Internal Medicine Volume 68, Issue 14 | April 14, 2021
Role of Nonopioid Medications in Chronic Pain Management
From the 2020 Congress of Clinical Rheumatology-East, presented by the Virginia Commonwealth
University, University Health Services-Professional Education Programs
Alan David Kaye, MD, PhD, Vice Chancellor of Academic Affairs, Chief Academic Officer and Provost Professor, Louisiana State
University School of Medicine, Department of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Shreveport, LA
Opioid misuse epidemic: top prescribers are internists, family Inhibitors of cyclooxygenase: include aspirin, indomethacin,
practice physicians, nurse practitioners, and physician assis- and NSAIDs
tants; 140,000 deaths from opioid overdose in 2018 to 2020; Aspirin: irreversibly binds and adds an acetyl group to cyclo-
after months of opiate use the production of endogenous opi- oxygenase (ie, prostaglandin-endoperoxide synthase); 40 mg
ates (eg, endorphins, dynorphins, and enkephalins) is shut of aspirin is required to block the majority of thromboxane,
down and the patient becomes dependent on exogenous pre- producing an inhibitory effect on platelet aggregation for the
scription opiate; without exogenous opiate, patients experience lifetime of the effective platelet (eg, 8-9 days)
hyperarousal of the central nervous system or withdrawal NSAIDs: are classified as selective or nonselective according to
COVID-19 and opioid misuse: reasons for the increasing num- their effects on Cox-1 and Cox-2 enzymes; all but one (cele-
ber of overdoses during the pandemic may include less priority coxib) are nonselective, meaning they reversibly bind and
given to urinary drug screenings, increased supplies of medi- inhibit Cox-1 and Cox-2 enzymes; have shorter effect than
cation administered through reduced visits, reduced access aspirin owing to their reversible inhibition; block thrombox-
to prescribers, and increase in use of alcohol, marijuana, and ane and prostacyclin; prostacyclin is replaced by the body but
illicit substances thromboxane is not, resulting in a relative decrease in throm-
Life expectancy: has been declining, in part related to drugs, boxane relative to prostacyclin; selective Cox-2 inhibitors are
alcohol, and suicide; between January and April 2020, inci- no longer used because they reduce both thromboxane and
dence of overdose increased 20%; suicides may be related to prostacyclin, which increases the risk for myocardial infarction
poorly treated pain and stroke; NSAIDs are the most used medication in the United
Reducing opiate prescription: laws minimize the number of States (60 million prescriptions annually)
days opiates can be prescribed after surgery for acute pain, ie, Adverse effects of NSAIDs: Cox-2 inhibitors (eg, celecoxib)
typically 5 to 7 days; much work has been done to improve were developed to reduce adverse gastrointestinal effects; clas-
acute pain management through enhanced recovery after sur- sic NSAIDs result in 15,000 to 20,000 deaths/yr in the United
gery (ERAS) protocols that include acetaminophen, nonsteroi- States owing to silent gastrointestinal bleeding caused by inter-
dal anti-inflammatory drugs (NSAIDs), gabapentin agents, and ference with the Cox-1 pathway; studies showed that 60% to
ultrasound-guided nerve blocks; physicians need to set realistic 80% of patients with gastrointestinal bleeding did not present
expectations for patients concerning pain after surgical proce- with pain or symptoms until the bleeding resulted in morbidity
dures; patients need to be active partners in recovery; goal is to or mortality
reduce the amount of opioid agents administered, thereby reduc- Combination products: combine NSAIDs and a second medica-
ing potential morbidity and mortality (by up to 20%-30%) tion (eg, misoprostol, famotidine [H2-blocker], proton-pump
Nonpharmacologic modalities: include meditation, massage, inhibitor); developed to reduce the incidence of gastrointestinal
physical therapy, acupuncture, transcutaneous electrical nerve bleeding or to treat migraine
stimulation (TENS), cognitive behavioral therapy, guided Ceiling effect: increasing dose does not increase the analge-
relaxation, hypnosis, and music therapy; other therapies with sic effect but does increase adverse effects; NSAIDs can be
less high-quality evidence include heat therapy, cryotherapy, used short-term for acute pain or sprain with inflammation and
and acupressure swelling; should not be used daily for >2 mo; longer use is asso-
Cannabis: is used as an adjunct medication to improve sleep ciated with increased risk for gastrointestinal bleeding; Cox-2
and reduce nausea; some data suggest cannabis reduces anxi- inhibitors can also cause gastrointestinal bleeding, although at
ety, depression, and suicide; however, some studies show that a lower incidence
tetrahydrocannabinol (THC), the active ingredient in cannabis, Mechanisms of action: glucocorticoids block the phospholipase
increases pain sensitivity; a 2017 analysis of 43 randomized 2 pathway and act as potent anti-inflammatory agents; steroid
controlled trials of cannabis use found that the majority of stud- pack can be useful for acute inflammation; lipoxygenase path-
ies did not report significantly improved pain way develops leukotrienes; drugs are available that interfere
Educational Objectives Faculty Disclosure
The goal of this program is to improve the management of acute In adherence to ACCME Standards for Commercial Support,
and chronic pain independent of opioid use. After hearing and Audio Digest requires all faculty and members of the planning
assimilating this program, the clinician will be better able to: committee to disclose relevant financial relationships within
1. Consider the use of complementary medicine to reduce the past 12 months that might create any personal conflicts of
use of opiates. interest. Any identified conflicts were resolved to ensure that
this educational activity promotes quality in health care and
2. Assess evidence on the efficacy of cannabis for improving
not a proprietary business or commercial interest. For this pro-
pain.
gram, members of the faculty and planning committee reported
3. Choose an appropriate nonsteroidal anti-inflammatory nothing to disclose.
drug for a patient with acute pain.
4. Compare the efficacy, risks, and tolerability of antipyret-
ics, tramadol, anticonvulsants, muscle relaxants, and anti-
depressant agents for pain management.
5. Recognize novel applications for pharmaceutical agents
used to treat chronic pain.
IM-68-14
Audio Digest Internal Medicine 68:14
with this pathway; Cox-2 pathway mediates inflammation, Anticonvulsant agents: depress neuronal discharges by raising
pain, and fever; because Cox-1 also produces thromboxane, the threshold for propagation of neural impulses; effective in
selective Cox-2 inhibitors do not have the blood-thinning effect neuropathic pain and headaches; initial dose should be low at
of other NSAIDs, leading to an increase in stroke and myocar- bedtime and be titrated up to desired effect; adverse effects
dial infarction; prostaglandins function in both the central and include sedation and medication interactions
peripheral nervous systems to increase pain sensitivity Applications and risks of anticonvulsant agents: carbamaze-
Indications: NSAIDs are effective for mild-to-moderate pain; pine — used for trigeminal neuralgia; adverse effects include
they lack the adverse effects of opiate agents, including respira- aplastic anemia; valproic acid — used for migraine and mood
tory depression; for patients with chronic pain, NSAIDs can be stabilization; rare complications of liver failure and pancreati-
taken over prolonged periods if drug holidays are taken tis; also associated with teratogenic effects; lamotrigine (eg,
Drug interactions: NSAIDs can interact with anticoagulant agents Lamictal) — has been prescribed incorrectly, causing Stevens-
(eg, warfarin [Coumadin], clopidogrel [Plavix]), causing an Johnson syndrome; topiramate (eg, Topamax) — used for
increase in bleeding; thiazole, methotrexate, and lithium, migraine; adverse effects include confusion; phenytoin (eg,
β-blockers, and angiotensin-converting enzyme (ACE) inhibitors Dilantin) — rarely used in pain management; has a mechanism
can also have complicated interactions of action similar to that of carbamazepine; has a narrow thera-
NSAID medication guide: addresses potential adverse effects of peutic window; can cause Stevens-Johnson syndrome and fetal
myocardial infarction or stroke and death by regular use; also hydantoin syndrome; can cause gingival hyperplasia in up to 1
addresses bleeding, ulcers, and tears along the gastrointestinal in 5 patients; is an inducer of the cytochrome P450 system; all
tract; patients with a higher incidence of bleeding are at higher anticonvulsant agents can increase the likelihood of suicidal
risk (eg, smokers, users of alcohol, patients taking anticoagu- thought
lant agents or corticosteroids, patients in poor health or with Use in migraine: calcitonin gene-related peptide (CGRP) antag-
advanced liver disease, older adults) onists reduce the incidence of migraine; can be taken once a
Therapeutic effects: used as anti-inflammatory agents for patients month or longer for prevention
with musculoskeletal disorders (eg, osteoarthritis, rheumatoid Gabapentinoid agents: gabapentin (eg, Neurontin, Gralise)
arthritis); used to treat acute flare-ups causing severe pain, such and pregabalin (eg, Lyrica) are calcium-channel blockers
as in knee and hip (eg, ketorolac [eg, Toradol] injection); ketor- with a high incidence of sedation, drowsiness, and dizzi-
olac injection can have effects on the liver and kidneys with ness; 50% of patients discontinue use after first prescription;
chronic use; topical formulations are used for stiffness, trouble new formulations have extended release to offset adverse
bending, and inflammation of hands and joint (eg, diclofenac effects but must be taken with food and are linked to weight
gel [eg, Voltaren]) gain; risk of misuse; used for neuropathic pain, including
Acetaminophen: has analgesic and antipyretic effects; can affect nerve root impingement in the lower back, diabetic neurop-
the liver in large doses; mechanism of action is likely through athy, and postherpetic neuralgia; additional indications for
the central nervous system by inhibiting the Cox pathway; pregabalin include fibromyalgia and restless leg syndrome;
different formulations are available (eg, tablets, gel capsules, adverse effects include potential serious breathing problems
liquid); speaker uses in ERAS protocols to reduce postopera- when used with other depressants of the central nervous
tive opiate use and to decrease hospital stay; acetaminophen system
given orally a few hours before surgery is less expensive and Adverse effects of anticonvulsant agents: include weight loss
as effective as when given intravenously; combination prod- (topiramate), rashes, and potential of Stevens-Johnson syn-
ucts (eg, with ibuprofen) are available drome; valproic acid has benefits on mood and is used in psy-
Adverse effects: all labels include a boxed warning concern- chiatry for mood stabilization
ing liver toxicity; acetaminophen-related liver toxicity is the Muscle relaxants: carisoprodol (eg, Soma, Vanadom) was shown
leading cause of acute liver failure globally, often in relation in small studies to have acute benefits for spasm or muscle-
to death by suicide; Food and Drug Administration (FDA) relaxant-type effects with use ≤2 wk; is associated with misuse;
reduced the number of milligrams per dosage unit in prod- in Louisiana, 86% of single-car accidents were attributed to its
ucts with acetaminophen to 325 mg and the maximum daily use; also include methocarbamol (eg, Robaxin), cyclobenzap-
dose from 4000 to <3000 mg; can cause severe skin reac- rine (eg, Flexeril), and tizanidine
tions including Stevens-Johnson syndrome or toxic epider- Antidepressant agents: amitriptyline and venlafaxine are effec-
mal necrolysis, which can lead to blindness or death; 2015 tive for migraine prevention; amitriptyline, duloxetine, and
data suggested use during pregnancy is associated with an milnacipran can be used to manage fibromyalgia; duloxetine
increased risk for attention-deficit/hyperactivity disorder in has been shown to be beneficial in hip, knee, or hand osteo-
offspring; further review of data by FDA showed limitations arthritis; antidepressant effects can be helpful for some pain
in study design and conflicting results; FDA recommends cases; can increase risk of suicidal thinking and behavior;
that patients and clinicians continue to weigh the risks and duloxetine is beneficial for depression, anxiety, fibromyalgia,
benefits in the setting of pregnancy and diabetic peripheral neuropathy; was approved in 2010 for
Tramadol: the 32nd most commonly prescribed medication in the managing chronic musculoskeletal pain
United States; 21 million prescriptions are written annually; an Novel agents for pain: buprenorphine — is a long-acting (half-
analogue of codeine that interferes with serotonin and norepi- life of 37 hr) partial agonist for the mu receptor that has kappa
nephrine reuptake; a Mu-opioid receptor agonist that increases antagonist effects and is used for treatment of opioid misuse;
serotonin levels to improve depression and pain; can cause seda- used for pain relief with a ceiling effect on respiratory depres-
tion, serotonin syndrome, and seizures and is not recommended sion, making it safe; preparations include buccal film strips,
for patients with suicidal thoughts; can also increase risk for tablets, and combination products; is combined with naloxone,
hypoglycemia, hyponatremia, fracture or fall, and death; can an opioid antagonist, to treat opiate misuse; long-acting for-
prolong the QT interval; taking ≥3 medications with this effect mulations are available (eg, Brixadi, which is a buprenor-
can increase risk for torsade de pointes and lethal arrhythmia; phine injectable that lasts >1 mo); long-acting injection
a combination product with acetaminophen is available; risks formulations can be used to treat schizophrenia; buprenor-
include renal failure and hyponatremia; can be used for moder- phine can lead to QT prolongation; lidocaine — is available
ate-to-severe pain in adults ≥18 yr of age; patients may metab- over-the-counter in a patch (eg, Lidoderm) that lasts for 24 hr;
olize the drug at different rates depending on their genetics; a has good local anesthetic effect; capsaicin — depletes and
2019 study in Cameroon showed that use of tramadol was linked prevents the reaccumulation of substance P; indicated for
to 80% of traffic accidents that led to hospitalization neuropathic pain
Audio Digest Internal Medicine 68:14
Questions and Answers schizophrenia: a meta-analysis of controlled trials. Neuropsychopharma-
Herbal products such as turmeric and cumin: treatment of col. 45, 1860–1869 (2020). https://doi.org/10.1038/s41386-020-0730-z;
Conaghan PG. A turbulent decade for NSAIDs: update on current con-
pain has a placebo effect, such that pain improves in 33% of cepts of classification, epidemiology, comparative efficacy, and toxicity.
patients given a placebo; consider adverse effects of various Rheumatol Int. 2012;32:1491-1502; doi:10.1007/s00296-011-2263-6;
herbal preparations to ensure safety even if efficacy is not vali- Mehl-Madrona L et al. Integration of complementary and alternative
dated; one study by speaker found that >98% of products do medicine therapies into primary-care pain management for opiate reduc-
not contain the amount of active ingredients stated tion in a rural setting. J Altern Complement Med. 2016;22(8):621-626.
Medications for sleep: melatonin, an agent that induces sleep, is doi:10.1089/acm.2015.0212; Moore N et al. Adverse drug reactions
safe; in adults >35 yr of age, the pineal gland starts to calcify and drug-drug interactions with over-the-counter NSAIDs. Ther Clin
and melatonin production is reduced; those individuals may Risk Manag. 2015;11:1061-1075. Published 2015 Jul 15. doi:10.2147/
TCRM.S79135; Pelzer D et al. Preoperative intravenous versus oral
benefit from supplementation with melatonin; emphasize good acetaminophen in outpatient surgery: a double-blinded, randomized con-
sleep hygiene; benzodiazepines are not recommended because trol trial [published online ahead of print, 2020 Nov 28]. J Perianesth
they cause lifelong dependency; other preparations can bind Nurs. 2020;S1089-9472(20)30246-X. doi:10.1016/j.jopan.2020.07.010;
valerian or magnesium to induce a restful state Tomson T et al. Teratogenicity of antiepileptic drugs. Curr Opin Neurol.
Suggested Readings 2019;32(2):246-252. doi:10.1097/WCO.0000000000000659; Weiner
SG et al. A health system-wide initiative to decrease opioid-related
Aviram J, Samuelly-Leichtag G. Efficacy of cannabis-based medi- morbidity and mortality. Jt Comm J Qual Patient Saf. 2019;45:3-13;
cines for pain management: a systematic review and meta-analysis of doi:10.1016/j.jcjq.2018.07.003; Wen LS and Sadeghi NB. The opioid
randomized controlled trials. Pain Physician. 2017;20(6):E755-E796; crisis and the 2020 US election: crossroads for a national epidemic.
Chen L et al. Efficacy and tolerability of duloxetine in patients with knee Lancet. 2020;396:1316-1318; doi:10.1016/S0140-6736(20)32113-9;
osteoarthritis: a meta-analysis of randomised controlled trials. Intern Yan M et al. Mechanisms of acetaminophen-induced liver injury and its
Med J. 2019;49:1514-1523; doi:10.1111/imj.14327; Clark SD et al. implications for therapeutic interventions. Redox Biol. 2018;17:274-283;
Opioid antagonists are associated with a reduction in the symptoms of doi:10.1016/j.redox.2018.04.019.
Acknowledgments
Dr. Kaye was recorded virtually at the Congress of Clinical Rheumatology-EAST, presented by the Congress of Clinical Rheumatology
and the Virginia Commonwealth University, University Health Services-Professional Education Programs, and held September 10-13,
2020. For information on future CME activities from this sponsor, please visit ccrheumatology.com and vcu.cloud-cme.com. Audio
Digest thanks Dr. Kaye, the Congress of Clinical Rheumatology, and the Virginia Commonwealth University for their cooperation in the
production of this program.
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Audio Digest Internal Medicine 68:14
Role of Nonopioid Medications in Chronic Pain Management
To test online, go to www.audiodigest.org and sign in to online services.
To submit a test form by mail or fax, complete Pretest section before listening and Posttest section after listening.
1. Which of the following nonpharmacologic modalities is supported by high-quality evidence as being beneficial in reducing
use of opiates?
(A) Acupressure (C) Heat therapy
(B) Cryotherapy (D) Meditation ****
2. Cannabis has been shown to _______ risk for suicide; a 2017 analysis of 43 randomized controlled trials of cannabis use
found that the majority of studies _______ significantly improved pain.
(A) Reduce; reported (C) Increase; reported
(B) Reduce; did not report **** (D) Increase; did not report
3. Which of the following statements about aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is true?
(A) NSAIDs irreversibly bind and add an acetyl group to cyclooxygenase (ie, prostaglandin-endoperoxide synthase)
(B) Aspirin is the most used medication in the United States
(C) Celecoxib is the only selective NSAID approved by the Food and Drug Administration
(D) Aspirin has an inhibitory effect on platelet aggregation for the lifetime of the effective platelet ****
4. Nonsteroidal anti-inflammatory drugs (NSAIDs) selective for the Cox-2 pathway are associated with an increase in which
of the following adverse events?
(A) Urinary tract stones (C) Myocardial infarction ****
(B) Gastrointestinal bleeding (D) Liver failure
5. Nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse interactions with all the following types of medications,
EXCEPT:
(A) Proton pump inhibitors **** (C) β-blockers
(B) Anticoagulants (D) Angiotensin-converting enzyme (ACE) inhibitors
6. Compared with intravenous acetaminophen, oral acetaminophen is _______ effective for preoperative analgesia.
(A) Less (B) Similarly **** (C) More
7. What is the leading significant adverse effect associated with acetaminophen use?
(A) Rental stones (C) Stevens-Johnson syndrome
(B) Stroke (D) Liver injury ****
8. Which of the following anticonvulsant agents used in the relief of pain is strongly associated with teratogenic effects?
(A) Lamotrigine (C) Phenytoin
(B) Topiramate (D) Valproic acid ****
9. Which of the following antidepressants is approved to manage chronic musculoskeletal pain associated with various forms
of osteoarthritis?
(A) Amitriptyline (C) Venlafaxine
(B) Duloxetine **** (D) Milnacipran
10. Which of the following agents with analgesic properties shows evidence of antipsychotic effects in patients with
schizophrenia?
(A) Pregabalin (C) Buprenorphine ****
(B) Tramadol (D) Carisoprodol
Answers to Audio Digest Internal Medicine Volume 68, Issue 12: 1-B, 2-A, 3-C, 4-B, 5-C, 6-A, 7-A, 8-D, 9-D, 10-A
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