Journal of Medical Toxicology (2018) 14:306–322

https://doi.org/10.1007/s13181-018-0685-1

REVIEW

Pharmacologic Treatment of Opioid Use Disorder: a Review

of Pharmacotherapy, Adjuncts, and Toxicity
Michael S. Toce 1,2 & Peter R. Chai 1,3 & Michele M. Burns 1,2 & Edward W. Boyer 1,2,3

Received: 18 May 2018 / Revised: 9 October 2018 / Accepted: 12 October 2018 / Published online: 30 October 2018
# American College of Medical Toxicology 2018

Abstract
Opioid use disorder continues to be a significant source of morbidity and mortality in the USA and the world. Pharmacologic
treatment with methadone and buprenorphine has been shown to be effective at retaining people in treatment programs, decreas-
ing illicit opioid use, decreasing rates of hepatitis B, and reducing all cause and overdose mortality. Unfortunately, barriers exist in
accessing these lifesaving medications: users wishing to start buprenorphine therapy require a waivered provider to prescribe the
medication, while some states have no methadone clinics. As such, users looking to wean themselves from opioids or treat their
opioid dependence will turn to alternative agents. These agents include using prescription medications, like clonidine or
gabapentin, off-label, or over the counter drugs, like loperamide, in supratherapeutic doses. This review provides information
on the pharmacology and the toxic effects of pharmacologic agents that are used to treat opioid use disorder. The xenobiotics
reviewed in depth include buprenorphine, clonidine, kratom, loperamide, and methadone, with additional information provided
on lofexidine, akuamma seeds, kava, and gabapentin.

Keywords Opioid . Withdrawal . Opioid use disorder . Heroin . Buprenorphine . Clonidine . Kratom . Loperamide . Methadone

Abbreviations FDA Food and Drug Administration

AAPCC NPDS American Association of Poison GABA γ-Amino butyric acid
Control Centers’ National Poison hERG Human ether-a-go-go-related gene
Data System I-1 Imidazoline-1
ADHD Attention-deficit hyperactivity disorder IKr Potassium rectifier channel
BUP Buprenorphine and IV Intravenous
buprenorphine/naloxone MAT Medication-assisted treatment
CNS Central nervous system MME Morphine milligram equivalents
COWS Clinical Opiate Withdrawal Scale OUD Opioid use disorder
CYP Cytochrome P450 QTcF Fridericia rate-corrected QT
DEA Drug Enforcement Agency P-gp P-glycoprotein
ECG Electrocardiogram RADARS Researched Abuse, Diversion, and
EDDP 2-Ethyl-1,5- Addiction-Related Surveillance
dimethyl-3,3-diphenylpyrrolidine TdP Torsades de pointes

* Michael S. Toce
[email protected] Introduction
1
Harvard Medical Toxicology Program, Boston Children’s Hospital, Six percent of individuals prescribed opioids continue to use
300 Longwood Avenue, Boston, MA 02115, USA opioids at 1 year [1]. This risk of continued opioid use increases
2
Division of Emergency Medicine, Department of Medicine, Boston exponentially after 5 days of exposure, contributing to the epi-
Children’s Hospital, Boston, MA, USA demic of non-medical opioid use, opioid use disorder (OUD),
3
Division of Medical Toxicology, Department of Emergency overdose, and deaths. Non-medical opioid use is a well-
Medicine, Brigham and Women’s Hospital, Boston, MA, USA described gateway to the use of injection opioid use like heroin,
J. Med. Toxicol. (2018) 14:306–322 307

fueling a persistent rise in opioid overdose death in the USA adrenergic agonists (clonidine, lofexidine), and alternative
[2–6]. The recent detection of synthetic opioids (e.g., clandestine agents (loperamide, kratom, gabapentin, akuamma, kava).
fentanyls and designer opioids) in heroin has contributed to a
dramatic 70% increase in overdose deaths in 2014–2015 [7].
There are some indications that public health efforts such as Mu-Opioid Receptor Agonists
provider education and implementation of the prescription mon-
itoring programs have impacted opioid prescribing as the number Buprenorphine
of opioid prescriptions have decreased from 782 morphine mil-
ligram equivalents (MME) per capita in 2010 to 640 MME per Introduction
capita in 2015; this is still roughly four times the amount distrib-
uted in Europe in 2015 [8–11]. Despite efforts to decrease opioid Buprenorphine and buprenorphine/naloxone (henceforth re-
prescribing, deaths attributed to opioid analgesics increased from ferred to as BUP) have been indicated for the treatment of opioid
16,651 to 22,598 over the same 5 years [12]. Mortality due to dependence since 2002 in the USA. In 2010, a sublingual film
non-medical use of opioids remains a serious concern. In 2015, formulation was approved for clinical use, providing users with
nearly 12.5 million people 12 years of age or older reported using an alternative to the tablet formulation [15]. The use of BUP as
prescription opioids non-medically [13]. MAT for OUD remains highly regulated in the USA; the Drug
Opioid use disorder can be treated with methadone or Addiction Treatment Act (2000) allows physicians to prescribe
buprenorphine, often in combination with behavioral therapy. BUP for 30 patients to manage of opioid use disorder after a
Alternatively, individuals may turn to non-Food and Drug series of training activities and competency tests (X-Waiver)
Administration (FDA)-approved medications to manage OUD. [16]. Providers can then petition the Drug Enforcement
For example, a physician may prescribe clonidine to address the Agency (DEA) for an increase to 100 patients. After a year of
physical effects of opioid withdrawal, or a user may consider the prescribing BUP to 100 patients, a further increase in this limit to
use of high doses of loperamide to manage opioid use. Finally, 275 patients is permitted [17]. There is also evidence that initi-
individuals may use herbal supplements like kratom to prevent ating BUP in the emergency department can increase engage-
opioid withdrawal. Each of these therapies for opioid use disor- ment in addiction treatment and decrease illicit opioid use [18,
der is associated with unique toxicities that providers should 19]. Despite relaxed limits on the number of patients treated,
recognize. Although medication-assisted treatment (MAT) of access to BUP remains difficult. One report describes 43% of
OUD can decrease the incidence of opioid overdose, addiction, counties in the USA still have no physicians who are X-waivered
and death, access to methadone or buprenorphine is limited due to prescribe BUP [20]. In adolescents, only 25% of individuals
to institutional burdens of establishing OUD treatment centers who require treatment for OUD are able to access BUP [21].
and legal requirements surrounding the prescribing of This has resulted in a phenomenon of informal treatment of
buprenorphine. Although recent initiatives to train physicians to OUD through BUP diversion. Individuals who are in BUP treat-
prescribe buprenorphine as MAT have seen increasing enroll- ment may divert a portion of their prescribed BUP to help treat
ments, most of these providers are located in major metropolitan others without access to a BUP prescriber [22, 23].
areas, restricting access to rural patients. Additionally, the amount Compared to methadone, BUP is administered by the indi-
of opioids prescribed has decreased every year since 2010 [14]. vidual in a setting of their choosing, removing the need for
The decreased availability of prescription opioids for non- daily clinic visits. Patients wishing to initiate BUP mainte-
medical use may force individuals to use alternative methods to nance therapy should abstain from opioids for 12 to 48 h or
maintain their high, prevent withdrawal, or treat OUD. exhibit mild to moderate signs and symptoms of opioid with-
In this manuscript, we review the basic pharmacology, ap- drawal measured using the Clinical Opiate Withdrawal Scale
plication, and toxicology of the various pharmacologic (COWS). For reference, a score of 5–12 indicates mild with-
methods of treating OUD. We will focus on treatment options drawal, 13–24 moderate withdrawal, 25–36 moderately se-
that are available in the USA with the understanding that man- vere withdrawal, and > 36 severe withdrawal [24, 25]. The
agement of OUD is complicated and treated differently in dif- starting dose is typically 4 to 8 mg, although additional doses
ferent countries. Given this complexity, it is not possible to can be administered depending on the patient’s needs [26].
address every treatment option and a preference is made to
discuss agents that can produce acute toxicity and that are often Pharmacology
illicitly obtained or used off-label to manage withdrawal. As
such, naltrexone, a μ-opioid receptor antagonist available as a Buprenorphine is a highly lipophilic, partial μ-opioid receptor
daily tablet or as a monthly extended release injectable formu- agonist with a long half-life (mean half-life ~ 37 h) and high
lation, will not be discussed. Agents will be grouped by those binding affinity for the μ-opioid receptor (more than 1000 times
that target the μ-opioid receptor and are considered first-line that of morphine) [27]. In addition to binding to the μ-opioid
treatment options (buprenorphine, methadone), central α2- receptor, BUP also binds to the κ- and δ-opioid receptors, albeit
308 J. Med. Toxicol. (2018) 14:306–322

with lower affinity [28, 29]. Buprenorphine’s activity at the κ- Abuse Warning Network showed that emergency department
opioid receptor is unclear, with studies reporting both partial visits involving BUP increased from 3161 in 2006 to 30,135
agonist and antagonist activity [29–31]. Antagonism of the κ- in 2010 [39]. This increase coincided with not only an increase
opioid receptor leads to decreased spinal analgesia, dysphoria, in the number of BUP prescriptions but also an increase in
miosis, and diuresis through inhibition of anti-diuretic hormone illicit use of BUP [40]. Daniulaityte et al. reviewed internet
release [32, 33]. Finally, BUP also binds to the opioid receptor- discussions of BUP and found that BUP-related posts peaked
like receptor (also known as NOP). Stimulation of this receptor in 2011 with 68% of posts discussing the use of BUP to self-
blocks the rewarding and antinociceptive actions of morphine treat opioid withdrawal [41]. Despite the rise, the overall rate
[28]. Sublingual bioavailability of BUP is approximately 30%, of illicit BUP use among the IV drug using community is rare,
with rapid absorption producing a peak plasma concentration with the majority of users reporting use of BUP to manage
within 1 h [34, 35]. Buprenorphine is frequently co-formulated withdrawal symptoms as opposed to seeking an euphoric ef-
with naloxone, a μ-opioid receptor antagonist, which serves as a fect [42]. Conversely, BUP use in incarcerated individuals is
deterrent to intravenous (IV) abuse of the medication as IV nal- common, with individuals inhaling or insufflating BUP in
oxone administration would quickly induce opioid withdrawal. order to obtain a long-lasting high [43].
Oral or sublingual administration of naloxone does not induce Despite being an opioid, single ingestion BUP-related mor-
opioid withdrawal due to the negligible oral bioavailability of bidity and mortality is rare. Per the 2015 Annual Report of the
naloxone. [35]. Importantly, due to its high binding affinity and American Association of Poison Control Centers’ National
ability to displace many full opioid receptor agonists, adminis- Poison Data System (AAPCC NPDS) 33rd report, there were
tration of BUP to individuals actively using opioids can precip- no reported deaths involving single-substance BUP exposure
itate opioid withdrawal [25]. Buprenorphine is metabolized to and only 56 major clinical outcomes, defined as Bthe patient
norbuprenorphine, its major metabolite, via cytochrome P450 exhibited signs or symptoms as a result of the exposure that
(CYP) 3A4 [27, 35]. Norbuprenorphine is thought to be respon- were life-threatening or resulted in significant residual disabil-
sible for the respiratory depressant effects of BUP [36]. Both ity or disfigurement^ [44]. Paone et al. retrospectively tested
BUP and norbuprenorphine are glucuronidated and excreted in consecutive drug overdose cases through the New York City
the feces and urine [35]. Office of the Chief Medical Examiner from June through
Buprenorphine can be administered in a variety of formu- October 2013 for BUP and norbuprenorphine and found that
lations, depending on whether the patient is using BUP for only 2% tested positive for BUP metabolites. Importantly,
OUD or pain control. Buprenorphine/naloxone combination each case involved multiple substances [45]. In adults, BUP
products that are FDA approved for the treatment of OUD can has a ceiling effect where higher doses do not cause increased
be found in both sublingual tablet and film formulations. levels of respiratory depression or euphoria [46–48]. This
Brand names include Suboxone® (tablet and film, see below pharmacologic effect is secondary to its partial μ-opioid re-
for further discussion), Zubsolv® (tablet), Bunavail® (film), ceptor agonism and is a protective mechanism for opioid-
and Cassipa® (film). Sublingual BUP tablets (without nalox- induced respiratory depression and failure. This protection,
one) are sold under the brand name Subutex®. Generic ver- however, does not apply in individuals who concomitantly
sions of sublingual tablet BUP and buprenorphine/naloxone use sedative agents like benzodiazepines or ethanol [49–51].
are available. In June 2018, the FDA approved the first gener- Unlike adult patients, unintentional pediatric BUP expo-
ic buprenorphine/naloxone sublingual film for the treatment sures can lead to significant morbidity and mortality
of OUD with the hope of increasing access to MAT [37]. [52–56]. In 2013, Lavonas et al. performed a retrospective
In addition to treating OUD, BUP is also used in the treat- root cause analysis of unintentional pediatric BUP exposures
ment of pain. Intravenous BUP (Buprenex®) was approved in utilizing data from the Researched Abuse, Diversion, and
1981 for the treatment of moderate to severe pain. Butrans® is Addiction-Related Surveillance (RADARS) System Poison
a BUP-containing transdermal patch used for around-the- Center Program and Reckitt Benckiser Pharmaceuticals’
clock pain control. Dosages range from 5 to 20 μg/h. pharmacovigilance system. They found that buprenorphine/
Finally, Belbuca®, a long-acting BUP-containing sublingual naloxone combination tablets had the highest rates of expo-
film, was approved in 2015 for the management of severe pain sure, when controlled for drug availability, and the most com-
that is resistant to other options. Compared to other BUP- monly identified root cause was medication that was stored in
containing sublingual products, Belbuca® has a higher abso- plain sight. Adverse effects included lethargy (82%), respira-
lute bioavailability, ranging from 46 to 65% [38]. tory depression (43%), miosis (37%), and emesis (28%).
There were four deaths in their cohort [57].
Toxicity Among unsupervised oral prescription medication ingestions
by children < 6 years of age that required hospitalization, 7.7%
As BUP prescribing has increased, so have emergency depart- were due to BUP, the highest percentage of any single agent
ment visits involving buprenorphine. Data from the Drug examined [58]. Due to the increasing number of pediatric
J. Med. Toxicol. (2018) 14:306–322 309

exposures to the tablet formulation of buprenorphine/naloxone opiates will be negative in individuals who use BUP. If there
(e.g., Suboxone®), Reckitt Benckiser (the pharmaceutical com- is concern regarding adherence to BUP therapy, or an uninten-
pany responsible for Suboxone®) discontinued the tablet formu- tional exposure in the pediatric population, physicians should
lation in 2012, directing patients to the film [59]. Fortunately, order a urine or serum specific screen for BUP or
interventions aimed at reducing unintentional pediatric expo- norbuprenorphine. Serum and urine BUP levels can be obtain-
sures, like unit-dose packaging, which began in 2013, and the ed, but results typically take several days, limiting clinical
development of medicated film strips, may be working. Budnitz utility.
et al. compared emergency department visits for unintentional The majority of adult patients who present with isolated
pediatric BUP exposures before and after these packing and BUP exposure are unlikely to develop significant respiratory
formulation changes and found that visits decreased by 65.3%, depression and most can be monitored in the emergency room
after accounting for prescribing frequency [60]. setting and safely discharged after a period of observation [67].
A more recent publication by Toce et al. examined a single- When BUP overdose results in respiratory depression, reversal
center cohort of pediatric patients with report of unintentional can be accomplished with naloxone [68]. Because of BUP’s
BUP exposure and found higher rates of respiratory depression high affinity for the μ-opioid receptor, larger doses of naloxone
(83%). In their cohort, median time from reported exposure to (2–4 mg) should be used to reverse respiratory depression [69].
respiratory depression was about 4 h, but 25% of patients had Interestingly, there appears to be a U-shaped dose-response
onset of respiratory depression more than 8 h after reported curve for reversal of BUP’s respiratory depressant effects.
exposure. Use of naloxone was common, with 55% of patients Doses of naloxone over 4 mg demonstrate a reduced ability
receiving at least one dose of naloxone. Despite the fact that a to antagonize BUP-induced respiratory depression [68]. In the
quarter of patients had onset of respiratory depression greater context of mixed ingestions with BUP and other sedative-
than 8 h from reported exposure, the vast majority (86%) of hypnotics or opioids, physicians should have a low threshold
patients who received naloxone did so within the first 4 h and for prolonged observation for potential delayed respiratory de-
only two patients received naloxone more than 8 h from time of pression. In the context of mixed overdoses where BUP is
exposure [61]. found in combination with other sedative-hypnotics, adminis-
The conflicting effects seen in children and adults might be tration of naloxone will only reverse the sedation associated
explained by the dramatic difference in the mg/kg administered with BUP. Patients, therefore, may be perceived to have
dose between each group; a 10-kg toddler inadvertently exposed Bfailed^ a naloxone challenge where they may still be experi-
to an 8 mg BUP tab would receive a massively supratherapeutic ence respiratory depression from a non-opioid agent.
dose compared to a 70-kg adult. The observed differences in Due to the risk of delayed respiratory toxicity, we recom-
toxicity between children and adults may also be related to the mend that all pediatric patients with possible exposure to BUP
ontogeny of P-glycoprotein (P-gp). P-glycoprotein functions as be admitted for overnight observation. In the event patient
an effective efflux transport preventing many different xenobi- develops depressed mental status or respiratory depression,
otics, including BUP, from crossing the blood-brain barrier there- 0.1 mg/kg IV naloxone should be administered and repeated
by minimizing the severity of respiratory depression. P- as necessary to ensure that the patient is protecting their air-
glycoprotein concentrations increase throughout gestation; adult way and is maintaining adequate ventilation. Adult patients
postmortem brain cortex tissue has significantly higher P-gp who are maintained on BUP should be counseled on the im-
staining than fetal and infant (age 0–3 months) tissue [62–64]. portance of safe opioid storage because prescription opioid
In a murine BUP model, blockade of this efflux transporter leads pain relievers are frequently accessible to young children [70].
to increased respiratory depression from BUP [36, 65]. The de-
creased concentration of P-gp in infants and in the pediatric brain Methadone
may lead to an increase in cerebral BUP and its major metabolite,
norbuprenorphine, resulting in respiratory depression and in- Introduction
creased toxicity. In addition to P-gp expression, it is possible that
polymorphisms in the ABCB1 gene that codes for P-gp may Methadone is a long-acting synthetic μ-opioid receptor ago-
account from some of the variable respiratory depressive effects nist used in the management of pain and opioid use disorder.
of BUP as individuals with certain mutations in the ABCB1 gene Methadone has been found to be efficacious in retaining indi-
can have greater respiratory depression after receiving IV fenta- viduals in treatment programs, decreasing illicit opioid use,
nyl, a P-gp substrate [66]. and reducing all cause and overdose mortality [71–73].
Methadone has been used as therapy for neonatal abstinence
Testing/Management syndrome [74].
The starting dose for methadone used as MAT is 15–30 mg
Buprenorphine does not share chemical structure similarity to daily, adjusted every 3–5 days as needed to control side effects
morphine and therefore a standard urine immunoassay for and withdrawal symptoms. A typical maintenance dose is 80–
310 J. Med. Toxicol. (2018) 14:306–322

100 mg/day [26]. Methadone is traditionally dispensed from deaths increased 22% per year. [94]. In 2006, the FDA re-
methadone clinics, where patients must present each day for leased new recommendations regarding the prescription of
their prescribed dose, although individuals who demonstrate methadone due to the increase in number of deaths involving
medication adherence can qualify for take-home doses. patients using methadone prescribed for pain. The sales of
Despite the proven benefits of methadone in treating opioid methadone peaked in 2007 and have declined each year there-
use disorder, the regulatory burdens of opening a clinic, a lack after. Unfortunately, fatalities involving methadone remain
of community support, a limited number of available spaces, common; of the single-substance opioid overdose deaths in
and social stigma continue to limit its use [75]. patients prescribed an opioid for pain relief, nearly 40% of
these deaths involved methadone in 2009, despite only
Pharmacology representing 9.8% of morphine milligram equivalents distrib-
uted among the referenced states [95].
Methadone is supplied as a racemic mixture of two enantio- Respiratory depression in methadone overdose or illicit use
mers (R- and S-), with R-methadone possessing 10× the af- is due to excessive agonism of μ-opioid receptors. While BUP
finity for the μ-opioid receptor [76]. Additionally, methadone has a ceiling effect limiting respiratory depression and eupho-
antagonizes the N-methyl-D-aspartate receptor, in vitro [77]. ria, no such ceiling effect exists for methadone. Non-medical
Unlike BUP, which is a partial μ-opioid receptor agonist, users of methadone will present with typical findings of the
methadone is a full opioid agonist. Liquid and pill methadone opioid toxidrome, including lethargy and respiratory depres-
formulations reach maximal plasma concentration in 2 and sion [67]. Mortality is not limited to non-medical users; pa-
3 h, respectively. [78–80]. Methadone has high oral bioavail- tients initiating opioid substitution therapy are at increased
ability (> 80%) and has a long, albeit variable, half-life (7– risk of death, particularly during the first 4 weeks of treatment.
65 h) [78, 79, 81]. Methadone is highly protein bound, limit- Risk of death is also increased in the first 4 weeks after
ing extracorporeal elimination as a treatment for overdoses discontinuing treatment [73, 96].
[82, 83]. QTc prolongation is a known side-effect of methadone
Methadone is primarily metabolized by phase I metabolism [97]. Methadone prolongs the QTc through blockade of cur-
utilizing CYP 2B6 producing the inactive metabolite 2-ethyl- rents through the human ether-a-go-go-related gene (hERG)
1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) [84]. Minor potassium rectifier channel (IKr) [98]. Recently, Isbister et al.
routes of metabolism include CYP 3A4, 2C9, and 2C19 used 12-lead Holter recordings to measure the QTc in 19 pa-
[81]. The CYP2B6 gene is highly polymorphic, with 60% of tients prescribed methadone (median daily dose 110 mg) and
some populations expressing a deficient gene (CYP2B6*6) compared it to 20 patients prescribed BUP and 19 controls and
[85]. Patients with the CYP2B6*6 polymorphism are poor showed that methadone was associated with prolonged QTc
metabolizers and can have increased plasma methadone con- intervals [99]. In their study, QTc prolongation was not asso-
centrations compared to wild-type individuals [86, 87]. ciated with methadone dose. Other studies have shown an
Various drug-drug interactions affect methadone’s metabo- association between methadone dose and degree of QTc pro-
lism. Co-administration of the CYP 2B6 inhibitor sertraline longation. Anchersen et al. examined the prevalence of QTc
has been shown to increase methadone plasma concentrations prolongation among patients in opioid maintenance therapy,
[88, 89]. CYP 3A4 inducers (e.g., anti-epileptic drugs: pheno- which consisted of either methadone or BUP. In their metha-
barbital, carbamazepine, oxcarbazepine, phenytoin; anti-vi- done cohort, nearly 50% had a QTc > 450 ms with 4.6% hav-
rals: nevirapine, efavirenz, ritonavir) accelerate methadone ing a QTc > 500 ms. No patient receiving BUP had a QTc >
metabolism and have been shown to precipitate withdrawal 450 ms. Further, they found a positive dose-dependent asso-
in methadone-dependent patients [90, 91]. Cytochrome P450 ciation between methadone dose and QTc prolongation; all
3A4 inhibitors can lead to opioid toxicity. Herrlin et al. report- patients with a QTc > 500 ms were given a dose of 120 mg
ed on a 42-year-old female on chronic methadone therapy of methadone or greater [100]. Florian et al. analyzed data
(140 mg/day) who developed profound sedation and respira- obtained from five prospective studies, each of which in-
tory depression that was reversed with 0.4 mg IM naloxone cluded individual methadone concentrations and multiple
after starting ciprofloxacin, a known inhibitor of CYP 3A4, Fridericia rate-corrected QT (QTcF) data points, to assess
for urosepsis [92, 93]. the relationship between methadone dose and QTcF. Based
off of their model, they estimate that a methadone dose of
Toxicity > 120 mg/day would increase the QTcF by > 20 ms. Doses
of 160–200 mg/day would cause a change of > 60 ms to
Toxicity from methadone use results in significant respiratory the QTcF with 0.3–2% of patients having a QTcF of >
depression, cardiotoxicity, sensorineural hearing loss and hy- 500 ms [101]. This increase is not trivial as a QTc >
poglycemia. Between 2002 and 2006, distribution of metha- 500 ms has been associated with syncope, cardiac arrest,
done increased 25% per year while methadone-associated torsades de pointes (TdP), and sudden cardiac death [102,
J. Med. Toxicol. (2018) 14:306–322 311

103]. Methadone has also been associated with TdP, partic- Central Alpha2-Adrenergic Agonists
ularly in patients receiving high (> 100 mg/day) doses [104,
105]. Clonidine
Methadone-associated hypoglycemia is a rare adverse
event of methadone exposure. In cancer patients receiving Introduction
methadone for pain control, methadone was associated with
hypoglycemia [106]. Patients are particularly vulnerable dur- Clonidine is marketed and approved by the FDA for the
ing periods of dose escalation [107]. Additionally, hypoglyce- treatment of hypertension and the treatment of attention-
mia has been reported in cases of unintentional pediatric in- deficit hyperactivity disorder (ADHD) in children.
gestion. One report detailed the case of an 11-month-old male Because of it α-adrenergic agonism, clonidine is also
who became hypoglycemic (serum glucose concentration an effective agent that is used off-label for management
17 mg/dL) after unintentional methadone exposure. of withdrawal from opioids [26, 116].Clonidine is par-
Interestingly, the patient was hyperinsulinemic, suggesting ticularly effective at decreasing signs and symptoms of
that methadone my induce insulin secretion [108]. This is in excessive autonomic activity (e.g., anxiety, tachycardia,
agreement with another report of methadone-associated hypo- chills, piloerection, hypertension) and as a result is used
glycemia with inappropriately elevated insulin levels in a 39- to help manage acute opioid withdrawal. Patients are
year-old female on chronic methadone therapy for pain [109]. started on 0.1 to 0.2 mg every 4 h while being moni-
A point of care glucose measurement should be obtained early tored for bradycardia and/or hypotension [26]. Adverse
in cases of severe methadone exposure. effects include sedation, dry mouth, hypotension, and
dizziness [116].

Management Pharmacology

Treatment of methadone overdose involves close monitoring Clonidine is an imidazoline with central α-adrenergic
of patient’s oxygenation and ventilation. Naloxone should be agonism. Clonidine’s oral bioavailability is 70–80% with peak
used in cases of bradypnea/respiratory failure, although care plasma concentrations occurring 1 to 3 h from administration
must be taken so as not to precipitate opioid withdrawal in [117]. There is moderate protein binding (20–40%). Roughly
opioid-dependent patients. Given methadone’s long half-life, half of the absorbed dose is metabolized in the liver with the
naloxone infusions may be required. Our practice is to take remainder being excreted unchanged in the urine. Elimination
two thirds of the effective reversal dose and infuse it over an half-life ranges from 5 to 20 h [118–121].
hour [110]. Particular attention should be paid in Clonidine exerts its cardiovascular effects through its ac-
polysubstance ingestions/exposures involving methadone tion as an α2-adrenergic receptor agonist as well as its action
and benzodiazepines as naloxone will only reverse the opioid on the imidazoline-1 receptor (I-1) [122]. Alpha2 receptors are
effects [49]. Due to the risk of QTc prolongation and TdP, found throughout the central nervous system (CNS) with high
electrocardiograms (ECG) should be obtained on patients concentrations in the locus ceruleus in the pons as well as the
whose daily methadone dose exceeds 100 mg/day or present nucleus tractus solitarii in the medulla. Agonism of these re-
with acute methadone overdose [111]. Additionally, all QTc- ceptors in the locus ceruleus by the α2-adrenergic receptor
prolonging medications should be discontinued, and electro- agonist dexmedetomidine induces sedation in rats [123].
lytes, including potassium, magnesium, and calcium should Stimulation of presynaptic α2-adrenergic receptors in the nu-
be repleted as necessary. A reasonable goal serum magnesium cleus tractus solitarii limits the release of norepinephrine,
concentration is 2 mEq/L, although the optimal magnesium which contributes to the decrease in blood pressure and heart
concentration for treating TdP is unknown. If a patient pro- rate [124]. In addition to binding to α2-adrenergic receptors,
gresses to TdP, they should be rapidly assessed and, if hemo- clonidine binds to the I-1 receptor and this binding is involved
dynamically stable, administered a single bolus of 2 g IV in the anti-hypertensive effects of clonidine [125]. The I-1
magnesium sulfate over 2–3 min. This can be repeated. receptor is in the rostral ventrolateral medulla within the
Magnesium infusions for the treatment of TdP have been re- CNS and in the periphery. Binding of clonidine to the I-1
ported in the literature [112–114]. In the event that the patient receptor leads to hypotension, bradycardia, and decreased
develops sustained TdP, becomes symptomatic (e.g., de- myocardial contractility [122, 126, 127]. Clonidine may also
creased level of consciousness), or pulseless, defibrillation is interact with the endogenous opioid system. In animal models,
necessary. It is important to note that there is significant var- naloxone can reverse the hypotensive and analgesic effects of
iability in the treatment of drug-induced QTc prolongation and clonidine, suggesting that clonidine may induce release of
TdP with the majority of treatment recommendations being endogenous opioids [128–131]. These results have not been
extracted from non-human studies and case series [115]. consistently replicated in humans. Clonidine has been shown
312 J. Med. Toxicol. (2018) 14:306–322

to potentiate the effects of morphine and oxycodone. This Management

effect is blocked by yohimbine, a selective α2-adrenergic re-
ceptor antagonist, indicating a role for the α2-adrenergic re- Treatment of clonidine overdoses involves careful assessment
ceptor in clonidine-mediated analgesia [132, 133]. of ventilation and oxygenation, peripheral perfusion, and
mental status. The need for vasopressors is rare and most
patients are able to maintain adequate blood pressure with
Toxicity IV fluid resuscitation. Endotracheal intubation should be per-
formed if clinically indicated, although this is rare.
The toxicity of clonidine is an extension of its therapeutic use. Bradycardia is common but can be tolerated if peripheral per-
Patients can develop CNS depression, miosis, respiratory de- fusion is adequate. In the event of symptomatic bradycardia,
pression, bradycardia, and hypotension [118]. Occasionally, atropine can be used to augment heart rate. Finally, naloxone
initial hypertension has been reported, likely due to peripheral can be used in cases of severe poisoning to reverse hypoten-
agonism of α-adrenergic receptors [134, 135]. Data on adult sion, bradypnea, and CNS depression, although its efficacy is
clonidine overdoses is limited. A recent report published by debatable [134, 136, 141]. Seger and Loden recently pub-
Isbister et al. examined clonidine ingestions (both isolated and lished a retrospective analysis of the use of high dose (>
with co-ingestions) in patients greater than 15 years of age and 10 mg) IV naloxone in pediatric clonidine exposures. They
found that while CNS depression and bradycardia were com- found that naloxone reversed CNS depression in ~ 80% of
mon (55% and 68%, respectively), serious adverse health out- patients and documented no adverse effects, even with high
comes were rare. In their cohort, the median duration of bra- doses of naloxone [142]. We recommend IV naloxone with a
dycardia was 20 h and the degree of bradycardia was associ- starting dose of 2–4 mg titrated to a reversal of CNS depres-
ated with the dose ingested [136]. sion in symptomatic pediatric patients with clonidine expo-
Severe hypertensive emergency has been reported, but only sure. In adult patients, care should be given in administering
in the setting of a medication filling error when clonidine naloxone especially in the individual maintained on opioids,
intended for an intrathecal pump reservoir was inadvertently or those with OUD, as this will precipitate withdrawal. In
injected subcutaneously [137, 138]. The mechanism of adult patients, supportive care with IV fluids and, if needed,
clonidine-induced hypertension remains unsolved, although vasopressor support, may be the most prudent approach.
it is postulated that massive doses of clonidine can lead to
agonism of peripheral adrenergic receptors and increased vas-
cular tone. Lofexidine
Unintentional pediatric exposures to clonidine are com-
mon. There were 3938 ingestions involving clonidine in Lofexidine is a structural analog of clonidine that functions as
patients less than 20 years of age in 2015 [44]. In one a central α2-adrenergic receptor agonist. Originally marketed
study, clonidine was the second most commonly implicat- as an anti-hypertensive agent, it was approved in 1992 in the
ed medication that resulted in emergency hospitalization UK for the treatment of opioid use disorder [143]. In
for unsupervised prescription medication ingestion in chil- May 2018, the FDA approved it as the first non-opioid treat-
dren less than 6 years of age [58]. Wang et al. examined ment for the management of opioid withdrawal symptoms
the national trends in pediatric exposures to three common [144].
α2 adrenergic receptor agonists (clonidine, guanfacine, and Several randomized double-blinded studies compared
tizanidine) and found moderate or major effects in nearly lofexidine and clonidine in the treatment of opioid withdrawal
20% of clonidine ingestions, with CNS depression and found that these drugs had similar effectiveness in con-
(45.3%), bradycardia (10.2%), and hypotension (8.5%) be- trolling signs and symptoms of opioid withdrawal and reduc-
ing the most common signs and symptoms [139]. Despite ing doses of methadone [145–147]. With regard to adverse
this, interventions like intubation and the use of vasopres- effects, hypotension was less common with lofexidine com-
sors were rare. pared to clonidine. Other adverse effects include dizziness and
Due to its use as a second-line treatment for ADHD in dry mouth [116]. QTc prolongation has been reported when
pediatric patients, clonidine can be compounded to a liquid lofexidine is combined with methadone [148].
formulation, introducing the possibility of compounding er- Given the mechanistic similarities, overdose with
rors as a source of overdose. Romano and Dinh describe a lofexidine would be expected to cause similar signs and symp-
case of a 1000-fold compounding error that lead to significant toms to clonidine, although detailed reports of lofexidine over-
toxicity in a 5-year-old male. The compounding pharmacy dose are lacking. Treatment should focus on good supportive
substituted milligrams for micrograms when preparing the care with careful assessment of the patient’s airway, breathing,
medication, and the patient required multiple boluses of atro- and circulation. Although there is no evidence to support its
pine and a naloxone infusion [140]. use, IV naloxone could be considered in cases of severe
J. Med. Toxicol. (2018) 14:306–322 313

toxicity, with the understanding that it may produce opioid Toxicity

withdrawal in those individuals with opioid dependency.
The use of loperamide for recreational purposes (e.g., to get
Bhigh^) and to combat opioid withdrawal is increasing. Using
Alternative Agents a web-based study, Daniulaityte et al. reported on the dramatic
increase in web-based discussions and posts related to the
Loperamide non-medical use of loperamide. They found that users primar-
ily discussed the use of loperamide to treat opioid withdrawal,
Introduction but that some users were discussing the potential to Bget high^
[168]. A retrospective review of intentional loperamide inges-
Loperamide was first synthesized in 1969 and has been avail- tions reported to the California Poison Control Systems be-
able without a prescription since 1982. Loperamide is FDA tween 2002 and 2015 showed a sharp increase in the number
approved for the treatment of diarrhea and is used off-label in of calls in 2014. Over the entire study period, three deaths
the treatment of opioid withdrawal. Anti-diarrheal doses range were reported as well as nine reports of patients who devel-
from 4 to 16 mg/day, which is far lower than the 200–400 mg/ oped cardiotoxicity. The ingestion size ranged from 200 to
day reported with loperamide abuse [26, 149]. 400 mg/day [149].
This recent increase in use has been substantiated on a
Pharmacology national level as well. Vakkalanka et al. queried the AAPCC
NPDS for reports of intentional misuse, abuse, and suspected
Loperamide is a phenylpiperidine derivative that is used in the suicide between January 1, 2010 and December 31, 2015
treatment of diarrhea [150, 151]. Structurally, it resembles a involving loperamide and found a 91% increase in reported
combination of haloperidol (a neuroleptic) and isopropamide exposures. Single-agent loperamide exposures increased at a
(an anti-cholinergic). Loperamide’s oral bioavailability is low rate of 25 cases per year while polysubstance ingestions in-
(< 1%) due to considerable first-pass metabolism. Systemic volving loperamide increased at a rate of 13 cases per year.
absorption is further limited by P-gp, which decreases gastro- There were 15 deaths in the study period, with 8 involving
intestinal uptake and enhances elimination through bile excre- single-agent loperamide exposure [169].
tion. Loperamide is highly lipophilic, is extensively protein Ventricular dysrythmias are an increasingly recognized
bound (97%), and is metabolized in the liver via CYP2C8 complication of loperamide overdose through prolongation
and CYP3A4 to desmethylloperamide [152, 153]. of the QRS and QTc intervals. Prolongation of the QRS can
Loperamide exerts its anti-diarrheal effects by decreasing lead to ventricular tachydysrhythmias and QTc prolongation
motility and fluid secretion via binding to μ-opioid receptors can induce TdP. Marraffa et al. presented a case series of five
in the myenteric plexus as well as modulation of enteric 5- patients with loperamide abuse, three developed life-
hydroxy-tryptamine release [154, 155]. In addition to the gas- threatening cardiac arrhythmias (monomorphic and polymor-
trointestinal tract, loperamide binds to peripheral μ-opioid re- phic ventricular tachycardia). Loperamide concentrations
ceptors, providing analgesia [156, 157]. Loperamide is able to ranged from 22 to 130 ng/mL (levels obtained in four of the
bind to brain μ-opioid receptors, but brain concentrations are five patients) [165]. For reference, a therapeutic dose of four
kept low via the activity of P-gp [155, 158, 159]. As such, 2 mg tabs of loperamide leads to a peak plasma concentration
traditional opioid effects like CNS depression and bradypnea of 1.18 ± 0.37 ng/mL [170]. Wightman et al. reported the case
are rare with therapeutic dosing. Administration of the P-gp of a 48-year-old woman who presented with somnolence and
inhibitor quinidine increases intestinal absorption and en- weakness and reported ingesting 20–40 2 mg tabs of
hances CNS entry at the blood-brain barrier leading to respi- loperamide a day for several weeks. Her initial ECG was
ratory depression [160]. notable for a QRS 164 ms and a QT 582 ms. She had several
In addition to binding to μ-opioid receptors, loperamide runs of non-sustained ventricular tachycardia that did not re-
binds to and inhibits the hERG-encoded subunit of the IKr as quire intervention. Her serum loperamide concentration was
well as the voltage-gated fast sodium channel, in vitro 210 ng/mL [167]. Finally, Bhatti et al. described the use of
[161–163]. Inhibition of the fast sodium channel leads to im- isoproterenol to prevent bradycardia-induced arrhythmias in a
paired ventricular depolarization and widening of the QRS 37-year-old woman who presented after ingesting ~ 200 tabs
while blockade of the IKr leads to ventricular repolarization of 2 mg loperamide. Her ECG was notable for a QTc >
delay and QTc prolongation. QRS widening and QTc prolon- 600 ms. Labs were notable for a negative loperamide concen-
gation have been reported in loperamide overdoses tration, but a desmethyllopermide level of 32 ng/mL [164].
[164–167]. Loperamide’s effect on the cardiac conduction Loperamide overdose may be lethal. Eggleston et al. re-
system is responsible for much of the morbidity and mortality ported on two deaths involving supratherapeutic loperamide
associated with loperamide overdoses. ingestion in individuals self-treating OUD. The first was a 24-
314 J. Med. Toxicol. (2018) 14:306–322

year-old male found pulseless and apneic who had been using withdrawal [179–181]. Outside of the USA, kratom has
loperamide as an opioid substitute. Postmortem cardiac blood gained popularity in Southeast Asia as a method to manage
analysis revealed a loperamide concentration of 77 ng/mL, in withdrawal from opioids as well as a means to induce eupho-
addition to clonazepam and buprenorphine. The second pa- ria [182]. Kratom can be purchased through internet pharma-
tient was a 39-year-old male who Bsuddenly gasped^ and cies in addition to local head shops [180, 183]. It comes in the
collapsed at home. CPR and resuscitative efforts were unsuc- form of leaves that can be chewed, smoked, brewed into tea,
cessful. Postmortem toxicology was positive for a loperamide or mixed with coffee or sweetened beverages [182].
level of 140 ng/mL [171]. Bishop-Freeman et al. published on
21 loperamide-related deaths in North Carolina and found the Pharmacology
median loperamide peripheral blood concentration to be
0.23 mg/L (230 ng/mL). They also report on the use of various Kratom contains multiple indole alkaloids, with the principle
P-gp inhibitors (e.g., quinine/quinidine) that are used to en- psychoactive components being mitragynine and 7-
hance the loperamide high by blocking P-gp-mediated efflux hydroxymitragynine [184]. The antinociceptive properties of
of loperamide from the CNS [172]. mitragynine and 7-hydroxymitragynine arise from agonism at
the μ-, δ-, and κ-opioid receptors. Additionally, mitragynine
Management binds directly to α2-adrenergic receptors (agonism) and sero-
tonin receptors (antagonism) in the bulbospinal descending
Treatment of loperamide toxicity is largely supportive and pathway [179, 185–188]. Mitragynine has one fourth the po-
should include careful assessment of patient’s airway, breath- tency of morphine, while 7-hydroxymitragynine has ~ 10× the
ing, and circulation. Naloxone should be used when potency of morphine [189, 190]. Mitragynine is rapidly
bradypnea or respiratory depression/failure are present [164, absorbed with a time to maximum plasma concentration of
173]. The lowest effective dose should be used in opioid- approximately 0.8 h. It is extensively distributed throughout
dependent individuals to avoid precipitating withdrawal. the body (volume of distribution ~ 38 L/kg). Both phase I and
Management of loperamide-associated cardiotoxicity is anec- phase II metabolism take place and multiple different metab-
dotal and based on therapies for other drugs that prolong the olites have been identified [184, 191].
QRS and QTc. There is no specific antidote for loperamide.
An ECG should be obtained early in the clinical course. In Toxicity
cases of QTc prolongation, the recommendations included in
the methadone section should be followed. Temporary trans- Kratom exposures reported to the AAPCC NPDS are increas-
cutaneous cardiac pacing as well as isoproterenol can also be ing. Anwar et al. examined AAPCC NPDS and found that
used to augment the heart rate and has been shown to provide calls reported to US poison control centers involving kratom
some benefit in the setting of loperamide-induced dysrhyth- increased 10-fold between 2010 and 2015 [192]. Users of
mias [149, 174, 175]. If the patient’s QRS is prolonged, a trial kratom range from individuals looking to get high, treat
of sodium bicarbonate (50–100 mEq) is a reasonable, with chronic pain, treat opioid dependence, or mitigate opioid with-
either repeated boluses or a bolus and continuous sodium bi- drawal symptoms [179, 180]. In 2007, Vicknasingam et al.
carbonate infusion of 150 mEq of sodium bicarbonate in 1 L performed a cross-sectional survey of active kratom users in
of 5% dextrose (D5W) to infuse at 150 cm3/h if there is clear Malaysia. They found that 90% of short- and long-term users
shortening of the QRS. It is unknown whether sodium bicar- reported using kratom to reduce addiction to other drugs while
bonate is beneficial in treating loperamide-induced QRS wid- 84% reported using kratom to alleviate opioid withdrawal
ening as patients typically receive a multitude of therapies symptoms [193]. Unfortunately, kratom use itself can lead to
[176, 177]. Hemodialysis is unlikely to be effective at remov- dependency, development of withdrawal symptoms, and crav-
ing drug given loperamide’s high degree of protein binding ing [194].
and large volume of distribution. The physical effects of kratom vary depending on the dose
ingested. In low doses (1–5 g of plant product), stimulant
Kratom effects predominate, with users experiencing increased alert-
ness, productivity, sociability, and sexual desire. In higher
Introduction doses (5–15 g of plant product), opioid effects prevail [184].
Serious morbidity and mortality has been reported, but cases
Kratom (Mitragyna speciosa Korth) is a plant native to are often confounded by co-ingestions. Seizures have been
Southeast Asia that has long been consumed for its stimulant reported [179, 195], as has intrahepatic cholestasis [196,
and analgesic properties [178]. It is used informally in the 197], but to date no mechanism has been identified. Karinen
USA to reduce or abstain from non-prescription opioid or et al. reported on the death of a middle-aged man with history
heroin use, manage chronic pain, or mitigate opioid of substance abuse that was found dead in his bed the morning
J. Med. Toxicol. (2018) 14:306–322 315

after consuming kratom. Autopsy identified congested and coldness, diarrhea, dysphoria, yawning, and muscle tension
edematous lungs, with areas of bronchopneumonia. compared to 900 mg/day of gabapentin plus methadone [205].
Toxicologic testing confirmed the presence of mitragynine Overuse of gabapentin alone is common with concomitant
and 7-hydroxymitragynine; zopiclone, citalopram, and opioid use. The top predictor of sustained overuse in
lamotrigine were also detected, but these were all within ther- gabapentin and opioid treated patients was detoxification
apeutic ranges [198]. Similarly, McIntyre described the death [206]. In one study of current non-medical users of diverted
of a 24-year-old male who died after consuming kratom in prescription opioids, 15% reported using gabapentin Bto get
addition to venlafaxine, diphenhydramine, and mirtazapine high^ within the past 6 months [207]. Baird et al. studied
[199]. gabapentinoid (defined as gabapentin or pregabalin) use
As an herbal supplement, kratom remains unregulated by the among patients in six substance misuse clinics in Scotland
FDA, leading to potential adulterants within products marketed and found that over 20% of study participants admitted to
as pure kratom. Lydecker et al. examined several commercially abusing gabapentinoids and of those patients, nearly 40%
available kratom products and assessed for the amount of used gabapentinoids to augment the high they get from meth-
mitragynine and the more potent 7-hydroxymytragynine. adone [208]. The combination of opioids and gabapentin has
Several products contained 7-hydroxymitragynine concentra- been shown to increase the risk of emergency department
tions that far exceeded levels found in naturally occurring visits, inpatient hospitalizations, and/or respiratory depression
plants, suggesting commercial adulteration to generate a more significantly [209]. Finally, Gomes et al. found that co-
potent product [200]. Similarly, Kronstrand et al. described a prescription of opioids and gabapentin was associated with a
case series of nine deaths attributed to a product called 49% increased odds of opioid-related death, with moderate
BKrypton,^ which was found to be a combination of kratom (900–1799 mg/day) dose and high (≥ 1800 mg/day) dose
and O-desmethyltramadol [201]. gabapentin exposure being associated with a nearly 60% in-
crease in opioid-related death compared to no gabapentin use
Management [210].

Treatment of kratom intoxication is largely supportive.

Akuamma
Careful assessment of respiratory status should be performed.
Benzodiazepines should be administered in the event of sei-
Various alternative plants have been described to alleviate
zure activity [195]. Naloxone should be considered if
opioid withdrawal. Seeds from the akuamma (Picralima
bradypnea is present, although bradypnea has yet to be report-
nitida) tree extract contain a variety of alkaloids (e.g.,
ed in isolated kratom exposures and the data for the use of
akuammidine, akuammine, akuammicine, akuammigine, and
naloxone in kratom intoxication is lacking. Isolated kratom
pseudoakuammigine) that have mild opioid receptor (μ-, δ-,
ingestions are unlikely to cause significant morbidity, but care
and κ-) affinity with pseudoakuammigine having analgesic
must be taken in cases of polypharmaceutical ingestion. As
and anti-inflammatory properties [211, 212]. Users describe
the literature above indicates, the combination of kratom with
mild effects similar to those of kratom, with nausea, vomiting,
other sedating xenobiotics can lead to life-threatening CNS
and unpleasant taste being frequently reported [213]. Detailed
depression and respiratory failure.
studies on human toxicity are lacking, but an animal study
showed inflammation and necrosis of the liver [214].
Gabapentin

Gabapentin has been used with varying levels of success to Kava

augment MAT. Gabapentin is a γ-amino butyric acid (GABA)
analog although it does not bind to the GABA receptors. Kava (Piper methysticum) is another herbal product that is
Although its exact mechanism of action is not fully elucidated, consumed for its anxiolytic properties and may be used to
there is evidence that gabapentin inhibits voltage-gated calci- mitigate opioid withdrawal symptoms [215, 216]. Kava con-
um channels leading to reduced excitatory neurotransmitter tains several liphophilic kavalactones concentrated in the root
release [202, 203]. Kheirabadi et al. performed a double-blind, of the plant that increase GABAergic tone, inhibit monoamine
randomized, placebo-controlled trial of methadone plus oxidase B, and block the reuptake of noradrenaline and dopa-
900 mg/day of gabapentin compared to methadone plus a mine. There does not appear to be any direct opioid receptor
placebo in controlling withdrawal symptoms and found no agonism [217]. Kava is effective at treating generalized anxi-
difference between the treatment groups [204]. In the second ety disorder compared to placebo, but its use is limited due to
phase of the same study, Salehi et al. showed that a higher reports of hepatoxicity [218]. Hepatotoxicity was initially
dose of gabapentin (1600 mg/day) plus methadone was supe- thought to be due to extraction techniques that utilized acetone
rior in controlling certain symptoms of withdrawal, namely and ethanol, but subsequent case reports have demonstrated
316 J. Med. Toxicol. (2018) 14:306–322

hepatotoxicity with traditional aqueous kava extracts 4. Grau LE, Dasgupta N, Grau LE, Dasgupta N, Harvey AP, Grau
LE, et al. Illicit use of opioids: is OxyContin® a Bgateway drug^?
[219–221].
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medical users of prescription opioid pain relievers—United States,
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7. Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-
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Financial Disclosure Statement None of the authors have any financial line July 6, 2017. https://doi.org/10.1001/jama.20.
disclosures relevant to this manuscript. 15. Strain EC, Harrison JA, Bigelow GE. Induction of opioid-
dependent individuals onto buprenorphine and buprenorphine/
Conflicts of Interests None. naloxone soluble films. Clin Pharmacol Ther. 2011;89(3):443–9.
16. United States Congress. Drug addiction treatment act of 2000.
Sources of Funding Dr. Boyer is supported by the National Institutes of [Internet]. 2000 [cited 2017 Jan 1]. Available from: https://www.
Health 1K24DA037109. Dr. Chai is supported by the National Institutes deadiversion.usdoj.gov/pubs/docs/dwp_buprenorphine.htm.
of Health K23DA044874. Dr. Burns is the Pediatric Toxicology 17. Substance Abuse and Mental Health Services Administration.
Section Editor for UpToDate®. No funding was provided for the produc- Apply to increase patient limits [Internet]. 2017 [cited 2018
tion of this manuscript. Jul 11]. p. 2728. Available from: https://www.samhsa.gov/
medication-assisted-treatment/buprenorphine-waiver-
management/increase-patient-limits.
Author Attestation No honorarium, grant, or other form of payment
was given to anyone to produce this manuscript. 18. D’Onofrio G, Chawarski MC, O’Connor PG, Pantalon MV,
Busch SH, Owens PH, et al. Emergency department-initiated
buprenorphine for opioid dependence with continuation in prima-
ry care: outcomes during and after intervention. J Gen Intern Med.
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