Pain Management and Opioids

TOPIC 6 SUMMARY

Opioid Pharmacology

INTRODUCTION AND GENERAL PRINCIPLES

Opioids are a broad class of drugs that include agents with widely variable clinical char-
acteristics and that interact in different ways with the characteristics of the individual
patient, including their genetics, concurrent drug use, and comorbidities. Knowledge
of these characteristics and interactions will allow clinicians to prescribe and monitor
opioids in a safer way.

PHARMACOGENETIC VARIABILITY
Because of complex pharmacogenetic variability, not all patients will have the same
response to the same opioid. The human mu opioid receptor gene has more than 100
polymorphisms, along with single nucleotide polymorphisms, that affect opioid
metabolism as well as transport across the blood–brain barrier, activity at target recep-
tors, and ion channels.
For example, codeine is a prodrug metabolized to its active form morphine by cyto-
chrome P-450 2D6 (CYP2D6) enzymes. Some allelic variants of the CYP2D6 gene cause
reduced metabolism of codeine to morphine, resulting in less analgesic effect; others
cause increased metabolism to morphine, resulting in possible toxicity. Depending on
the mutation and population group studied, the prevalence of either rapid or delayed
metabolism ranges from <1% to 34% of patients, with the highest prevalence of both
seen in Africans and African-Americans.

Pharmacogenetic testing to guide management is not yet readily available.

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The specific choice of opioid is typically individualized to the patient based on a range
of factors, including:

• Prior experience with opioids

• Level of opioid tolerance
• Indication for opioid therapy
• Cost of the medication
• Insurance formularies
• Patient age
• Special characteristics such as absorption, route of administration,
and renal or liver clearance

OPIOID FORMULATIONS AND PREPARATIONS

Opioid analgesics are classified as either short-acting or extended-release/long-acting
(ER/LA). Short-acting opioids are typically used for patients who are opioid naive and
have episodic pain, whereas ER/LA opioids are reserved for patients who have estab-
lished opioid tolerance and continuous pain. More detail about the indications, features,
and risks of these medications, as well as examples of each, can be found in Topic 4:
Basics of Opioid Prescribing — Part II.
Opioid Preparations
Opioid analgesics are available in a variety of preparations, including tablets, buccal
films, liquids, and transdermal patches.

• Most patients without swallowing problems will use tablets if the oral route is
used.
• Liquid formulations can be helpful in patients with dysphagia or in those taking
their medication via gastrostomy tube, although most short-acting opioid tablets
can be crushed to accommodate these.
• Transdermal patches may be helpful for patients with reduced gastrointestinal
absorption and for those who cannot have anything by mouth. Only fentanyl
and buprenorphine are available as patches. Both have convenient dosing, slow
peak onset (>24–72 hours), delayed offset (serum half-life >17–26 hours), and
sustained release.
Abuse-Deterrent Formulations
Abuse-deterrent formulations (ADFs) of opioids are specifically designed to reduce the
risks of opioid misuse and diversion by:

• Limiting the potential for the opioid to be chewed, crushed, or dissolved

• Adding nasal irritants to deter patients from snorting the medication
• Combining the opioid with an opioid receptor antagonist like naloxone, which
is only active if the medication is injected

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Although ADFs are formulated to reduce the risk of opioid misuse, there is little evi-
dence to support their success in achieving this goal. Postmarketing studies do show a
reduction in diversion and the street price of these opioids. However, ADFs do not pre-
vent individuals from taking large numbers of intact tablets, which is the most common
way that people misuse prescription opioids and develop opioid use disorder (OUD).
ADFs are also expensive, and some insurers do not cover them.

DRUG–DRUG INTERACTIONS
Cytochrome P-450 Inhibitors
Certain opioids, such as fentanyl, codeine, oxycodone, methadone, and tramadol, are
metabolized by the liver’s cytochrome P-450 (CYP450) enzymes. Medications that inhibit
the CYP450 pathway (see box) have the potential to reduce the clearance of these opioids
and lead to dangerous dose accumulation, thus placing the patient at risk for uninten-
tional opioid overdose. Of note, hydromorphone is primarily metabolized by metabolic
pathways other than the CYP450 system, making it less likely to have a drug–drug inter-
action via this mechanism.

Common CYP450 Inhibitors That May Reduce Opioid Clearance

Antibiotics: ciprofloxacin, erythromycin, clarithromycin
Antifungals: fluconazole, voriconazole, ketoconazole
Antidepressants: fluoxetine, paroxetine, sertraline
Cardiac medications: amiodarone, verapamil, diltiazem
Grapefruit juice

Other Potential Drug–Drug Interactions

Several types of medications should be avoided in the setting of opioid therapy because
of their potentiating effects on sedation and respiratory depression:

• Benzodiazepines
• Sedative hypnotics
• Tricyclic antidepressants
• Monoamine oxidase inhibitors

Methadone is especially likely to interact with other medications. Because it causes pro-
longation of the corrected QT (QTc) interval, extreme caution should be exerted before
combining this medication with others that can prolong the QTc interval. Before pre-
scribing methadone — and before prescribing any new medications to a patient already
taking methadone — clinicians should verify the patient’s medication list and check for
interactions. (See Tools for Clinical Practice below for a searchable database of drugs
that cause QTc prolongation.)

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Interactions with Alcohol
Alcohol interacts with opioids in two main ways:

• It can potentiate the risk of opioid overdose due to its effects as a respiratory
depressant.
• If coingested with certain ER opioids, it can affect the extended-release
mechanism, leading to accelerated release of the opioid (so-called dose
dumping), which can increase the risk of unintentional overdose.

OPIOID METABOLISM IN SPECIAL SETTINGS

Renal Disease
Renal dysfunction can alter the metabolism of opioids and should therefore be consid-
ered both in the choice of opioid and in the dosing. If a patient with renal dysfunction
requires an opioid:

• A medication with less renal metabolism is preferred, such as hydromorphone,

methadone, fentanyl, or buprenorphine.
• The medication is typically started at a lower dose than usual.
• Morphine and codeine are not recommended in patients with renal
dysfunction, because active metabolites of these medications can accumulate
in the bloodstream and lead to nausea, vomiting, somnolence, and signs of
neurotoxicity (e.g., hallucinations, delirium, and myoclonus).
Advanced Liver Disease
Patients with advanced liver disease may pose a challenge to pain management, as
several nonopioid and opioid medications are relatively contraindicated in this setting.
• Nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided because of
increased risk of bleeding and decreased natriuresis, which can worsen the
volume overload in these patients.
• Acetaminophen is generally safer than NSAIDs but should be used with caution
and never at a dose >2 grams daily.
• Other nonopioid analgesics such as anticonvulsive medications, antidepressants,
and muscle relaxants should also be considered, depending on the origin of the
pain.

Opioids are extensively metabolized in the liver with both phase I (CYP450) and phase
II enzymes. Thus, most opioids have reduced clearance and increased accumulation in
patients with liver failure or cirrhosis. If opioids are considered, they should be used
with care and will require reduced dosing and prolonged dosing intervals. The most
appropriate opioids to use in this setting are hydromorphone and fentanyl.

Notably, advanced liver disease is associated with a higher incidence of encephalopathy;

thus, prophylaxis for encephalopathy is recommended if opioids are initiated.

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SPECIFIC OPIOIDS WITH UNIQUE PROPERTIES
Buprenorphine
Buprenorphine is a partial opioid agonist with two different indications: treatment of
opioid use disorder (OUD) and management of chronic pain.

Treatment of OUD
Higher-dose formulations (often coformulated with naloxone to avoid any euphoric effect
from injecting the drug) are indicated for the treatment of OUD and can be prescribed
only by clinicians who have completed specific training and received a waiver from the
U.S. Drug Enforcement Agency that allows them to prescribe for this indication.

Buprenorphine can precipitate opioid withdrawal if it is administered to a patient who

has opioid physical dependence and whose receptors are currently occupied by opioids.
Thus, patients should not have any residual opioid effect from their last dose of opioid
before receiving a first dose of buprenorphine.
Management of Chronic Pain
Lower-dose formulations of buprenorphine are indicated for the treatment of chronic
pain and can be prescribed by any clinician with a license to prescribe opioid analgesics.

As a partial opioid agonist, buprenorphine is less likely to cause respiratory depression

than full opioid agonists. Thus, buprenorphine may be safer than other opioids in
patients with chronic pain who are at high risk for respiratory depression from medical
conditions such as sleep apnea and chronic obstructive pulmonary disease. Although
buprenorphine does inhibit respiration, this effect does not increase at higher doses.
Notably, the relative advantage of buprenorphine with regard to respiratory depression
is lost when the drug is taken with other respiratory depressants such as benzodiaze-
pines or alcohol.

All opioid-tolerant patients should have their current opioid tapered to no more than
30 morphine milligram equivalents (MMEs) before initiating buprenorphine for pain.
The initial buprenorphine dose will then be determined by the patient’s previous opioid
dose before the taper.
Methadone
Methadone is a unique full opioid receptor agonist that can be used to effectively treat
OUD through a licensed opioid treatment program and also to treat chronic pain in the
outpatient setting.

Methadone is an effective, low-cost option for chronic pain. It has a long duration
of action and, because its long-acting properties are not based on the formulation,
it is the only ER/LA opioid available in low doses that can be divided. It also blocks
the N-methyl-D-aspartate (NMDA) receptor, which may provide additional benefit in
situations of neuropathic pain, opioid tolerance, and opioid-induced hyperalgesia.

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One adverse effect of methadone, as noted above, is prolongation of the QTc interval,
which can lead to torsades de pointes, a life-threatening cardiac arrhythmia. Current
guidelines recommend obtaining a screening electrocardiogram (ECG) before initiating
methadone in any patient who has a risk factor for QTc prolongation, such as:

• Structural heart disease

• Genetic predisposition
• Use of other medications with QTc-prolonging properties

Given the dose-related effects of methadone on the QTc interval, an ECG is also recom-
mended in low-risk patients if their methadone dose is adjusted to exceed 30 to 40 mg
daily — and then again if the dose reaches 100 mg daily. Methadone should be avoided
in patients with a QTc interval ≥500 msec and should be used only cautiously in those
with QTc intervals between 450 and 500 msec.
Dual-Action Opioids
Tramadol and tapentadol are dual-mechanism opioids that are structurally related to
morphine and codeine.

• Tramadol is a mu opioid receptor agonist that also inhibits norepinephrine and

serotonin reuptake.
• Tapentadol is a mu opioid receptor agonist that also inhibits norepinephrine
reuptake.

These medications carry the same risks as other opioids, including the risks of physi-
cal dependence and addiction, and should therefore not be considered “nonabusable”
opioids. In addition, both medications carry seizure risk and have been associated with
serotonin syndrome, particularly if combined with other serotonergic medications.

TOOLS FOR CLINICAL PRACTICE

• DailyMed: Searchable database (from the National Library of Medicine) of label

information for drugs marketed in the United States
• CredibleMeds: Searchable database of drugs that prolong the QT interval and
induce torsades de pointes
• Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression
(RIOSORD): A questionnaire used to estimate the risk of overdose in opioid-
treated patients
• Risk Classes and Predicted Probability of Serious Opioid-Induced Respiratory
Depression during the Next 6 Months: A guide to interpreting the RIOSORD
score

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LEARNING RESOURCES

• DSM-5 OUD Criteria: A complete list of diagnostic criteria for opioid use
disorder
• Initiating Buprenorphine: An infographic describing the four key steps to
starting buprenorphine for OUD treatment, from the producers of the podcast
The Curbsiders Internal Medicine
• Challenges of Managing Chronic Pain with Opioids – Part 1: A 23-minute
episode of the NEJM Resident 360 Curbside Consults podcast in which experts
examine a series of case scenarios about worrisome opioid use and discuss how
clinicians can handle their feelings during these difficult patient visits
• Challenges of Managing Chronic Pain with Opioids – Part 2: A 21-minute
episode of the NEJM Resident 360 Curbside Consults podcast in which a
patient receiving opioid therapy for chronic pain discusses how he manages his
relationship with his clinician, his pharmacy, and society at large

Last reviewed Mar 2020. Last modified Mar 2020. The information included here is
provided for educational purposes only. It is not intended as a sole source on the subject
matter or as a substitute for the professional judgment of qualified health care professionals.
Users are advised, whenever possible, to confirm the information through additional sources.

© 2020 Massachusetts Medical Society. All rights reserved.

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