Pain Management Opioids Summaries

Pain Management and Opioids
TOPIC 1
Musculoskeletal Pain............................................................ 1
TOPIC 2
Common Non-Musculoskeletal Pain..................................... 6
TOPIC 3
Basics of Opioid Prescribing — Part I..................................10
TOPIC 4
Basics of Opioid Prescribing — Part II.................................19
TOPIC 5
Complex Situations in Opioid Prescribing............................27
TOPIC 6
Opioid Pharmacology..........................................................34
TOPIC 7
Acute Pain..........................................................................41
TOPIC 8
Opioid Use Disorder...........................................................46
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.

TOPIC 1 SUMMARY
Musculoskeletal Pain
INTRODUCTION AND GENERAL PRINCIPLES

Musculoskeletal complaints are highly prevalent in clinical practice. Acute or chronic
low back pain is one of the most common reasons for patients to seek care, and chronic
pain in general has been reported in 20% to 30% of the population. There are multiple
etiologies of musculoskeletal pain, including specific diagnoses such as osteoarthritis
and lumbar disk disease, as well as nonspecific pain.
Importantly, stress, depression, and anxiety have all been linked to an increased risk for
developing chronic pain. This association is considered bidirectional: people with mood
disorders seem more likely to develop chronic pain, and people who have chronic pain
syndromes are at risk for developing mood disorders. Thus, it is important to conduct a
psychosocial evaluation in all patients who present with chronic pain symptoms and to
actively manage both the chronic pain and any comorbid mood disorder.
In general, musculoskeletal pain can be managed with pharmacologic or nonpharma-

cologic interventions. Nonpharmacologic or self-management options are usually rec-
ommended initially given their safety profiles and other benefits, although they do not
all have strong evidence to support their use, and the exact modality recommended
depends on the specific clinical scenario. Examples include:
• Physical therapy, which has the strongest evidence base and is therefore typically
recommended as a preferred treatment modality
• Psychological approaches
• Complementary therapies
If pharmacologic therapy is necessary, nonopioid analgesics, such as acetaminophen

or nonsteroidal antiinflammatory drugs (NSAIDs), are strongly preferred. Muscle relax-
ants are often used but carry the risk of sedation; in particular, carisoprodol and ben-
Topic 1: Musculoskeletal Pain knowledgeplus.nejm.org 1

zodiazepines should be avoided. Opioids are typically not recommended for chronic
musculoskeletal pain, as they are high-risk medications with very little evidence for
long-term benefit in these disorders and are therefore best avoided if possible.
Interventional therapies may be indicated in some settings. These include glucocorti-

coid injections, approved medical devices for pain, and, in certain scenarios, surgical
approaches.
LOW BACK PAIN

Low back pain is one of the most common reasons for medical visits in the United
States, and it is important for clinicians to have a diagnostic and management heuristic
to quickly identify patients in whom additional testing is indicated.
Acute Low Back Pain
In most patients, acute low back pain is benign and will resolve without intervention.
In these patients, no imaging evaluation is required, and the patient can be prescribed
6 weeks of conservative therapy consisting of NSAIDs and activity modification (i.e., con-
tinuing physical activity but avoiding those activities that exacerbate the pain). Physical
therapy can be recommended if the pain does not resolve with these initial measures.
Muscle relaxants are also sometimes used but with caution because of the potential for
sedation.
Certain so-called red flags would prompt a more active evaluation strategy, with imaging
to rule out more-concerning etiologies such as infection or malignancy. Examples of
red flags include:
• Neurologic deficits (saddle anesthesia, muscle weakness)

• Fecal or urinary incontinence
• Constitutional symptoms (fever, chills, night sweats, weight loss)
• History of injection drug use
• Immunocompromised state
• Recent infection (urinary, skin, bloodstream)
• History of malignancy (especially breast, lung, or prostate)
• Osteoporosis
• Age >65 years
• Pain lasting more than 4 to 6 weeks
Glucocorticoid Injections
In certain cases, epidural, nerve-root, or facet-joint glucocorticoid injections are used.
These are generally considered only after a 4- to 6-week trial of conservative therapy
fails, and an MRI is usually a prerequisite to use. These injections may help speed short-
term pain relief but do not alter long-term outcomes. Although systemic glucocorticoids
(e.g., prednisone) are frequently given, they have not been shown in randomized trials
to improve outcomes for patients with sciatica or lumbar radiculitis and are therefore

not recommended. Similarly, surgical interventions are rarely appropriate in the acute
setting.
Progression of Acute to Chronic Low Back Pain
Some patients with acute low back pain go on to develop chronic low back pain. Risk
factors for such progression include:
• Obesity (BMI >30)

• Female sex
• Older age (>65 years)
• Lower educational status
• Physically demanding occupations
• Psychosocial factors, such as anxiety and depression
Validated tools are available to screen for progression to chronic low back pain (see
Tools for Clinical Practice below). If a patient is found to be at high risk, the treatment
can be intensified or focused on the basis of that risk.
Chronic Low Back Pain
Management options for chronic low back pain are similar to those for acute low back
pain, including physical therapy and simple analgesics such as acetaminophen and
NSAIDs. Glucocorticoid injections can be used, especially if MRI results confirm nerve-
root compression corresponding to the clinical findings.
Surgical interventions for chronic low back pain (e.g., lumbar spinal fusion, laminec-
tomy, diskectomy) are controversial. Surgery is commonly used in patients with radicular
symptoms recalcitrant to nonoperative care, in those with neurogenic claudication from
lumbar spinal stenosis, and in those with sustained or worsening neurologic deficits.
However, its role in nonspecific low back pain without these features is much less well
established. In studies comparing surgery with structured nonoperative interventions
that included a cognitive behavioral component, functional outcomes were similar, but
adverse effects were much more frequent with surgery. Nevertheless, surgery can be
considered if other options have been unsuccessful.
There is little evidence to support the use of opioids for long-term management of low
back pain. Although there may be individual patients in whom the benefits outweigh the
risks, opioids are generally used only as a last resort.
KNEE AND HIP OSTEOARTHRITIS

The diagnosis of knee and hip osteoarthritis is based primarily on a compatible clinical
history. Both conditions manifest with gradual onset of pain in the affected joint, which
worsens with activity. In hip osteoarthritis, physical examination typically reveals lim-
itations in range of motion without other abnormalities. In knee osteoarthritis, crepitus
and tenderness along the joint line may be found on physical examination. Features of

inflammation, including fevers, chills, night sweats, and warm effusions, are not typi-
cally seen, although cool effusions may be present.
Plain-film radiographs of the affected joints can be obtained to confirm the diagnosis
but are not required.
Nonpharmacologic Management
Physical therapy and lifestyle interventions, including physical exercise to build muscle
strength and promote weight loss, are first-line treatments for knee and hip osteo-
arthritis. These are the only interventions that have been shown in multiple studies to
provide significant short- and long-term benefits in patients with degenerative joint dis-
ease. Knee braces can also help reduce pain in patients who are amenable and adherent
to this intervention.
Nonopioid Analgesics
Acetaminophen may provide sufficient pain relief if symptoms are mild.
Systemic NSAIDs — taken alone or in conjunction with acetaminophen, and as needed

or standing — are effective at reducing pain in patients with degenerative joint disease,
but they are also associated with an increased risk of adverse cardiac events, stroke,
kidney injury, and gastrointestinal bleeding.
Topical NSAIDs have minimal systemic absorption and are associated with a lower risk
of adverse effects. Topical NSAIDs are an appropriate first-line therapy for knee and
hand osteoarthritis given the superficial location of these joints.
Injections and Surgery
Glucocorticoid injections are effective in reducing pain temporarily without causing
significant adverse events in the short term. However, this treatment does not slow
progression of osteoarthritis, and repeated injections have not been shown to lead to
long-term reduction of pain. These injections are therefore typically reserved for patients
in whom more conservative treatment options have failed.
If conservative treatment options fail, then referral to an orthopedic surgeon for joint
replacement should be considered. Although there are surgical risks, these are usually
acceptable or can be mitigated.
Opioid Analgesics
Opioid analgesics should be used only with caution in this setting, given the adverse
effects of these agents, the lack of evidence for long-term benefit (as seen in the SPACE
trial), and the chronic nature of osteoarthritis (long-term use of opioids has less evi-
dence of benefit, with more risk of harm, than short-term use). Typically, joint replace-
ment should be considered a better option than chronic opioid therapy. However, there
are still individual patients who may benefit from opioid analgesics, and therefore opi-
oids can be considered in select cases.

If an opioid is attempted, the clinician should follow best practices for chronic opioid
therapy, including:
• Signing a structured agreement with the patient

• Planning frequent face-to-face visits to assess the risks and benefits of the
therapy
• Monitoring for opioid misuse, including urine drug testing, pill counts, and
checking prescription drug monitoring program data
WHEN TO REFER TO A PAIN SPECIALIST

Referrals to pain specialists are indicated in a variety of situations, including:
• When there is uncertainty about the specific pain diagnosis or pain generator
• When specialist input is required, such as when interventional treatment options
may be indicated
• When patients may require chronic opioid therapy but are at high risk for opioid
misuse
Pain specialists offer a wide variety of services, ranging from behavioral therapies to
interventional therapies to comprehensive multimodal care. Clinicians should be aware
of the specific services offered by a given pain specialist to ensure that the specialist
offers the services required for a particular patient.
TOOLS FOR CLINICAL PRACTICE
• STaRT Back Screening Tool: A 9-item questionnaire used to screen primary care
patients with low back pain for prognostic indicators that are relevant to initial
decision-making
LEARNING RESOURCES
• Opioid Efficacy for Chronic Pain: A slide (from Boston University School of
Medicine) summarizing the available evidence on the use of opioids for chronic
pain
• Diagnosis and Treatment of Low Back Pain and Dianosis and Treatment of
Osteoarthritis: Algorithms from NEJM Knowledge+ that describe how to
diagnose and treat low back pain (including simple back pain, radiculopathy,
and stenosis) and osteoarthritis.
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.
TOPIC 2 SUMMARY
Common
Non-Musculoskeletal
Pain

Although musculoskeletal conditions are the most prevalent cause of chronic pain, a
range of other common conditions may also cause such pain, including neuropathic
pain syndromes, fibromyalgia, and headache.
In each of these conditions, establishing the underlying diagnosis is important and may
allow treatment of causative or exacerbating factors. For example, achieving restorative
sleep is paramount in both fibromyalgia and migraine. Similarly, although diagnosis
and adequate treatment of diabetes mellitus is necessary for controlling small-fiber
neuropathy, screening for common comorbid causes of peripheral neuropathy, such as
vitamin B12 deficiency and thyroid disease, is also important.
Once the diagnosis is made, additional nonpharmacologic therapies and pharmacologic

treatments can be initiated.
DIABETIC NEUROPATHY
Diabetic neuropathy can manifest in a variety of ways, such as:
• Painful, small-fiber neuropathy

• Entrapment neuropathy
• Diabetic amyotrophy
• Length-dependent, large-fiber sensorimotor neuropathy
Initial treatment consists of improved glycemic control, physical exercise, and gait train-
ing; pharmacologic options can be added if needed.
Topic 2: Common Non-Musculoskeletal Pain knowledgeplus.nejm.org 6

First-line medications for pain from diabetic neuropathy include:
• T
he tricyclic antidepressant (TCA) amitriptyline
• The serotonin–norepinephrine reuptake inhibitors (SNRIs) duloxetine and
venlafaxine
• The anticonvulsants pregabalin and gabapentin
When deciding among these agents, clinicians should consider each medication’s
adverse-effect profile and the individual patient’s comorbidities.
Although there are some moderate-quality data supporting the use of opioids (e.g.,
oxycodone, tramadol) for alleviating neuropathic pain, these medications are not con-
sidered first-line agents because of concerns about their overall risk–benefit ratio.
POSTHERPETIC NEURALGIA
Postherpetic neuralgia is characterized by severe neuropathic pain in a dermatomal
distribution that persists for more than 90 days after herpes zoster reactivation. The
risk of developing this condition increases with advancing age. Treatment is symp-
tomatic and can consist of topical agents, oral neuropathic pain medications, and
interventional pain techniques.
If the pain is in an accessible area (excluding the face, V1 distribution), topical therapies
can be used, such as lidocaine patches (once daily) and capsaicin cream (up to four
times daily). Typically, these agents are reasonably well tolerated except for occasional
local adverse effects such as rashes and stinging. They have limited absorption, and
systemic adverse reactions are rare.
First-line oral agents for postherpetic neuralgia include gabapentin, pregabalin, and
TCAs such as amitriptyline. A specific concern with gabapentin and pregabalin is the
risk of misuse, which is increasingly being recognized. In addition, there are consid-
erations with the use of any of these agents in older patients because of the expected
age-related decrease in therapeutic index. Specifically, all of these medications are asso-
ciated with sedation and should therefore be started at low doses, with careful monitor-
ing for adverse effects while the dose is titrated upward.
Opioids have mixed evidence of a benefit in postherpetic neuralgia, but their use is best
avoided (especially in the elderly) because of their potential risks.
FIBROMYALGIA
Fibromyalgia is characterized primarily by widespread myofascial pain and often involves
chronic fatigue and sleep disturbances. Other common symptoms include cognitive dif-
ficulties, depressed mood, anxiety, headaches, and digestive problems such as irritable
bowel syndrome.
Guidelines from the European League Against Rheumatism (EULAR) offer the most com-
prehensive evidence-based review of management principles for patients with fibromyalgia.

Data are mixed across large meta-analyses but generally favor the following nonphar-
macologic interventions:
• hysical exercise (recommended as first-line therapy)

P
• Acupuncture
• Cognitive behavioral therapy
• Mindfulness practice
• Meditative movement (yoga, tai chi)
Certain pharmacologic treatments have also been found to be effective, including

duloxetine and pregabalin (which are preferred if pain is the main symptom), the
SNRI milnacipran, and low-dose amitriptyline (which is preferred if insomnia is the
main symptom or if there is concurrent depression). Nonsteroidal antiinflammatory
drugs (NSAIDS), glucocorticoids, and opioids do not have a role in the management of
fibromyalgia.
MIGRAINE
Migraine headache afflicts more than 10% of the population and is a global burden
on quality of life. Therapy involves avoidance of triggers, management of risk factors,
pharmacotherapy, and other treatment modalities. Treatment options depend on the
episodic versus chronic nature of the headaches, comorbid associated features, and the
patient’s medical profile.
For an acute migraine attack, treatments include:
• N
onpharmacologic interventions, such as moving into a darkened room,
reducing light stimulation and noise levels, and engaging in osteopathic
manipulative treatment
• Acetaminophen
• Triptans, such as sumatriptan
• NSAIDs, such as ibuprofen or ketorolac
• Butalbital–acetaminophen–caffeine
• Metoclopramide (if nausea and vomiting are prominent, other antiemetics can
also be used, such as diphenhydramine, prochlorperazine, or chlorpromazine)
Opioids are almost never indicated for treatment of migraine; they are typically only
used as a last resort and then only briefly.
LEARNING RESOURCES
• Diagnosis & Treatment of Fibromyalgia: An algorithm from NEJM Knowledge+

detailing the diagnosis, evaluation, and treatment of fibromyalgia

• Diagnosis & Treatment of Neuropathic Pain: An algorithm from NEJM
Knowledge+ that describes how to diagnose and treat neuropathic pain,
including painful peripheral neuropathy and postherpetic neuralgia.
TOPIC 3 SUMMARY
Basics of Opioid
Prescribing — Part I

Prescription opioids are medications that work as agonists at the opioid receptors, which
are distributed throughout the brain, spinal cord, peripheral nerves, and digestive track.
These medications can be classified as follows:
DESCRIPTION EXAMPLES
Natural opiates Derived from the opium Codeine, morphine
poppy
Semisynthetic opioids Directly derived from natural Hydrocodone, hydromorphone,
opiates oxycodone, oxymorphone, and
buprenorphine
Synthetic opioids Created in the laboratory Methadone, meperidine, and fentanyl
Opioids are powerful analgesic medications that can be effective in treating chronic
pain. They work by directly affecting ascending and descending pain signals in the cen-
tral nervous system and preventing activation of peripheral nociceptors. All opioids also
activate the reward system in the brain and, with chronic exposure, cause physiologic
adaptations, namely tolerance and physical dependence.
Opioids also have the potential to cause severe adverse effects, and opioid misuse can
be fatal. The challenge for the clinician then is to reduce opioid prescriptions where
possible while ensuring safer prescribing when indicated.
WHEN TO CONSIDER OPIOID THERAPY FOR CHRONIC PAIN

Nonpharmacologic therapies and nonopioid therapies are preferred for management
of chronic non–cancer-related pain and can also be effective in patients with cancer-
Topic 3: Basics of Opioid Prescribing — Part I knowledgeplus.nejm.org 10

related pain. These therapies include acetaminophen, nonsteroidal antiinflammatory
drugs (NSAIDs), medications with proven benefit for neuropathic pain (serotonin–
norepinephrine reuptake inhibitors, tricyclic antidepressants, gabapentinoids), and top-
ical agents such as lidocaine or capsaicin. Engagement in self-management is important
in chronic pain as in all chronic illnesses.
Opioids are not first-line therapy for chronic non–cancer-related pain because of their
potential risks, lack of evidence of long-term efficacy, and the possibility of tolerance
or hyperalgesia. However, opioids may be appropriate on a trial basis for patients with
chronic pain if the following conditions are met:
• The pain is severe and has a significant effect on function and quality of life.
• The pain has not responded favorably to other appropriate interventions, or the
other available interventions represent higher risk (e.g., NSAIDs in a patient with
chronic kidney disease).
• The benefits of opioid therapy are expected to outweigh the risks.
Opioids are a mainstay for severe cancer pain, where they can help achieve pain control
in 70% to 90% of patients. They are also beneficial for symptom control in palliative
and end-of-life care.
STEPS FOR INITIATING OPIOID THERAPY

Opioid therapy should only be initiated after careful considerations of the risks and
benefits of treatment, and every effort should be made to reduce the risks. The steps are
as follows:
1. Determine whether there is an indication for opioid therapy.
2. Establish clear functional goals with the patient. Goals should be SMART:
• Specific about what the patient will set out to do
• Measurable, so that you and the patient can determine whether the goal has
been met
• Action-oriented (rather than passive)
• Realistic with respect to the patient’s current condition
• Time-bound, so that the goal is being measured within a very specific time frame
3. Plan to continue nonopioid medications for complementary and synergistic effects

as helpful.
4. Assess the potential risks of opioid therapy, including:

• Risk of misuse (discussed below)
• Medical risks, such as sleep apnea, renal or hepatic dysfunction, or use of other
central nervous system (CNS) depressants
5. Consider referral to an appropriate specialist if you identify a high risk of misuse or

a need for interventional pain management.
6. Institute a patient–provider agreement. Such agreements typically outline the
following:
• The planned frequency of follow-up visits to assess pain, function, adverse effects,
and progress toward established goals; follow-up is typically at least every 4 weeks
initially, progressing to at least every 3 months
• Review of all medications in the planned regimen, including name, dose,
frequency, and instructions for taking the medication
• Review of risky medication-associated behaviors, such as requesting early refills
or obtaining refills for controlled substances from other providers
• Tools to be used for risk monitoring, such as urine drug testing, pill counts, and
reports from the prescription drug monitoring program (PDMP)
7. Provide an at-home naloxone rescue kit.
8. For opioid-naive patients, start with a short-acting agent.

• In general, these agents should be initiated at a low dose and kept at the lowest
dose possible.
• Exercise caution with dosing in patients with risks such as obstructive
sleep apnea, hepatic or renal dysfunction, or concomitant use of other CNS
depressants.
Once a patient has been taking a short-acting opioid for at least one week, he or she
may transition to an extended-release/long-acting (ER/LA) opioid. The main reason to
do this is the longer duration of analgesia; studies have not demonstrated any substan-
tial benefit otherwise. Of note, there is a higher risk of harm with misuse of ER/LA
opioids because of the concentrated doses. Patients must be instructed to never disrupt
(e.g., break or crush) the ER/LA opioid formulation.
Risk of Opioid Misuse and Opioid Use Disorder
One of the major risks of opioid therapy is the potential for misuse. Medication misuse
is defined as use contrary to the prescribed use, regardless of the presence or absence of
harm or adverse effects. Opioid use disorder (OUD) is defined as a pattern of continued
opioid use with experience of, or potential for, harm. All patients should be evaluated for
risk of opioid misuse before being prescribed opioids; this includes patients receiving
opioid analgesics for cancer-related pain.
A multifaceted approach is needed to help identify patients at risk. The first step is a
patient interview and medical record review to identify risk factors for the development
of OUD. These include:
• Longer duration of opioid use

• Higher-dose opioid use
• Personal history of OUD
• Personal or family history of any substance use disorder (tobacco, alcohol,
cannabis, or other substances)
• Personal history of major depressive disorder
• Use of psychotropic medications
• Age <40 years
• History of sexual trauma
• Lack of employment
Other important steps in this approach include:
• Communication with past prescribers

• Review of old medical records
• Focused physical examination for signs of opioid use (e.g., injection sites, signs
of intoxication or withdrawal)
• Review of the state’s PDMP
• Urine drug testing
Formal screening tools can be used to help identify patients at risk for misuse (see Tools
for Clinical Practice below), but they do not reliably predict misuse and should therefore
be used only with other clinical information, including longitudinal monitoring.
Importantly, even individuals who are initially deemed to be at low risk for misuse are
still at some risk. Furthermore, the risk of misuse can change over time. All patients
should therefore be monitored for misuse or risk of misuse with:
• Face-to-face evaluations (interview and examination)

• Intermittent urine drug testing
• Intermittent pill counts
• PDMP checks
• Communication with co–care providers and significant others as indicated
Moderate- and higher-risk patients may be candidates for opioid therapy but should be
monitored with greater frequency and provided more support; in these cases, comanage-
ment with an addiction medicine, psychiatric, or pain specialist should be considered as
appropriate.
If misuse of a medication is identified, the patient should be assessed for a substance

use disorder, and there should be either tightening of prescribing to assure safety or
tapering and cessation of opioids.
ASSESSING RESPONSE TO OPIOID THERAPY

The general goals of opioid therapy are to reduce pain, improve quality or enjoyment of
life, and enhance function or activity level.
Response to treatment should be assessed at each visit; therapy can be continued if there
is good analgesia, improved function and quality of life, no or manageable adverse
effects, and no misuse or risk behaviors.

Several scales are available to assess response to treatment. Unidimensional pain scales
(numerical rating scales) assess only the intensity of pain, whereas multidimensional
pain scales assess the intensity of pain as well as its effect on function and quality of
life. An example is PEG, a short, validated assessment scale with a 0-to-10 rating for
each of three dimensions: Pain intensity, Enjoyment of life, and General activity level. A
30% improvement is considered clinically meaningful. Achieving complete relief of pain
may not be possible in some cases.
Worsening Pain
If a patient reports worsening pain after previous control on a stable opioid regimen, a
variety of causes and corresponding interventions should be considered:
CAUSE INTERVENTION
Disease progression • Rule out disease progression as appropriate.
Co-occurring distress, such as increased • Advise lifestyle changes, medical interventions,
stress, depression, anxiety, poor sleep, or counseling, or referrals as indicated.
changes in physical activity
Opioid tolerance • If doses are low and tolerance is suspected: Consider
increasing the dose. Of note, it can take 5 half-lives
(2–3 days for most opioids) before the full effect of
the increased dose is apparent.
• If doses are higher and tolerance is suspected:

Consider rotating to an alternative opioid.
Withdrawal-mediated pain (due to • If frequent doses of a short-acting opioid are being
fluctuating blood opioid levels) used, consider a change to long-acting.
Opioid-induced hyperalgesia (increasing • Consider tapering (as the pain may improve off
diffuse pain worsened with increased opioids or with lower doses) or rotating to an
opioids and lessened with reduced alternative opioid.
opioids)
Opioid misuse or OUD (signaled by loss • Evaluate for OUD or refer for assessment.
of control, compulsive use, continued use
• Control opioids for safety, or transition to opioid
despite adverse consequences, craving)
agonist therapy for OUD (buprenorphine by qualified
prescribers or methadone treatment in a licensed
opioid treatment program).
Diversion • Discontinue opioids if there is evidence or strong
suspicion of diversion.
Breakthrough Pain
In patients taking ER/LA opioids, breakthrough pain can occur. This happens most
commonly with physical activity, stressors, or other triggers but can also occur sponta-
neously in some conditions (e.g., cancer, certain neuropathies).

Management options for breakthrough pain include:
• Lifestyle adjustments to limit triggers as reasonable

• Self-management interventions when effective, including cold, heat, stretching,
transcutaneous electrical nerve stimulation (TENS), meditation, breathing, mild
exercise, and change of focus
• Use of nonopioids, including NSAIDs or acetaminophen, as helpful
Judicious, occasional use of short-acting opioids may be appropriate in some patients.

Common Adverse Effects
Opioids have a range of adverse effects, and patients should be assessed for these at each
visit. Many adverse effects are transient, except for constipation, which is the most com-
mon adverse effect from chronic opioid use and often persists. The table on page 16 lists
some of the most common adverse effects of opioids, along with specific management
strategies.
If an adverse effect persists, general management approaches include:
• Reducing the opioid dose

• Switching to an alternative opioid (known as opioid rotation)
• Treating the adverse effect with medication if needed
OPIOID ROTATION
Opioid rotation may be beneficial not only in the setting of persistent adverse effects but
also in other situations, such as:
• Poor analgesic response

• Progressive tolerance to initial analgesia
• Opioid-induced hyperalgesia
• Risks associated with high-dose opioids
When patients rotate opioids, they generally end up taking a lower dose (as measured in
morphine milligram equivalents [MMEs]), so there are often fewer adverse effects but at
least an equivalent analgesic response. However, there are limited data on the effective-
ness of opioid rotation.
In addition, because of unpredictable cross-tolerance, patients may develop sedation and

overdose (or pain and withdrawal) on the new opioid, so caution and careful monitoring
are advised.
(continued on page 17 )

ADVERSE EFFECTS OF OPIOIDS MANAGEMENT STRATEGIES
Constipation (due to opioid • Advise preventive measures, including using the lowest effective
receptor binding in the gut) doses of opioids, increasing fluid and fiber intake, and increasing
physical activity.
• Recommend a bowel stimulant (e.g., senna) in combination with

either a stool softener (e.g., docusate) or bulking agent (e.g.,
psyllium) for prevention and/or treatment.
• If the constipation is persistent, consider a peripherally acting

mu opioid antagonist (PAMORA), such as methylnaltrexone or
naloxegol.
Sedation/psychomotor and • Advise patient not to drive, operate heavy machinery, or engage in
cognitive impairment (most work requiring close attention until he or she is without sedation or
common with initial use, cognitive blurring, which often requires at least one week on the new
intermittent use, an increased dose, opioid regimen.
or rotation to a new opioid; usually
• Consider discontinuing other sedative medications if possible.
resolves as tolerance develops)
• If sedation persists, consider reducing the opioid dose or rotation to
a different opioid.
Urinary retention (usually mild) • If persistent, reduce the opioid dose, rotate to an alternative opioid,
or both.
Pruritus (usually mild) • If persistent, reduce the opioid dose, rotate to an alternative opioid,
or both.
• Consider short-term antihistamine therapy.

Nausea and vomiting (usually • Consider short-term antiemetic therapy.
resolve quickly)
Male hypogonadism or abnormal • Measure appropriate hormone levels if indicated based on
menstrual cycles, with reduced symptoms, and consider sex hormone replacement.
bone density (due to suppression
• Consider obtaining dual-energy x-ray absorptiometry in patients with
of hypothalamic–pituitary–gonadal
confirmed hypogonadism.
function)
Low cortisol or adrenocorticotropic • Consider evaluation for adrenal insufficiency and glucocorticoid
hormone (ACTH) levels/adrenal replacement therapy in select patients.
insufficiency (due to suppression
of hypothalamic–pituitary–adrenal
function)

Steps to Rotating Opioids
A complete opioid rotation involves the following steps:
1. Determine the total usual dose of each opioid per 24 hours.
2. C
onvert the 24-hour intake of each opioid to MMEs using equivalency charts or
conversion factors, and determine the current total daily MME.
• Although opioid equivalency charts are useful, they are based on single studies in
non–opioid-tolerant, healthy volunteers and do not reflect individual differences
in genetics, comorbidities, or polypharmacy.
3. Calculate the equivalent 24-hour MME dose of the new opioid.
4. R
educe the calculated daily dose by 25% to 75% to account for incomplete
cross-tolerance. (Greater reductions may be required for methadone.)
5. P
rescribe the new opioid at the reduced calculated dose in appropriately divided
doses (once or twice daily for most ER/LA opioids). Consider making immediate-
release opioids available to the patient in case of increased pain.
6. Monitor carefully and adjust for sedation, adverse effects, or unrelieved pain.

Screening for Risk of Opioid Misuse
• Opioid Risk Tool (ORT) (9-item scale)
• Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R)
(24-item scale)
• Diagnosis, Intractability, Risk, and Efficacy Inventory (DIRE) (8-item scale)
Counseling Patients About Opioid Therapy
• Prescription Opioids: What You Need to Know: A 2-page document for patients
(from the U.S. Centers for Disease Control and Prevention) that lists the risks
and adverse effects of opioids as well as safety-related steps that patients can
take
Sample Patient–Provider Agreements from:
• Boston Medical Center
• National Institute on Drug Abuse
Assessing Pain Intensity and Interference
• Brief Pain Inventory (15-item scale)
• PEG assessment tool (3-item scale derived from the Brief Pain Inventory)
• Roland Morris Disability Questionnaire (24-item scale to assess low back pain
specifically)

MME Charts and Calculators
• Calculating Total Daily Dose of Opioids for Safer Dosage (from the U.S. Centers
for Disease Control and Prevention)
• Opioid Conversion Calculator (from Oregon Pain Guidance)
• Opioid Conversion Calculator Morphine Equivalents — Advanced (from Global RPh)
LEARNING RESOURCES
• Opioid Efficacy for Chronic Pain: A slide (from Boston University School of
Medicine) summarizing the available evidence on the use of opioids for chronic
pain
• Minimum Level of Monitoring Based on Risk: A chart (from Boston University
School of Medicine) showing how frequently various tools should be used to
monitor opioid safety depending on the patient’s risk for opioid misuse
• Rotating Opioids to Manage Chronic Pain: An infographic from NEJM
Knowledge+ that describes why opioid rotations work, when to consider opioid
rotation, what to consider when selecting a new drug and the dose of the new
drug, how to counsel patients during a rotation, and the steps involved in one
rotation method.

TOPIC 4 SUMMARY
Basics of Opioid
Prescribing — Part II

Managing opioid therapy in a patient with chronic pain comes with a host of clinical
considerations, including making decisions about short-acting versus long-acting opi-
oids; mitigating and managing the risk for misuse, including addiction and overdose;
and deciding when and how to taper the opioid, if necessary.
SHORT-ACTING VS. EXTENDED-RELEASE/LONG-ACTING OPIOIDS

Opioid analgesics can be divided into two groups: short-acting opioids and extended-
release/long-acting (ER/LA) opioids. Overall, the two types of medications have similar
efficacy and are associated with a similar risk for developing misuse. Thus, the decision
of which type to use depends on the individual clinical scenario, with a goal of meeting
the patient’s specific needs and preferences. Indications for these medications as well as
their features and risks are shown in the table on page 20.
Switching from a Short-Acting Opioid to an ER/LA Opioid
Switching from short-acting to ER/LA opioids is simplest if the same opioid molecule
is used, because there is no concern about lack of cross-tolerance, and thus the patient
can transition to the same total daily dose. Often, patients are even able to transi-
tion to a somewhat lower total daily dose, because the extended-release opioid largely
avoids peaks and troughs in drug levels and, as a result, may provide more-stable and
improved analgesia.
If a patient is switched from a short-acting opioid to a different, ER/LA opioid molecule,

the process is the same as when a patient rotates from one ER/LA opioid to another,
given uncertainty about individual responses to the new opioid in terms of both anal-
gesia and adverse effects. For more details about opioid rotation, see Topic 3: Basics of
Opioid Prescribing — Part I.
Topic 4: Basics of Opioid Prescribing — Part II knowledgeplus.nejm.org 19

SHORT-ACTING OPIOIDS ER/LA OPIOIDS
Indications • Intermittent or occasional pain • Severe pain requiring around-the-clock,
long-term relief when other interventions
• Severe pain in opioid-naive patients
have not provided adequate symptom
control
• Should only be used in patients who have

developed opioid tolerance (defined as
taking at least 60 morphine milligram
equivalents [MMEs] daily of a short-acting
opioid for at least one week)
Features • Analgesia typically lasts 3 to 6 hours • More-stable blood levels, resulting in less
fluctuation in analgesia
• Easier to safely titrate for symptom control
• Reduce risk for opioid withdrawal–
• Provide intermittent relief for (a) pain that
mediated pain
is intermittent and for (b) pain that is
persistent but from which a patient seeks
only intermittent relief
• Can provide around-the-clock pain relief

when dosed at appropriately spaced
intervals
Risks • May lead to end-of-dose lapses in pain • May have increased risk of overdose
control, including waking during the night compared with short-acting opioids,
with pain especially when the dose is initiated or
increased. Should therefore be used with
• Frequent dosing for around-the-clock
particular caution in patients with hepatic
analgesia may be disruptive
or renal dysfunction, sleep apnea, or
• Fluctuations in blood levels may result concomitant use of benzodiazepines or
in withdrawal-mediated symptoms in other sedative hypnotics
physically dependent patients, including
• Higher risk of overdose if a patient
increased pain, distress, irritability, or
disrupts the extended-release mechanism,
other symptoms
leading to rapid absorption of a high dose
of opioid
Examples • Codeine • Fentanyl and buprenorphine patches
• Immediate-release formulations of • Methadone

morphine, hydrocodone, hydromorphone,
• Extended-release formulations of the
oxycodone, oxymorphone, tramadol,
short-acting opioids listed to the left
tapentadol, and fentanyl

RISK OF RESPIRATORY DEPRESSION, SEDATION, AND OVERDOSE
One of the major risks associated with opioid use is opioid overdose, characterized
by sedation, respiratory depression, and potentially death. Opioids cause respiratory
depression by depressing the medullary respiratory center, resulting in reductions in
tidal volume, minute ventilation, and responsiveness to carbon dioxide. Therefore,
patients and family should be educated about manifestations of opioid overdose, ways
to prevent overdose, and use of naloxone if overdose is suspected.
Some of the major risk factors for opioid overdose are:
• Concurrent use of sedative medications, including benzodiazepines

• Coexisting mental health or substance use disorder
• Higher doses of opioids (especially >100 MMEs daily)
• Prior opioid overdose
• Use of ER/LA opioid formulations
• Older age (>65)
• Sleep-disordered breathing
In addition, patients are more likely to overdose during initiation of treatment (espe-
cially the first 2 weeks of treatment with ER/LA opioids), with dose increases, and after
incarceration or rehabilitation (because their opioid tolerance has diminished).
Calculating and Managing Risk
The revised Risk Index for Overdose or Severe Opioid-Induced Respiratory Depression
(RIOSORD) is a validated instrument that uses the risk factors above to estimate the risk
for overdose in opioid-treated patients. When an opioid prescription is necessary in a
patient at high calculated risk for respiratory depression, clinicians should:
• Put interventions in place to reduce risk factors

• Prescribe naloxone
• Consider buprenorphine (a partial opioid agonist) as the best opioid option,
given its ceiling effect and therefore lower risk of respiratory depression
Concurrent use of benzodiazepines is seen in 30% of opioid overdoses nationally.

Therefore, when managing anxiety and related disorders in patients taking opioids,
clinicians should consider approaches other than benzodiazepines, such as psycholog-
ical therapies (e.g., cognitive behavioral therapy, acceptance and commitment ther-
apy, mindfulness-based stress reduction) or a carefully dosed nonsedative medication,
such as a selective serotonin-reuptake inhibitor (SSRI) or a serotonin–norepinephrine
reuptake inhibitor (SNRI).
If a benzodiazepine must be added or continued when an opioid is part of a patient’s

therapy, the patient should be counseled on the added risk and instructed to hold medi-
cation doses if sedated and not increase the dose of either medication without consulting
the prescriber.

Sleep-Disordered Breathing
Opioid-induced changes in respiratory function are also seen during sleep. Sleep-
disordered breathing affects up to 70% of patients on chronic opioid therapy and is
often unrecognized. The two types of sleep apnea, described below, may occur together
and compound patient risk.
• Central sleep apnea can occur because opioids reduce the ventilatory response to
carbon dioxide and hypoxemia, which leads to slowing of one’s breathing and
potential apnea. Risk increases with the opioid dose and with concurrent use of
benzodiazepines, alcohol, or other sedative hypnotics.
• Obstructive sleep apnea can occur because of soft-tissue obstruction in the airway
and is more common with but not limited to higher BMIs.
Common signs and symptoms of sleep apnea include poor concentration, daytime
sleepiness, morning headaches, insomnia, nightmares, snoring, depression, irritability,
mood swings, and difficult-to-control pain related to poor sleep quality.
When sleep apnea is suspected, a sleep study should be performed and medications
adjusted to improve safety.
MONITORING AND MANAGING PSYCHIATRIC COMORBIDITIES IN

CHRONIC PAIN
Chronic pain often leads to increased stress, depression, and anxiety, and preexisting
depression and anxiety are risk factors for the development of chronic pain. Thus, cli-
nicians should screen all patients with chronic pain for psychiatric comorbidities using
a brief, validated assessment tool (see Tools for Clinical Practice below). Effectively
addressing such comorbidities can often reduce the experience of pain.
If a mood disorder is present:
• Engage the patient in counseling aimed at both mood management and self-
management of pain.
• Consider antidepressant therapy, but be aware of drug–drug interactions.
– Serotonin syndrome may occur when opioids are combined with monoamine
oxidase inhibitors, tricyclic antidepressants, or SNRIs. The risk is greater
with opioids such as tramadol and tapentadol that have nonopioid analgesic
mechanisms involving serotonin or norepinephrine reuptake inhibition.
– Some antidepressants inhibit metabolism through certain cytochrome P-450
pathways, thus increasing blood levels of opioids that utilize these pathways
for elimination.
MONITORING FOR UNSAFE OPIOID USE

When opioid therapy is prescribed, a strict plan should be put into place to monitor for
unsafe opioid use, including misuse and diversion. Key monitoring tools include pill

counts, urine drug testing, and reports from the state’s prescription drug monitoring
program (PDMP). Pill counts involve asking the patient to bring their opioid into the
office, and the number of pills is counted and compared with the expected number of
pills based on the prescribed amount. Urine drug testing is discussed in further detail
in Topic 5: Complex Situations in Opioid Prescribing.
Prescription Drug Monitoring Programs
PDMPs are online systems of searchable information about controlled-substance pre-
scription fills, including the location and date of the fill, the names of the prescriber
and recipient, and the dose and quantity of medications.
States vary in whether they require clinicians to consult PDMPs before prescribing and
at what interval. In addition, some states require reporting of buprenorphine for treat-
ment of opioid use disorder (OUD) within an opioid treatment program and some do
not; methadone used in an opioid treatment program is not reported to PDMPs.
Information of potential concern in a PDMP report may include:
• Multiple concurrent opioid prescriptions

• Prescriptions from different prescribers
• Early refills
• Potentially dangerous drug combinations (e.g., involving opioids,
benzodiazepines, stimulants, and muscle relaxants)
• Filling of opioid prescriptions at unexpected or multiple pharmacies
• Payment for opioid prescriptions with cash rather than through insurance
coverage (if insured)
Next Steps Following Signs of Potential Misuse
When worrisome behavior is noted, clinicians sometimes respond by abruptly discon-
tinuing opioids for that patient, but this may in turn be associated with a transition to
illicit opioids and an increased risk of overdose. Therefore, it is preferable to discuss
findings suggestive of misuse with the patient and, if concerns persist, with other care
providers or significant others who may be able to shed light on the concerns.
The clinician should also assess whether the patient has OUD. The care plan should
be revised as appropriate to both meet the patient’s clinical needs and assure safety; if
OUD is diagnosed, this may include offering or facilitating appropriate treatment and
tapering of opioids.
TAPERING OF OPIOIDS
Tapering of opioids allows a patient to either stop the opioid altogether or to continue
it but at a lower dose. In a patient with physical dependence on opioids, any reduction
in the opioid dose should be done gradually, with a slow taper, to avoid withdrawal
symptoms.

When to Consider a Taper
Tapering may be considered for a variety of reasons:
• Lack of adequate benefit

– Declining function despite pain control
• Presence of opioid-related harms
– Evolution of medical comorbidities that increase opioid-related risks
– Persistent adverse effects from the opioid
– Worrisome opioid-related behaviors; these patients should be assessed for
OUD and considered for transition to opioid agonist treatment for OUD
• Patient desire for a trial off opioids
• Resolution of pain but persistent physical dependence on the opioid
• To determine if a patient with good pain control on stable opioid doses still
requires the opioid
• Suspicion of opioid-induced hyperalgesia
• Unrelenting opioid tolerance without resolution on rotation
Note that many of the reasons to consider a taper of opioids are the same as those for
which clinicians may consider rotation of opioids (i.e., presence of adverse effects or
lack of adequate benefit); thus, clinical judgment must be used to determine the best
course of action for an individual patient. Sometimes initial tapering is appropriate,
but then rotation becomes necessary if elimination of opioids is not successful due to
recurrent pain that is not controlled with other means.
Approaches to Tapering
The best approach to opioid tapering depends on many variables, including the reason
for the taper (i.e., possible harm vs. lack of adequate benefit), opioid doses used, dura-
tion of opioid use, type of pain, and patient preferences.
The ideal taper allows time for the body to adjust to

declining doses of opioid and thus avoid signs and SIGNS AND SYMPTOMS OF
symptoms of withdrawal, which can be associated WITHDRAWAL:
with increased pain and inability to continue the taper
• Increased heart rate
(see box).
• Increased pupil size
Although withdrawal is most common when there is a • Yawning
sudden, >25% drop in the opioid dose, its occurrence • Rhinorrhea or tears in the eyes
is highly variable. In clinical practice, a taper of 10% • Sweating
per month is often used for patients who have been • Restlessness
taking opioid therapy long-term (for many years) for • Arthralgia
chronic pain; a taper of 10% per week is used for • Gastrointestinal disturbances
patients who have been taking opioids for weeks to • Tremor
months. This pacing is consistent with recommenda- • Irritability or anxiety
tions from the U.S. Centers for Disease Control and • Piloerection
Prevention and is generally well tolerated by patients.

In some cases, withdrawal symptoms still occur, and these are often managed with an
alpha2-adrenergic agonist such as lofexidine, clonidine, or tizanidine.
If a more rapid taper is necessary, many patients appear to tolerate an initial reduction
of 20%, followed every 3 to 5 days by a reduction of 10% to 20% of the remaining dose.
Whatever taper schedule is planned, revision should be made as indicated based on
patient response.
Ultra-rapid tapers have been described, some using sedation or anesthesia, but stud-
ies do not support long-term advantages of these tapers compared with more-gradual
tapers, and they engender both risks of withdrawal and complications of sedation when
used.
Of note, tapers are not necessary when diversion is identified by a non–physically depen-
dent person.
Tapering During Pregnancy
Tapering of opioids is generally best avoided during pregnancy given the risk of preg-
nancy loss; however, if tapering must be pursued, the risk of pregnancy loss is lowest
in the second trimester.
Pain Management During a Taper
Some patients with chronic pain may experience a reduction in pain as opioids are
tapered (presumably due to lessening of opioid-induced hyperalgesia); however, many
patients require intensified pain management with nonopioid therapies while tapering.
Approaches may include:
• Physical approaches, such as exercise, physical therapy, massage, thermal

modalities, and movement therapies (yoga, qi gong, stretching)
• Psychological interventions, such as mindfulness, meditation, and therapies such
as cognitive behavioral therapy, acceptance and commitment, and dialectical
behavioral therapies as indicated
• Nonopioid medications as indicated, including acetaminophen or nonsteroidal
antiinflammatory drugs, SNRIs or tricyclic antibiotics, anticonvulsants, or muscle
relaxants such as tizanidine
• Carefully targeted interventionalist procedures

Assessing Depression and Anxiety
• Patient Health Questionnaire (PHQ)-2: A 2-item questionnaire used to screen for
depression; to be followed by the PHQ-9 if positive
• Generalized Anxiety Disorder (GAD)-2: A 2-item questionnaire used to screen for
anxiety

Assessing Withdrawal
• Clinical Opiate Withdrawal Scale (COWS): An 11-item scale scoring the
frequency and severity of withdrawal symptoms
MME Charts and Calculators
• Calculating Total Daily Dose of Opioids for Safer Dosage (from the U.S.
Centers for Disease Control and Prevention)
• Opioid Conversion Calculator (from Oregon Pain Guidance)
• Opioid Conversion Calculator Morphine Equivalents — Advanced (from
Global RPh)
LEARNING RESOURCES
• Opioid Taper Decision Tool: A 3-page guide from the U.S. Department of
Veterans Affairs that outlines sample taper plans and treatments for specific
withdrawal symptoms
• BRAVO! A Collaborative Approach to Opioid Tapering: A 15-page document
(from Oregon Pain Guidance and Dr. Anna Lembke) outlining a safe and
compassionate strategy to approaching opioid tapering with patients
• BRAVO Overview: A one-page overview of the BRAVO approach to opioid
tapering
• DSM-5 OUD Criteria: A complete list of diagnostic criteria for opioid use
disorder
• Rotating Opioids to Manage Chronic Pain: An infographic from NEJM
Knowledge+ that describes why opioid rotations work, when to consider opioid
rotation, what to consider when selecting a new drug and the dose of the new
drug, how to counsel patients during a rotation, and the steps involved in one
rotation method.

TOPIC 5 SUMMARY
Complex Situations in
Opioid Prescribing

Patients who are prescribed chronic opioid therapy require ongoing monitoring for effec-
tiveness and safety, as well as evaluation for the development of opioid use disorder (OUD).
During this management, complex scenarios may arise regarding concern for misuse,
OUD, diversion, and overdose. This summary reviews some common situations and their
appropriate management.
Importantly, when a clinician notes concerning patient behaviors — such as requests for
early refills or rapid dose escalation, use of other clinicians for opioid prescriptions, or urine
drug test results that are inconsistent with prescribed use — the clinician should discuss
their concerns with the patient in an open, nonjudgmental, and honest manner.
USE OF ADDITIONAL DOSES

When prescribing opioids for chronic pain, clinicians should clearly state up front how
the medication should be taken and explain the risks of taking more than prescribed. In
follow-up visits, patients should be asked exactly how they are taking their opioids; pill
counts can be used for confirmation.
When a patient is found to be taking additional doses of opioids, clinicians should explore
the reasons for this behavior. Although increased use may be due to an increase in pain
or the development of opioid analgesic tolerance, it can also be an early warning sign of
the development of OUD. Mandatory opioid tapering or discontinuation is not usually
required and may result in negative outcomes for patients.
Topic 5: Complex Situations in Opioid Prescribing knowledgeplus.nejm.org 27

Clinicians can consider the following options instead:
• Assess for progression of the underlying condition or presence of a new cause

of pain.
• Assess for new or worsening psychiatric comorbidities (e.g., depression, anxiety,
insomnia).
• Evaluate the patient for evidence of OUD (see diagnostic criteria on page 30).
• Review the patient–provider agreement (PPA) with the patient, in which
expectations about opioid use are outlined, and emphasize the safety concerns with
taking more than prescribed.
• Optimize nonopioid and nonpharmacologic pain management strategies.
• Increase monitoring with tools like shorter prescription durations, more-frequent
follow-up visits, urine drug testing, and pill counts.
EARLY REFILL REQUESTS

PPAs should outline clinic policies for opioid refills, including management of early refill
requests. When patients request a refill of their chronic opioid therapy earlier than expected,
clinicians should again explore the reasons for this. Potential explanations include use of
more opioids than prescribed, opioid diversion, and loss or theft of the opioids. Clinicians
should:
• Assess for causes of taking too much of the prescribed opioid, as outlined above.
• Review the PPA with the patient to clarify expectations for opioid refills, including
that the patient agrees to take the opioids as prescribed and not take more than
prescribed.
• Ask the patient about safe opioid storage to minimize the risk for unintentional
diversion and about intentional diversion of the prescribed opioid to others.
• If the patient has an acceptable explanation for an early refill request (e.g., having
accidentally left the prescribed opioids at home before a trip), an early refill is
appropriate to avoid withdrawal. Enough medication can be provided to last the
patient until they return home, and the subsequent prescription is then adjusted to
account for the additional prescription.
– If the patient increased their opioid use temporarily in the setting of acute pain,
the clinician can review the PPA and expectations for safe opioid use and consider
a one-time early refill with increased monitoring as above.
– If the patient states that their opioids were stolen, discontinuing the opioids may
be appropriate to consider because the patient is unable to keep them safe from
others.
SUSPECTED DIVERSION
Given the high-risk nature of chronic opioid therapy, clinicians should monitor for possible
diversion of medication.

Diversion should be considered in the following scenarios:
• The patient runs out of their opioids earlier than expected.

• Urine drug testing is negative for the prescribed opioid.
• The patient refuses or continually forgets to bring in their pills for pill counts.
Unintentional opioid diversion may occur if someone else has access to a patient’s medications.
Patients should be asked about other people in their home who could be taking some of
their opioids and about how opioids are stored. Safe opioid storage, preferably in a locked
container, can reduce unintentional diversion by children, adolescents, and adults. If a
patient is unable to keep their medications safe from others, it is appropriate to consider
discontinuing the opioid.
Intentional opioid diversion can occur for financial reasons (e.g., reselling of the medication),
social reasons (e.g., providing the medication to a coercive partner), or even altruistic rea-
sons (e.g., providing the medication to someone without health insurance). If a patient
admits to intentional opioid diversion, he or she should be counseled on the risks of this,
and opioid prescribing should be discontinued.
• A taper is not necessary if the patient has not been taking the opioid and therefore
does not have physical dependence.
• If the patient has been taking some of the opioid and diverting the rest, a taper off
opioids may be necessary to prevent withdrawal.
• The patient should not be dismissed from the clinician’s care. The clinician should
work to retain the patient in care for their other needs, including nonopioid pain
management.
UNEXPECTED RESULTS ON URINE DRUG TESTING

Urine drug testing (UDT) is a helpful and accessible way to assess for the presence of
prescribed opioids and/or other substances that may increase risk for adverse outcomes.
Clinicians who order UDT should be familiar with opioid metabolism and the test char-
acteristics at their laboratory to avoid misinterpretation of results. Key aspects of UDT
interpretation include the following:
• UDT assays designed to test for opiates (the opioids that are naturally derived from
opium; i.e., morphine and codeine) will not detect synthetic opioids, including
fentanyl and methadone, or the semisynthetic opioid buprenorphine.
• Oxycodone, a semisynthetic opioid, will trigger a positive opiate assay at higher
concentrations but not at lower concentrations.
• Clinicians wishing to identify synthetic or semisynthetic opioids in a urine sample
should order specific testing for the opioid.
If a patient’s UDT result is negative for the prescribed opioid, the clinician should first
discuss the finding with the laboratory to explore possible reasons, such as presence of the

opioid at a level below the laboratory cutoff, dilution of the urine (as evidenced by low urine
creatinine), a false-negative result, or rapid metabolism. If there is no reasonable explana-
tion from the laboratory, then the clinician should discuss the finding with the patient and
explore whether the patient might have run out of medication early or diverted the medica-
tion to others (either intentionally or unintentionally).
If a patient’s UDT result is positive for both the prescribed opioid and any nonprescribed
opioids or other high-risk medications like benzodiazepines, this finding should also be
addressed, given the safety risks of combining these medications.
SUSPECTED OPIOID USE DISORDER

Patients on chronic opioid therapy require ongoing monitoring for OUD, which may
develop at any point in the course of treatment. All clinicians who prescribe opioids should
familiarize themselves with the diagnostic criteria for OUD as outlined in the Diagnostic and
Statistical Manual of Mental Disorders (DSM-5):
Impaired Control
1. Use of an opioid in larger amounts or for longer than intended
2. Persistent wish or unsuccessful effort to cut down or control opioid use
3. Excessive time spent obtaining opioids, using them, or recovering from their use
4. Strong desire or urge to use an opioid
Social Impairment
5. Interference of opioid use with important obligations
6. Continued opioid use despite resulting social and/or interpersonal problems
7. Elimination or reduction of important activities because of opioid use
Risky Use
8. Use of an opioid in physically hazardous situations (e.g., while driving)
9. Continued opioid use despite resulting physical and/or psychological problems
Physiological Effects
10. Need for increased dose of an opioid for effects, diminished effect per dose, or both
11. Withdrawal when the opioid dose is decreased and/or use of the drug to relieve withdrawal
At least two criteria must be fulfilled to diagnose mild OUD. Of note, the physiological
effects — opioid tolerance and withdrawal (#10 and #11 above) — are two of the criteria for
OUD, but their presence in the setting of medically supervised opioid use does not neces-
sarily indicate evidence of OUD.
When OUD is suspected, providers should assess for the diagnostic criteria, refer to an
addiction specialist, or both. Not all concerning behaviors are evidence of OUD.
If a patient is found to have OUD, he or she should receive evidence-based treatment, which
has been shown to reduce risk of relapse, risky opioid use behaviors, and premature death.
Treatment options include buprenorphine, methadone, and naltrexone.

UNINTENTIONAL OVERDOSE
Opioid overdose is a serious risk of chronic opioid therapy, and when it occurs, it is a sign
that continued opioid therapy is unsafe. Despite this, data show that more than 90% of
patients who experience nonfatal overdose receive subsequent opioid prescriptions, with
7% experiencing repeat overdose. Therefore, after an unintentional overdose, patients
should be counseled that the risks of chronic opioid therapy outweigh the benefits.
• Clinicians may choose to taper opioids while augmenting nonopioid and

nonpharmacologic pain management.
• Stopping opioids abruptly may be appropriate after some cases of overdose, but in
many patients still taking chronic opioid therapy, this can precipitate withdrawal.
Admission for supervised opioid taper may be necessary.
• Patients taking chronic opioid therapy, especially ≥50 morphine milligram
equivalents, should be prescribed naloxone and trained on its use for unintentional
overdose.
• If appropriate, patients should be connected to treatment for mental health or opioid
use disorders.
OPIOID USE DURING PREGNANCY AND BREASTFEEDING

Opioid analgesia is occasionally used in the treatment of severe pain that persists during
pregnancy despite other interventions. In addition, pregnant women may be exposed to
opioids through use of illicit drugs or through use of opioid agonists such as methadone or
buprenorphine to treat OUD.
The main concern with opioid use in pregnant women is the risk of neonatal opioid
withdrawal syndrome (NOWS), which can occur in 30% to 70% of infants born to mothers
using opioids. In addition, some studies have suggested that pregnancy may alter opioid
metabolism, leading to different dose requirements, especially for methadone used in the
treatment of OUD, but whether this applies to other opioids is unknown.
• Infants at risk for NOWS should be monitored closely after birth for symptoms of
neurologic excitability and gastrointestinal dysfunction.
• Having mothers room-in with their infants, and encouraging skin-to-skin contact
and breastfeeding, is the optimal management of mild cases of NOWS.
• Frequent feeding from the breast or bottle can alleviate irritability, as hunger
exacerbates NOWS.
• Pharmacologic treatment is only indicated for persistent, moderate-to-severe
symptoms of NOWS.
Some opioids are lipophilic, with a low molecular weight, and therefore cross into breast
milk. These opioids convert to potent metabolites that can have significant analgesic and
sedative effects on infants. For this reason, the U.S. Food and Drug Administration recom-
mends against breastfeeding while using medications that contain codeine or tramadol.

Screening for Risk of Opioid Misuse
• Opioid Risk Tool (ORT) (9-item scale)
• Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R)
(24-item scale)
• Diagnosis, Intractability, Risk, and Efficacy Inventory (DIRE) (8-item scale)
Counseling Patients about Opioid Therapy
• Prescription Opioids: What You Need to Know: A 2-page document for
patients (from the U.S. Centers for Disease Control and Prevention) that
lists the risks and adverse effects of opioids as well as safety-related steps
that patients can take
Sample Patient–Provider Agreements from:
• Boston Medical Center
• National Institute on Drug Abuse
Naloxone Training
• How to Use the VA Auto-Injector Naloxone Kit or Naloxone Nasal Spray: Two
7-minute videos from the Veterans Health Administration for teaching patients how
to use the different formulations of naloxone in case of overdose
LEARNING RESOURCES
Tapering Opioids
• Opioid Taper Decision Tool: A 3-page guide from the U.S. Department of Veterans
Affairs that outlines sample taper plans and treatments for specific withdrawal
symptoms
• BRAVO! A Collaborative Approach to Opioid Tapering: A 15-page document (from
Oregon Pain Guidance and Dr. Anna Lembke) outlining a safe and compassionate
strategy to approaching opioid tapering with patients
• BRAVO Overview: A one-page overview of the BRAVO approach to opioid tapering
Difficult Conversations
• Words That Work: An infographic (from Opioid Life Saver Training) with suggested
wording that clinicians can use when talking with patients about
their opioid use
• 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
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
• Motivational Interviewing: Inspiring Patients to Change: An infographic and four-
part video series introducing the principles of motivational interviewing to help
clinicians increase the chances of a successful discussion with patients.
» Infographic: Motivational Interviewing: Inspiring Patients to Change
» Video: Motivational Interviewing, Part 1: Engaging
» Video: Motivational Interviewing, Part 2: Focusing
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Recognizing Opioid Use Disorder
• Stages of the Addiction Cycle: Infographic from the New England Journal of
Medicine explaining the neurobiology of addiction.
• DSM-5 OUD Criteria: A complete list of diagnostic criteria for opioid use disorder
Managing Opioid Use Disorder
• Managing Opioid Use Disorder for the Generalist: A 60-minute podcast from The
Curbsiders Internal Medicine that reviews the art of building a therapeutic relationship
with people who have substance use disorders, the differences between the
three FDA-approved medications for OUD, and the nitty-gritty of prescribing
buprenorphine for OUD
• Medications to Treat Opioid Use Disorder (OUD): A chart comparing methadone,
buprenorphine, and naltrexone for the treatment of OUD
• Buprenorphine Waiver Management: A resource from the Addiction Society
of America detailing the steps that clinicians must take to become qualified to
prescribe buprenorphine for OUD
• 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
• Buprenorphine for Pain Management & Treatment of Opioid Use Disorder (OUD):
An infographic comparing the various uses of buprenorphine
Preventing Overdose
• Frequently Asked Questions about Prescribing Naloxone: A list of 15 questions
clinicians commonly ask about naloxone, answered by experts from the organization
Prescribe to Prevent
Other
• Urine Drug Testing in Chronic Opioid Therapy — Clinical Considerations &
Common Laboratory Methodologies: These two linked infographics provide
information on how to conduct urine drug testing — the first deals with clinical
considerations and what to say to the patient in case of concerning findings, and the
second explores the laboratory methodologies involved and how to interpret results.

TOPIC 6 SUMMARY
Opioid Pharmacology

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.
Topic 6: Opioid Pharmacology knowledgeplus.nejm.org 34

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

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.)

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.

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.

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.
• 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

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
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
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

TOPIC 7 SUMMARY
Acute Pain

Acute pain, including postoperative pain and pain from trauma, is a life-sustaining
symptom and must be treated appropriately. Otherwise, it can lead to increased mor-
bidity, affect the quality of a patient’s recovery, increase the likelihood of chronic pain
development, and contribute to premature death.
Acute pain is best managed with multimodal analgesia, which involves the adminis-
tration of two or more analgesic agents via one or more routes that exert their effects
through different analgesic mechanisms. The synergistic effects of this approach
help provide superior analgesia with fewer adverse effects relative to single-modality
approaches. Some of the modalities that can be used are:
• N
onopioid analgesics, such as nonsteroidal antiinflammatory drugs (NSAIDs),
acetaminophen, antidepressants, anticonvulsants, and muscle relaxants
• Opioid analgesics, including systemic and neuraxial formulations
• Regional analgesia (neuraxial and perineural)
• Intravenous lidocaine
• N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine or
memantine
OPIOID THERAPY
Opioid analgesics are appropriate to consider in the management of severe acute
pain if nonopioid modalities have failed or are likely to be inadequate — or if the
risks of opioid treatment are lower than the risks of alternative modalities. However,
caution should be exercised when prescribing opioids, because these medications
can have adverse effects that can compromise a patient’s recovery.
Topic 7: Acute Pain knowledgeplus.nejm.org 41

One of the risks with short-term opioid therapy is that it can lead to long-term opioid
therapy, for which the evidence of benefit is less clear. To reduce this risk, when an opi-
oid is prescribed in the outpatient setting, it should be a short-acting agent at the lowest
effective dose in the smallest amount necessary for a limited number of days. According
to guidelines from the U.S. Centers for Disease Control and Prevention, 3 days of opi-
oids or less is often sufficient for acute pain, and more than 7 days is rarely needed.
Prescriptions for larger numbers of pills increase risk not only for the patient but also
for the community because of the possibility of theft or diversion of leftover pills.
Extended-release/long-acting (ER/LA) formulations are generally not recommended for

acute pain and are reserved for the management of chronic pain that is severe enough
to require daily, around-the-clock, long-term opioid treatment.
Intravenous or intramuscular opioids can be used to treat acute pain in the hospital,
given their rapid and reliable onset of analgesia.
Required Education with Opioid Therapy
All patients receiving an opioid prescription — even if only short-term for acute pain —
should be educated about the risks and adverse effects of opioid treatment and the safe
storage of these medications. Patient should also be advised to dispose of any leftover
opioids promptly and correctly (ideally through a formal take-back program or kiosk).
ACUTE PAIN MANAGEMENT IN SPECIAL POPULATIONS

Opioid-Tolerant Patients
Patients who are already receiving opioid therapy for chronic pain may occasionally
need management of acute pain (e.g., after surgery or trauma), and this can present
a challenge. However, adequate pain management in this population is important, as
undertreated pain can lead to drug-seeking behaviors and loss of trust between the
patient and the clinician. To ensure adequate pain control in opioid-tolerant patients,
the following steps can be taken:
• B
efore elective surgery, formulate a comprehensive analgesic plan and discuss it
with the entire treatment team.
• Continue the previous ER/LA opioid, and add a short-acting opioid if further
analgesia is needed.
• If a short-acting opioid is prescribed:
– Do not replace the ER/LA opioid with the short-acting opioid, as the patient
may experience withdrawal from the ER/LA opioid and analgesia will be
inadequate.
– Keep in mind that an opioid-tolerant patient may require a higher dose of the
opioid given at a short dosing interval to achieve adequate analgesia.
– If the ER/LA opioid cannot be given by mouth, try parenteral administration,
but reduce the dosage because of lower bioavailability with the oral
formulation.
– Perform frequent assessment of the patient for central nervous system and
respiratory depression, especially during the initial phase of therapy until a
stable dose is reached.
– Use of nonopioid analgesics, such as NSAIDs and acetaminophen, can help
reduce pain from inflammation and reduce the use of opioids; however,
caution should be exercised, given the increased risk of bleeding and reduced
bone healing with NSAIDs.
– Multimodal analgesia, such as regional analgesia, should be started early in
opioid-tolerant patients to reduce the total amount of opioids administered.
– NMDA receptor antagonists, such as ketamine, potentiate the analgesic effects
of opioids and may help reduce opioid tolerance.
Elderly Patients and Those with Cognitive Dysfunction
Elderly patients are a vulnerable group. They often suffer from pain without reporting it
and have clinical factors that complicate their pain management:
• Most have at least one chronic condition.

• Most take at least one medication, and many are prone to polypharmacy, which
predisposes them to many risks, including falls, delirium, and potentially lethal
drug–drug interactions.
Despite these complicating factors, controlling elders’ pain in the postoperative period
is important, because undermanagement can result in poor ambulation, higher rates of
postoperative complications (including delirium), longer hospital stays, and increased
health care costs.
Nonopioid analgesics are preferred in this setting because they do not impair cognitive
function. Acetaminophen is considered the first-line agent for treatment of mild-to-
moderate pain in elderly patients, given its safer profile with respect to gastrointestinal,
renal, and cardiovascular events as compared with NSAIDs.
Opioids are effective for the treatment of severe pain; however, they should be used only
cautiously, given their adverse effects.
Impaired Cognitive Function
Impaired cognitive function including delirium can make the assessment and man-
agement of pain particularly challenging in the elderly population. To assess pain in
delirium, self-report cannot be used. Instead, clinicians can use reliable and valid pain-
behavior observation tools, proxy reporting from family or friends, or some combina-
tion thereof.
Delirium is often multifactorial, and all causes should be thoroughly investigated,

including opioids; even if one cause is found, the evaluation should continue, because
other factors may be contributing as well. An analgesic trial (preferably nonopioid) or
nerve block may be needed to evaluate if pain is the cause of the delirium. Use of multi-
modal analgesia, including regional analgesia, can minimize the sedation and cognitive

dysfunction associated with opioids, help control pre- and postoperative pain if surgery
is required, and potentially reduce the patient’s overall opioid requirements.
Children and Adolescents
Nonopioid analgesics such as acetaminophen and NSAIDs are considered first-line
treatment for mild-to-moderate acute pain in children and adolescents and may be
equivalent to opioids in many situations. However, opioids still have a role in con-
trolling severe pain that is not controlled with alternatives.
When a decision is made to consider opioids in this population, all risks and potential
adverse effects should be discussed in detail with the patient and guardian. Specific
focus should be given to the risk of addiction. Approximately 5% to 7% of youth will
progress to long-term opioid use, opioid misuse, or opioid use disorder if provided with
an opioid prescription after a surgical procedure.
To mitigate such risk, any opioid that is required should be given for only a short course
and at the lowest effective dose. Patients should be screened for substance use disorders
and mental health disorders, and guardians should monitor the medication closely and
dispose of it appropriately after pain is resolved.
Codeine and tramadol should be avoided in this population because they increase the
risk of death from breathing problems, especially if underlying risk factors are present,
such as obesity, obstructive sleep apnea, or severe lung disease. According to the U.S.
Food and Drug Administration, codeine and tramadol are contraindicated in children
<12 years of age, and tramadol is contraindicated in adolescents (ages 12–18) with
underlying risk factors.
• Prescription Opioids: What You Need to Know: A 2-page document for

patients (from the U.S. Centers for Disease Control and Prevention) that lists
the risks and adverse effects of opioids as well as safety-related steps that
patients can take
• Drug Disposal: Drug Take-Back Locations: A resource from the U.S. Food and
Drug Administration that allows you to find drop-off locations near you via a
searchable database or Google maps — and that also provides information on
periodic take-back events
• MedWatch Online Voluntary Reporting Form: A portal to report all suspected
overdoses from prescribed medications, including opioids, to the U.S. Food and
Drug Administration
7-minute videos from the Veterans Health Administration for teaching patients
how to use the different formulations of naloxone in case of overdose

LEARNING RESOURCES
• Frequently Asked Questions About Prescribing Naloxone: A list of 15 questions

clinicians commonly ask about naloxone, answered by experts from the
organization Prescribe to Prevent

TOPIC 8 SUMMARY
Opioid Use Disorder

Opioid use disorder (OUD) is a chronic, relapsing brain disease characterized by recur-
rent use of opioids despite functional impairment and harm. At least 2 million people
in the United States suffer from OUD, and a larger number of people have tried illicit
opioids or misused prescription opioids.
The recent increase in prevalence is multifactorial but is likely due, at least in part,
to increased opioid prescribing and increased availability of heroin and illicit fentanyl
analogues.
Although many of the people who experiment with illicit opioids or take prescribed
opioids will intentionally or unintentionally experience intoxication or euphoria, most
people will not go on to develop OUD. However, when OUD develops, it needs to be
recognized, diagnosed, and treated to avoid the risks of untreated disease.
DIAGNOSIS OF OPIOID USE DISORDER

OUD is diagnosed based on 11 criteria within four core areas, according to the Diagnostic
and Statistical Manual of Mental Disorders (DSM-5). At least two criteria, as outlined on page
47, must be fulfilled to diagnose OUD.
Because opioid tolerance and withdrawal are expected to occur when a patient is taking
opioids long-term (many days to weeks), these two criteria are not considered to be met
if a patient is taking opioids solely under appropriate medical supervision; such patients
must meet at least two of the other nine criteria to have a diagnosis of OUD.
Topic 8: Opioid Use Disorder knowledgeplus.nejm.org 46

Diagnostic Criteria for Opioid Use Disorder
Impaired Control
1. Use of an opioid in larger amounts or for longer than intended
2. Persistent wish or unsuccessful effort to cut down or control opioid use
3. Excessive time spent obtaining opioids, using them, or recovering from their use
4. Strong desire or urge to use an opioid
Social Impairment
5. Interference of opioid use with important obligations
6. Continued opioid use despite resulting social and/or interpersonal problems
7. Elimination or reduction of important activities because of opioid use
Risky Use
8. Use of an opioid in physically hazardous situations (e.g., while driving)
9. Continued opioid use despite resulting physical and/or psychological problems
Physiological Effects
10. Need for increased dose of an opioid for effects, diminished effect per dose, or both
11. Withdrawal when the opioid dose is decreased and/or use of the drug to relieve withdrawal
TREATMENT OF OPIOID USE DISORDER

All patients with diagnosed OUD should be offered evidence-based treatments and
compassionate care.
Opioid agonist medications (buprenorphine and methadone) are the mainstay of treatment
for OUD. They are the only treatments that have been shown to reduce morbidity (includ-
ing rates of HIV infection and hepatitis), opioid-related mortality, and all-cause mortality.
Other treatments include the opioid antagonist naltrexone, residential treatment, out
patient counseling, and recovery groups; however, none of these has proven morbidity or
mortality benefits.
Recovery groups are community-based programs that are peer-led and are often an adjunct
to other treatments. Although studies do demonstrate the efficacy of recovery groups, there
is no evidence that these programs are better than other types of interventions. Treatment
should therefore be individualized.
MEDICATIONS TO TREAT OPIOID USE DISORDER

Methadone, buprenorphine, and naltrexone are all approved by the U.S. Food and Drug
Administration (FDA) for the treatment of OUD. These medications reduce opioid crav-
ings and create opioid blockade, thus preventing reward or euphoria from any opioids taken
concurrently.

Which medication to recommend depends on many factors, including:
• Patient preference
• Practical access to care (e.g., availability of clinic or prescriber)
• Prior treatment experience (successes and challenges)
• The clinician’s assessment of the risks and benefits of each medication for the
individual patient (e.g., medical comorbidities, overdose risk)
An overview of the three medications is shown below:
METHADONE BUPRENORPHINE NALTREXONE
Mechanism of Full opioid agonist Partial opioid agonist Opioid antagonist

action
Classification Schedule II opioid Schedule III opioid Nonopioid
Formulations and • Liquid (most common), • Transmucosal • Pill once daily

dosing frequency diskette, or tablet once formulations (sublingual
• Extended-release
daily, dispensed by a tablet or film; buccal
intramuscular injection
federally licensed opioid film) once or twice daily
(with customized
treatment program
• Extended-release needle) monthly
(OTP) with observed
subcutaneous
dosing, at least initially
injection monthly
• Subdermal implant every

6 months
Can this No, it must be ordered and Yes, but only by clinicians Yes, by any licensed
medication be dispensed by a federally who have a special waiver clinician.
prescribed legally licensed OTP in a separate from the U.S. Drug
in outpatient system not involving Enforcement Agency. • Pills can be prescribed
settings for OUD primary care or pharmacies. with refills and can
treatment? • Tablets and films can be picked up at
be prescribed for up the pharmacy and
to one month’s supply self-administered.
at a time, with refills,
• Injections are available
and can be picked up
only through specialty
at the pharmacy and
pharmacies that send
self-administered.
the medication to the
• Injections and implants prescriber’s office for
are available only administration.
through specialty
pharmacies that send
the medication to the
prescriber’s office for
administration.

Can it be used Yes, if it is on the hospital Yes, if it is on the hospital Yes, if it is on the hospital
on the inpatient formulary, it can be ordered formulary, it can be ordered formulary, it can be ordered
service or in by any clinician with opioid- and administered in the and administered in the
the emergency prescribing privileges hospital without the need hospital.
department? and administered in the for a waiver.
hospital.
Practical •C
overed by Medicaid in • Covered by Medicaid in • Covered by Medicaid in
considerations for most states most states most states
patients
• Highly structured • Good for patients who
treatment with do not want opioid
potential for onsite agonist therapy
comprehensive
• Medical alert bracelet
addiction care
required, as patients
• Potential stigma who experience severe
and lack of pain while taking
privacy with OTP naltrexone will not
respond to usual doses
• Patients may be eligible
of opioids
for take-home doses
later in the treatment • Can treat OUD and
course depending on alcohol use disorder
federal, state, and OTP simultaneously, as it is
regulations FDA-approved for the
treatment of both
Ease of induction Induction performed More difficult induction Very difficult induction, as
in OTPs over a period than methadone, with risk the patient must be fully
of months; relatively of precipitated withdrawal withdrawn from opioids
easy given absence of for 7 to 10 days to prevent
precipitated withdrawal first precipitated withdrawal
Evidence of benefit • More than 50 years of • Noninferior to • When taken, highly
for OUD treatment use in OUD treatment methadone, although effective in reducing
methadone may be opioid use, but poor
• Shown to reduce opioid
associated with better treatment retention is a
use, improve treatment
treatment retention problem
retention, decrease
HIV and viral hepatitis • Insufficient evidence of a
seroconversion, and reduction in all-cause or
reduce all-cause and opioid-related mortality
opioid-related mortality

Risk of Significant risk of severe Ceiling effect with less risk No risk of overdose by
overdose respiratory depression of respiratory depression the drug itself, although if
(similar to other full opioid and overdose than relapse occurs, the risk of
agonists); thus, initial methadone overdose will be increased
dosing is low, and titration because of loss of tolerance
is slow to opioids
Due to its long and variable

half-life, methadone can
accumulate in the body
and increase the risk of
overdose
Risk of misuse or Limited risk with observed Some risk of misuse, but No risk
diversion dosing, although some reduced with transmucosal
patients may receive doses formulations, which are
to take at home, which then typically prescribed in a
increases the risk combination product with
naloxone, which acts as an
opioid antagonist if injected
High risk of diversion,

mostly to individuals self-
medicating to treat acute
withdrawal or OUD
Other safety issues Can prolong the corrected Can prolong the QTc Not suitable for patients
QT (QTc) interval and interval, but lower risk than with severe liver disease
cause arrhythmias such as methadone
torsades de pointes
DURATION OF TREATMENT FOR OPIOID USE DISORDER

Medications for OUD should be continued for as long as the benefits outweigh the risks,
with ongoing discussions to revisit the risks, benefits, and alternatives — and a recognition
that one of the major risks of discontinuing medications for OUD is relapsing to other opi-
oids. Some patients may need lifelong treatment.
In select patients, tapering off methadone or buprenorphine after several years of treatment
may be reasonable. This approach is typically considered in patients who have remained in
long-term remission, who are motivated to stop the medication, and who have appropri-
ate social supports and life circumstances. If a patient does decide to taper, then that taper
should occur slowly over months to years while the patient continues to be monitored and
receive other therapies.

PAIN MANAGEMENT DURING TREATMENT OF OPIOID USE DISORDER
Concerns about appropriate management may arise when a patient who is on maintenance
therapy for OUD experiences acute pain (e.g., after surgery or trauma). The appropriate
next steps will depend on whether the patient is taking an opioid agonist treatment (i.e.,
methadone or buprenorphine) or naltrexone.
In Patients Taking an Opioid Agonist Treatment
If a patient requires pain management while taking methadone or buprenorphine for OUD,
this maintenance medication will provide very little if any analgesia. Options for pain man-
agement in this setting are as follows:
• M
aximize the use of nonopioid pain medications, including acetaminophen and
nonsteroidal antiinflammatory drugs, and local or regional anesthesia.
• Consider adjusting the dosing of the opioid agonist, such as splitting the dose from
once daily to multiple times daily, to maximize the analgesic properties of this
medication.
• For moderate-to-severe acute pain, consider adding concurrent short-acting opioid
analgesics.
– When added to an opioid agonist treatment, opioid analgesics have been found to
be effective for managing severe acute pain.
– Buprenorphine may potentially reduce the effectiveness of opioid analgesics
because of its high affinity for and partial agonist effect at the mu opioid receptor,
but analgesia can still be achieved with adequate opioid doses.
– Patients on an opioid agonist treatment may need higher-than-usual doses of the
short-acting opioid because of cross-tolerance and increased pain sensitivity.
In Patients Taking Naltrexone
For patients on naltrexone, opioid analgesics are likely to be ineffective until the naltrexone
has worn off:
• With oral naltrexone, 50% of the blockade effect is gone after 72 hours; thus, oral
naltrexone should be discontinued 72 hours before any scheduled surgery.
• With extended-release monthly intramuscular depot naltrexone, plasma drug levels
peak within 2 to 3 days and begin to decline in 14 days; thus, if possible, elective
surgery should be delayed until one month after the last dose of naltrexone.
• If opioids are needed in an emergency for a patient on naltrexone (e.g., in the
setting of a severe trauma), then the patient should be monitored closely (e.g., in
an intensive care setting) in case the dose of opioids needed to overcome the opioid
blockade causes respiratory depression.
MANAGING OPIOID WITHDRAWAL IN HOSPITALIZED PATIENTS WITH

OPIOID USE DISORDER
Hospitalizations can be challenging for patients with untreated OUD, as they may expe-
rience symptoms of opioid withdrawal, such as tachycardia, diaphoresis, restlessness,

arthralgias, gastrointestinal disturbances, irritability, and anxiety. These symptoms and
other findings of opioid withdrawal (such as miosis, yawning, rhinorrhea, tremor, and
piloerection) may occur as early as a few hours — or as late as several days — after the
last dose of opioid in a patient who is chronically using opioids, depending on whether
the patient last used short-acting opioids (e.g., fentanyl) or extended-release/long-acting
opioids (e.g., methadone).
The opioid agonists methadone and buprenorphine are effective treatments for acute opi-
oid withdrawal and should be considered in this scenario. When used outside the hospital
for treatment of OUD, methadone can only be dispensed by licensed clinics, and buprenor-
phine can only be prescribed by waivered clinicians; however, when a patient with OUD is
hospitalized for other active medical problems, either of these medications can be ordered
by the inpatient provider team. Such inpatient treatment is essential for allowing the patient
to comfortably complete his or her medical care and for preventing the patient from leaving
against medical advice. This is also a good time to link the patient to long-term addiction
treatment.
OVERDOSE PREVENTION
All patients with OUD, including those in treatment, should be offered education on
overdose and a prescription for naloxone. Overdose education includes educating the
patient about signs of overdose (apnea, unresponsiveness, blue color of skin) and about
appropriate responses including:
• Administering sternal rub

• Administering naloxone
• Calling emergency medical services
• Performing cardiopulmonary resuscitation
Naloxone is a short-acting opioid antagonist that is used to reverse opioid overdoses.

Although individuals cannot use naloxone on themselves, providing naloxone training to
people who use opioids results in greater knowledge about overdose and in successful over-
dose reversals in peers.
Prescribing of naloxone is effective, does not increase illicit drug use or encourage riskier
use, and is likely to be cost-effective.

• SAMHSA treatment Locator: A search tool, from the Substance Abuse and Mental
Health Services Administration (SAMHSA), to locate treatment facilities for
substance use disorder and practitioners authorized to prescribe buprenorphine for
OUD
7-minute videos from the Veterans Health Administration for teaching patients how
to use the different formulations of naloxone in case of overdose
• Clinical Opiate Withdrawal Scale (COWS): An 11-item scale scoring the frequency
of withdrawal symptoms
LEARNING RESOURCES
Understanding and Diagnosing OUD
• Stages of the Addiction Cycle: Infographic from the New England Journal of Medicine
explaining the neurobiology of addiction
• DSM-5 OUD Criteria: A complete list of diagnostic criteria for opioid use disorder
Managing OUD
• Managing Opioid Use Disorder for the Generalist: A 60-minute podcast from The
Curbsiders Internal Medicine that reviews the art of building a therapeutic relationship
with people who have substance use disorders, the differences between the
three FDA-approved medications for OUD, and the nitty-gritty of prescribing
buprenorphine for OUD
• Medications to Treat Opioid Use Disorder (OUD): A chart comparing methadone,
buprenorphine, and naltrexone for the treatment of OUD
• Buprenorphine Waiver Management: A resource from the Addiction Society
of America detailing the steps that clinicians must take to become qualified to
prescribe buprenorphine for OUD
• 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
• Buprenorphine for Pain Management & Treatment of Opioid Use Disorder (OUD):
An infographic comparing the various uses of buprenorphine
Preventing Overdose
• Frequently Asked Questions About Prescribing Naloxone: A list of 15 questions
clinicians commonly ask about naloxone, answered by experts from the organization
Prescribe to Prevent

OTHER RESOURCES
• PCSS Mentoring Program: A mentoring program where clinicians can: (1) post
questions in an online discussion forum moderated by addiction specialists and receive
answers from clinical experts and other colleagues; (2) ask clinical questions related to
substance use disorder and receive a prompt response via email; and (3) match up with
a mentor in their region who will discuss specific clinical issues with them and provide
individualized, one-on-one guidance in person or via email or phone

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Pain Management and Opioids

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INTRODUCTION AND GENERAL PRINCIPLES

In general, musculoskeletal pain can be managed with pharmacologic or nonpharma-

If pharmacologic therapy is necessary, nonopioid analgesics, such as acetaminophen

Topic 1: Musculoskeletal Pain knowledgeplus.nejm.org 1

Interventional therapies may be indicated in some settings. These include glucocorti-

LOW BACK PAIN

• Neurologic deficits (saddle anesthesia, muscle weakness)

Topic 1: Musculoskeletal Pain knowledgeplus.nejm.org 2

• Obesity (BMI >30)

KNEE AND HIP OSTEOARTHRITIS

Topic 1: Musculoskeletal Pain knowledgeplus.nejm.org 3

Systemic NSAIDs — taken alone or in conjunction with acetaminophen, and as needed

Topic 1: Musculoskeletal Pain knowledgeplus.nejm.org 4

• Signing a structured agreement with the patient

WHEN TO REFER TO A PAIN SPECIALIST

TOOLS FOR CLINICAL PRACTICE

INTRODUCTION AND GENERAL PRINCIPLES

Once the diagnosis is made, additional nonpharmacologic therapies and pharmacologic

• Painful, small-fiber neuropathy

Topic 2: Common Non-Musculoskeletal Pain knowledgeplus.nejm.org 6

Topic 2: Common Non-Musculoskeletal Pain knowledgeplus.nejm.org 7

•  hysical exercise (recommended as first-line therapy)

Certain pharmacologic treatments have also been found to be effective, including

For an acute migraine attack, treatments include:

• Diagnosis & Treatment of Fibromyalgia: An algorithm from NEJM Knowledge+

Topic 2: Common Non-Musculoskeletal Pain knowledgeplus.nejm.org 8

INTRODUCTION AND GENERAL PRINCIPLES

WHEN TO CONSIDER OPIOID THERAPY FOR CHRONIC PAIN

Topic 3: Basics of Opioid Prescribing — Part I knowledgeplus.nejm.org 10

STEPS FOR INITIATING OPIOID THERAPY

1. Determine whether there is an indication for opioid therapy.

3. Plan to continue nonopioid medications for complementary and synergistic effects

4. Assess the potential risks of opioid therapy, including:

5. Consider referral to an appropriate specialist if you identify a high risk of misuse or

7. Provide an at-home naloxone rescue kit.

8. For opioid-naive patients, start with a short-acting agent.

• Longer duration of opioid use

Other important steps in this approach include:

• Communication with past prescribers

• Face-to-face evaluations (interview and examination)

If misuse of a medication is identified, the patient should be assessed for a substance

ASSESSING RESPONSE TO OPIOID THERAPY

Topic 3: Basics of Opioid Prescribing — Part I knowledgeplus.nejm.org 13

• If doses are higher and tolerance is suspected:

Topic 3: Basics of Opioid Prescribing — Part I knowledgeplus.nejm.org 14

• Lifestyle adjustments to limit triggers as reasonable

Judicious, occasional use of short-acting opioids may be appropriate in some patients.

If an adverse effect persists, general management approaches include:

• Reducing the opioid dose

• Poor analgesic response

In addition, because of unpredictable cross-tolerance, patients may develop sedation and

Topic 3: Basics of Opioid Prescribing — Part I knowledgeplus.nejm.org 15

• Recommend a bowel stimulant (e.g., senna) in combination with

• If the constipation is persistent, consider a peripherally acting

• Consider short-term antihistamine therapy.

Topic 3: Basics of Opioid Prescribing — Part I knowledgeplus.nejm.org 16

1. Determine the total usual dose of each opioid per 24 hours.

3. Calculate the equivalent 24-hour MME dose of the new opioid.

• hysical exercise (recommended as first-line therapy)

3. Plan to continue nonopioid medications for complementary and synergistic effects

5. Consider referral to an appropriate specialist if you identify a high risk of misuse or