reported the use of small-­ (BP), linear IgA disease, epidermolysis bullosa
molecule inhibitors targeting Janus kinase acquisita and lichen planus pemphigoides.
(JK) pathway (i.e., tofacitinib, baricitinib, Approximately 20% of the patients with bullous
ruxolitinib, upadacitinib) in treating LP pemphigoid have oral lesions. Lichen planus
(Didona et al. 2022). However, only 10% pemphigoides share microscopic features of
patients with oral LP participated in the lichen planus (i.e., lichenoid infiltrate), bound
JK-inhibitor studies. and circulating autoantibodies against BPAg1
• Unfortunately, larger randomized trials to sup- (Hubner et al. 2019).
port the effectiveness of these biologicals are
lacking, and many treatments are recom- Clinical Findings
mended based on anecdotal evidence. Most of • MMP is more common among women with a
these medications are associated with several female to male ratio of 2:1 and frequently
adverse effects including immunosuppression affects the elderly population (age range:
and should be used under close medical super- 60–80 years).
vision. Moreover, biological targeting TNF-­ • MMP may involve all mucosal sites sur-
alpha and small molecular inhibitors of Janus faced by stratified squamous epithelium but
kinase used for treating other autoimmune rarely affects the skin. Oral (90% of cases)
diseases are reported to trigger oral LP (lichen- and ocular mucosa (65% of the cases) are
oid drug reaction). the most commonly affected sites. MMP
• In a number of cases, oral LP may undergo spon- involving the genital, esophageal, nasopha-
taneous remission or may remain inactive for ryngeal, and laryngeal mucosal surfaces are
years with occasional flare-up resulting in symp- less frequent.
tomatic lesions. Flare up of oral LP is associated • MMP patients with lesions limited to oral
with a long list of triggers, the most important mucosa have a better prognosis compared to
being stress and anxiety (Chen et al. 2017). patients with MMP involving other mucosal
surfaces. The disease severity and extent of
the involvement is highly variable from
Mucous Membrane Pemphigoid mild cases with gingival lesions only (low
risk) to severe cases with ocular, genital,
Description and esophageal mucosa (high risk) with
Mucous membrane pemphigoid (MMP), also increased morbidity and poor prognosis (Du
known as cicatricial pemphigoid, is a chronic et al. 2022).
autoimmune disease characterized by develop- • Oral mucosal lesions of MMP initially present
ment of painful vesiculobullous lesions predom- as blisters and bullae, which are short-lived
inantly involving the mucosa. MMP is a humoral and rapidly break into painful ulcers.
autoimmune disorder in which affected patients • The most common oral manifestation of MMP
have autoantibodies directed against specific is desquamative gingivitis, which presents as
adhesion molecules localized within the swollen bright red attached gingiva with
hemidesmosomes of the basal keratinocytes and focally denuded and ulcerated areas extending
in the basal lamina of the basement membrane into the unattached gingival mucosa. More
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 117

than 85% of patients with MMP have gingival 2015).

involvement. In contrast, only 25% of patients • Similar to other immunologically mediated
with oral lichen planus and 18% of patients mucocutaneous diseases affecting the oral
with pemphigus vugaris have gingival mucosa, topical and systemic corticosteroids
involvement. remain the mainstay of MMP therapy. For
• The palate represents the second most com- choosing the appropriate therapy, MMP
mon site affected by MMP and the affected patients are subdivided into “low risk” and
area appears as localized erythema with super- “high risk” based on the severity and the
ficial chronic ulcers covered by necrotic pseu- extent of the disease involvement.
domembrane, which may heal with scars. • Low-risk MMP patients with limited oral
• Scarring of the ocular lesions of MMP may mucosal and gingival involvement are typi-
lead to blindness. cally managed by moderate- to high-potency
topical corticosteroids (Table 6).
Diagnosis • Desquamative gingival lesions associated
• Clinical, histopathologic, and immunopatho- with MMP are managed more effectively
logic studies are necessary for diagnosing with topical corticosteroid gels applied using
MMP and distinguishing from other immune-­ the medication carrier trays. Low-risk MMP
mediated mucocutaneous diseases such as patients with diffuse oral ulcerations who
lichen planus, pemphigus vulgaris, and ery- are not responding adequately for topical
thema multiforme. corticosteroid treatment are treated with a
• An incisional biopsy of the affected and non-­ low dose of systemic corticosteroid therapy
ulcerated mucosa should be taken for routine with antifungal prophylaxis (Table 6).
histopathologic and direct immunofluores- Alternatively, localized oral ulcerative MMP
cence testing. Microscopically, MMP exhibits can be treated with an intralesional injection
a subepithelial split with a chronic inflamma- of triamcinolone acetonide (Kalinska-
tory cell infiltrate with a few neutrophils and Bienias et al. 2016).
eosinophils. • High-risk MMP patients with severe disease
• Direct immunofluorescence studies are posi- are treated with a combination systemic corti-
tive for a linear deposition of IgG, C3, and costeroid and cyclophosphamide.
occasionally IgA along the basement mem- • Corticosteroid-sparing treatments are neces-
brane zone. Indirect immunofluorescence test- sary in low-risk MMP patients to reduce
ing for the detection of circulating corticosteroid-­related adverse effects, espe-
autoantibodies is not indicated for MMP cially in patients with diabetes mellitus.
because the titer of these autoantibodies is low • Treatment with a combination of doxycycline
in MMP patients and does not correlate with and nicotinamide is effective, safe, and well-­
the disease activity. tolerated in low-risk MMP patients with mild
oral disease.
Therapeutic Guidelines • Corticosteroid-sparing agents used in the
• Patients diagnosed with MMP involving the treatment of high-risk MMP patients include
oral mucosa should consult an ophthalmolo- dapsone, azathioprine, mycophenolate
gist to rule out conjunctival involvement. mofetil, rituximab, and intravenous immuno-
MMP patients experiencing soreness, pain, globulin (IVIg).
and ulcerations of genital mucosa or other • There is insufficient evidence to determine
anatomical sites should be referred to the optimal therapies for MMP and the advan-
appropriate specialist for further evaluation, tages of using corticosteroid-sparing therapies
assessment, and/or treatment (Taylor et al. over systemic corticosteroid monotherapy.
118 N. Vigneswaran and S. Muller

Table 6 Commonly prescribed pharmacologic therapy for mucous membrane pemphigoid (MMP)
a
Gingivitis associated Low-risk MMP with mild to moderate High-risk MMP with severe oral ulcerations,
MMP oral ulcerations ocular and other mucosal involvement
b
Clobetasol propionate gel b
Mild disease with widespread: b
Prednisone (0.5–1.5 mg/kg/day with slow
0.05%; 2–3 times/day Dexamethasone oral solution, tapering for
using medication carrier 0.05 mg/5 mL 3–6 months) + cyclophosphamide (1–2 mg/
tray for 2–3 weeks 4× daily for 2–3 weeks swish and spit kg/day for 1 year)
c
Doxycycline 100 mg, QD Localized chronic and painful ulcers: b
Prednisone (0.5–1.5 mg/kg/day with slow
for 2–6 months Triamcinolone acetonide 40 mg/mL tapering for 3–6 months) + azathioprine
(Kenalog-40); 0.1–0.2 mL/cm2; can be (1–2 mg/kg/day for 1 year)
repeated every 4–8 weeks
b
Moderate disease with widespread:
Prednisolone 1.0 mg/kg or
dexamethasone oral solution (0.16 mg/
kg) with slow tapering for 3–6 weeks
Mild disease with widespread: Steroid
sparing Rx:
c
tetracycline (1–2 g/day) + nicotinamide
(2–2.5 g/day) 1–2 months
Moderate disease with widespread:
Steroid sparing Rx
Dapsone, start with 25 mg/day and
increase daily dose by 25 mg every
2 weeks to 75–100 mg/day
a
For managing gingivitis associated with MMP doxycycline (anti-collagenolytic effect) is used for the initial 2–6 months
of treatment and then topical steroids are used for maintenance. Important: remember that doxycycline may decrease
the effectiveness of birth control pills, so those patients will need supplemental birth control. Also, remember to warn
about possible photosensitivity
b
Prescribe chlorhexidine oral rinse or fluconazole for antifungal prophylaxis
c
Off-label use

Pemphigus Vulgaris 2018). PNP is a rare disorder that clinically and

microscopically resembles ­pemphigus, and hence,
Description it is regarded as a “mucocutaneous ­phenotype” of
Pemphigus vulgaris (PV) is an extremely debili- PAMS (Amber et al. 2018). Both humoral and
tating, potentially life-threatening, chronic vesic- cell-mediated autoimmune responses are impli-
ulobullous disease of the skin and mucous cated in the pathogenesis of PNP/PAMS contrast-
membrane (Black et al. 2005; Didona et al. ing the PV, which exclusively mediated by
2019). It is a humorally mediated autoimmune humoral immunity (Amber et al. 2018). Patients
disorder caused by circulating antibodies against with PNP have serum autoantibodies against
desmosomal proteins, desmogleins-1 and -3, members of the plakin family of proteins, namely,
resulting in acantholysis and intraepithelial blis- envoplakin, periplakin, desmoplakin I and II, and,
tering. In rare instances, PV can be induced by less frequently, with BP230, plectin, and epipla-
certain drugs such as penicillamine and kin (Amber et al. 2018).
angiotensin-­converting enzyme inhibitors.
Paraneoplastic pemphigus (PNP), also known Clinical Findings
as paraneoplastic autoimmune multi-organ syn- • PV is a rare vesiculobullous and ulcerative
drome (PNP/PAMS), is a rare life-threatening disorder affecting the oral mucosa with an
autoimmune disease with mucocutaneous and estimated incidence of one to ten people per
multi-organ involvement seen in patients with million worldwide.
lymphoproliferative malignancies (i.e., leukemia • Although PV mainly afflicts adults between
or lymphoma) (Amber et al. 2018; Flood et al. the ages of 40–60 years, it may be seen in chil-
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 119

dren and young adults. PV does not have a involve both upper and lower respiratory
gender predilection. PV is more common tracts, and PAMS patients present with pro-
among persons of Jewish, Mediterranean, and gressive dyspnea due to obstructive lung dis-
Asian descent. ease and bronchiolitis obliterans, which is one
• The oral cavity is the primary and initial site of of the leading causes of death in PNP/PAMS
disease manifestation in the majority of PV patients, next to sepsis secondary to immuno-
patients; skin lesions do not appear until months suppressive treatment. The mortality rate of
or even years later. The bullous lesions of the PNP/PAMS is significantly high (50–90%)
skin remain localized at early stages and become compared to pemphigus vulgaris with a mor-
widespread after 6–12 months if left untreated. tality rate of approximately 5–15% (Amber
PV may also affect anogenital mucosa, naso- et al. 2018; Lim et al. 2021).
pharynx, pharynx, and esophagus.
• Oral lesions of PV develop as vesicles or small Diagnosis
bullae that burst rapidly leaving painful ero- • Clinical, histopathological, direct, and indi-
sions and ulcers. Established PV lesions may rect immunofluorescence examinations are
resemble major aphthous ulcers or large necessary to diagnose PV and distinguish it
superficial ulcers surfaced by a necrotic pseu- from other immune-mediated mucocutaneous
domembrane with erythematous and irregular diseases. Gentle rubbing of perilesional
outlines. mucosa leads to the stripping of the epithelial
• The most common intraoral sites affected by surface known as a positive Nikolsky sign.
PV in descending order are soft palate, hard • Microscopically, PV is characterized by
palate, buccal mucosa, ventral tongue, and floor suprabasilar clefting with intraepithelial acan-
of the mouth. Gingival involvement by PV tholysis resulting in free-floating Tzanck cells.
(desquamative gingivitis associated with PV) is The underlying lamina propria typically
less frequent (15–20%) compared to mucous exhibits mild chronic inflammation with occa-
membrane pemphigoid and lichen planus. sional eosinophils. Direct immunofluores-
• Mucocutaneous manifestations of paraneo- cence (DIF) examination reveals intercellular
plastic pemphigus/paraneoplastic autoim- IgG and C3 positivity, which is considered to
mune multi-organ syndrome (PNP/PAMS) are be the gold standard for diagnosing pemphi-
highly variable and polymorphic. Five distinct gus vulgaris. Indirect immunofluorescence
clinical manifestations of PNP/PAMS are rec- testing is positive for circulating autoantibod-
ognized in the skin, which are (1) pemphigus-­ ies that bind to the intracellular junction of
like lesions, (2) pemphigoid-like lesions, (3) stratified squamous epithelium of normal
lichen planus-like lesions, (5) erythema esophagus. Enzyme-linked immunosorbent
multiforme-­like lesions, and (6) graft versus assay (ELISA) can be used to quantify the
host disease-like lesions. All patients with serum autoantibodies against Dsg-1 and Dsg-3
PNP/PAMS have oral involvement and ­present for confirming the diagnosis and therapeutic
with severe oral vesiculoulcerative ­mucositis monitoring (Schmidt et al. 2010).
affecting the entire oral cavity (pan-stomati- • Immunoblotting studies and indirect immu-
tis), in contrast to pemphigus vulgaris, which nofluorescence testing using rat bladder tran-
preferentially affects the palate, buccal sitional epithelium as substrate are necessary
mucosa, and ventral surface of the tongue. to distinguish PV from PNP/PAMS.
PNP/PAMS presents as hemorrhagic erosive/
ulcerative mucositis resembling a severe case Therapeutic Guidelines
of erythema multiforme. Oral ulcerative • Treatment with high-dose corticosteroid
mucositis is the earliest manifestation of PNP/ alone or in combination with other systemic
PAMS that tends to be treatment resistant. immunosuppressive drugs is the standard of
Systemic manifestations of PAMS frequently care for PV (Harman, Albert et al. 2003;
120 N. Vigneswaran and S. Muller

Ingen-Housz-­Oro et al. 2015). Patients with • PV patients may need to be on a minimum

PV should be under the care of a dermatolo- effective maintenance low-dose corticosteroid
gist with expertise in managing patients with as a long-term management strategy. PV
PV (Didona et al. 2019; Lim et al. 2021). patients undergoing treatment with systemic
Patients diagnosed with PV should be treated corticosteroids and other immunosuppressive
immediately with prednisolone (1 mg per kg drugs are at high risk for developing oral can-
per day) irrespective of extent and severity of didiasis and concurrent treatment with anti-
the disease (Table 7). The initial dose of cor- fungal medication is critical (Table 7).
ticosteroid should be continued for a mini- • Other immunosuppressive and immunomod-
mum period of 2-weeks before attempting to ulating drugs currently used in the treatment
taper the dosage (Didona et al. 2019; Lim of PV with refractory systemic corticoste-
et al. 2021). Rapid tapering of corticosteroid roid include cyclophosphamide, dapsone,
treatment should be avoided to prevent severe methotrexate, intravenous immunoglobulin,
flare-ups. Coordination with the patient’s pri- rituximab, and infliximab (Ingen-Housz-Oro
mary care physician is important to manage et al. 2015; Didona et al. 2019; Lim et al.
corticosteroid-induced adverse effects, espe- 2021).
cially in patients with a history of diabetes • Therapeutic plasma exchange (plasmaphere-
mellitus. sis), immunoadsorption for rapid removal of
• Other immunosuppressive drugs that can be circulating autoantibodies against Dsg-1 and
used in combination with corticosteroids to Dsg-3, and extracorporal photochemotherapy
treat more severe and refractory cases of PV are used as adjuvant therapies for selected
include azathioprine, cyclophosphamide, cases of PV that are refractory conventional
methotrexate, mycophenolate, and rituximab drug treatments (Lim et al. 2021).
(Table 7). This treatment should be continued • Treatment for PNP/PAMS is challenging,
until the cessation of new bulla formation, and especially for oral lesions, which are cortico-
oral mucosa and skin surfaces are negative for steroid treatment resistant. Early detection and
Nikolsky sign. Subsequently, the dosage can treatment of underlying malignancy is critical
be reduced to half and continued until all of for the resolution of the PNP/PAMS and long-
the lesions are resolved. term survival of the patients. Systemic pred-

Table 7 Commonly prescribed pharmacologic therapy for pemphigus vulgaris (PV)

a
Gingivitis-associated Severe PV with cutaneous and oral
Pemphigus vulgaris PV-limited to oral mucosa mucosal involvement
Clobetasol propionate gel 0.05%; 2–3 c
Prednisolone 1.0 mg/kg or c
Prednisone (2.0–2.5 mg/kg/day with
times/day using medication carrier 0.16 mg/kg dexamethasone oral slow tapering for
tray for 2–3 weeks + cchlorhexidine solution with slow tapering for 3–6 months) + mycophenolate mofetil
oral rinse for antifungal prophylaxis 3–6 weeks (500 mg to 2 g/day)
b
Doxycycline 100 mg, QD for Localized chronic and painful Prednisone (2.0–2.5 mg/kg/day with
2–6 months ulcers: slow tapering for
Triamcinolone acetonide 40 mg/mL 3–6 months) + azathioprine (2–3 mg/
(Kenalog-40); 0.1–0.2 mL/cm2; can kg/day for 1 year)
be repeated every 4–8 weeks
Steroid sparing Rx
Mycophenolate mofetil, 500–
1500 mg; 4–8 weeks
a
For managing gingivitis associated with pemphigus vulgaris, doxycycline (anti-collagenolytic effect) is used for the
initial 2–6 months of treatment and then topical steroids are used for maintenance. Important: Remember that doxycy-
cline may decrease the effectiveness of birth control pills, so those patients will need supplemental birth control. Also,
remember to warn about possible photosensitivity
b
Off-label use
c
Prescribe chlorhexidine oral rinse or fluconazole for antifungal prophylaxis
Pharmacologic Treatment of Common Oral Mucosal Inflammatory and Ulcerative Diseases 121

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 Pediatric Considerations in Clinical
Pharmacology

Cristiane S. Fonteles

Introduction Prior to the late 1990s, children were com-

monly excluded from therapeutic trials, and
During childhood, age-related differences labels failed to include information pertaining
between children and adults may increase toxic- specifically to pediatric populations. Until the
ity and reduce pharmacological responses to vari- present day, the pharmacokinetics of many com-
ous drugs of clinical use in dentistry. Specific age monly prescribed drugs in pediatrics are based
groups, including neonates (≤40 weeks post-­ on extrapolations from data obtained from clini-
conception), infants (0–6 months old), infants cal trials in adult populations, and though off-
(6–12 months old), toddlers (1–3 years old), chil- label prescriptions have declined considerably
dren (4–6 years old), children (7–12 years old), compared to earlier years, up until the present, it
and adolescents (13–18 years old) (Abdel-­ remains a reality in the United States, Canada,
Rahman et al. 2012), carry inherent stages of ana- and Europe (Juárez-Hernández and Carleton
tomical, physiological, and biochemical 2022). Inasmuch as there is a paucity of labels
maturation that may account for important varia- containing information that address pediatric
tions in drug kinetics, frequently generating age groups, for years, the FDA has placed effort
drug-exposure differences of clinical significance into bridging this gap by incentivizing and
and, subsequently, enhanced toxicity in compari- requesting pharmaceutical companies to carry
son to adult populations, compromising thera- out dose-­finding studies, as well as to assess
peutics. To minimize the influence of pediatric safety and efficacy of drugs in children, in order
developmental changes over time on treatment to update current labels and improve labeling
outcomes, therapeutic trials must be designed to information for novel medications. The Best
factor in each age category, from neonates to ado- Pharmaceuticals for Children Act (BPCA) and
lescence. This premise has been advocated and the Pediatric Research Equity Act (PREA)
incentivized by the Food and Drug Administration attempt to mitigate these issues and change this
(FDA) for decades. scenario (Malkawi et al. 2022). In spite of
efforts and advances obtained thus far, pediatric
drug development remains a challenge to be
C. S. Fonteles (*) overcome, and the term “therapeutic orphans”
Postgraduate Program in Dentistry, Faculty of first mentioned in 1960s (Shirkey 1968) still loi-
Pharmacy, Dentistry and Nursing, Federal University ters as a reality for the pediatric population in
of Ceara, Fortaleza, Brazil
e-mail: [email protected] many parts of the world.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 123
A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_10
124 C. S. Fonteles

 rug Administration and Pediatric

D avoiding unnecessary multidrug combinations
Compliance (Yin et al. 2021).
Liquid medications and suspensions are the
Historically, medications have been preferably most frequently prescribed formulations for
administered by mouth to children and adults. young children and also the type of dose form
Safety, convenience and reduced cost are some of routinely associated with incorrect or imprecise
the reasons why the oral route is favored by par- administration by parents compared with solid
ents and healthcare professionals. However, com- formulations, such as tablets and capsules that
pliance is an undeniable requirement in the are traditionally dispensed in milligrams (mg)
administration of medications by the oral route, (Smith et al. 2014). Though solid formulations
so in addition to providing safety and stable bio- present the advantages of encompassing greater
availability, formulations must be designed to technological advancements, stability, lower risk
please the pediatric patient in order for pharma- of medication errors, and cost-effectiveness, the
cotherapy to work. Specific formulation and inability of young children to swallow solid for-
prescription-­linked factors may concomitantly mulations validates the preference for liquids
impact compliance, increasing the odds of treat- (Lajoinie et al. 2014). To minimize medication
ment refusal by different pediatric age groups. errors and increase safety and compliance, pre-
For instance, previous work demonstrates that scriptions of liquid formulations require the
size and quantity of solid formulations, dispensed adoption of metric measurements for weight
volume of liquid medications, texture, and the (kilograms, kg) and volume (milliliters, mL).
ability of the formulation to mask bitter taste of Oral or written instructions to parents should
active ingredients and deliver palatability may advise on the choice of adequate dosing tools to
strongly influence the child’s ability to accept be used for the prescribed volume, such as oral
and cope with drug therapy (Venables et al. syringes when small volumes must be dispensed,
2015). Out of all these factors, taste remains by avoiding nonmetric units and unmarked dosing
far the greatest reason for noncompliance to pre- utensils, such as spoons that may not precisely
scribed medications. These factors directly cor- dispense the correct volume (Yin et al. 2021). In
relate with age, and the younger the child, the these instances, it has been suggested that vol-
more challenging oral pharmacotherapy can umes should not surpass a threshold of 5 mL and
become (Venables et al. 2015). 10 mL per administered dose for children under
Other previously reported barriers to pediatric and above 5 years of age, respectively (Committee
medication compliance include prescribed treat- For Medicinal Products For Human Use (CHMP)
ment regimen (dose, frequency, and duration), 2023). Also, meeting children’s taste preferences
side effects, and parental perception of treatment by previous assessment improves his or her toler-
results (Wilson et al. 2021). Informing parents of ance of larger volumes (Venables et al. 2015).
the most frequently expected side effects and Failure to acknowledge these premises not only
requesting feedback of treatment results from lessens treatment adherence but also ultimately
both parents and children should also help guar- compromises treatment outcome and safety.
antee treatment adherence. In light of these find-
ings, the success of pediatric prescribing warrants
professionals to choose a formulation tailored for Pediatric Formulations
each patient, considering the child’s age, devel-
opmental phase, medical history, and illness. The caveat of reduced bioavailability of drugs in
Furthermore, to increase pediatric compliance specific age groups generates the need for age-­
and prevent administration errors by parents, the appropriate formulations and routes of adminis-
dosing schedule should be simplified, by reduc- tration capable of delivering adequate and stable
ing frequency and duration of treatment, by limit- levels of a given medication at the site of action,
ing the number of prescribed medications, and by overcoming differences imposed by physical and
Pediatric Considerations in Clinical Pharmacology 125

physiologic factors such as anthropometric mea- and may affect drug absorption, causing gastroin-
surements, ontogeny of digestive and metabolic testinal symptoms in children, such as diarrhea,
pathways, protein expression and bonds, among nausea, and vomiting (Reker et al. 2019). These
others. Furthermore, these formulations must be symptoms may be easily misconstrued as being a
suited with the right ingredients for specific toxic reaction to a medication’s active ingredient.
routes of administration, also taking into account Thus, it is important to be aware of these vari-
the choice of dosing regimen, safety, stability, ables and possible reactions when prescribing to
and regulatory aspects (Malkawi et al. 2022). children.
The incorporation of excipients with a low Pediatric formulations encompass oral dosage
likelihood of inducing toxicity and allergic reac- forms (e.g., solutions, suspensions and emul-
tions is another difficult challenge for the indus- sions, tablets) and oral transmucosal buccal dos-
try, since not all excipients compounded into age forms (e.g., chewable tablets, gummies,
adult formulations are safe for pediatric use. lozenges, lollipops) (Malkawi et al. 2022). Oral
Excipients or inactive ingredients are compo- forms are most commonly administered as solu-
nents of a drug formulation that are not meant to tions and suspensions because they are easy to
and therefore should not exert active pharmaceu- swallow and often have a more pleasant taste. In
tical effect, nor generate unneeded toxicity these formulations, the active components are
(Reker et al. 2019). Excipients play an important solubilized or suspended in aqueous solutions
role in the manufacture of pharmaceutical formu- containing excipients to mask taste and result in
lations, to assure palatability to children, drug appropriate drug delivery to the gastrointestinal
stability, and solubility while disguising the poor tract (Malkawi et al. 2022). These formulations
taste of the active ingredient(s). However, many face greater physiological challenges to be
of the commonly used inactive ingredients are absorbed, distributed, metabolized, and excreted.
toxic or potentially allergenic to children. Allergic Transmucosal dosage forms are administered
reactions to these inactive ingredients are less through intranasal, buccal, sublingual, and rectal
common than adverse reactions or intolerance. routes. These formulations require absorption
Nonetheless, when present, hypersensitivity across the mucosa and carry the advantage of
reactions are frequently immunoglobulin-E minimizing first pass metabolism in addition to
mediated, causing urticaria, angioedema, bron- avoiding degradation in the gastrointestinal tract.
chospasm, and anaphylaxis in children (Reker One of difficulties faced with the oral transmuco-
et al. 2019). Many inactive ingredients added to sal formulations is the contact time required to
oral formulations are deemed allergenic, and reach absorption, considering that children are
these include food substances like lactose and often unable to keep these formulations in place
starch, polymers like polyethylene glycol and intraorally for the required time, limiting absorp-
povidone, disintegrant-like carboxymethylcellu- tion. Since the oral mucosa is highly vascular-
lose, and dyes such as sunset yellow FCF and ized, drugs administered by means of these
Allura red. The following excipients were identi- formulations rapidly reach detectible levels in
fied as having a greater chance to cause pediatric blood, and peak concentrations can be achieved
toxicity: propylene glycol, ethanol, polysorbate within 10–15 min (Madhav et al. 2009). The rec-
80, benzyl alcohol, parabens, benzalkonium tal route has the added advantages of allowing
chloride, aspartame, sorbitol, benzoic acid, and administration of higher doses, without risk of
sodium benzoate (Rouaz et al. 2021). Lactose, vomiting episodes. This can be particularly help-
gluten, and peanut oil are also examples of sub- ful in the operating room and in-patient settings.
stances that are frequently allergenic or toxic to Transmucosal formulations constitute excellent
children but can be present in drug formulations. noninvasive, alternative routes of administration
Intolerance to excipients is more widely observed for office-based sedation, allowing faster onset
in the population than hypersensitivity reactions and recovery time (Wolfe and Braude 2010).
126 C. S. Fonteles

 rug Absorption, Disposition,

D acids like penicillin G (pKa = 2.73) and ampicil-
and Bioavailability in Pediatric lin (pKa = 2.5, 7.3 at 23 °C) and reduce concen-
Patients trations of itraconazole (pKa = 3.7), a highly
lipophilic weak base (Batchelor and Marriott
During childhood, the right drug provided in a 2015; Lu and Rosenbaum 2014).
less-than-ideal form or dose to the wrong age-­ Fasting versus feeding conditions exert great
group can increase toxicity, ultimately determin- influence on the digestive function of neonates
ing a successful or unsuccessful therapeutic and infants (Kwatra et al. 2020). It was previ-
outcome. Drug absorption and disposition (distri- ously postulated that neonates have a slower
bution, metabolism, and excretion) fluctuate digestive system than adults, with an extended
according to various physiological parameters gastric emptying time of calorie-containing liq-
that are influenced by sex, ethnicity, fed versus uids that matures to adult values by 6–8 months
fasting state, presence of disease, and age of life (Strolin Benedetti and Baltes 2003).
(Johnson et al. 2006). This is especially true dur- However, a comparable gastric emptying time
ing the first month of life, but as a result of growth was observed in children and adults under fed
and development, constant physiological changes conditions, and food type appears to be an impor-
extend throughout infancy and childhood, fre- tant modulator of gastric emptying time (Bonner
quently modifying how various drugs are et al. 2015; Kwatra et al. 2020; Yu et al. 2014).
absorbed, distributed, metabolized, and elimi- Once drugs reach the intestines, pH resembles
nated from the body. Thus, gastric and intestinal adult levels (6.4–7.4) and exhibits less variability
pH, gastric emptying time, gastrointestinal transit than gastric pH (Fallingborg et al. 1990). A meta-­
time, drug distribution, metabolism, and clear- regression analysis found no significant age-­
ance are some of the parameters that strongly related difference in intestinal transit time
influence the speed and efficiency of drug bio- (Maharaj and Edginton 2016).
availability in pediatric patients that will be dis- Food composition and eating habits are addi-
cussed in this section. tionally important in infants and young children,
Gastric acid secretion results from the inter- impacting drug absorption. Breastfed infants
play of neuronal, hormonal, and endocrine path- have fat as the main source of caloric intake,
ways (Prozialeck and Wershil 2017). Gastric pH which as they grow is slowly replaced by carbo-
measurements made soon after birth may provide hydrates (Batchelor 2015). Meals with a high fat
neutral values (pH 6–7) due to the presence of content may enhance solubilization and ulti-
swallowed amniotic fluid inside the stomach mately absorption of lipophilic or poorly water-­
(Avery et al. 1966), but fasting pH declines and soluble drugs, augmenting bioavailability and
remains acidic (< 3) within the following weeks, treatment efficacy (Cheng and Wong 2020).
comparable to those seen in adults, though a wide Absorption of penicillin V has been shown to be
pH fluctuation is described in the literature, likely reduced when administered in an oily liquid
due to the buffering effect caused by frequent preparation (Finkel et al. 1981). Peak plasma
feedings during this time (Ali et al. 2014; concentrations of penicillin and cephalexin were
Chapron et al. 2022). Preterm infants (24–29 ges- reduced by 60% in the presence of milk, as
tational age) have been reported to present acidic opposed to drug administration under fasting
gastric pH, and an inverse correlation between conditions in 2- to 46-month-old infants and chil-
intragastric pH and gestational age was previ- dren (McCracken et al. 1978). High-fat intake
ously observed (Kelly et al. 1993). Most drugs has been demonstrated to increase griseofulvin
are classified as weak acids or bases (Charifson bioavailability (Crounse 1961). On the other
and Walters 2014). Higher gastric pH in new- hand, high-carbohydrate meals were shown to
borns will favor greater concentrations of weak affect acetaminophen absorption, causing a delay
Pediatric Considerations in Clinical Pharmacology 127

in mean peak plasma concentrations (Forrest Bioavailability of different drugs can also be
et al. 1982). influenced by metabolism and efflux transporters
In newborns, human serum albumin closely present in the intestinal lumen. Efflux transport-
matches adult levels (75–80%). Conversely, ers appear to mature early in life. However, intes-
alpha-1-acid glycoprotein is approximately half tinal and hepatic clearance of drugs do not mature
that of the adult concentration at birth (McNamara early and may modify drug clearance. The cyto-
and Alcorn 2002). The reduced plasma concen- chrome P450 (CYP) family of enzymes are key
trations of these proteins, coupled with their lim- players in hepatic and extrahepatic (mainly
ited drug-binding capacity, can increase the within the gut wall) drug metabolism. The rate
unbound fraction of specific drugs, affecting dis- and efficiency of hepatic metabolism of drugs is
tribution (Fernandez et al. 2011). Furthermore, a product of blood flow, protein binding, and
increased bilirubin concentrations in the plasma enzyme activity. In young children, the liver (5%
of neonates and infants will compete for albumin-­ at birth) constitutes a greater percentage of body
binding sites, either increasing plasma concentra- weight compared with adults, contributing
tion of unbound drug or generating bilirubin toward an increased hepatic blood flow during
toxicity (Andersen et al. 1956). this time (Yaffe 1986).
Body composition changes with time and During infancy and childhood, certain meta-
drug distribution in the young relate to total body bolic pathways (CY1A2, CYP2C9, and CYP3A4)
water content. In newborns, 75–85% (higher val- may surpass, be similar to or lower (CYP2C19,
ues in premature infants) of the body weight is CYP2D6, UGTs, or NAT2) than their activity
composed of water, which is significantly greater during adulthood (Anderson and Lynn 2009).
than observed values in children and adults. The Expression of CYP1A2 is markedly low in neo-
water content slowly reduces to approximately nates, approximating 50% of adult expression by
60% by 12 months of age, becoming similar to 9-month age (Johnson et al. 2006). CYP2B6 is
adults (Yaffe 1986). This impacts the extracellu- minimally expressed in neonates and rises to
lar fluid compartment (plasma and interstitial 50% of adult expression by approximately
space) that is mainly composed of water and rep- 15 months of age (Anderson and Lynn 2009).
resents 40% of body weight at birth, but declines The CYP2C subfamily represents approximately
to 27% by age one. The intracellular fluid com- 18% of adult hepatic CYP content and metabo-
partment also suffers fluctuations until 3 months lizes many drugs of importance in the pediatric
of age. Overall, water content will rise and fall to dental clinic, such as ibuprofen, diclofenac, and
adult values from ages 1 to 3 (Yaffe 1986). diazepam. The main expressed isoforms include
Clinically, a water-soluble drug will have greater CYP2C9, CYP2C19, and CYP2C8. Great varia-
volume of distribution per body weight in infants tion was previously observed in the expression of
than adults. In addition, lower plasma concentra- CYP2C9, from the neonatal period up to 5 months
tions of hydrophilic substances can be caused by of age, and adult levels were reached prior to
dose reductions based on weight (Chapron et al. 12 months, while CYP2C19 showed progressive
2022). Body fat content also differs between neo- increase from birth to 5 months and demonstrated
nates/infants and adults. Neonates have less body great variation from 5 months to 10 years of age
fat content, whereas infants have more body fat (Koukouritaki et al. 2004). Age and genotype are
than older children and adults, which favors dis- strong determinants of CYP2D6 expression. This
tribution of lipophilic drugs, such as diazepam. isoform accounts for approximately 2% of adult
The blood-brain barrier is not fully formed, being hepatic CYP content and plays a very important
more permeable than in older children and adults, role in the metabolism of close to 20% of fre-
facilitating permeation of lipophilic drugs. quently used and clinically relevant drugs. In
regard to ethnic differences in enzyme activity,
128 C. S. Fonteles

there are different percentages of poor metaboliz- with potential to significantly reduce clearance
ers among African Americans (up to 19%), secondary to intestinal metabolism by the as-yet
Caucasians (5–10%), and Asians (approximately immature CYP3A4 in infants. In vivo derived
1%) (Stevens et al. 2008). Activity of CYP2D6 ontogeny data from a recent meta-analysis of
increases for the first 2 weeks postnatally and CYPs demonstrated enzymatic activity above
remains stable up until age 12 months, following adult values for CYP1A2, CYP2C9, and
highly polymorphic patterns of expression of CYP3A4, whereas CYP2B6 and CYP2D6 did
poor, intermediate, extensive, or ultrarapid not show remarkable changes (Anderson and
metabolizers (Stevens et al. 2008). Another very Lynn 2009). All other CYPs expressed a 50%
important CYP isoform is CYP3A4, which rep- activity or less by 4-month age (Upreti and
resents the most abundant CYP isoform in the Wahlstrom 2016). Anderson and Lynn (2009)
liver and intestines. Expression of CYP3A4 (Anderson and Lynn 2009) predicted that due to
occurs in the first weeks of life, and based on physiologic variability, drugs metabolized by
in vitro data, CYP3A4 activity reaches 72% of CYP2C19 and CYP2D6 require weight-cor-
adult enzymatic activity by age 1 year (Johnson rected doses that resemble adult dosing. Age-
et al. 2008). Midazolam is an important example related pharmacokinetics are summarized in
of a drug frequently used in dentistry for children Table 1.
Table 1 Age-related pharmacokinetic variations. (Table adapted from Anderson and Lynn (2009), Batchelor and Marriott (2015), Fernandez et al. (2011), Lu and Rosenbaum
(2014))
Physiological parameters Age-related differences Example of affected drugs Observation References
Absorption Gastric pH ↑ at birth, ↓ thereafter Anticonvulsant Phenytoin, ↓F Higher concentration of weak acids, Batchelor and Marriott
Barbiturate Phenobarbital, ↓F and lower concentrations of weak (2015), Lu and
Antiviral Ganciclovir, ↓F bases in infants than in older children Rosenbaum (2014)
and adults
Antifungal Itraconazole, ↓Cmax
Antibiotics Penicillin G, ↑F
Ampicillin, ↑F
Gastric ↑ ≤ 6 months-age Antibiotics Sulfonamides, delayed In all age groups, gastric emptying Bonner et al. (2015),
emptying time absorption becomes slower as volume of food Kwatra et al. (2020),
Barbiturates Phenobarbital, delayed intake increases Lu and Rosenbaum
absorption More affected by meal type than by (2014)
age
Intestinal bile ↓ < 1 month Corticosteroids Hydrocortisone, ↓F Important for drug solubility Batchelor and Marriott
concentration (2015)
Pediatric Considerations in Clinical Pharmacology

Distribution Plasma protein ↓ ≤ 12 months-age NSAIDs Salicylates, ↑ unbound Plasma protein concentrations, Lu and Rosenbaum
binding fraction reduced binding capabilities, other (2014), McNamara
Antibacterial Sulfonamides, ↑ unbound molecules that compete for same and Alcorn (2002)
fraction protein binding sites
Ampicillin, ↑ unbound
fraction
Anticonvulsants Phenytoin, ↑ unbound
fraction
Body ↓ Body fat, ↑ water content Benzodiazepines Diazepam, ↑Vd in infants The Vd will depend on drug’s Batchelor and Marriott
composition <1 month-age; ↑ body fat hydrophilicity or lipophilicity, and (2015)
>3 months of age body composition at time of
administration
(continued)
129
Table 1 (continued)
130

Physiological parameters Age-related differences Example of affected drugs Observation References

Metabolism CYP2C9 ~ Expression ≤5 months-­ Anticoagulant Warfarin, ↑ Anderson and Lynn
age, adult levels CL < 12-years-age (2009), Fernandez
≥12 months-age NSAIDs Celecoxib, ↑ CL et al. (2011),
7–16 years-age Koukouritaki et al.
(2004)
CYP2C19 ↑ Levels ≤5 months-age, ~ Proton-pump Omeprazole, pantoprazole, ↓ Anderson and Lynn
expression inhibitors CL < 1 month-age (2009), Fernandez
5 months–10 years-age et al. (2011),
Koukouritaki et al.
(2004)
CYP2D6 ↑ Activity ≤2 weeks-age, Analgesic Codeine, tramadol <1-month-age: ↓ weight-corrected Fernandez et al.
stable ≤12-months Antihistamine Diphenhydramine doses (2011), Stevens et al.
Anticonvulsants Carbamazepine >1-month-age: Weight-corrected (2008)
Benzodiazepines Midazolam doses approximately same as adults
CYP3A4 ↓ Activity <12 months-age Benzodiazepines Midazolam, ↓ CL preterm Anderson and Lynn
infants, ↑ CL from (2009), Chapron et al.
2–12 years-age compared (2022), Fernandez
with 12–16 years-age et al. (2011)
Local anesthetic Lidocaine, ↑ ½-life in
children compared with
adults
Excretion Renal CL ↓ GRF at birth, 90% of Antihistaminic Cetirizine, excreted mostly Slower maturation of tubular Anderson and Lynn
adult values by 12 months unchanged, ↑ CL secretion than GRF. Post-conceptual (2009), Chapron et al.
of age age must be considered to assess (2022), Lu and
renal function. Greater reduction of Rosenbaum (2014)
renal CL in premature infants
↑ increased values, ↓ decreased values, ~ variable values, CYP cytochrome P450, UGT uridine diphosphate glucuronosyl transferase, (+) increased pediatric dose compared with
adults, (−) decreased pediatric dose compared with adults, same pediatric dose is same as adults, n.a. not applicable or not available, F bioavailability, Vd volume of distribution,
CL clearance
C. S. Fonteles
Pediatric Considerations in Clinical Pharmacology 131

Saliva environment (Gittings et al. 2015). The influence

of salivary parameters in drug dissolution in
Saliva plays a role in absorption of drugs admin- pediatric populations of different age groups war-
istered by oral and transmucosal (buccal and sub- rants investigation. Moreover, unbound portions
lingual) routes. The rate of saliva secretion of certain drugs diffuse from plasma into saliva,
decreases with age, so the younger the patient, making saliva a relevant tool to monitor concen-
the greater the quantity of secreted unstimulated tration of various substances in neonates and
saliva (Lopez-Jornet and Bermejo-Fenoll 1994). infants (Hutchinson et al. 2018).
Salivary secretion increases from birth to 6-month
age and slowly decreases, reaching by 12-month
age values that are similar to flow rates described  requently Prescribed Medications
F
for older children. Most importantly, when secre- for Children in Dentistry
tory values were adjusted for weight, higher
secretory levels are observed (Collares and Antibiotics
Fernandes 2015). The approximate range of
unstimulated whole saliva secretion in children Antibiotics are the most frequently prescribed
6–15 years of age was reported by different drugs in the pediatric dental setting, and odonto-
authors to be within 0.32–1.05 mL/min (Forcella genic infections remain the most common reason
et al. 2018; Gutman and Ben-Aryeh 1974; for prescribing these medications (Goel et al.
Rotteveel et al. 2004), whereas stimulated flow 2020). In dentistry, pediatric prescriptions are
rate is 0.2–3.0 mL/min (Leonor et al. 2009). usually aimed at treatment of acute manifesta-
Adults aged 20–35 years demonstrated mean tions of chronic conditions, such as dental caries
flow rates of 0.58 ± 0.24 (unstimulated) and and periodontal disease, which are also the most
1.51 ± 0.72 mL/min (stimulated) (Gittings et al. frequent cause of pediatric emergency dental vis-
2015), while unstimulated flow rates in adults its (Zou et al. 2018). Other conditions that com-
aged 60–76 years of age were within 0.09– monly require antibiotic prescription for children
0.65 mL/min and presented high variability. include salivary gland infections, intraoral lacer-
Longitudinal data show a certain stability in ations, aggressive periodontitis, prevention of
unstimulated and stimulated salivary flow rates in infection following dental avulsions, and prophy-
children aged 7–12 years and tend to follow con- laxis against bacterial endocarditis (American
stant patterns of low, medium, or high stimulated Academy of Pediatric Dentistry 2022).
secretion throughout childhood (Salvo et al. Particularly, during childhood, pulpal necrosis
2007; Sánchez-Pérez et al. 2016). secondary to caries or dental trauma favors bacte-
Stimulated saliva has a greater secretory vol- rial access into the pulp, furcation, periodontal,
ume, is less viscous, retains greater water content and periradicular tissues. Pediatric anatomic and
and higher pH levels, and has superior buffering immunologic factors may favor the spread of
ability than resting saliva in young adults infection through a path of least resistance with
(Gittings et al. 2015). Once drugs are orally infiltration of tissues and spaces, eventually caus-
administered, salivary glands are stimulated to ing facial cellulitis or abscesses (Lin and Lu
secrete saliva. Salivary pH, viscosity, and buffer- 2006; Okoje et al. 2018; Schnabl et al. 2019).
ing capacity are also variables that may influence Absence of an early and suitable therapeutic
drug dissolution, absorption, and bioavailability approach allows microbial pathogens to further
along with salivary secretory patterns. More vis- migrate and become the source of fascial space
cous saliva reduces drug dissolution. High or low infections. These infections have the potential of
pH also affects drug dissolution depending on its developing into rare, dangerous, rapidly pro-
dissociation constant, among other properties, gressing complications, among which are
and buffering capacity of saliva determines a Ludwig’s angina, cavernous sinus thrombosis,
drug’s ability to resist pH variations in the oral brain abscesses, and sepsis (Lajolo et al. 2019;
132 C. S. Fonteles

Parkins 2018), and the number of children that reduce morbidity, guidelines support antibiotic
develop sepsis from odontogenic etiology prescription when clinical signs and symptoms
increases with caries experience. Previous work indicate the spread of infection into other ana-
has identified a high prevalence of gram-positive tomical sites (American Academy of Pediatric
facultative and anaerobic bacteria (e.g., Dentistry 2022; IAPD 2021). In most cases, anti-
Staphylococcus spp., Streptococcus spp., microbial drug therapy is not recommended as a
Actinomyces naeslundii), gram-negative faculta- substitute for dental management but should be
tive anaerobes (e.g., Haemophilus parainfluen- considered an adjunct to the indicated treatment
zae, Klebsiella pneumoniae), and aerobes (e.g., approach.
Neisseria subflava) associated with odontogenic Since infections that originate within the oral
cellulitis in children (Słotwińska-Pawlaczyk cavity are intrinsically polymicrobial, an
et al. 2023; Unkel et al. 1997). Gram-positive extended- spectrum penicillin, that is, amoxicil-
aerobes were also identified (e.g., diphtheroids) lin with or without clavulanic acid, remains the
(Unkel et al. 1997). first line of treatment in outpatient therapy of
When prescribing, special attention must be odontogenic infections, intraoral lesions, and
given to the child’s immunity, preexisting comor- salivary gland infections, as well as in the preven-
bidities, source of infection, affected anatomical tion of metastatic infections and bacterial endo-
spaces, and signs and symptoms that are consis- carditis. Amoxicillin has a low incidence of
tent with systemic response to infection. Presence associated adverse reactions. A recent systematic
of fever in association with facial swelling is review of common amoxicillin-related side
important initial indicators of systemic involve- effects in pediatric patients with meta-analysis of
ment and warrant careful attention when choos- placebo-controlled clinical trials (Gillies et al.
ing antibiotics, treatment regimen, route of drug 2015) reported diarrhea as a frequent finding in
administration (intravenous versus oral), and children taking amoxicillin-clavulanic acid,
need for hospitalization, especially in young chil- whereas superinfections with candidiasis were
dren that present with these findings and an added common in children taking amoxicillin with or
history of dental pain (Słotwińska-Pawlaczyk without clavulanic acid. The use of amoxicillin
et al. 2023). Other symptoms that commonly fol- and amoxicillin/clavulanic acid did not increase
low and should be taken into account include rashes, nausea, vomiting, or abnormal liver func-
malaise, dysphagia, and other complications, tion tests in this study. Nonetheless, comparison
such as dehydration and breathing difficulties. between amoxicillin monotherapy and
There is no scientific evidence supporting ­amoxicillin/clavulanic acid showed an associa-
antibiotic prescription to treat uncomplicated tion of the latter with higher rates of severe
localized dental abscesses in children without cutaneous hypersensitivity reactions (Stevens-
­
clear evidence of a spreading infection or signs Johnson syndrome), hematological disorders,
and symptoms consistent with systemic involve- and liver toxicity (Salvo et al. 2007). In another
ment (Leroy et al. 2021). Prescription of antibiot- recent work, amoxicillin (with or without clavu-
ics should be avoided when odontogenic lanic acid) accounted for a greater number of
infections remain limited to the pulp and perira- penicillin-­
associated hypersensitivity reactions
dicular tissues. Blood flow within these confined (PHR) compared with other beta-lactam antibiot-
anatomic sites is reduced or absent due to pulp ics (Azevedo et al. 2019). Amoxicillin has also
necrosis or accumulation of fluids (pus), limiting been implicated in tooth discoloration in children
drug bioavailability in these areas, which favor under 8 years of age (Wang et al. 2023). These
the development of bacterial resistance. In these findings suggest that differences in toxicity
instances, removal of the cause of infection (e.g., between amoxicillin and amoxicillin/clavulanic
pulpotomies, pulpectomy, dental extraction, inci- acid must be considered when prescribing.
sion, and drainage) should provide the means to In the event of PHR, cephalosporins and mac-
improve the clinical condition. Nonetheless, to rolides can be prescribed. The prescription of
Pediatric Considerations in Clinical Pharmacology 133

cephalosporins should be avoided in the presence considered safe for use in pediatric populations
of true immunoglobulin E (IgE)-mediated PHR for up to 21 days (American Academy of
(e.g., positive skin test or drug provocation test) Pediatrics (AAP) 2021; Stultz and Eiland 2019).
and in children with a medical history significant Azithromycin and clarithromycin are second-­
for anaphylaxis, severe hypersensitivity, and drug generation macrolides with good safety margins,
reactions, especially in the presence of systemic uncommon reports of allergenicity, and broad
symptoms (Ponvert et al. 2011). However, in case antibacterial spectra that cover most bacteria
of non-IgE-mediated PHR, cephalosporins can implicated in odontogenic and other forms of
be prescribed with a good margin of safety. A oral infection. In addition, immunomodulation
child is at the highest risk of cross-reactivity may be an added benefit of this class of antibiot-
when structural similarities between R1 side ics (Zimmermann et al. 2018). Previous work
chains are the greatest. Based on a recent meta-­ showed a higher frequency of hypersensitivity
analysis performed with calculated similarity reactions to azithromycin compared with clar-
scores between R1 side chains of penicillins, and ithromycin among children suspected of macro-
cephalosporins (Picard et al. 2019), the risk of a lide allergy (Barni et al. 2015). Cross-reactivity
child with PHR to react to at least one cephalo- between azithromycin and clarithromycin has
sporin varies from 16.45% (high score), 5.60% also been described (Mori et al. 2014). The most
(intermediate score), and 2.11% (low score). common adverse events related to azithromycin
First-generation (cefadroxil, cephalexin, and in children are gastrointestinal. Data from pro-
cefatrizine) and second-generation (cefprozil, spective studies show that the risk of diarrhea
cefaclor) amino-cephalosporins carry identical caused by azithromycin is reduced in comparison
R1 side chains with amoxicillin and ampicillin with amoxicillin/clavulanate and greater than
and should be avoided in patients with PHR. Risk penicillin V (Zeng et al. 2020). Azithromycin is a
of cross-reactivity was the lowest with cefazolin proarrhythmic drug that has been shown to exert
(first generation); cefuroxime (second genera- a slight absolute increase in the risk of death by
tion); cefixime, cefotaxime, ceftriaxone, ceftazi- cardiovascular reasons, including sudden cardiac
dime, cefpodoxime, and ceftibuten third (third deaths and death by any causes, during 5-day
generation); and cefepime (fourth generation). treatment in adults, predominantly among
Recent data linking a single dose of clindamy- patients at a higher risk of cardiovascular disease
cin to an increased rate of life-threatening adverse (Ray et al. 2012). In pediatric populations, the
drug reactions, most of which associated with risk of cardiotoxicity by azithromycin relates to
Clostridioides difficile infection (Thornhill et al. an increased risk of polymorphic ventricular
2015), led the American Heart Association tachycardia caused by QTc prolongation (tors-
(AHA) to no longer recommend clindamycin as ades des pointes) and the highest the prescribed
an alternative in the prophylaxis of infective dose (10–30 mg/kg/day), the greater the
endocarditis and to include doxycycline as a safer cardiotoxicity-­related risk. Doses up to 10 mg/kg/
option in the advent of hypersensitivity to peni- day were associated with a lower incidence of
cillin, cephalosporin or macrolides (Wilson et al. cardiotoxicity (Zeng et al. 2020) in children.
2021). First marketed in the late 1960s, doxycy-
cline was for many years labelled as having the
same adverse effects as first-generation tetracy- Pediatric Pain Management
clines in the developing dentition and was there-
fore contraindicated for use in children under the Pain assessment in the pediatric population is
age of 8 years. This paradigm changed with usually a difficult task, considering that most
recent data (Todd et al. 2015; Volovitz et al. children either provide unreliable information
2007). Doxycycline has low calcium affinity, due to young age and have limited communica-
demonstrating reduced risk of dental staining in tion skills or an unwillingness to offer informa-
comparison with other tetracyclines, and is now tion as a result of stress, fear, and anxiety
134 C. S. Fonteles

generated by pain and discomfort. The child’s patients (opioids and non-opioids) should spare
inability to communicate imposes great suffering opioids when possible and favors non-opioids to
and emotional burden on the patient and their reduce unwanted adverse events (American
families. These limitations make pain manage- Academy of Pediatric Dentistry 2022).
ment in pediatric patients challenging, often lead- Four basic premises previously stated by the
ing dentists to prescribe based on parents’ World Health Organization lay the foundation for
interpretation and their own professional under- successful pediatric analgesia (Vargas-Schaffer
standing of the child’s experience/perception of 2010): (1) preferably prescribe oral forms of med-
pain. Furthermore, the failure to recognize pain ications, when possible; (2) use regular intervals
in children leads pain to be frequently misman- when prescribing based on pain intensity and
aged in hospitalized and outpatient settings duration of analgesia provided by the drug of
(Orzalesi 2018). Behavioral assessment by choice; (3) the analgesic regimen should be based
instruments like the Frankl scale during a dental on the level of pain identified by the patient, using
visit can be a helpful tool. Age-appropriate pain pain assessment scales; (4) dosing should be cus-
assessment scales, such as the Wong-Baker tomized for each patient and aimed to provide
FACES, Faces Pain Scale, and visual analogue adequate pain relief by balancing out the dose that
scale (VAS), can enable the child to communi- provides best analgesia at minimal adverse drug
cate their level of pain in emergency and postop- effects; and (5) the patient’s progress should be
erative settings (Garra et al. 2010; Jain et al. monitored in detail and analgesic regimen read-
2012). Assessment of physiological parameters justed as required after the initial 24 h.
such as the child’s heart rate, blood pressure, The choice of dosing regimen for pain control
respiratory and oxygen saturation rates, and in pediatric populations remains to be established
sweating of the hands can also be useful (Jain (Pillai Riddell and Craig 2003). One might argue
et al. 2012). Timely pain assessment is a critical that the “as needed” (PRN) regimen may lead to
step in managing pain in a dental setting and administration of significantly less medication
must be carefully considered before prescribing than scheduled administration (ATC) in the man-
to pediatric patients. agement of postoperative pain, though at the
Management of acute pain has a more favor- expense of greater and sometimes unnecessary
able outcome when a multimodal approach is exposure to analgesics, ATC in postoperative
adopted, encompassing pharmacologic and non-­ pain may assure continuous relief and better pain
pharmacologic concepts (Brown et al. 2019; management (Chiaretti et al. 2013). The use of
Hyland et al. 2021). Therefore, planning antino- ATC alternating regimen of ibuprofen (10 mg/kg)
ciception for children and adolescents in den- and acetaminophen (10 mg/kg) every 2 h, follow-
tistry should follow a similar rationale by ing surgery in children with cerebral palsy, was
anticipating presence/level of pain likely to be compared with a retrospective group of 20 chil-
experienced during and after surgical procedures dren subjected to the same surgical procedure but
and planning pre-, trans-, and postoperative receiving PRN epidural morphine every 3–4 h
approaches to pain control. This concept gains (Tubbs et al. 2007). Their results showed the
further significance when the possibility of need for a single morphine dose in only 1/22
moderate-­to-severe pain is anticipated. The com- patients in the study group, demonstrating an
bination of adequate local anesthesia and pre- opioid-sparing effect, shorter hospitalization
emptive analgesia reduces the need for time, and less requirement for antiemetics.
postoperative pain analgesics and has an opioid-­ Another study showed the lack of efficacy of
sparing effect, shortening treatment regimen, ATC regimens to adequately control pain follow-
which diminishes risk of adverse drug events, ing tonsillectomies (Sutters et al. 2004), and
producing greater analgesia with less analgesics. more recent work showed superior pain control
The arsenal of drugs from which we can choose post-tonsillectomies using ATC compared with a
to manage mild-to-moderate pain in pediatric PRN regimen of acetaminophen/hydrocodone
Pediatric Considerations in Clinical Pharmacology 135

(Sutters et al. 2010). Interestingly, there is not morphine, codeine) showed the lowest safety,
enough evidence in the literature to affirm that with a higher risk of adverse events affecting the
pediatric postoperative pain management would gastrointestinal tract, skin (e.g., itchiness, rash,
be more effective if prescribed analgesics were and pruritus), and central nervous system (e.g.,
administered under ATC versus PRN regimens headache, drowsiness, dizziness). Codeine
(Hobson et al. 2015). Traditionally, the practice monotherapy doubled the risk of dermatologic
of postoperative pain management in hospital symptoms compared with NSAIDs, possibly sec-
settings has given preference to ATC regimens, ondary to drug-induced histamine release.
under the understanding that scheduled, round-­ Ibuprofen/oxycodone, ibuprofen/codeine, and
the-­clock prescriptions prevent pain, and by acetaminophen/codeine combinations demon-
doing so provide comfort and lessen the need for strated a greater margin of safety than opioid
other medications. However, it is the authors monotherapy. The overall risk of adverse events
opinion that PRN schedules in the management caused by acetaminophen and NSAIDs was low
of mild-to-moderate pain may suffice in most compared with opioid monotherapy. Severe side
clinical outpatient cases, particularly when pre- effects are uncommon in the pediatric popula-
emptive analgesia is adopted, potentially reduc- tion, but use should be carefully considered,
ing the amount of consumed analgesics and side especially in cases of hepatic and renal dysfunc-
effects. Further studies are warranted to create tion or coagulation disorders.
specific protocols for children in dentistry. Acetaminophen and ibuprofen are the most
commonly used over-the-counter pain and fever
medications by children under 12 years of age in
Non-opioid Analgesics the United States (Lu and Rosenbaum 2014;
Vernacchio et al. 2009). Acetaminophen
Clinical trials evaluating adverse events caused (N-acetyl-p-aminophenol, APAP, or paracetamol,
by commonly prescribed analgesics in pediatric PARA) is a pro-drug that acts on pain and fever
populations remain scarce, and most of the avail- by various mechanisms not yet fully understood.
able data relate to adult populations. A systematic Upon entrance into the body, acetaminophen is
review of studies conducted in eight different subjected to a complex metabolic pathway that is
countries, published between 1991 and 2014, essential for its pharmacodynamics but also car-
reported on adverse drug events caused by acet- ries a potential for toxicity. Roughly 80% of a
aminophen and nonsteroidal anti-inflammatory therapeutic dose is converted to glucuronide and
drugs, NSAIDs (ibuprofen, naproxen, ketopro- sulfate conjugates. Glucuronide conjugation is
fen, nimesulide, ketorolac), opioids (morphine, deficient in young children and infants (Prescott
codeine, oxycodone, tramadol), and NSAID/opi- 1980). Therefore, children up to 10 years of age
oid combinations (ibuprofen/oxycodone, ibupro- form less glucuronide conjugates but produce
fen/codeine, acetaminophen/codeine) in children larger amounts of sulphate metabolites (Forrest
and adolescents (Hartling et al. 2016). et al. 1982). Deacetylation produces a p-­
Acetaminophen and ibuprofen exhibited compa- aminophenol derivative able to cross the blood-­
rably low rates (<10%) of adverse events affect- brain barrier to be subsequently converted to
ing the gastrointestinal tract (e.g., nausea, AM404 (N-arachidonoyl phenolamine) by conju-
vomiting, diarrhea), whereas children taking gation with arachidonic acid via the fatty acid
naproxen were at a higher risk (>10%) than acet- amide hydrolase (FAAH) (Högestätt et al. 2005).
aminophen and ibuprofen of manifesting nausea For pharmacodynamic purposes, AM404 is a key
and vomiting. Ibuprofen demonstrated a greater metabolite that (1) transitorily activates transient
risk of drowsiness/sleepiness than acetamino- receptor potential vanilloid subtype 1 (TRPV1)
phen. Ketoprofen showed a greater risk of adverse and/or cannabinoid CB1 receptors in the brain
events affecting the skin than ibuprofen and acet- and spinal cord; (2) weakly inhibits cyclooxy-
aminophen. Opioid monotherapy (oxycodone, genase (preferably COX-2 or physiologically-­
136 C. S. Fonteles

dependent isoform preference), explaining its istration. Acetaminophen is highly bioavailable

lack of anti-inflammatory action; (3) and opioid once administered by the oral route (Eandi et al.
and serotonergic pathways (Esh et al. 2021; 1984), but rectal administration is frequently
Ohashi and Kohno 2020). used to attain faster onset of action and has
A small percentage of acetaminophen under- advantages that include ease of administration
goes oxidation catalyzed by P450 enzymes, and low cost compared with parenteral adminis-
mainly CYP2E1, forming the toxic breakdown tration and is a well-tolerated option for children
product N-acetyl-p-benzo-quinone imine unable to take medications by mouth (Thibault
(NAPQI). This metabolite is inactivated by con- et al. 2023). The rectal route produces high inter-
jugation with the sulfhydryl groups of glutathi- individual variations in pharmacokinetics
one to form nontoxic metabolites, cysteine and (Montgomery et al. 1995). Since higher and less
mercapturate, that are excreted in the urine. variable blood concentrations are provided by
Depletion of glutathione stores by either toxic intravenous administration, this can be a safe and
amounts of acetaminophen or systemic condi- effective alternative in hospital settings when
tions that may diminish glutathione stores cause stable and higher drug levels are required (Dela
toxic NAPQI to accumulate and bind cellular Cruz Ubaldo et al. 2014). A risk of transient
proteins, thereby incurring cell injury (Mitchell hypotension during intravenous administration
et al. 1973). Obesity, liver steatosis, malnutrition, can be a concern (Thibault et al. 2023). Absolute
and glutathione synthetase deficiency are among bioavailability (using the intravenous route as a
systemic conditions that may deplete glutathione reference) of acetaminophen following the oral
stores, increasing the risk of hepatotoxicity route of administration is high (60–70%) regard-
induced by accumulation of NAPQI (Hodgman less of the chosen formulation and presence of
and Garrard 2012; Tokatli et al. 2007). gastric contents, whereas the rectal route pro-
N-Acetylcysteine (NAC) is the antidote for duces lower (30–40%) and unpredictable bio-
acetaminophen-­induced hepatotoxicity and acts availability after single-dose administration to
by increasing glutathione supply (Hodgman and healthy adults. Studies evaluating the relative
Garrard 2012). Chances of avoiding severe bioavailability of rectal compared with oral acet-
hepatic damage are greater if NAC is adminis- aminophen formulations for pain control in chil-
tered within the first 8 h of toxicity (Reid and dren are few and inconsistent in their results
Hazell 2003). It is important to note that acet- (Anderson et al. 1996; van der Marel et al. 2001)
aminophen administration of a single dose above and do not provide enough evidence to support
7 g in adults and 150 mg/kg in children, or cumu- equivalence of analgesic efficacy between the
lative repeated doses put the patient at a high risk rectal and oral routes in children. Nonetheless, a
of liver toxicity. For safety reasons, the maximum recent systematic review and metanalysis demon-
therapeutic dosages of 4 g/24 h for adults and strated comparable efficacy of rectal versus oral
50–75 mg/kg/24 h children should be respected acetaminophen in fever control, with no signifi-
(Table 2). Overall, there are no significant differ- cant differences in temperature decline 3 h post
ences in the excretion of acetaminophen between administration, maximum temperature reduction,
children and adults. or average time taken to cause temperature reduc-
Acetaminophen is rapidly and widely tion of 1 °C (Goldstein et al. 2008).
absorbed by the oral route in a dose-dependent Due to the risk involved in opioid use in pedi-
fashion, does not significantly bind plasma pro- atric postoperative pain, many pediatric clinical
teins, and has a plasma half-life of 1.9–2.5 h trials have focused on comparing the analgesic
(Forrest et al. 1982). Choosing the right mode of efficacy of NSAIDs and opioids. The central
administration for children is important to assure effects of acetaminophen coupled with the
the best combination of good pharmacokinetics opioid-­sparing properties of both acetaminophen
and effective pharmacodynamics. The oral and and NSAIDs have justified clinical trials testing
rectal routes are both safe modes of drug admin- the analgesic efficacy of alternating ibuprofen
Table 2 Commonly prescribed dosage forms, dosages and potentially toxic excipients of nonopioid analgesics used to treat or prevent mild-to-moderate, moderate and moderate-­
to-­severe pediatric pain. in dentistry. (Table adapted from (Lee 2018; Jeske 2021; Reker et al. 2019; Rouaz et al. 2021)
Medications Dosage forms Use Dosages Excipients
Acetaminophen Oral capsule, oral tablet: Mild-to-moderate pain Oral/rectal Starch
(Tylenol, Tempra, 325, 500 mg Neonates: 10–15 mg/kg/doses Q6–8h as needed Povidone
Panadol, Ofirmev, Oral granule (effervescent): Children: 10–15 mg/kg/dose Q4–6h as needed. PR loading dose: Butylparaben
among others) 650 mg 40–45 mg/kg dose. Max: 75 mg/kg/24 h not exceeding 4 g/24 h High fructose corn syrup
Oral liquid 160 mg/5 mL, Adults: 325–650 mg Q4–6h or 1 g t.i.d. or q.i.d. max: 4 g/24 h, 5 Carboxymethylcellulose
325 mg/10.15 mL, 500 mg/15 mL, doses/24 h sodium propylene glycol
650 mg/20.3 mL Sodium benzoate
Sucralo
Oral suspension 160 mg/5 mL,
FD&C red no. 40D&C red no.
650 mg/20.3 mL
33
Oral tablet (chewable): Intravenous FD&C blue no. 1
160 mg; 80 mg Infant/children < 2 year: 7.5–15 mg/kg/dose Q6h. Max:60 mg/
Oral tablet (disintegrating): 160, 325, kg/24 h
80 mg Child (2–12 year) and adolescents/adults ≤ 50 kg: 15 mg/kg Q6h
Oral tablet (extended release): OR 12.5 mg/kg Q4hmax single dose: 15 mg/kgmin dosing interval:
650 mg Q4hmax dose: 75 mg/kg/24 h, not to exceed 3750 mg/24 h
Pediatric Considerations in Clinical Pharmacology

Suppositories: 80, 120, 325, 650 mg Adolescents (>12 year) and adults ≥ 50 kg: 1 g Q6h OR 650 mg Q4h Alcohol (injectable solution)
Ketorolac Film-coated tablet: 10 mg Acute, moderate-to-­severe max single dose: 1 g min dosing interval: Q4 hmax dose: 4 g/24 h
tromethamine (generic (short-term use, 5 days Oral
Injectable solution ampoules:
equivalents of Toradol, max) Adults and adolescent ≥ 16 year (>50 kg): 10 mg Q6 h. Max dose:
15 mg/mL (1 mL); 30 mg/mL (1, 2,
Sprix nasal spray) 40 mg/24 h
10 mL); 60 mg/2 mL
Intravenous
Children 2–16 year: 0.5 mg/kg/dose Q6–8h
Max dose: 30 mg Q6h, not to exceed 120 mg/24 h
Single dose for moderate-severe pain: 0.5 mg/kg. Max dose: 15 mg
Children ≥ 17 and adults (>50 kg): Multiple dose: 30 mg Q6h. Max
dose: 120 mg/24 h single dose: 30 mg
Children ≥ 17 and adults (<50 kg or renal impairment): Multiple
dose: 15 mg Q6h. Max dose: 60 mg/24 h single dose: 15 mg
Nasal spray 15.75 mg/100 microL Intranasal
spray; 8 sprays/1.7 g bottle Adults ≥ 50 kg: 31.5 mg Q6–8h (max dose: 126 mg)
<50 kg: 15.75 mg Q6–8 h (max dose: 63 mg)
Naproxen/naproxen Oral tablets: 250, 375, 500, 750 mg Acute, chronic, mild-to- Oral Sucrose Magnesium
sodium (Naprosyn, Delayed-release tablets: 375, 500 mg moderate pain Child ≥ 2 year: 5–7 mg/kg/dose Q8–12h. Max dose: 1 g/24 h aluminum silicate
Anaprox, Naprelan, Naproxen sodium oral tablet: Adolescents and adults: 250 mg naproxen Q8–12h PRN, or 500 mg Methylparaben FD&C yellow
Aleve among others) 220, 275, 375, 500, 550, 750 mg (275–550 mg naproxen sodium) Q12h PRN. Max dose: 1,25 g/24 h no. 6 (sunset yellow)
Oral suspension: 125 mg/5 mL Controlled release tablets: 750–1000 mg q.d.
137
Table 2 (continued)
138

Medications Dosage forms Use Dosages Excipients

Ibuprofen (Advil, Solid formulations: Acute, chronic, mild-to- Oral Butylparaben
Motrin, Caldolor) Oral capsule: 200 mg moderate pain Infant and children ≥ 6-Mos: 5–10 mg/kg/dose Q6–8h. Max single D&C red #33
Oral tablet: 100, 200, 400, 600, dose: 400 mg, max dose: 40 mg/kg/24 h FD&C yellow #6
800 mg Children ≥12-year and adults: 200–400 mg/dose Q4–6h P.R.N. (max High fructose corn syrup
Oral tablet (chewable) dose: 1.2 g/24 h) Polysorbate 80
50,100 mg Propylene glycol
Liquid formulations Sodium benzoate
Oral suspension: 100 mg/5 mL, Injection solution: Sodium
50 mg/1.25 mL acetate trihydrate and water
Oral solution: 5 mg/mL for injections
Intravenous solution Intravenous
100 mg/mL (4, 8 mL) Infants and children 6–12 months: 10 mg/kg/dose, max of 400 mg/
dose Q4–6 h PRN. Max dose: 40 mg/kg/24 h
Children and adolescents 12–17 year: 400 mg/dose Q4–6h
PRN. Max dose: 2.4 g/24 h
Adults: 400–800 mg/dose Q6h P.R.N. Max dose: 3.2 g/24 h
C. S. Fonteles
Pediatric Considerations in Clinical Pharmacology 139

and acetaminophen regimens in children. The severe asthma symptoms, rhinoconjunctivitis,

results showed superior efficacy of this alternat- and eczema at 6–7 years of age. Similar results
ing protocol in comparison with ibuprofen or were observed among 13–14 years old (Beasley
acetaminophen monotherapies (Liu and Ulualp et al. 2011), with a greater risk of asthma symp-
2015). toms, rhinoconjunctivitis, and eczema dependent
Ketorolac is a very effective NSAID for mod- upon exposure to acetaminophen. A Taiwanese
erate and moderate-to-severe acute onset pain, study used the National Health Insurance
with available FDA-approved IV and intranasal Research Database in 2005 to evaluate severe
formulations for pediatric use. Mucosal atomiza- asthma exacerbation in children taking fever
tion devices are available for intranasal formula- medications (acetaminophen versus NSAID) and
tion for children. This NSAID has a significant demonstrated a higher risk of asthma exacerba-
opioid-sparing effect, with the benefit of acting tion in children taking acetaminophen for fever
against inflammation, and has been advocated for control, compared with NSAIDs and absence of
use in postoperative and preemptive pain man- fever medication (Chung et al. 2020).
agement in children and may be used in oral and A randomized, double-blind, clinical trial was
dental pain for children (American Academy of conducted to evaluate whether the use of ibupro-
Pediatric Dentistry 2022). In spite of its advan- fen by asthmatic children increased the risk of
tages, dentists should be cautioned about its high asthma exacerbation (Lesko et al. 2002). Two
cicloxygenase-1 predilection (Warner et al. 1999) groups of children (aged 6 months to 12 years)
and risk of increased trans and postoperative were assigned to receive either acetaminophen
bleeding when used preemptively. Risk of gastro- (12 mg/kg) or ibuprofen (5 or 10 mg/kg). Children
intestinal side effects must also be carefully con- who took ibuprofen had lower rates of both hos-
sidered. In the United States, the oral form is pitalization and outpatient visits for asthma rela-
approved only for use following a parenteral tive to those who took acetaminophen either
regimen. because ibuprofen reduced or acetaminophen
increased risk of asthma-related morbidity. The
proportion of children at risk of developing
 sthma and Other Allergic
A asthma-related symptoms (based on hospitaliza-
Disorders tion or outpatient visit) was highest for children
who received acetaminophen at average doses
An emergent body of scientific evidence has ≥11 mg/kg.
pointed toward a possible increase in the risk of An earlier clinical trial failed to demonstrate a
asthma for children and adolescents exposed to difference in adverse effects (including asthma/
acetaminophen prenatally and during childhood bronchiolitis) between 2-year-old children taking
(Beasley et al. 2008, 2011; Perzanowski et al. acetaminophen or ibuprofen (Lesko and Mitchell
2010; Shaheen et al. 2005). Phase 3 of the 1999). In addition, a cross-sectional study evalu-
International Study of Asthma and Allergies in ated questionnaires and medical files of children
Childhood (ISAAC) gave rise to two retrospec- aged 6 months to 6 years who were admitted to
tive, cross-sectional studies with 6–7 (parents/ the emergency department with fever due to vari-
guardians completed written questionnaires) and ous causes and found no association between
13–14 (children completed written/video ques- either acetaminophen or ibuprofen and an
tionnaires) year old children. The first published increased risk for wheezing (Matok et al. 2017).
work (Beasley et al. 2008) demonstrated that It is important to mention that in this study sig-
exposure to acetaminophen as an anti-fever med- nificantly less children with wheezing used ibu-
ication in the first year of life showed an associa- profen. Most studies reporting an association
tion of moderate magnitude (odds ratio 1·5, 95% between prenatal or early childhood administra-
CI 1·4–1·6) with an increased risk of asthma tion of acetaminophen and risk of asthma or
symptoms, including a dose-dependent risk of asthma symptoms are observational and retro-
140 C. S. Fonteles

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 Biologic Agents

Katherine France

Introduction of cancer and other diseases.” While broad, this

characterization encompasses all isolated natural
Biologic agents are novel immunomodulatory products used in medical treatment, including, as
medications targeted to control disease processes per the NCI, “antibodies, interleukins, and vac-
through modulation of inflammatory and immu- cines” (NCI 2021). For the ongoing treatment of
nologic pathways. They are a relatively recently chronic conditions, the medications tend to be
developed class of drugs that has expanded in delivered repeatedly over time, and it is these
number and scope over the course of the twenty-­ agents rather than vaccines or single-dose treat-
first century, growing to be one of the most ments that will be the focus of this chapter.
employed and fastest growing types of medica- Each biologic agent is formulated to target
tions today. Biologic agents are employed across specific immunologic pathways, either through
areas of medicine, including frequently in the activating or suppressing elements of the immune
treatment of autoimmune diseases and cancers. system through the provision of isolated, biologi-
Their impact on dental treatment and their use in cally active products. An expanding understand-
dental contexts remain poorly characterized, with ing of the physiologic processes underlying a
only limited evidence focused directly on this variety of diseases, as well as a growing under-
setting to date. standing of how they may be targeted, has
Biologic agents are defined broadly as thera- allowed for maturation of this field into new con-
peutics isolated from natural sources, which texts and more selective use of particular agents
imbues both their function and their risk of in different diseases (Strand et al. 2021). On the
adverse effects. While the scope and nature of other hand, growth of this field has also allowed
this specification varies across classes, one com- for increasing recognition of immunogenicity
monly used definition comes from the National and its ability to limit the use of these agents,
Cancer Institute (NCI) of the United States (US) especially over prolonged time periods. There is
National Institutes of Health (NIH), which also a concern, both in children and adults, that
defines a biologic agent as: “a substance that is prolonged use of these agents may lead to immu-
made from a living organism or its products and nosuppression (Axelrod and Adams 2021). This
is used in the prevention, diagnosis, or treatment concern is shared with many of the traditional
medications used to treat autoimmune and malig-
K. France (*)
nant diseases. Despite the targeted impacts of
Penn Dental Medicine, Philadelphia, PA, USA biologic agents, acting in a focused manner on
e-mail: [email protected] well-defined processes, this potential for long-­

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 145
A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_11
146 K. France

term immune activation or suppression is increas- As biologic agents continue their expansion in
ingly recognized. the market and define their uses in various dis-
As the understanding of the potential of these ease contexts, long-term use of these agents in
drugs has grown over the last few decades, so larger populations may clarify as-yet unknown or
have their market distribution and share. incompletely investigated concerns. This may
Innovative products that target constitutively hinder their overall growth, limit their use in vari-
active pathways, these agents are broadly thought ous settings, and narrow their scope of applica-
of, and generally found to be, relatively safer bility across conditions. However, given that this
alternatives to traditional treatments like disease-­ category is defined by their organic, or “bio-
modifying antirheumatic drugs (DMARDs) and logic,” nature and not by a single mechanism of
conventional chemotherapy for cancer treatment action, any limit may well be expected to pertain
(Maini and Taylor 2000). Their formulations and only to certain members of this class. The vary-
use are also innovative, contributing both to the ing mechanisms as well as variable modes of
spread of their use and to their cost, which tends delivery and impact on different physiologic pro-
to be significantly higher than their traditional cesses will continue to mean that any concerns
counterparts. In fact, as of 2022, it was estimated identified are expected to be agent- or mechanism-­
that biologic agents accounted for 35.9% of the specific and not generalizable to all biologic
market for treatment of autoimmune diseases and agents.
42.2% of the market for treatment of cancer, with
use in cancer contexts expected to grow the fast-
est over the coming years. Overall, the market for Classification of Biologic Agents
biologics accounted for $324.78 billion US dol-
lars in 2020 and is expected to grow to $749.62 Biologic agents are distilled from an organic
billion by 2028 as the number of products and source and named in part based on their source of
range of applications continues to expand. This origin, with the suffix of the agent distinguishing
equates to a compounded annual growth rate of the origin. Monoclonal antibodies, a cellular
10.8% as demand for novel therapeutic options expansion of an isolated or fabricated antibody
and governmental support increases (BioSpace that comprises the medication, are the most com-
2022). mon type of biologic agent, accounting for 39.0%
In addition, the growth of these agents is of the market (BioSpace 2022). These are iso-
explained in part by the increase in chronic dis- lated and clonally expanded populations derived
ease that has occurred in the general population, from various origins. The suffix “-mab,” most
including the increased diagnosis of especially commonly found, denotes a human source, while
rare diseases and the continued increased in life “-zumab” denotes a humanized source and
expectancy, which results in a larger population “-ximab” a chimeric source, frequently a fusion
impacted by chronic diseases and receiving long-­ of mouse and human antibodies. Biologic agents
term targeted treatment. Further, the population also include variant fusion proteins, which tend
receiving biologic agents, to be further character- to carry the suffix “-cept” and are fabricated
ized below, may include both pediatric and adult through the combination of distinct antibody
patients and, particularly soon after diagnosis, components (Yeoh et al. 2019).
may require repeated adjustments to the medica- The specific agents are further characterized
tion used, or may require treatment with multiple by the molecules they target. The most common
agents in this class and across classes over time classes of biologic agent by prevalence and the
(Burgess et al. 2022). most expansive in number are the tumor necrosis
However, across all areas of medicine and par- factor (TNF)-α inhibitors, lymphocyte modula-
ticularly in dentistry, the full range of adverse tors, and interleukin inhibitors (Maini and Taylor
effects experienced by and risks to patients tak- 2000). As evident in their categorization, these
ing these medications remains to be elucidated. drugs target central components of the immune
Biologic Agents 147

system, decreasing overactive signaling of these are required to have all routine vaccinations up to
biologic compounds as found in diverse disease date to minimize the risk of preventable disease
contexts (Murdaca et al. 2009). These are far during immunomodulation (Kane 2011). Patients
from the only classes of biologic agents avail- are also screened for infectious conditions that
able, however, with additional classes targeting may be activated by this treatment, generally
various receptors such as human epidermal including tuberculosis, human immunodefi-
growth factor receptor 2 (HER2), activated in ciency virus (HIV), hepatitis B and C, and vari-
breast cancer (i.e., trastuzumab), and vascular cella zoster virus (VZV). Baseline laboratory
endothelial growth factor (VEGF), which is over- testing is another central component of patient
active in both multiple malignancies and in vari- selection and preparation through its evaluation
ous ocular diseases such as age related macular of the patient’s general health status and risks
degeneration (i.e., ranibizumab) (Wynn and Tang (Koo et al. 2011). This includes complete blood
2022; Jain 2014). Biologics may also target count (CBC), basic or comprehensive metabolic
immunoglobulins, such as the binding of IgE by panel (BMP/CMP) including liver function test-
omalizumab in the treatment of persistent asthma ing, C-reactive protein and possibly other tests to
(Jardieu and Fick Jr. 1999). These are only a few evaluate systemic inflammation, and tests such as
examples of the mechanisms and uses of biologic VZV antibody to determine long-term risks dur-
agents. The scope of these medications is pro- ing treatment (Findeisen et al. 2021).
hibitively broad to review in full in this chapter. Delivery of biologic agents and frequency of
dosing is widely variable according to agent and
mechanism. In essence, however, all members of
Principles of Prescribing this class are protein-based drugs, and the size of
the active molecules included means that they
Before starting treatment with biologic agents, require delivery via infusion or injection and,
patients are required to undergo careful pretreat- with few exceptions, tend not to be orally admin-
ment screenings inspired by the immunomodula- istered (O’Neill and Scully 2012a). Dosing of
tory actions of these medicines. When treatment commonly used biologic agents ranges from
with these agents is considered, patient selection every 1–2 weeks to every 6 months depending on
proceeds carefully to minimize the risks of the disease being targeted and the response to the
immune activation or suppression as well as to agent, with flexibility according to disease activ-
pre-emptively evaluate any risks of adverse ity (Edwards et al. 2017). The delivery mecha-
effects. This may include consideration of past nisms of these agents contribute to their costs as
treatments used and their successes, the nature well as to the logistical hurdles required to obtain
and severity of the disease being treated, the them, particularly for those given via infusion,
availability of alternative strategies (medications, which must be delivered in a specialized center
surgical treatments, or other interventions), and by trained healthcare providers, who also moni-
logistical considerations such as cost and avail- tor for any immediate adverse events (Skalko-­
ability of the agent in question (Chebli et al. Basnet 2014).
2014). Adverse reactions to biologic agents include
During pretreatment evaluation, several gen- both reactions that develop immediately on
eral principles apply across biologic agents. administration and those that develop over time
Underlying diseases that may complicate treat- with continued use (Patel and Khan 2017).
ment, including untreated infection, uncontrolled Infusion reactions occur commonly during
heart failure, and undiagnosed or untreated administration of biologic agents and can include
comorbid autoimmune processes, particularly fevers, chills, rigors, muscle pain, nausea, and
multiple sclerosis, must all be ruled out as they vomiting as well as other symptoms such as gas-
can be activated or worsened by treatment with trointestinal upset, flushing and pruritis, tachy-
biologics (O’Neill and Scully 2012a). Patients cardia, increased blood pressure, and palpitations.
148 K. France

Each of these tend to be temporary and result in ment with biologic agents, Cochrane reports low
minimal to no long-term impact on the patient, confidence in this finding, and the rates have no
and infusion reactions may be deceased over clear association with aging (Singh et al. 2011;
repeated exposure to the agent and with supple- Borren and Ananthakrishnan 2019). Worsening
mental medications provided during the infusion of congestive heart failure does seem to be asso-
such as corticosteroids and antihistamines. In ciated with treatment using biologics, which is
addition, infusion rates can be decreased to why screening for this condition is recommended
improve patient tolerance, and dosage adjust- before commencement of the drugs. Some have
ments can be considered as needed. Infusion also suggested that these patients may be at
reactions are a relatively common finding in increased risk of developing other autoimmune
patients receiving biologic agents formulated in conditions due to the impact of the biologic agent
this manner (Khan 2016). Other adverse r­ eactions on overall immune signaling, but little evidence
to biologic agents vary according to agent, class, to date bears out this concern (Ito et al. 2020). As
and patient, including their background and other described below, however, some oral autoim-
medical conditions. mune reactions have been theorized to result
The most concerning adverse reactions asso- from treatment with biologic agents.
ciated with biologic agents tend to take the forms
of infection (including reactivation of latent
infections), increased risk of malignancy, and Impact on Dental Treatment
worsening of congestive heart failure. Other con-
cerns can include development or worsening of Currently, very little is known about the impact
hematologic disorders and dermatologic disor- of biologic agents on dental treatment and dental
ders (Shivaji et al. 2019). A Cochrane Review of outcomes. Minimal research has been conducted,
adverse effects associated with biologics found and the research that does exist is limited in scope
that there was a statistically higher overall rate of and generalizability through small sample sizes,
adverse effects in patients taking biologic agents flawed study designs, and lack of reproduction of
compared to patients receiving alternative treat- results to date. For example, no research exists to
ment regimens, as well as statistically elevated date on the impact of biologic agents on restor-
rates of medication withdrawal when using these ative need, endodontic treatment indication or
agents (Singh et al. 2011). Infection is a central tolerance, or the impact, if any, of these agents on
concern for patients receiving biologics and can oral hygiene and general oral status including
include life-threatening infections due to immune salivary flow rates and composition of the oral
compromise, reactivation of tuberculosis and microbiome. The evidence that does exist is
other latent infectious organisms such as acute reviewed here and is expected to increase in the
reactivation of herpesviruses, and development coming years.
of new infections (Bharmal and Chia 2022). The largest amount of available evidence
Older adult patients taking biologic agents have relating to biologic agents and dental medicine
been found to be at statistically significantly exists in the periodontal literature. It has long
increased risk of infection, although the same been recognized that interleukin (IL)-1 and
patients were at no associated increased risk of TNF-­α, among other signaling molecules, play a
death (Borren and Ananthakrishnan 2019). damaging role in the development and progres-
Increased rate of development and progres- sion of periodontal disease through increasing
sion of malignancy has long been theorized with pro-­inflammatory signaling and decreasing bone
these agents given their impact on the immune remodeling (Graves and Cochran 2003). In
system (Jain and Singh 2013). While there are patients treated with biologic agents, the major-
cases suggesting increased rates of lymphoma or ity of evidence comes from those receiving anti-­
development of malignancies (including oral TNF-­α treatment. In patients treated with
squamous cell carcinoma) associated with treat- adalimumab for rheumatoid arthritis (RA), for
Biologic Agents 149

example, one study found a decrease in peri- confirmed using clinical data (Krishnan and
odontal disease parameters including gingival Davidovitch 2006).
index (GI), bleeding on probing (BOP), and Relative to the ability of patients taking bio-
probing depths (PD), as well as decreased RA logics to tolerate dental treatment, general rec-
disease activity despite similar plaque levels in ommendations include monitoring of disease
patients with and without biologic therapy control to understand patient status and ability to
(Kobayashi et al. 2014). Similarly suggesting withstand the stress of dental procedures, as well
positive periodontal disease outcomes from bio- as to heal appropriately after procedures
logic agents, another study found improvements (Georgakopoulou and Scully 2015a). One small
in both psoriatic arthritis disease activity and study has evaluated adverse effects after dental
periodontal parameters after TNF-α treatment in extractions in patients taking biologic agents at a
a cohort that at baseline exhibited moderate to single academic center and found that major and
severe periodontal disease (Ancuta et al. 2017). minor complications occurred during 10.9% of
Patients treated with TNF-α antagonists were encounters across classes of biologic agent
also found to have decreased systemic inflamma- (Davila et al. 2022). Of these, pain was the most
tion as measured by erythrocyte sedimentation common complication and was found to be over-
rate (ESR) and TNF-α levels and improved peri- represented in patients taking anti-VEGF agents.
odontal parameters when receiving both nonsur- Another study completed using an animal model
gical periodontal therapy and TNF-α inhibitors suggested a possible decrease in bone remodel-
compared to those receiving alternate medica- ing in subjects treated with the TNF-α antagonist
tion or no periodontal treatment (Ortiz et al. infliximab (Ferreira-Junior et al. 2020). This
2009). Of interest, the patients receiving routine study reported more scar tissue formation in mice
periodontal therapy in this study also displayed receiving this agent, as well as lower circulating
improved RA disease control after treatment. neutrophil, monocyte, and osteoclast levels and
Other studies have failed to demonstrate a posi- decreased reactivity of TNF-α, receptor activator
tive benefit of TNF-α antagonism, but a recent of nuclear factor kappa beta ligand (RANKL),
systematic review combined the evidence avail- and osteoprotegerin. These findings in sum would
able and found that patients with RA treated with suggest a possibility of delayed or compromised
TNF-α antagonists had improved periodontal healing in patients on biologics but need to be
health during treatment including early decreases confirmed and replicated.
in BOP and GI with later improvements of PD In other surgical settings, research on adverse
and clinical attachment loss (CAL) (Zamri and outcomes has been mixed. In inflammatory bowel
de Vries 2020). Other medications, including the diseases, a common indication for biologic agent
anti-CD20 agent rituximab and the IL-6 inhibi- therapy, studies have reached mixed conclusions
tor tocilizumab, have also demonstrated positive of variable significance about the impact of the
periodontal disease outcomes including medications on patient outcomes (Zaghiyan et al.
decreased inflammation (Papathanasiou et al. 2015). In Crohn’s disease, both adults and chil-
2021). In general, the mechanisms of action of dren treated with TNF-α antagonists exhibit a
biologic agents and their use to control systemic trend toward higher rates of complication,
inflammation and inflammatory conditions although the overall rate of complication has
would suggest the potential for a positive impact been found to not be significantly different in
on periodontal parameters during treatment. patients treated with biologic agents compared to
During orthodontic treatment, a theoretical patients treated with other medications (Ahmed
chance of delayed tooth movement has been pro- Ali et al. 2014; Yung et al. 2018; Law et al. 2018;
posed. This suggestion was based solely on the Kotze et al. 2018; Lightner et al. 2019a). Within
mechanisms of action of biologic agents and biologic agents, there is also no clear difference
their interplay with the anatomic processes active in risk according to class of agent used (Lightner
during orthodontia, however, and has yet to be et al. 2019b; Shah et al. 2021; Yang et al. 2012).
150 K. France

Given the trend toward increased risk in patients remain most frequently associated with the devel-
treated with TNF-α antagonists, however, evalua- opment of MRONJ, this serious complication has
tion of a patient’s circulating levels of TNF-α has also been identified in association with treatment
been recommended before surgical intervention, using antiresorptive biologic agents, antiangio-
with the consideration of a drug holiday or pause genic agents including the VEGF inhibitors, and
in treatment for patients with Crohn’s disease other biologics (Kanwar et al. 2020). Denosumab,
that have high medication levels (Zaghiyan et al. a humanized monoclonal antibody that targets
2015). In ulcerative colitis, unlike in Crohn’s, the IgG2, which binds to the RANK ligand
low bioavailability of the medication nullifies (RANKL), is the most common antiresorptive
this recommendation. agent. Denosumab exerts its therapeutic effect by
Studies have also evaluated surgical risks for reversibly inhibiting signaling associated with
patients taking biologic agents in other disease bone remodeling through the RANKL/osteopro-
contexts. In rheumatoid arthritis, one of the most tegerin pathway. This medication is frequently
common indications for biologic therapy, prescribed for treatment of osteoporosis, in which
research to date has found no single agent that case it is often dosed in 6-month intervals, or for
carries a higher rate of complication after surgi- prevention of fractures in patients with solid
cal intervention (George et al. 2019; Diaper et al. tumors that have metastasized to bone, when it is
2017). In psoriasis, similarly, a consensus of commonly given in higher doses and at shorter
treating dermatologists has recommended con- intervals. Given its reversible inhibition, the
tinuation of biologic therapy during minor sur- effects of denosumab wear off after 12–24 months
geries (Menter et al. 2019). The scope and nature without treatment. In these patients, MRONJ has
of this recommendation may translate to dentistry been observed with a frequency of 0.7–1.9%, and
given the nature of the interventions in dental further data is needed to determine the relative
medicine. wisdom of discontinuing treatment in patients
who need dental treatment given the unclear
long-term impacts of this therapy and incom-
 ral Complications of Biologic
O pletely characterized changes to MRONJ risk
Agents over time (Eguia et al. 2020).
Antiangiogenic agents including VEGF inhib-
During treatment with biologic agents, several itors have also been associated with development
oral adverse events, in addition to the systemic of MRONJ (Zarringhalam et al. 2017). The caus-
risks reviewed above, have been identified. A few ative mechanism in these cases is theorized to
reviews have compiled and discussed this evi- relate to the therapeutic decrease in new vascula-
dence, which comes primarily from case reports ture caused by these agents as well as to a possi-
and small case series as well as occasionally from ble decrease in macrophage honing and osteoclast
the combined adverse event reporting that accom- maturation (Georgakopoulou et al. 2018). The
panies approval and prescribing information for first case of a patient developing MRONJ during
individual agents (France et al. 2023; treatment with VEGF antagonists was reported in
Georgakopoulou and Scully 2015b). The overall 2008 in a patient receiving bevacizumab, with
results are reviewed below and expect to be fur- additional cases following during treatment with
ther clarified over time. aflibercept and others (Van Poznak 2010). In
Osteonecrosis is a condition commonly asso- addition, patients taking these agents may be at
ciated with antiresorptive agents (termed medica- risk of impaired wound healing, although this
tion related osteonecrosis of the jaw, MRONJ), as concern is mainly theoretical at this time.
well as with radiation therapy for head and neck Biologic agents of other classes, including the
cancers (termed osteoradionecrosis, ORN) TNF-α inhibitors infliximab and adalimumab and
(Ruggiero et al. 2022). Although bisphospho- the lymphocyte modulator rituximab, have also
nates are the medications that were first and been associated with MRONJ (Eguia et al. 2020).
Biologic Agents 151

These latter cases lack a clear mechanistic expla- found to develop palatal pigmentation during
nation for how the medications would contribute treatment (Yuan and Woo 2020). This complica-
to MRONJ risk, and all biologic agents associ- tion is shared with small molecule inhibitors,
ated with MRONJ require further long-term data which are similar to but distinct from biologic
and controlled evidence to fully understand the agents (Georgakopoulou et al. 2018). Patients
overall risks and their modifiability over time. taking these and other targeted biologic agents
Other oral complications reported during treat- for cancer treatment have also been found to
ment with biologic agents include development of exhibit xerostomia and hyposalivation as well as
angioedema, oral ulcers, oral infections including mucositis. Mucositis is a common complication
candidiasis and viral infection reactivation, devel- resulting from various treatments for malignancy
opment of oral lichenoid reactions, and manifes- and in its assorted stages ranges from erythema
tation of oral sarcoidosis among others (France to widespread ulceration that can prevent a
et al. 2023). An increased risk of oral infection patient’s ability to tolerate oral alimentation
such as oral candidiasis is in keeping with an (Georgakopoulou and Scully 2015b).
overall increased risk of infection in these patients As with the general risks of malignancy, data
and therefore may have a mechanistic connection on the development of oral malignancies is sparse
to the biologic agent. Oral lichenoid reactions in and mixed. However, there have been several
these patients have been associated temporally cases of newly diagnosed oral squamous cell car-
with the onset of the medications and are theo- cinoma and malignant melanoma in patients tak-
rized to relate to the immune modulation inherent ing TNF-α antagonists as well as rituximab
to the use of these agents (Georgakopoulou and (France et al. 2023). Lymphoma of various sites
Scully 2015b). These reactions have been associ- has also been associated with the use of biologic
ated particularly with agents targeting pro- agents and has been found to present in the oral
grammed cell death protein 1 (PD-1) and its cavity (Baecklund et al. 2006).
ligand (PDL-1), commonly used in treatment of
oral and oropharyngeal squamous cell carcinoma
and other malignancies (i.e., pembrolizumab,  iologics in the Treatment of Oral
B
nivolumab, atezolizumab) (Ai et al. 2020). Lichen Conditions
planus is a T cell-mediated reaction and thus
shares a mechanistic pathway with certain bio- Biologic agents have been used off-label in the
logic agents, while lichenoid mucositis can be treatment of oral diseases, primarily in immune-­
reactively triggered by a variety of medications mediated and autoimmune diseases with oral
and external substances (Yuan and Woo 2020). manifestations. Many of these examples involve
Although biologic agents have also been pro- treatment of patients with evidence of disease in
posed for use in the treatment of oral lichen pla- the oral cavity in addition to other body systems,
nus (see below), there does exist a physiologic although other evidence does exist on the use of
rationale for how modulation of the T-cell path- biologic agents in oral-only disease. While many
way could lead to development of lichenoid reac- agents may have potential to provide benefit to
tions. Erythema multiforme has also been found these patients, use of a biologic agent should be
to develop during treatment with TNF-α antago- considered only by providers who are appropri-
nists, likely also through modulation of inflamma- ately knowledgeable of the risks of these medica-
tory pathways (Goncalves et al. 2019). tions and who are experienced in their use, such
Ulcerated mucositis and oral ulcers have sim- as certain oral medicine specialists. In addition,
ilarly been associated with checkpoint inhibitors the logistical considerations of delivery of these
including the PD-1 and PDL-1 inhibitors above drugs, including the cost and in many cases the
as well as inhibitors of cytotoxic T lymphocyte need for delivery through an infusion center,
associated protein 4 (CTLA-4, i.e., ipilimumab). often limit their use in outpatient oral medicine
Patients taking these medications have also been practice.
152 K. France

Pemphigus vulgaris (PV) is the oral mucosal studies to further evaluate appropriate use
disease with the most evidence for effective treat- (Gueiros et al. 2019). Specifically, belimumab
ment with biologic agents (Mays et al. 2019). has been found to improve both salivary function
Two randomized controlled trials have proven the and the symptoms of xerostomia, the subjective
efficacy of rituximab in the treatment of PV, one experience of dry mouth (De Vita et al. 2015).
of which proved that treatment with rituximab Abatacept also shows promise for the improve-
was superior to steroids alone and led to US Food ment of both subjective and objective symptoms.
and Drug Agency (FDA) approval of this medica- Rituximab use in Sjӧgren’s syndrome improves
tion for this use (Joly et al. 2017; Kanwar et al. objective measures including ultrasound scores
2014; Press Release 2018). There is also promis- and salivary function but shows less benefit to
ing evidence from a randomized controlled trial subjective symptoms (Fisher et al. 2018; Meijer
on the treatment of PV with intravenous et al. 2010). A newer agent, iscalimab, an anti-
­immunoglobulin (IVIg) and some evidence of the ­CD40 biologic, showed significant promise in
use of local adjunctive treatment with platelet- early studies for improvement of oral symptoms
rich plasma (PRP) (Mays et al. 2019). and signs of Sjӧgren’s syndrome and is in contin-
In bullous and mucous membrane pemphi- ued development for possible use in this and
goid, there is a lower level of still convincing evi- other settings (GlobalData 2023).
dence of the efficacy of rituximab for control of Other disease contexts with oral components
the oral and systemic manifestations of these dis- and isolated oral conditions so far have signifi-
eases (Mays et al. 2019). Bullous pemphigoid cantly less evidence on the use of biologic agents.
also has been proven to respond to omalizumab, In the treatment of advanced oral and oropharyn-
which binds free IgE in serum, but given this dis- geal squamous cell carcinoma, cetuximab targets
ease’s infrequent oral presentation and a lack of epidermal growth factor receptor (EGFR) and is
evidence on the use of omalizumab to treat oral found to potentiate treatment of conventional
mucosal lesions of pemphigoid, this treatment chemotherapeutics in hopes to stop tumor growth
should be considered carefully before use and improve patient responses to radiation ther-
(Kremer et al. 2019). A recent systematic review apy (Naruse et al. 2016). Other biologic agents
did find benefit to IVIg and TNF-α inhibitors as have also been evaluated in the treatment of oral
well as rituximab for the treatment of pemphi- cancers for their ability to reduce inflammation
goid, although with the chance of incomplete and pro-inflammatory signaling and modulate the
resolution or relapse (Lytvyn et al. 2022). In fact, tumor microenvironment. These drugs remain in
many patients with pemphigoid are found to testing (Brierly et al. 2023).
relapse after treatment and may need to receive a In Behçet’s disease and the treatment of
combination of biologic agents, corticosteroids, recurrent aphthous stomatitis, the TNF-α inhibi-
and other immunosuppressants, albeit often at tors infliximab, adalimumab, and etanercept
lower doses than when used as monotherapy, to have all been found to be helpful as adjuvant
maintain appropriate disease control (Veilleux therapies or as monotherapy for control of oral
and Shear 2017). Based on all of this evidence, in ulcers, including major aphthous ulcers
the United Kingdom, the National Health Service (Connolly et al. 2005; Vujevich and Zirwas
(NHS) has approved rituximab for use in both 2005; Robinson 2003; Melikoglu et al. 2005). In
pemphigus vulgaris and pemphigoid (NHS oral lichen planus, T-cell mediation provides
England 2016). theoretical promise for treatment with biologic
Multiple studies have evaluated the efficacy of agents, which have shown mixed results in clini-
biologic agents for the treatment of Sjӧgren’s cal testing (Zhang et al. 2011). This includes
syndrome, both for overall disease control and reports of patients developing lichenoid lesions
specifically for improvement of the oral compo- during treatment with biologics as well as some
nent of the disease. These studies have resulted in evidence of benefit with various biologics
mixed evidence with the need for confirmatory (France et al. 2023). To date, however, there is
Biologic Agents 153

no consensus on recommended treatment options research required to fully characterize this class.
in this class for patients with oral lichen planus. These limitations aside, biologic agents, are her-
In orofacial granulomatosis, infliximab (as used alded for the role they will continue to play in
in intestinal disease) may control oral symptoms, shaping the future of medical care and are
particularly on a short-­term basis. In Steven’s increasingly recognized for an associated impact
Johnson Syndrome, chronic graft versus host on dental medicine.
disease, and others, some evidence exist and While data is currently limited, the impact of
require confirmation and reproduction of thera- biologic agents on oral disease processes, treat-
peutic effect (France et al. 2023; Elliott et al. ment of oral lesions, and ability to tolerate dental
2011; O’Neill and Scully 2012b). While none of care are beginning to be recognized. With
these diseases have to date shown definitive increased attention to this area in future years,
response under biologic agent therapy, studies additional data is expected to further clarify any
are ongoing and employ both established and positive or negative impacts of this class of medi-
new biologic agents. cation on dental health and the ability of patients
to safely undergo dental treatment. Currently,
best practice recommendations include for any
Conclusion oral health-care provider to monitor the patient’s
overall health status and disease activity and to
Biologic agents are a continually expanding and prioritize treatment during periods of relative
increasingly prevalent class of medications used control. In addition, patients should as always be
to treat a wide variety of diseases affecting a full monitored for development of oral infections and
range of organ systems, primarily those with should be treated in a timely manner as needed.
malignant or immunologic etiology. New agents Ideal oral health in these patients may contribute
are continually developed and introduced, and to overall disease control and quality of life, met-
expanded applications are investigated for avail- rics that tend to be positively impacted by the
able biologic agents, continually increasing the efficacy and tolerability of biologic agents.
reach and functionality of these agents. The first
commercially available biologic agent, etaner-
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 Basic Emergency Drugs
and Non-­intravenous Routes
of Administration

Arthur H. Jeske

Emergency drugs in the dental outpatient setting Antihistamines

are considered to be adjunctive to physical mea-
sures, for example, airway opening and oxygen- Antihistamines are appropriate for mild, delayed-­
ation. As such, the array of drugs listed here is a onset allergic reactions, as are corticosteroids.
basic list, and many of these agents can be They lack important actions necessary to allevi-
obtained through purchase of emergency kits. ate the rapid pathophysiologic effects of Type 1
Before purchasing such kits, the dentist should (anaphylactic) allergic reactions. In anaphylaxis,
consider the following: antihistamines, corticosteroids, and beta agonists
are secondary treatments (LoVerde et al. 2018).
1. No single kit meets the requirements of all Outcomes from the administration of oral or
dental offices, especially in regard to reversal intramuscular antihistamines include sedation
(“antidotal”) agents. and anticholinergic actions, which must be con-
2. Emergency drugs go out of date at different sidered prior to discharge and in the follow-up
intervals, and expiration dates must be moni- care of the patient.
tored accordingly.
3. Dose forms must be compatible with the abili-
ties of the dental teams to use various routes  ntiplatelet Drugs (Aspirin,
A
of administration. This can be problematic Clopidogrel)
when drugs indicated for intravenous use only
are administered by nonvascular routes, which According to the American Heart Association’s
reduces efficacy and prolongs onset. Advanced Cardiac Life Support protocols, an
4. The training of the dentist(s) and staff mem- antiplatelet drug is an important component of
bers, requirements of the practice’s licensing the first intervention in cases of acute coronary
jurisdiction, and the types of patients in the syndrome (American Heart Association 2016).
practice and the sedation modalities employed Current, high-quality scientific evidence sup-
in the practice (Rosenberg 2010). ports the beneficial actions of orally adminis-
tered aspirin in patients with acute coronary
syndrome, while other agents historically indi-
cated in this emergency condition (morphine,
A. H. Jeske (*) oxygen, nitrates) are supported only by limited
UTHealth School of Dentistry, Houston, TX, USA evidence and may actually result in less favor-
e-mail: [email protected] able post-­ event outcomes (McCarthy et al.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 157
A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_12
158 A. H. Jeske

2017). A recent systematic review also high- mercially available drug kits, it is an important
lighted the potential application of a clinical agent for the management of acute bradycardia,
decision tool to optimize the use of antiplatelet as may occur in local anesthetic overdose reac-
agents in cases of acute coronary syndrome tions. Clinically, significant bradycardia is
(Reynard and Body 2017). Nonsteroidal anti- defined as a heart rate lower than 60 bpm in
inflammatory drugs should not be used in place awake individuals and nonathletes (American
of aspirin or clopidogrel for an antiplatelet Heart Association 2016; Barstow and McDivitt
action in cardiac-related emergency situations 2017). When bradycardia occurs acutely, atro-
(American Heart Association 2016). pine is the drug of choice for its management
(Deal 2013). Available in prefilled syringes, the
typical dose for management of bradycardia in
Antiseizure Agents an adult is 0.4 mg intramuscularly, and an aggre-
gate dose of 2 mg will produce total loss of vagal
In the dental office setting, benzodiazepines are control of the heart, which must be considered
recommended as being both safe and effective when repeat doses are administered. Atropine
for the management of status epilepticus prior to autoinjectors (e.g., AtroPen®) are available with
hospital admission. Typically, midazolam or several concentrations of atropine, from 0.25 mg
lorazepam is recommended for terminating the to 2 mg per administration.
potentially life-threatening seizures of status
epilepticus. Outcomes from the RAMPART
Study of interventions for this serious emer- Beta Adrenergic Agonists
gency, based on a total sample of 800 patients,
indicated that intramuscular administration of The principal indication for beta agonists (e.g.,
10 mg midazolam in adults (5 mg in children isoproterenol, albuterol) is the management of
<40 kg) was equivalent to the administration of acute bronchial constriction. These agents are
4 mg of lorazepam administered intravenously in typically available in dental emergency drug
adults (2 mg in children <40 kg) and that the kits in inhalational dose forms, which can accu-
overall interval until seizure termination (includ- rately meter the dosage. Importantly, beta ago-
ing both the time actual drug administration and nists are powerful cardiac stimulants and may
the onset of action of the drug) was essentially cause excessive cardiac workload when improp-
the same in both the i.m. and i.v. drug groups erly administered. In the management of acute
(Silbergeit et al. 2013). A recent systematic bronchial constriction, albuterol is typically
review of various routes of administration of administered by inhalation, using a propellant-
midazolam and diazepam for status epilepticus driven aerosol liquid. The dose is commonly
has confirmed that non-­intravenous midazolam 90 μg per actuation of the inhaler device.
is as effective and safe as intravenous or rectal Adverse effects of albuterol can be serious and
diazepam in terminating early status epilepticus include cardiac stimulation, due to activation of
in children and probably also in adults (Brigo cardiac beta receptors. It is important to note
et al. 2015). Other drugs evaluated for this indi- that corticosteroid-based inhalers used by asth-
cation include lorazepam, phenobarbital, phe- matic outpatients are not rescue inhalers, due to
nytoin, and paraldehyde (Appleton et al. 2008). the long onset of action of the corticosteroid. A
recent systematic review has confirmed that
inhaled, short-acting beta-2 adrenergic agonists
Atropine such as albuterol remain the mainstay of treat-
ment for acute asthma and that the metered-
Like many of the drugs described in this chapter, dose inhaler delivers improved lung function as
atropine is available in preloaded syringes. the nebulizer or intravenous administration
While atropine is not typically included in com- (Green 2011).
Basic Emergency Drugs and Non-intravenous Routes of Administration 159

Corticosteroids Glucagon

Glucocorticoids are typically stocked in dental Like glucose, glucagon is used to manage acute
office emergency kits for the management of hypoglycemia, but unlike glucose, it requires
anaphylaxis. While they are regularly used in parenteral administration and may be indicated
the medical management of asthma and as when the patient lapses into an unconsciousness
adjuncts to epinephrine and antihistamines in as a result of hypoglycemia and can no longer
cases of anaphylaxis, their therapeutic benefit safely be given oral glucose. According to a
and adverse effects in anaphylaxis have not recent systematic review (Villani et al. 2017),
been scientifically validated (Choo et al. 2012). 1 mg glucagon administered intramuscularly
Their therapeutic effect appears to be optimal can be effective for the emergency management
when administered intravenously, likely due to of hypoglycemia in the unresponsive adult
the relatively slow onset of action when admin- (Vaccine Administration n.d.). Glucagon is
istered by other routes. Typically, a corticoste- available as a lyophilized solid and must be sol-
roid with a high ratio of anti-inflammatory to ubilized using the manufacturer-provide dilut-
salt-retaining activity is preferred, such as ing solution. It is important to note that the
dexamethasone, administered intravenously or efficacy of glucagon is dependent on the pres-
intraosseously. ence of glycogen in the patient’s liver, where
glucagon stimulates its breakdown to glucose.
There are few adverse effects of glucagon when
Epinephrine administered in a single dose for the manage-
ment of acute hypoglycemia. However, gluca-
Despite lack of validation from randomized and gon is best reserved for use when intravenous
quasi-randomized controlled clinical trials glucose is not available or cannot be given (see
(Sheikh et al. 2008), epinephrine remains the next section, 11.9 Glucose).
drug of first choice for the management of Type 1 A new form of glucagon, dasiglucagon
allergic reactions, that is, anaphylaxis (American (Zegalogue®), is now available in prefilled
Heart Association 2016). Its benefits derive from syringes for the treatment of severe hypoglyce-
direct agonist effects at beta-2 adrenoceptors that mia in adults and children over the age of 6 and
mediate bronchial dilation, as well as cardiac has been shown to have a higher rate of absorp-
stimulation mediated by beta-1 adrenoceptors tion and longer half-life than traditional forms of
and alpha-1-mediated vasoconstriction glucagon (Xu et al. 2021).
(American Heart Association 2016). The optimal
route of administration in nonhospital settings
intramuscular, usually at a dose 0.3 mg for adults. Glucose
Epinephrine is widely available in pre-filled auto-
injectors but can be obtained in ampuls and vials. In the past, table sugar and sweet beverages (e.g.,
Recent reviews suggest that autoinjectors are cola, orange juice) were considered “front-line”
associated with accidental injection of thumbs sources of glucose for diabetic patients experi-
and insufficient needle lengths in obese patients, encing acute hypoglycemia. However, the sugars
while syringe-administered epinephrine is asso- found in substances like cake icing (sucrose) are
ciated with inadvertent subcutaneous or i.v. more complex than the simple sugar glucose
administration, as well as dosing errors (Chime molecule. Nevertheless, mild hypoglycemia
et al. 2017). The adult dose is 0.3 mg adminis- appears to be manageable with carbohydrate-­
tered intramuscularly, and the pediatric dose is containing foods and beverages (Evert 2014). A
0.15 mg, also i.m. These doses are accurately study of hypoglycemic children with Type 1 dia-
metered by autoinjector devices, if the devices betes found that sucrose derived from candy is
are used properly. equally effective with glucose tablets for elevat-
160 A. H. Jeske

ing blood glucose, while fruit-derived fructose Oxygen

was less effective than either glucose or sucrose
(Husband et al. 2010). A recent systematic In many emergencies in which airway compro-
review found that high-quality scientific evi- mise or other respiratory embarrassment may
dence for the management of hypoglycemia is occur (e.g., overdose of CNS depressant drugs
lacking, and therefore, recommendations for with depression of the respiratory center), oxy-
various treatments are, therefore, limited (Villani gen is considered an important first-choice agent
et al. 2017). However, there is consensus that when combined with ventilation in cases involv-
15–20 g of oral sucrose or glucose (i.e., fast-act- ing significant hypoxemia (PaO2 < 94%).
ing carbohydrates) should be used in conscious However, recent evidence has called into ques-
patients with glucose levels less than 70 mg/dL, tion the standard practice of administering high-­
and those with blood glucose levels less than flow oxygen in acute coronary syndrome. In such
50 mg/dL should eat 30 g of fast-acting carbohy- cases, oxygen would be indicated only in hypoxic
drates, and this dose can be repeated in patients with an O2 Saturation less than 90%
10–15 min, as indicated (Cornelius 2017). The (McCarthy et al. 2017). Concerns about the use
recommended treatment for unresponsive of high-flow oxygen therapy in normoxic patients
patients is 10% glucose administered intrave- with acute coronary syndrome include reduction
nously or 1 mg of glucagon administered intra- of cardiac output and left ventricular perfusion,
muscularly. Both 50 mL of dextrose 50% or increased coronary vascular resistance, and the
500 mL of dextrose 5% will elevate blood glu- potential development of reactive oxygen radi-
cose levels approximately 75–125 mg/dL cals, which can cause cardiac dysrhythmias
(Cornelius 2017). (McCarthy et al. 2017).

Nitrates Reversal (Antidotal) Drugs

Nitrates, such as nitroglycerin, were considered Naloxone

front-line agents for combination drug therapy
(MONA) in cases of acute coronary syndrome by Naloxone (e.g., Narcan®) is a nonselective opioid
virtue of reducing peripheral vascular resistance receptor antagonist that is now being marketed in
with corresponding decreases in cardiac work- multiple preparations as a result of the current
load and myocardial oxygen demand (American opioid overdose crisis in the United States.
Heart Association 2016). It should not be admin- Naloxone is characterized clinically by a rela-
istered if systolic blood pressure is less than tively short duration and the complete reversal of
90 mmHg, or if there is marked bradycardia or all actions of opioids in patients, including pain
tachycardia (McCarthy et al. 2017). Because control, and may precipitate severe withdrawal in
nitroglycerin appears to possess an analgesic individuals who are addicted to opioids. Naloxone
action, it is important to note that relief of chest is typically administered parenterally, either i.m.
pain after the administration of nitroglycerin is or i.v., with the i.v. route producing the most reli-
not diagnostic of acute coronary syndrome. The able actions with the fastest onset of action. In
victim is given one sublingual tablet or one spray nonhospital settings, naloxone is typically used
dose every 3–5 min as appropriate and indicated, by first responders by the intramuscular route,
up to a total of three administrations. Recently with a prefilled autoinjector (e.g., Evzio®) at a
published scientific evidence suggests that the dose of 0.4 mg. However, recent case reports sug-
benefits of nitrate administration in acute coro- gest that individuals who have acutely overdosed
nary syndrome may be only marginal, although with fentanyl or fentanyl analogs may require
its use in acute coronary syndrome continues much higher, repeated doses as high as 4 mg
(LoVerde et al. 2018). (Tomassoni et al. 2017). With the recent
Basic Emergency Drugs and Non-intravenous Routes of Administration 161

a­ ppearance of nitazene opioids in the illicit drug patients with epilepsy. Recently, the need for
market, antagonists with higher affinity than nal- adherence to the FDA’s label indication, “for
oxone for the mu opioid receptor are needed for intravenous use only” has been emphasized
intoxication with higher-potency opioid agonists. (Weaver 2011). Typically, a 1- to 3-mg i.v. dose
Nalmefene (e.g., Revex®) has been introduced in should be safe and effective when administered
the United States as a longer-acting, high-affinity in cases of benzodiazepine-induced unconscious-
opioid antagonist, and a nasal spray form is also ness and apnea. Importantly, the short duration
being developed. At this time, naloxone can be (20–45 min) of a single dose of flumazenil can
administered by the nasal route with good effi- result in recurrence of benzodiazepine-induced
cacy (Krieter et al. 2019). A recent systematic CNS depression, which can also be significant if
review of the effect of the route of administration the flumazenil has been administered to simply
of naloxone in cases of out-of-hospital opioid reawaken the patient to reduce recovery time.
overdose found that a higher concentration intra- The actual dose of flumazenil required for emer-
nasal dose of naloxone (2 mg/mL) appears to gency management will vary directly with the
have efficacy equivalent to that of intramuscular total dose of benzodiazepine that has been admin-
naloxone with a comparable rate of adverse istered to the patient for sedation. Small doses
events (e.g., agitation) (Chou et al. 2017). The (e.g., 0.2 mg) have been incorrectly recom-
intranasal route of administration can be accom- mended by the sublingual or intramuscular route,
plished with a commercially available prepara- as both this dose and these routes of administra-
tion, illustrated in Fig. 1. tion are unlikely to achieve therapeutic concen-
trations in time to prevent serious, permanent
injury to the patient (Weaver 2011).
Flumazenil

Flumazenil (e.g., Romazicon®) is a nonselective Vascular Access/Intraosseous

benzodiazepine receptor antagonist, which, like Administration
naloxone, lacks inherent efficacy at these recep-
tors (pure antagonist). Also, like naloxone, it has Developed initially by the US military forces for
a relatively short duration and the potential to vascular administration of drugs and fluids under
induce severe withdrawal in individuals who battlefield conditions, intraosseous drug adminis-
have taken benzodiazepines long term, including tration is now a mainstream route that is routinely
seizures, and may precipitate seizure activity in employed by emergency medical technicians and
is included in the American Heart Association’s
for Advanced Cardiac Life Support guidance for
several management protocols, which cite the
following advantages of this route of administra-
tion (American Heart Association 2016):

• Access can be established in all age groups.

• Access can often be achieved in 30–60 s.
• Preferred over endotracheal route.
• May be easier to establish than the endotra-
cheal route in cardiac arrest.
• Any ACLS drug that is administered intrave-
nously can be given IO.
Fig. 1 Commercially available naloxone nasal spray
preparation, with atomization device. (Image courtesy of Intraosseous infusion can be accomplished at
Adapt Pharma, Inc.) two sites in both adult and pediatric patients
162 A. H. Jeske

(­ tibial and humeral sites only). The driver is illus- administered prior to administration of the actual
trated in Fig. 2, and a schematic drawing of the interventional drug, the single administration of
indwelling needle, tubing connection to the nee- an urgently required emergency drug in the emer-
dle, and the syringe is seen in Fig. 3. The non-­ gent prehospital setting (e.g., a reversal agent)
collapsible marrow venous plexus in the proximal could be significantly delayed if this step is taken.
head of the tibia, as well as the humerus, allows
rapid administration and vascular uptake of med-
ications delivered, including crystalloids, col- Intranasal (Inhalational)
loids, and even blood (Leidel et al. 2009). Administration
However, because the humerus provides more
rapid delivery to the heart, it may be preferred for The intranasal route of drug administration has
specific cardiovascular emergencies. been used in medicine for decades, including
Caution must be exercised in performing uses in over-the-counter preparations and pre-
intraosseous emergency medications in con- scription drugs for respiratory diseases (e.g.,
scious patients, as the pressure from the drug asthma). Recently, there has been a resurgence in
infusion can elicit temporary, sharp pain. While a interest in this route of administration for emer-
small amount of a plain lidocaine solution can be gency drugs, including naloxone for opioid over-
doses (Corrigan et al. 2015). Based on currently
available studies, the advantages of this route
include the following:

• Needles not required, less painful.

• Rapid drug delivery.
• Pharmacokinetics more favorable than i.m. in
obese and elderly patients.
• Minimizes risk of needlestick injuries and
spread of blood-borne diseases.

There are, however, several limitations to this

technique, including the following:
Fig. 2 Intraosseous driver insertion in proximal head of
tibia. (Image courtesy of Teleflex, Inc.) • Limited volume of medication (<1 mL).
• Limited data/evidence for safety and efficacy.
• Costs greater than those of i.v.
• Contraindicated in cases of nasal trauma or
recent use of nasal vasoconstrictors.
• Less reliable than i.v. or i.o. routes.
• Patient acceptance (palatability) variable.
• May cause nasal mucosal irritation.

At this time, two emergency drugs commonly

stocked in dental offices—midazolam and nalox-
one—may be effectively used by the intranasal
route, for the management of seizures and opioid
overdose, respectively, when the preferred intra-
venous route is unavailable or impractical (Rech
Fig. 3 Intraosseous injection technique at proximal head
of tibia, syringe-to-cannula-indwelling needle in place et al. 2017). The armamentarium for intranasal
(image courtesy of Teleflex, Inc.) drug administration includes a conventional
Basic Emergency Drugs and Non-intravenous Routes of Administration 163

Table 1 Current evidence-based doses and routes of

administration recommended for basic emergency drugs
in adults without contraindicationsa
Drug Dose Route(s)
Albuterol (bronchodilator) 90 μg Inhalation
Antihistamine 50– i.m.
(diphenhydramine) 100 mg
Antiplatelet drug (clopidogrel) 300 mg Oral
Antiplatelet drug (non-­ 160– Oral,
enteric-­coated aspirin) 325 mg chewed
Anti-seizure drug (lorazepam) 4 mg i.v.
Antiseizure drug (midazolam) 10 mg i.m.,
intranasal
Atropine 0.4 mg i.m.
Corticosteroid i.m. or i.v.
Fig. 4 Medication atomization device (MAD), showing (dexamethasone)
nasal cone, attached to conventional Luer-lock disposable Epinephrine 0.3 mg i.m.
syringe. (Image courtesy of Teleflex, Inc.) Flumazenil i.v., i.o.,
intranasal
Glucagon 1 mg i.m.
syringe and a special medication atomization Glucose 15–20 g Oral
device that is attached to the syringe after the Naloxone 0.4 mg i.m.
medication is drawn up and that provides a seal Nitroglycerin 0.4 mg Sublingual
when inserted into the nasal orifice (Fig. 4). Oxygen 100% (high-flow, 15 lpm Inhalation
non-rebreathing
Other drugs that have been documented to be bag-valve-mask)
effective when administered intranasally include a
Initial dose only; re-administration should be based on
fentanyl, sufentanil, ketamine, hydromorphone, recurrence of emergent symptoms, physiologic status of
flumazenil, and glucagon (Corrigan et al. 2015). the patient, etc

Intramuscular Administration References

American Heart Association. Advanced cardiovascular
Perhaps, the simplest parenteral route of drug life support: provider manual. Chicago: American
administration, i.m. injection is reliable and rela- Heart Association; 2016. p. 2.
tively safe and is used with autoinjectors for Appleton R, Macleod S, Martland T. Drug management
bystander treatments of anaphylaxis and opioid for acute tonic-clonic convulsions including convul-
sive status epilepticus in children. Cochrane Database
overdoses. Recent scientific evidence from stud- Syst Rev. 2008;3:CD001905.
ies in children and adolescent patients has con- Barstow C, McDivitt JD. Cardiovascular disease update:
firmed that the intramuscular administration of bradyarrhythmias. FP Essent. 2017;454:18–23.
midazolam with a commercial autoinjector Brigo F, Nardone R, Tezzon F, Trinka E. Nonintravenous
midazolam versus intravenous or rectal diazepam
device is as effective as rectally or intravenously for the treatment of early status epilepticus: a sys-
administered diazepam for the acute manage- tematic review with meta-analysis. Epilepsy Behav.
ment of seizures (Mula 2017). However, the 2015;49:325–36.
proper armamentarium may include filter needles Chime NO, Riese VG, Scherzer DJ, Perretta JS,
McNamara L, Rosen MA, Hunt EA. Epinephrine
(for drugs drawn from ampuls) and may require auto-injector versus drawn up epinephrine for anaphy-
various gauges and needle lengths, depending on laxis management: a scoping review. Pediatr Crit Care
the age/size of the target muscle (Vaccine Med. 2017;18:764–9.
Administration n.d.). Evidence-base recommen- Choo KJ, Simons FE, Sheikh A. Glucocorticoids for the
treatment of anaphylaxis. Cochrane Database Syst
dations for adult dosages and routes of adminis- Rev. 2012;4:CD007596.
tration of emergency drugs are summarized in Chou R, Korthuis PT, McCarty D, Coffin PO, Griffin JC,
Table 1. Davis-O’Reilly C, Grusing S, Daya M. Management
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of suspected opioid overdose with naloxone in out-of-­ Mula M. New non-intravenous routes for benzodiaze-
hospital settings: a systematic review. Ann Intern Med. pines in epilespy: a clinician perspective. CNS Drugs.
2017;167(12):867–75. 2017;31(1):11–7.
Cornelius BW. Patients with type 2 diabetes: anesthetic Rech MA, Barbas B, Chaney W, Greenhalgh E, Turck
management in the ambulatory setting: part 2: phar- C. When to pick the nose: out-of-hospital and emer-
macology and guidelines for perioperative manage- gency deparment intranasal administration of medica-
ment. Anesth Prog. 2017;64(1):39–44. tions. Ann Emerg Med. 2017;70(2):203–11.
Corrigan M, Wilson S, Hampton J. Safety and efficacy Reynard C, Body R. 15 a clinical decision tool for pre-
of intranasally administered drugs in the emergency scribing anti-platelet medication with suspected
department and prehospital settings. Am J Health Syst acute coronary syndrome (PAM). Emerg Med J.
Pharm. 2015;72(18):1544–54. 2017;34(12):A870–1.
Deal N. Evaluation and management of bradydysrhyth- Rosenberg M. Preparing for medical emergencies. The
mias in the emergency department. Emerg Med Pract. essential drugs and equipment for the dental office. J
2013;15(9):1–15. Am Dent Assoc. 2010;141(5 suppl):14S–9S.
Evert AB. Treatment of mild hypoglycemia. Diabetes Sheikh A, Shehata YA, Brown SGA, Simons
Spectr. 2014;27(1):58–62. FER. Adrenaline (epinephrine) for the treatment
Green RH. Asthma in adults (acute). Brit Med J Clin of anaphylaxis with and without shock. Cochrane
Evid. 2011;4:1513. Database Syst Rev. 2008;4:CD006312.
Husband AC, Crawford S, McCoy LA, Pacaud D. The Silbergeit R, Lowenstein D, Durkalski V, Conwit R,
effectiveness of glucose, sucrose, and fructose in treat- NETT Investigators. Lessons from the RAMPART
ing hypoglycemia in children with type 1 diabetes. study—and which is the best route of administration
Pediatr Diabetes. 2010;11(3):154–8. of benzodiazepines in status epilepticus. Epilepsia.
Krieter P, Gyaw S, Crystal R, Skolnick P. Fighting fire 2013;54(Suppl 6):74–7.
with fire: development of intranasal nalmefene to treat Tomassoni AJ, Hawk KF, Jubanyik K, Nogee DP, Durant
synthetic opioid overdose. J Pharmacol Exp Ther. T, Lynch KL, Patel R, Dinh D, Ulrich A, D’Onofrio
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Leidel BA, Kirchhoff C, Bogner V, Stegmaier J, Mutschler Connecticut, June 23, 2016. Morb Mortal Wkly Rep.
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 Internet Resources for Dental
Pharmacology

Arthur H. Jeske

The list of internet-based resources for informa- Oral Medicine Oral Pathology Oral Radiololgy.
tion on dental pharmacology is not intended to be This can be accessed using the top tool button
comprehensive, and the site URLs and their con- labeled “Publications and News,” then accessing
tent may change without notice. They are “OOOO Journal.” Past issues of this journal are
included here because they meet three criteria: archived and can be easily searched within the
site using the search feature.
1. They are publicly accessible at no cost.
2. They are based strictly on scientific or US
government-vetted information.  merican Academy of Pediatric
A
3. In most cases, they contain summaries that Dentistry
can easily be understood and communicated
to members of the healthcare team and aapd.org
patients. The AAPD publishes an extensive list of clini-
cal guidelines at its internet site, and most of
The reader should note that some for-profit these documents are regularly revised, ideally on
(.com) sites are included, but they offer useful, their every-3-year cycle. Those AAPD Guidelines
no-cost features of importance to dental pharma- with particular relevance to dental pharmacology
cology. Neither the author nor Springer can be found under the category “Publications,”
Publications has any financial interest in these “Oral Health Policies and Recommendations,”
sites. “Clinical Practice Guidelines,” and “Oral Health
Policies” and include the following:

 merican Academy of Oral

A 1. Use of Local Anesthesia for Pediatric Dental
Medicine Patients.
2. Use of Nitrous Oxide for Pediatric Dental
aaom.com Patients.
Perhaps, the best tool available at this website 3. Use of Antibiotic Therapy for Pediatric Dental
is access to the authoritative journal, Oral Surgery Patients.
4. Antibiotic Prophylaxis for Dental Patients at
Risk for Infection.
A. H. Jeske (*) 5. Useful Medications for Oral Conditions.
UTHealth School of Dentistry, Houston, TX, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 165
A. H. Jeske (ed.), Contemporary Dental Pharmacology,
https://doi.org/10.1007/978-3-031-53954-1_13
166 A. H. Jeske

American Heart Association 1. Periostat® as an Adjunct to Scaling and Root

Planing.
heart.org 2. Use of Moderate Sedation by Periodontists.
Of greatest importance at this website is a
variety of patient and practitioner resources for
the management of patients with cardiovascular American Association
diseases that increase the risk of serious systemic of Endodontists
and cardiovascular device infections. While there
is a great deal of information at this site, many of aae.org
its features are written in plain English for the lay No dental specialty utilizes antibiotics, anti-­
person, and it can easily be searched using the inflammatory drugs, analgesics, and local anes-
simple alphabetical search tool at the top of the thetics to a greater extent in the outpatient setting
web page. The most relevant documents available that endodontics. The authoritative US resource
from the AHA site can be found under the search for guidelines in this area is the American
key “Guidelines and Statements” and include the Association of Endodontists (AAE), which regu-
following: larly publishes its Colleagues for Excellence
information newsletter, and all issues of this pub-
1. Infective endocarditis (include guidelines for lication are archived at the AAE website.
antibiotic prophylaxis for dental patients and Searches at this site related to dental pharma-
a downloadable “wallet card” for patients, in cology would begin at the “For Professionals”
both English and Spanish). tool. The dentist can then select “Publications &
2. Cardiac Medications At-A-Glance (includes Research” to access the “Journal of Endodontics”
an overview of all categories of cardiovascu- archives and the “ENDODONTICS: Colleagues
lar drugs, with explanations of their mecha- for Excellence” publications. This is the current
nisms of action, indications, etc.) location for the document, “Endodontic and
Antibiotic Update.”
Selection of the tab “Clinical Resources” fol-
American Academy lowed by “Guidelines & Position Statements”
of Periodontology allows access to two other useful documents
related to antibiotic use:
perio.org
This site contains several features with rele- 1. AAE Guidance on the Use of Systemic
vance to dental pharmacology. At the website, Antibiotics in Endodontics.
select “Research and Science” from the top 2. AAE Guidance on Antibiotic Prophylaxis for
toolbar, then “AAP Clinical and Scientific Patients at Risk of Systemic Disease.
Papers.” At this page, the dentist can select
“Position Papers” for information on the follow-
ing topics:  merican Association of Oral
A
and Maxillofacial Surgeons
1. 2017 Classification of Periodontal and Peri-­
Implant Diseases and Conditions. aaoms.org
2. Systemic Antibiotics in Periodontics. Two very significant publications reside at this
3. Tobacco Use and the Periodontal Patient. website. The first is the AAOMS’ Position Paper on
Medication-Related Osteonecrosis of the Jaw
Also at this page, by selecting “Academy (recently updated) and the White Paper on Opioid
Statements,” the following relevant papers may Prescribing are perhaps the most significant
be accessed: resources for the general dentist. The paper on
Internet Resources for Dental Pharmacology 167

MRONJ is addressed in this book in Chap. as they are based on outcomes from multiple
“Introduction to Contemporary Dental systematic reviews and are vetted by ADA
Pharmacology and Special Topics”, and the latter expertise, including the ADA Council on
publication on opioid prescribing is described in Scientific Affairs, ADA Division of Science.
greater detail in Chap. “Opioid Analgesics,
Benzodiazepines, and Other Controlled Substances”.
Cochrane Library

 merican Dental Association (ADA)

A cochrane.org
Center for Evidence-Based Widely regarded as the world’s most authori-
Dentistry tative library of systematic reviews, the Cochrane
Library, established in 1941, only accepts reviews
ada.org/en/resources/research/science-and- based on randomized controlled trials (RCTs)
research-institute/evidence-based-dental- (Fig. 1). In spite of this high standard, the health-
research care professional can access thousands of sys-
This site contains Clinical Practice tematic reviews of medical and dental
Guidelines, Dental Evidence, and Systematic interventions. The site features a “Browse by
Reviews developed under the auspices of the Topic” search tool, under which two topics par-
ADA’s Center for Evidence-Based Dentistry. ticularly suited to this textbook can be found:
The Clinical Guidelines feature of this website
represent the strongest evidence for various 1. Pain and anesthesia.
dental interventions, materials, and procedures, 2. Dentistry abnd oral health.

Fig. 1 Cochrane library homepage

168 A. H. Jeske

Under this item (Pieper et al. 2015), the reader dictions within the United States and US-related
can access a number of dentally relevant reviews. locations within DEA jurisdiction. Also, the order-
For example, “Pharmacological interventions for ing, administration, and prescription of controlled
preventing dry mouth and salivary gland dys- substances in the United States is also regulated by
function following radiotherapy.” After selecting applicable state law and rules and regulations of
a review of interest, the dentist can select the dental and medical licensing boards.
abstract, which briefly describes the background
for the systematic review, the objectives, the
search methods, the selection criteria (used for Drugs.com
identifying those studies which were included
and excluded), the methods used to collect and drugs.com
analyze data, the main results of the systematic This commercial website is very useful and
review, the authors’ conclusions, and an easy-to-­ efficient when information on adverse drug inter-
interpret “Plain language summary.” Finally, a actions is needed. At top of the website, the tool-
search tool allows the reader to access the entire bar contains an “Interactions Checker.” The
systematic review (“Get access to the full text of practitioner enters a series of drug names and then
the systematic review”). Throughout this book, clicks “Check for Interactions.” The software
the reader can see the use of Cochrane systematic does not limit the number of drugs that can be
reviews (e.g., in Chap. “Non-opioid Analgesics entered in this feature. The information is pro-
in Dental Practice”). vided both in plain-English and professional for-
mat and includes a severity rating in regard to
specific interactions, as well as advice of manage-
 rug Enforcement Administration
D ment of interactions. Like other websites of this
(United States) nature, it also contains package insert information
on prescription drugs, as well as links to a variety
https://www.dea.gov of apps and important patient-oriented descrip-
This site is primarily concerned with legal, regu- tions of commons diseases through links to the
latory, and administrative information related to Harvard Health Guides and Mayo Clinic Disease
controlled substances for the United States. For References. The site also has an “advanced search
practitioners who prescribe controlled substances, feature,” a phonetic search feature and drug infor-
there are several very helpful tools and documents mation downloadable in Spanish.
that reside here. Examples include the following In a “Q&A” section, questions about various
major headings, with selected resources following: drugs can be posted and responded to, and there
Drug Info is a list of support groups for patients with vari-
ous serious systemic diseases.
1. Drug Fact Sheets. Additional important features of this website
2. Drug Scheduling. include the following:
3. Controlled Substances Act.
• Master list of drugs A–Z.
Resource Center • Drugs by condition.
• Drugs by class.
1. Drug disposal. • Drug comparisons.
2. How do I… (this feature addresses commonly • Generic drugs.
asked questions, including how to change reg- • OTC drugs.
istration address, etc.) • International drugs.
• Natural products.
The reader is cautioned that this agency, and its • Veterinary products.
web-based information is only applicable to juris- • Drug side effects.
Internet Resources for Dental Pharmacology 169

• Dosage guides. of Medicine’s PubMed database is relatively easy

• Drugs in pregnancy. to use and allows customization of search criteria
• Breastfeeding warnings. to make literature searches very efficient. A com-
• Pricing and coupon availability. plete description of the operation of this website
• Inactive ingredients. is beyond the scope of this textbook. However,
the reader is advised to take advantage of several
Finally, there is a “Pro Edition” tool with an features of this website:
A–Z professional drug list, FDA prescribing
data, AHFS Drug Information Monographs, A–Z 1. On the first page of the site, under the “Using
drugs facts, natural products, Stedman’s Medical PubMed,” “PubMed Tutorials” can be
Dictionary, a list of current medical conferences, accessed to become more familiar with use of
and a comprehensive list of international pharma the site.
companies. 2. On the first page of the site, under the
This website is one of several internet-based “PubMed Tools” category, a “Clinical
drug information services, which also includes Queries” feature can be activated to help
commercial healthcare and pharmaceutical adver- guide a very specific search of relevant
tising and is described here as an example of such articles.
sites, rather than as an endorsement by the author. 3. On the first page of the site, under “More
Resources,” the “MeSH” tool can be activated
(Medical Subject Headings), to help make
 ood and Drug Administration
F searches by subject more efficient.
(United States)
After a specific abstract has been located by
www.fda.gov/ entering a search term in the top search field, a
As the official informational website of the US list of “Similar Articles” appears to the right of
Food and Drug Administration, this site is very the main search outcome screen, and the avail-
likely the most information-intensive one of all ability of free, complete texts of articles is noted
those included in this chapter. For the busy dental in the upper right of the screen, as well as just
practitioner, it can be somewhat challenging to below the abstract, and these may allow down-
navigate. The recommended starting point is the loads of the article in pdf format at no cost or
tool button “Drugs” at the top of the first page. direct the user to a fee-based subscription site.
Second, the tab “Find Information about a Drug”
opens a wide variety of resources, and particularly
useful are links to “Consumer-friendly Information” University of Washington
and the link “Drugs@FDA,” which leads to the full
label information for all FDA-­ approved drugs, ­ ental.washington.edu/dept-­oral-­med/special-­­
d
including approval history. Another potentially needs/patients-­with-­special-­needs/
useful tab is “Orange Book Search,” which pro- While not comprehensive for all disease enti-
vides access to therapeutic equivalencies of differ- ties, this site contains descriptions of appropri-
ent brands of a particular medication. ate dental and medical considerations and
treatment modifications required for the man-
agement of many patients with special needs.
 ational Library of Medicine/
N Once at the homepage, the tool “Additional
PubMed Guidance” can be selected, which then leads to
“Special Needs Fact Sheets.” At this page, there
www.ncbi.nlm.nih.gov/pubmed are four categories of information designed for
Among the most powerful scientific search “Parent/Caregiver,” “Children,” “Adults,” and
engines ever developed, the US National Library “Medical.” While this site does not comprehen-
170 A. H. Jeske

sively cover all serious systemic conditions, it Conclusion

addresses many of the more common ones,
which carry serious implications for possible There are many reliable, scientifically vetted
modifications in dental management and dental internet resources to obtain a variety of informa-
drug therapy. tion related to dental pharmacology. Most are
free of cost and commercial interests and, if used
efficiently, can significantly augment the dental
Evaluation of Randomized practitioner’s access to reliable and, perhaps most
Controlled Trials and Systematic importantly, up-to-date information. At this tran-
Reviews sitional time in the dental profession, that is,
moving from practice based largely on historical
There is a wealth of literature related to various uses of drugs and the application of medical drug
methodologies used for the evaluation of the information to off-label dental prescribing sce-
validity of systematic reviews and randomized narios to evidence-based dental practice, the
controlled trials. Perhaps, the simplest and most practitioner must carefully assess both the quali-
reliable for systematic reviews is the AMSTAR tative and quantitative attributes of scientific lit-
tool (Assessment of Multiple Systematic erature and filter it based on the various levels of
Reviews), which has been published in an scientific evidence. While it is often tempting to
updated, refined format as AMSTAR 2 (Shea adopt a procedure, material or drug to dental
et al. 2017). The AMSTAR instrument is based practice based solely on the recommendation of
on a simple list of 11 items, each of which is cat- an “expert” speaker (level 6 evidence), such deci-
egorized into a standardized set of four possible sions must be weighed carefully against the
responses: “yes,” “no,” “can’t answer,” and “not availability—or lack thereof—of higher levels of
applicable,” and a summary score is determined scientific evidence from randomized controlled
as the sum of all of the “yes” responses. Recently, trials (RCTs) and systematic reviews (level 1 sci-
the AMSTAR instrument and a modified form of entific evidence). Caveat emptor.
it were critically evaluated, and it was determined
that AMSTAR is simple, reliable, and valid,
although additional research is needed for sys- References
tematic reviews of mixed study designs, such as
diagnostic accuracy test studies, studies of dis- Begg C, Cho M, Eastwood S, et al. Improving the qual-
ity of reporting of randomized controlled trials: the
ease etiologies, and studies of prognoses (Pieper CONSORT statement. JAMA. 1996;276:637–9.
et al. 2015). Moher D, Schulz KF, Altman DB, LePage L. The
With regard to the reporting of randomized tri- CONSORT statement: revised recommendations for
als, an instrument termed “CONSORT” is now improving the quality of reports of parallel-group ran-
domised tirals. Lancet. 2001;357:1191–4.
widely accepted as a standard reporting format Pieper D, Buechter RB, Lun L, Prediger B, Eikermann
and is acknowledged routinely in many journals M. Systematic review found AMSTAR, but not
in which the CONSORT-compliant studies are R(evised)-AMSTAR, to have good measurement
published (Begg et al. 1996; Moher et al. 2001). properties. J Clin Epidemiol. 2015;68:574–83.
Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran
Practitioners should familiarize themselves with J, Moher H, Tugwell P, Welch V, Kristjansson E,
the fundamental evaluations provided in these Henry DA. AMSTAR 2: a critical appraisal tool for
publications prior to making changes in patient systematic reviews that include randomised or non-­
care based on published literature. randomised studies of healthcare interventions, or
both. BMJ. 2017;358:400–8.