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Treatment of Pain


James C. Watson

, MD, Mayo Clinic

Last full review/revision Feb 2020| Content last modified Feb 2020
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Nonopioid and opioid analgesics are the main drugs used to treat pain. Antidepressants, antiseizure drugs, and other central nervous system (CNS)–active drugs may also be used for chronic or neuropathic pain and are first-line therapy for some conditions. Neuraxial infusion, nerve stimulation, injection therapies, and neural blockade can help selected patients. Cognitive-behavioral interventions (eg, changes in relationships in the home; systematic use of relaxation techniques, hypnosis, or biofeedback; graduated exercise) may reduce pain and pain-related disability and help patients cope.

(See also Overview of Pain.)

Nonopioid Analgesics

Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are often effective for mild to moderate pain (see table Nonopioid Analgesics). Of these, only ketorolac, diclofenac, and acetaminophen can be given parenterally. Nonopioids do not cause physical dependence or tolerance.


Nonopioid Analgesics



Usual Dosage Range*



50–100 mg, followed by 50 mg every 8 hours

75 mg every 12 hours IV or IM


200–400 mg every 6–8 hours


25–50 mg every 6–8 hours


150–200 mg every 12 hours


200–400 mg every 6–8 hours



1000–2000 mg every 24 hours



20–40 mg every 24 hours

Para-aminophenol derivative


650–1000 mg every 6–8 hours

Propionic acids


200–600 mg every 6 hours


50–200 mg every 12 hours


400 mg every 4 hours to 800 mg every 8 hours (maximum: 3200 mg/day†)


25–50 mg every 6–8 hours


250–500 mg every 12 hours

Naproxen sodium

275–550 mg every 12 hours


600–1200 mg every 24 hours



650–1000 mg every 4–6 hours

Choline magnesium trisalicylate

870 mg every 12 hours


250–500 mg every 8–12 hours


750–2000 mg every 12 hours



50–100 mg every 6–8 hours

Mefenamic acid

250 mg every 6 hours



100 mg every 6–8 hours up to 7 days

Pyrrolo-pyrrolo derivative


15–30 mg IV or IM every 6 hours or 20 mg orally, followed by 10 mg orally every 4–6 hours for maximum 5 days (assess creatinine every 4–6 doses, particularly in patients who are older or at risk of renal failure [eg, postoperative patients])

Selective COX-2 inhibitor


100–200 mg every 12 hours

* Route is oral, except for ibuprofen, ketorolac, diclofenac, and acetaminophen, which can be given parenterally as well as orally. There is a topical form of diclofenac.

† For ibuprofen, dosages ≤ 2400 mg reduce cardiovascular risk and are recommended for patients with cardiovascular risk factors.

COX = cyclooxygenase.

Acetaminophen has no anti-inflammatory or antiplatelet effects and does not cause gastric irritation.

Aspirin is the least expensive NSAID but has prolonged antiplatelet effects and increases the risk of gastrointestinal (GI) bleeding.

NSAIDs also include nonselective COX (cyclooxygenase [COX-1 and COX-2]) inhibitors and selective COX-2 inhibitors (coxibs); all are effective analgesics. Coxibs have lowest risk of ulcer formation and GI upset. However, when a coxib is used with low-dose aspirin, it may have no GI benefit over other NSAIDs.

Studies suggest that inhibition of COX-2, which occurs with both nonselective COX inhibitors and coxibs, has a prothrombotic effect that can increase risk of myocardial infarction, stroke, and claudication. This effect appears to be drug-related, as well as dose- and duration-related. Although there is some evidence that the risk is very low with some of the nonselective COX inhibitors (eg, ibuprofen, naproxen) and coxibs (celecoxib) and although data are still limited, it is prudent to consider the potential for prothrombotic effects as a risk of all NSAID therapy, suggesting that all NSAIDs should be used cautiously in patients with clinically significant atherosclerosis or multiple cardiovascular risk factors.

If an NSAID is likely to be used only short-term, significant adverse effects are unlikely, regardless of the drug used. Some clinicians use a coxib first whenever therapy is likely to be long-term (eg, months) because the risk of GI adverse effects is lower; others limit coxib use to patients predisposed to GI adverse effects (eg, older patients, patients taking corticosteroids, those with a history of peptic ulcer disease or GI upset due to other NSAIDs) and those who are not doing well with nonselective NSAIDs or who have a history of intolerance to them.

All NSAIDs should be used cautiously in patients with renal insufficiency; coxibs are not renal-sparing.

If initial recommended doses provide inadequate analgesia, a higher dose is given, up to the conventional safe maximum dose. If analgesia remains inadequate, the drug should be stopped. If pain is not severe, another NSAID may be tried because response varies from drug to drug. It is prudent during long-term NSAID therapy to monitor for occult blood in stool and changes in the complete blood count (CBC), electrolytes, and hepatic and renal function.

Topical NSAIDs may be applied directly to the painful region for disorders such as osteoarthritis and minor sprains, strains, and contusions. A 1.5% solution of diclofenac has been shown to effectively treat pain and limited joint function caused by osteoarthritis of the knees; dose is 40 drops (1.2 mL) applied 4 times a day to each affected knee. Other topical diclofenac formulations that may be useful for local pain relief include a patch (applied 2 times a day over the affected area) or a 1% gel (2 g 4 times a day for the upper extremities or 4 g 4 times a day for the lower extremities).

Opioid Analgesics

(See also Centers for Disease Control and Prevention: 2018 Annual surveillance report of drug-related risks and outcomes—United States. Surveillance special report. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.)

“Opioid” is a generic term for natural or synthetic substances that bind to specific opioid receptors in the central nervous system (CNS), producing an agonist action. Opioids are also called narcotics—a term originally used to refer to any psychoactive substance that induces sleep. Opioids have both analgesic and sleep-inducing effects, but the two effects are distinct from each other.

Some opioids used for analgesia have both agonist and antagonist actions. Potential for abuse among those with a known history of abuse or addiction may be lower with agonist-antagonists than with pure agonists, but agonist-antagonist drugs have a ceiling effect for analgesia and induce a withdrawal syndrome in patients already physically dependent on opioids.

In general, acute pain is best treated with short-acting (immediate-release) pure agonist drugs at the lowest effective dosage possible and for a short time; Centers for Disease Control and Prevention (CDC) guidelines recommend 3 to 7 days (1). Clinicians should reevaluate patients before re-prescribing opioids for acute pain syndromes. For acute pain, using opioids at higher doses and/or for a longer time increases the risk of needing long-term opioid therapy and of having opioid adverse effects.

Chronic pain, when treated with opioids, may be treated with long-acting formulations (see tables Opioid Analgesics and Equianalgesic Doses of Opioid Analgesics). Because of the higher doses in many long-acting formulations, these drugs have a higher risk of serious adverse effects (eg, death due to respiratory depression) in opioid-naive patients.


Opioid Analgesics


Adult Dose*

Pediatric Dose†


Opioid agonists in combination products‡ for moderate pain


Oral: 30–60 mg every 4 hours

0.5–1 mg/kg

Less potent than morphine


Oral: 5–10 mg every 4–6 hours

0.135 mg/kg

More potent than codeine

Opioid agonists for moderate-to-severe pain


Transdermal: 12 or 25 mcg/hour every 3 days

Transmucosal: 100–200 mcg every 2–4 hours

Intranasal: 100–200 mcg every 2–4 hours

Parenteral: 25–100 mcg every 30–60 minutes IV or as patient-controlled analgesia

Transmucosal: 5–15 mcg/kg

Parenteral: 0.5–1.0 mcg/kg

May trigger less histamine release and thus may cause less hypotension than other opioids

Transdermal: When used in cachexic patients, may result in erratic absorption and blood levels

Supplemental analgesia required at first because peak analgesia does not occur until 18–24 hours after application

May take many hours for adverse effects to resolve after removing patch

Short-acting transmucosal and intranasal forms: Used for breakthrough pain in opioid-tolerant adults and for conscious sedation in children

IV form: Sometimes used for procedural sedation


Oral tablets: 2–4 mg every 4–6 hours

Oral liquid: 2.5–10 mg every 4–6 hours

Parenteral: 0.2–1 mg every 4–6 hours or as patient-controlled analgesia

Extended-release: 8–32 mg every 24 hours

Rectal: 3 mg every 6–8 hours

Short half-life

Rectal form: Used at bedtime


Oral: 2 mg every 6–8 hours

Parenteral: 2 mg every 6–8 hours

Long half-life


Oral: 50–300 mg every 4 hours

Parenteral: 50–150 mg every 4 hours

1.1–1.75 mg/kg

Not preferred because its active metabolite (normeperidine) causes dysphoria and central nervous system excitation (eg, myoclonus, tremulousness, seizures) and accumulates for days after dosing is begun, particularly in patients with renal failure; no longer used in some practices because of these risks


Oral: 2.5–10 mg every 6–8 hours

Parenteral: 2.5–5 mg every 6–8 hours

Used for treatment of heroin withdrawal, long-term maintenance treatment of opioid use disorder (addiction), and analgesia for chronic pain

Establishment of a safe, effective dose for analgesia complicated by its long half-life (usually much longer than duration of analgesia)

Requires close monitoring for several days or more after amount or frequency of dose is increased because serious toxicity can occur as the plasma level rises to steady state

Risk of QT-interval prolongation; ECG monitoring recommended


Oral immediate-release: 10–30 mg every 4 hours

Oral controlled-release: 15 mg every 12 hours

Oral sustained-release: 30 mg every 24 hours

Parenteral: 5–10 mg every 4 hours or as patient-controlled analgesia

0.05–0.2 mg/kg every 4 hours

Standard of comparison

Triggers histamine release more often than other opioids, causing itching


Oral: 5–10 mg every 6 hours

Oral controlled-release: 10–20 mg every 12 hours

Also in combination products containing acetaminophen or aspirin


Oral: 5 mg every 4 hours

Oral controlled-release: 5–10 mg every 12 hours

IM or subcutaneously: 1–1.5 mg every 4 hours

IV: 0.5 mg every 4 hours

Rectal: 5 mg every 4–6 hours

May trigger less histamine release than other opioids

Opioid agonist-antagonists§


IV or IM: 0.3 mg every 6 hours

Sublingual: 2 mg every 12 hours

Transdermal patch: 5–20 mcg/hours applied once a week (in European Union, doses may exceed 20 mcg/hour)

Use only in patients > 13 years (same as adult dose)

Psychotomimetic effects (eg, delirium, sedation) less prominent than those of other agonist-antagonists, but other effects similar

Lower risk of respiratory depression with buprenorphine than with traditional analgesics (eg, morphine, fentanyl) but not fully reversible with naloxone

Higher affinity for mu receptors than traditional analgesics

May induce acute withdrawal if added to long-term opioid therapy

Analgesic effect of traditional analgesics possibly limited when they are added to long-term therapy with buprenorphine

Sublingual and transdermal buprenorphine used occasionally for chronic pain

May be used as agonist therapy in opioid use disorder (addiction) but requires special licensure


IV: 1 (0.5–2) mg every 3–4 hours

IM: 2 (1–4) mg every 3–4 hours

Nasal: 1 mg (1 spray), repeated in 1 hour as needed

Not recommended

2-dose nasal sequence, repeated every 3–4 hours if needed


Parenteral: 10 mg every 3–6 hours

Not recommended

Psychotomimetic effects less prominent than those of pentazocine but more prominent than those of morphine; 2.5–5 mg IV (lower dose) possibly useful for pruritis (may repeat dose once)


Oral: 50–100 mg every 3–4 hours

Parenteral: 30 mg every 3–4 hours (not to exceed 360 mg/day)

Not recommended

Usefulness limited by the following:

  • Ceiling effect for analgesia at higher doses

  • Potential for opioid withdrawal in patients physically dependent on opioid agonists

  • Risk of psychotomimetic effects, especially for nontolerant, nonphysically dependent patients with acute pain

Available in tablets combined with naloxone, aspirin, or acetaminophen

Can cause confusion and anxiety, especially in older patients

Mu-opioid agonists/norepinephrine reuptake inhibitors


Oral immediate-release: 50 to 100 mg every 4 to 6 hours, a second dose ≥ 1 hour later (≤ 700 mg total dose on 1st day); After 1st day, 50 to 100 mg every 4 to 6 hours (≤ 600 mg total daily dose)

Oral extended-release: 50 mg every 12 hours (usual therapeutic dose of 100 to 250 mg every 12 hours; maximum 500 mg/day)

Used to treat neuropathic pain due to diabetes, moderate to severe acute pain, and moderate to severe chronic pain


Oral immediate-release: 50 to 100 mg every 4 to 6 hours; maximum 400 mg/day

Oral extended-release: 100 mg once a day; increase by ≤ 100 mg/day every 5 days to a dose of ≤ 300 mg total daily dose

Not recommended

Less potential for abuse than with other opioids

Not as potent as other opioid analgesics

* Starting doses are for opioid-naive patients. Patients with opioid tolerance or severe pain may require higher doses.

† Not all drugs are appropriate for analgesia in children.

‡ These opioid agonists may be combined into a single pill with acetaminophen, aspirin, or ibuprofen. They are often used alone so that acetaminophen, aspirin, or ibuprofen dosing limits do not limit opioid dosing. If combination therapy is desired, acetaminophen, aspirin, or ibuprofen can be added separately while maximizing flexibility in dosing the opioid agonist.

§ Opioid agonist-antagonists are not usually used for chronic pain and are rarely drugs of choice for older patients.

Opioid analgesics have proven efficacy in the treatment of acute pain, cancer pain, and pain at the end of life and as part of palliative care. They are sometimes underused in patients with severe acute pain or in patients with pain and a terminal disorder such as cancer, resulting in needless pain and suffering. Reasons for undertreatment include

  • Underestimation of the effective dose

  • Overestimation of the risk of adverse effects

Generally, opioids should not be withheld when treating acute, severe pain; however, simultaneous treatment of the condition causing the pain usually limits the duration of severe pain and the need for opioids to a few days or less. Also, opioids should generally not be withheld when treating cancer pain; in such cases, adverse effects can be prevented or managed, and addiction is less of a concern.

Duration of opioid trials for chronic pain due to disorders other than terminal disorders (eg, cancer) has been short. Thus, there is little evidence to support opioid therapy for long-term management of chronic pain due to nonterminal disorders. Also, serious adverse effects of long-term opioid therapy (eg, opioid use disorder [addiction], overdose, respiratory depression, death) are being increasingly recognized. Thus, in patients with chronic pain due to nonterminal disorders, lower-risk nonopioid therapies should be tried before opioids; these therapies include

  • Nonopioid drugs

  • Complementary (integrative) medicine techniques (eg, acupuncture, massage, superficial electrical stimulation)

  • Cognitive-behavioral techniques

  • Interventional therapies (epidural injections, joint injections, nerve blocks, nerve ablation, spinal or peripheral nerve stimulation)

In patients with chronic pain due to nonterminal disorders, opioid therapy may be considered, but usually only if nonopioid therapy has been unsuccessful. In such cases, opioids are used (often in combination with nonopioid therapies) only when the benefit of pain reduction and functional improvement outweighs the risks of opioid adverse effects and misuse. Obtaining informed consent may help clarify the goals, expectations, and risks of treatment and facilitate education and counseling about misuse.

Patients receiving long-term (> 3 months) opioid therapy should be regularly assessed for pain control, functional improvement, adverse effects, and signs of misuse. Opioid therapy should be considered a failed treatment and should be tapered and stopped if the following occur:

  • Patients have persistent severe pain despite increasing opioid doses.

  • Patients do not adhere to the terms of treatment.

  • Physical or mental function do not improve.

Physical dependence (development of withdrawal symptoms when a drug is stopped) should be assumed to exist in all patients treated with opioids for more than a few days. Thus, opioids should be used as briefly as possible, and in dependent patients, the dose should be tapered to control withdrawal symptoms when opioids are no longer necessary. Patients with pain due to an acute, transient disorder (eg, fracture, burn, surgical procedure) should be switched to a nonopioid drug as soon as possible. Dependence is distinct from opioid use disorder (addiction), which, although it does not have a universally accepted definition, typically involves compulsive use and overwhelming involvement with the drug, including craving, loss of control over use, and use despite harm.


Equianalgesic Doses of Opioid Analgesics*


Parenteral (mg)

Oral (mg)
































* Equivalences are based on single-dose studies influenced by clinical experience. Cross-tolerance between drugs is incomplete, so when one drug is substituted for another, the equianalgesic dose should be reduced by 50%; methadone should be reduced by 75–90%. Some experts have suggested that morphine:methadone equivalence is nonlinear and that it changes when morphine dosage is higher, as in the following morphine-to-methadone conversion ratios:

  • < 100 OMME/day: 3:1

  • 101–300 OMME/day: 5:1

  • 301–600 OMME/day: 10:1

  • 601–800 OMME/day: 12:1

  • 801–1000 OMME/day: 15:1

  • ≥ 1001 OMME/day: 20:1

Methadone dosage should still be reduced by 75–90% even when this more conservative equivalence calculation is used.

† Parental oxycodone is available in Europe but not in the US.

OMME = oral morphine milligram equivalents.

Route of administration

Almost any route can be used for opioids.

The oral or transdermal route is preferred for long-term use; both are effective and provide stable blood levels. Modified-release oral and transdermal forms allow less frequent dosing, which is particularly important for providing overnight relief.

The IV route provides the most rapid onset and thus the easiest titration, but duration of analgesia is short. Large, rapid fluctuations in blood levels (bolus effect) can lead to toxicity at peak levels early in the dosing interval or later to breakthrough pain at trough levels. Continuous IV infusion, sometimes with patient-controlled supplemental doses, eliminates this effect but requires an expensive pump; this approach is used most often for postoperative pain.

The IM route provides analgesia longer than IV but is painful, and absorption can be erratic; it is not recommended.

Long-term continuous subcutaneous infusion can be used, particularly for cancer pain.

Transmucosal (sublingual) formulations of fentanyl are available. Lozenges are used for sedation in children and as treatment of breakthrough pain in patients who have cancer and have taken opioids before.

Intraspinal opioids (eg, morphine 5 to 10 mg epidurally or 0.5 to 1 mg intrathecally for acute pain) can provide relief, which is prolonged when a hydrophilic drug such as morphine is used; they are typically used perioperatively. Implanted infusion devices can provide long-term neuraxial infusion, usually for cancer-related pain. These devices can also be used with other drugs (eg, local anesthetics, clonidine, ziconotide).

Dosing and titration

Initial dose in an opioid-naive patient is usually the lowest available starting dosage of the immediate-release formulation, and it is increased incrementally by the smallest amount practical until analgesia is satisfactory or adverse effects limit treatment. Long-acting opioids should not be used as first-line treatment in opioid-naive patients and should not be prescribed for intermittent use.

When initially prescribing opioids for acute pain or postoperative pain, clinicians should limit treatment to the lowest dosage and the shortest duration of treatment. Higher dosages and/or longer durations of treatment with initial opioid exposure appear to increase risk of chronic use.

Sedation and respiratory rate are monitored when opioids are given parenterally to relatively opioid-naive patients. Opioid therapy, particularly for opioid-naive patients, should start with a short-acting drug because many longer-acting opioids are given at higher doses and their adverse effects (including serious ones such as respiratory depression) last longer.

The Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for chronic pain (1) recommend the following:

  • Limiting total daily oral morphine milligram equivalents (OMME) to < 50 when possible

  • Considering the individual harm/benefit ratio at doses > 50 OMME daily

  • When possible, avoiding doses > 90 OMME daily

  • Justifying daily doses > 90 OMMME after weighing the needs for analgesia and functional improvement against the risks of higher-dose therapy

  • Tapering and then stopping opioid therapy if the goals for pain relief and functional improvement are not met or if maintaining them requires dose escalation

Of all prescribed opioids, methadone has the highest rate of opioid-induced deaths (per prescription). It should be prescribed only by practitioners trained in its use. Methadone's pharmacokinetics are variable; methadone should be started at a low dose, use should be closely monitored, and dose should be increased slowly (≤ once a week), especially in an unmonitored outpatient setting. Because methadone can prolong the cardiac QT interval, the QTc interval should be assessed by ECG before methadone initiation and before and after any significant change in methadone dosing. Methadone should be used with extreme caution, if at all, in patients taking other drugs that may affect the QT interval.

Older patients are more sensitive to opioids and are predisposed to adverse effects; opioid-naive older patients typically require lower doses than younger patients. Neonates, especially when premature, are also sensitive to opioids because they lack adequate metabolic pathways to eliminate them.

For moderate, transient pain, an opioid may be given as needed. For severe or ongoing pain, doses should be given regularly, without waiting for severe pain to recur; supplemental doses are given as needed when treating cancer pain. The doses for patients with chronic noncancer pain are typically decided case by case.

Patient-controlled analgesia provides a safe, flexible way to administer opioids in a hospital setting when pain is severe or oral analgesics are inadequate. The physician controls the amount and interval of the bolus and maximum dosage available over a set time interval (usually 4 hours); this maximum dose is called the lockout dosage. A bolus dose (eg, morphine 1 mg or hydromorphone 0.2 mg as often as every 6 minutes) is provided when patients push a button. As a safety measure, if the set time interval has not passed since the last administered dose or if the cumulative lockout dosage has been reached in the set time period, a bolus dosage is not administered when the button is pushed. Only the patient is allowed to push the administration button. If patients are sedated because of their drugs or medical condition, they are not alert enough to push the administration button, thus adding another layer of safety.

Occasionally, a baseline infusion (eg, morphine 0.5 to 1 mg/hour) can be considered, but if it is used with a patient-controlled bolus opioid, risk of adverse effects is higher. Thus, a baseline infusion should be used with caution in such cases, and it should be used only in patients who are alert enough to manage patient-controlled analgesia and who will use it only when needed. Patients with prior opioid exposure or with chronic pain require a higher bolus and baseline infusion dose; the available dose is further adjusted based on response.

Patients with dementia cannot use patient-controlled analgesia, nor can young children; however, adolescents often can.

During long-term treatment, the effective opioid dose can remain constant for prolonged periods. Some patients need intermittent dose escalation, typically in the setting of physical changes that suggest an increase in the pain (eg, progressive neoplasm). In such cases, fear of tolerance should not inhibit appropriate early, aggressive use of an opioid. If a previously adequate dose becomes inadequate, that dose must usually be increased to control pain.

Nonopioid analgesics (eg, acetaminophen, NSAIDs) are often given concomitantly. Products containing both drugs are convenient, but the nonopioid may limit upward titration of the opioid dose.

Adverse effects

In opioid-naive patients, adverse effects common at the start of therapy include

  • Sedation and mental clouding

  • Nausea and vomiting

  • Constipation

  • Itching

  • Respiratory depression

  • Myoclonus

Because steady-state plasma levels are not approached until 4 to 5 half-lives have passed, drugs with a long half-life (particularly levorphanol and methadone) have a risk of delayed toxicity as plasma levels rise. Modified-release opioids typically require several days to approach steady-state levels.

In older patients, opioids tend to have more adverse effects (commonly, constipation and sedation or mental clouding). Falls are a particular risk in older patients. Opioids may cause urinary retention in men with benign prostatic hyperplasia.

Although tolerance to opioid-induced sedation, mental clouding, and nausea usually develops within days, tolerance to opioid-induced constipation and urinary retention usually occurs much more slowly. Any adverse effect may be persistent in some patients; constipation is particularly likely to persist.

Opioids should be used cautiously in patients with certain disorders:

  • Hepatic disorders because drug metabolism is delayed, particularly with modified-release preparations

  • COPD because respiratory depression is a risk

  • Untreated obstructive sleep apnea because respiratory depression is a risk

  • Some neurologic disorders, such as dementia and encephalopathy, because delirium is a risk

  • Severe renal insufficiency because metabolites may accumulate and cause problems (accumulation least likely with fentanyl and methadone)

Sedation is common. Patients should not drive and should take precautions to prevent falls and other accidents for a period of time after initiation of opioids and after an increase in dose until they can judge the drug's effect on their ability to do these types of activities. Patients and family members should be instructed to contact one of their practitioners if patients experience sedation. If sedation impairs quality of life, certain stimulant drugs may be given intermittently (eg, before a family gathering or other event that requires alertness) or, to some patients, regularly. Drugs that can be effective are

  • Methylphenidate (initially, 5 to 10 mg orally 2 times a day)

  • Dextroamphetamine (initially, 2.5 to 10 mg orally 2 times a day)

  • Modafinil (initially, 100 to 200 mg orally once a day)

These drugs are typically given in the morning and as needed later. The maximum dose of methylphenidate seldom exceeds 60 mg/day. For some patients, caffeine-containing beverages provide enough stimulation. Stimulants may also potentiate analgesia.

Nausea can be treated with one of the following:

  • Hydroxyzine 25 to 50 mg orally every 6 hours

  • Metoclopramide 10 to 20 mg orally every 6 hours

  • An antiemetic phenothiazine (eg, prochlorperazine 10 mg orally or 25 mg rectally every 6 hours)

Itching is caused by histamine release and may be relieved by an antihistamine (eg, diphenhydramine 25 to 50 mg orally or IV). In hospitalized patients with intractable itching caused by epidural or parenteral opioids, nalbuphine 2.5 to 5 mg IV every 4 hours is generally more effective than diphenhydramine or hydroxyzine.

Constipation is common among patients who take opioids for more than a few days. Preventive treatment should be considered for all patients when opioids are started, especially for predisposed patients (eg, older patients, immobile patients). Dietary fiber and fluids should be increased (but are rarely sufficient alone), and initially, a stimulant laxative (eg, senna) and/or an osmotic laxative (eg, polyethylene glycol) should be given daily. If needed, a drug that is specific for opioid-induced constipation may also be used (2). Effective drugs include

  • Peripherally acting mu–opioid receptor antagonists (PAMORAs) such as naloxegol 25 mg orally once a day (morning) and methylnaltrexone (subcutaneously) 12 mg/0.6mL or 450 mg orally once a day

  • Chloride channel agonists (activators), such as lubiprostone (oral) 24 mcg orally 2 times a day

Both PAMORAs and chloride channel agonists can be used throughout the course of opioid therapy for noncancer pain. The goal should be a bowel movement at least every other day with the daily use of the drug; additional measures (eg, bisacodyl, milk of magnesia, magnesium citrate, lactulose, enema) should be used later on day 2 if no bowel movement has occurred. Persistent constipation can be managed with magnesium citrate 240 mL orally once a day, lactulose 15 mL orally 2 times a day, or propylethylene glycol powder (dose is adjusted as needed). Some patients require regular enemas.

For urinary retention, double voiding or using the Credé method during voiding may help; some patients benefit from adding an alpha-adrenergic blocker such as tamsulosin 0.4 mg orally once a day (starting dose).

Neuroendocrine effects, typically reversible hypogonadism, are possible. Symptoms may include fatigue, loss of libido, infertility due to low levels of sex hormones, and, in women, amenorrhea. Low levels of androgens also lead to osteoporosis. Patients taking long-term opioid therapy require intermittent bone density testing.

Most patients who overdose or have respiratory depression are misusing the drug (not taking it as prescribed) or taking high doses (> 100 OMME). However, most opioid overdoses are unintentional, and respiratory depression can occur when the opioid dose is low (< 20 OMME).

Risk of overdose or respiratory depression is higher when patients

  • Take other sedatives, such as benzodiazepines, muscle relaxants, gabapentin, and alcohol (risk is highest with benzodiazepines, which, when possible, should not be used with opioid therapy)

  • Have comorbidities that affect hepatic or renal metabolism

Risk factors for respiratory depression also include

  • History of stroke, renal disease, heart failure, or chronic pulmonary disease

  • Untreated or undertreated obstructive sleep apnea or chronic obstructive pulmonary disease (COPD)

  • Substance use disorder

  • Psychiatric disorders

  • Concurrent use of some common psychoactive drugs

  • Use of long-acting opioids, high-dose opioids (> 100 OMME), or methadone

Modifiable risk factors for overdose or respiratory depression should be managed; strategies include

  • Treating sleep apnea

  • Advising patients not to drink alcohol when they take the opioid

  • Not prescribing benzodiazepines with opioids when possible

  • Not prescribing long-acting opioids when possible

  • Prescribing methadone only if trained in its unique adverse effect profile

  • Assessing the risk of overdose or serious opioid-induced respiratory depression using the Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD)

If patients are at increased risk of overdose or respiratory depression, practitioners should discuss the risk with them and their family members and should prescribe naloxone for them. If patients are taking long-term opioid therapy, practitioners should explain the potential harms and benefits of long-term opioid therapy.

Opioid misuse, diversion, and abuse

Opioids are now the leading cause of accidental death and fatal drug overdose in the US. Risk of fatal drug overdose increases significantly when opioid analgesics are used with benzodiazepines. Also, rates of misuse, diversion, and abuse (aberrant drug-taking behaviors) are increasing.

Opioid misuse may be intentional or unintentional. It includes any use that contradicts medical advice or deviates from what is prescribed.

Diversion involves selling or giving a prescribed drug to others.

Abuse refers to recreational or nontherapeutic use (eg, euphoria, other psychotropic effects).

Up to one third of patients taking long-term opioids for chronic pain may misuse prescribed opioids (not use them as directed) or may abuse them.

Addiction, typically marked by impaired control and craving, refers to compulsive use despite harm and negative consequences. Some definitions of addiction include tolerance (an increasingly higher dose is required to maintain the same level of analgesia and efficacy over time) and withdrawal (discontinuation of the drug or a significant decrease in the dose causing withdrawal symptoms). However, both of these characteristics are expected physiologic effects of opioid therapy and therefore not useful in defining opioid addiction.

Opioid use disorder is preferred over the term addiction. Opioid use disorder is defined as compulsive, long-term self-administration of opioids for nontherapeutic purposes, causing significant impairment or distress. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides specific additional criteria for diagnosing this disorder, which include the following:

  • Taking larger amounts or for a longer time than was intended

  • A persistent desire or unsuccessful efforts to cut down

  • Excessive time spent obtaining the opioid, taking the opioid, or recovering from its effects

  • Craving opioids

  • Recurrent use despite failure to meet obligations or adverse social consequences resulting from or worsened by taking opioids

Risk of opioid use disorder depends on frequency of use and dose:

  • 0.004%: No regular opioid use

  • 0.7%: Use of low-dose opioids (< 36 mg/day OMME)

  • 6.1%: Use of high-dose opioids (> 120 mg/day OMME)

  • 2 to 15%: In other studies (not stratified by dose)

When considering prescribing opioid therapy, particularly long-term therapy, clinicians should evaluate patients for risk factors for abuse and diversion and counsel them against intentional and inadvertent misuse. Before opioid therapy is started, clinicians should obtain informed consent and assess the patient's risk of developing opioid use disorder.

Risk factors for developing opioid use disorder include

  • Patient history of alcohol or drug abuse

  • Family history of alcohol or drug abuse

  • Major psychiatric disorder (current or past)

  • Use of psychoactive drugs

  • Younger age (< 45)

Screening tools can help identify patients at higher risk of opioid use disorder; the opioid risk tool (ORT) may be the best. However, no risk assessment tool is sufficient to determine whether treating a patient with opioids is safe or has a low risk. Therefore, all patients being treated with opioids should be monitored closely during treatment to make sure opioid therapy is used safely.

Routine monitoring should include periodic unannounced urine drug screens to check for the presence of the prescribed drug and absence of illicit drugs.

Unannounced screens are more likely to identify aberrant use or misuse but are more challenging to incorporate into a clinic's workflow. Current recommendations are to do urine drug screens as follows:

  • At initial prescription

  • At least annually

  • More frequently if risk is high or concerns develop

The patient's history of controlled substance use should be reviewed using information from state prescription drug monitoring programs (PDMPs). Current recommendations include routine screening using the PDMP as follows:

  • When opioids are initially prescribed

  • When each refill is prescribed or at least every 3 months

Routine PDMP inquiries help clinicians make sure a single prescribing physician and pharmacy are used.

Even when risk factors for developing an opioid use disorder are present, treatment may still be appropriate; however, clinicians should use more stringent measures to prevent abuse and addiction (3). Measures include

  • Prescription of only small amounts (requiring frequent visits for refills)

  • Urine drug screening to monitor treatment adherence (ie, to confirm that patients are taking the drugs and not diverting them)

  • No refills for “lost” prescriptions

  • Use of tamper-resistant opioid formulations that have been developed to deter abuse by chewing or by crushing and injecting oral preparations

  • Consideration of a buprenorphine formulation that can be useful for analgesia and that has a ceiling effect on risk of sedation and respiratory depression—properties that make it an effective treatment for any opioid use disorder

Clinicians may need to refer problematic patients to a pain specialist or a substance use specialist experienced in pain management.

When the opioid is first prescribed, clinicians should provide relevant information to patients. Clinicians should explain the measures that will be taken to ensure safe use of ongoing prescribing and use and the consequences of a history or an evaluation (eg, urine drug screening, prescription drug monitoring) that suggests aberrant use, misuse, abuse, or diversion (ie, opioid tapering). Patients should also be told that nonopioid pain management strategies will be continued and that they may be referred to a substance use specialist.

If patients develop opioid use disorder, prescribing physicians are responsible for offering and arranging evidence-based treatment (usually drug-assisted treatment with buprenorphine or methadone plus cognitive-behavioral therapies).

To avoid misuse of their drug by others, patients should keep opioids in a safe place and dispose of any unused drugs by returning them to the pharmacy.

All patients should be counseled regarding the risks of combining opioids with alcohol and anxiolytics and self-adjustment of dosing.

Opioid antagonists

Opioid antagonists are opioid-like substances that bind to opioid receptors but produce little or no agonist activity. They are used mainly to reverse symptoms of opioid overdose, particularly respiratory depression.

Naloxone acts in < 1 minute when given IV and slightly less rapidly when given IM. It can also be given sublingually or endotracheally. Duration of action is about 60 to 120 minutes. However, opioid-induced respiratory depression usually lasts longer than the duration of antagonism; thus, repeated doses of naloxone and close monitoring are necessary.

The dose for acute opioid overdosage is 0.4 mg IV every 2 to 3 minutes as needed (titrated to adequate respirations, not alertness). If repeated doses are necessary, the dose can be increased (to a maximum of 2 mg IV per dose). If there is no response after 10 mg has been given, the diagnosis of opioid toxicity should be reconsidered.

For patients receiving long-term opioid therapy, naloxone should be used only to reverse respiratory depression and must be given more cautiously to avoid precipitating withdrawal or recurrent pain.

Naloxone is also available as a nasal spray and an auto-injector (IM). For the nasal spray, a single spray (2 or 4 mg in 0.1 mL) is sprayed into one nostril. For the auto-injector, the dose is 2 mg injected IM or subcutaneously into the anterolateral thigh (through clothing if necessary).

Nalmefene is similar to naloxone, but its duration of action is about 4 to 8 hours. Nalmefene is occasionally used to ensure prolonged opioid reversal.

Naltrexone, an orally bioavailable opioid antagonist, is given as adjunctive therapy in opioid and alcohol addiction. It is long-acting and generally well-tolerated.

Opioid analgesics references

  • 1. Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain—United Stat 2016. JAMA 315 (15):1624–1645, 2016. doi: 10.1001/jama.2016.1464.

  • 2. Argoff CE, Brennan MJ, Camilleri M, et al: Consensus recommendations on initiating prescription therapies for opioid-induced constipation. Pain Med 16 (12):2324-2337, 2015. doi: 10.1111/pme.12937.

  • 3. Babu KM, Brent J, Juurlink DN: Prevention of opioid overdose. N Eng J Med 380:2246–2255, 2019. doi: 10.1056/NEJMra1807054.

Adjuvant Analgesic Drugs

Many drugs are used as adjuvant analgesics, including antiseizure drugs (eg, gabapentin, pregabalin), antidepressants (eg, tricyclics, duloxetine, venlafaxine, bupropion), and many others (see table Drugs for Neuropathic Pain). These drugs have many uses, most notably to relieve pain with a neuropathic component.

Gabapentin is the most widely used drug for such purposes. For effective analgesia, the dose should usually be > 600 mg orally 3 times a day, and many patients need a higher dose. Maximum dosage is usually considered 1200 mg orally 3 times a day. Gabapentin is widely used for neuropathic pain and headache syndromes.

Pregabalin is similar to gabapentin but has more stable pharmacokinetics; dosing 2 times a day is as efficacious as dosing 3 times a day and results in better compliance. The dosing goal is at least 300 mg/day orally (eg, a starting dose of 75 mg 2 times a day, increased to 150 mg 2 times a day within 1 week). Neuropathic pain syndromes may require up to 600 mg/day. Some patients who do not respond well to or do not tolerate gabapentin do respond to or tolerate pregabalin and vice versa, even though the 2 drugs have a similar primary mechanism of action (binding to the alpha-2 delta ligand of the presynaptic calcium channel). Pregabalin is effective for neuropathic pain (including central pain due to spinal cord injury) and fibromyalgia; some evidence suggests it is effective as an anxiolytic.

For tricyclic antidepressants (amitriptyline, nortriptyline, desipramine), the primary mechanism of action is blocking the reuptake of serotonin and norepinephrine. Analgesic doses (75 to 150 mg orally once a day) are usually insufficient to treat depression or anxiety. Anticholinergic and adrenergic adverse effects often limit effective dosing. Secondary amine tricyclic antidepressants (nortriptyline and desipramine) have a more favorable adverse effect profile than tertiary amine tricyclic antidepressants (amitriptyline). Tricyclic antidepressants are effective for neuropathic pain, myofascial pain syndromes, some central neuropathic pain syndromes, visceral pain syndromes, and headache syndromes.

Duloxetine is a mixed mechanism (serotonin and norepinephrine) reuptake inhibitor, which appears to be effective for diabetic neuropathic pain, fibromyalgia, chronic musculoskeletal pain (including low back pain), and chemotherapy-induced neuropathy. Doses that are efficacious for depression and anxiety and for pain management are similar.

Venlafaxine has similar effects.


Drugs for Neuropathic Pain




Antiseizure drugs†


200–400 mg twice a day

Monitor CBC and liver function during treatment

May decrease efficacy of oral contraceptives

First-line treatment for trigeminal neuralgia


300–1200 mg 3 times a day

Starting dose usually 300 mg once a day

Dosing goal: 600–1200 mg 3 times a day

Adjust dose in patients with renal insufficiency


600–900 mg twice a day

Starting dose usually 300 mg once a day

Considered as efficacious as carbamazepine for trigeminal neuralgia and useful for other paroxysmal neuropathic pain

May cause hyponatremia or decrease efficacy of oral contraceptives

Unlike carbamazepine, no CBC or liver function monitoring necessary


300 mg once a day

Limited data; 2nd-line drug


150–300 mg 2 times a day

Starting dose usually 75 mg 2 times a day, increased by the same dosage weekly as necessary to a maximum of 300 mg orally 2 times a day

Mechanism similar to gabapentin but more stable pharmacokinetics

Adjust dose in patients with renal insufficiency


250–500 mg 2 times a day

Limited data, but strong support for treatment of headache



10–25 mg at bedtime (starting dose), increased weekly by the same dose to a maximum of 150 mg at bedtime

Dosing goal: About 100 mg/day (dosing for pain unlikely to be adequate for relieving depression or anxiety)

Not recommended for older patients or patients with a heart disorder because it has strong anticholinergic effects

May increase dose to 150 mg or sometimes higher

Desipramine or nortriptyline

10–25 mg at bedtime (starting dose), increased weekly by the same dose to maximum of 150 mg at bedtime

Better tolerated than amitriptyline; adverse effect profile better with desipramine than nortriptyline

Dosing goal: About 100 mg/day (dosing for pain unlikely to be adequate for relieving depression or anxiety)

Not recommended for older patients or patients with a heart disorder because it has strong anticholinergic effects

May increase dose to 150 mg or sometimes higher


20–60 mg once a day

Starting at 20–30 mg once a day and increasing by the same dosage weekly to a goal of 60 mg/day; in some cases, increasing to 60 mg 2 times a day (especially in patients with concomitant depression or anxiety)

Better tolerated than tricyclic antidepressants

Dosing goal for pain (60 mg/day) usually sufficient to treat concomitant depression or anxiety


Extended-release (easiest to use): 150–225 mg once a day

More norepinephrine reuptake inhibition at higher doses (≥ 150 mg/day); lower dosages ineffective for neuropathic pain

Similar mechanism of action as duloxetine

Effective for pain, depression, and anxiety at this dose

Central alpha-2 adrenergic agonists


0.1 mg once a day

Also can be used transdermally or intrathecally


2–20 mg 2 times a day

Less likely to cause hypotension than clonidine



0.5–4 mg 4 times a day

Used only for pain with an inflammatory component


5–60 mg once a day

Used only for pain with an inflammatory component

NMDA-receptor antagonists


10–30 mg once a day

Limited evidence of efficacy


30–120 mg 4 times a day

May have a role in neuropathic pain in patients who have developed tolerance or a lower pain threshold due to central sensitization

In > 90% of whites, rapid metabolism via hepatic cytochrome P-450 2D6, reducing the therapeutic effect

Metabolism of dextromethorphan blocked by quinidine

Combination dextromethorphan/quinidine available for pseudobulbar affect in patients with amyotrophic lateral sclerosis

Oral sodium channel blockers


150 mg once a day to 300 mg every 8 hours

Used only for neuropathic pain

For patients with a significant heart disorder, cardiac evaluation recommended before the drug is started


Capsaicin 0.025–0.075% (eg, cream, lotion)

Apply 3 times a day

Some evidence of efficacy in neuropathic pain and arthritis

Capsaicin 8% patch

Up to 4 at one time‡

Causes a severe sunburn-like skin reaction; oral opioids often required for up to 1 week after application of capsaicin 8% to manage the worsening cutaneous pain

Meaningful pain relief for 3 months after a single application


Apply 3 times a day, under occlusive dressing if possible

Usually considered for a trial if a lidocaine patch is ineffective; expensive

Lidocaine 5%


Available as patch



20–60 mg 2 times a day

May act via GABA-B receptor

Helpful in trigeminal neuralgia; used in other types of neuropathic pain

Pamidronate (injection)

60–90 mg/month IV

Evidence of efficacy in complex regional pain syndrome

* Route is oral unless otherwise indicated.

† Newer antiseizure drugs have fewer adverse effects.

‡ Topical lidocaine 4–5% applied 1 hour before applying capsaicin can help limit irritation.

CBC = complete blood count; EMLA = eutectic mixture of local anesthetics; GABA =gamma-aminobutyric acid; NMDA =N-methyl-d-aspartate; WBCs = white blood cells.

Topical drugs are also widely used. Capsaicin cream, topical NSAIDs, other compounded creams (eg, local anesthetics), and a lidocaine 5% patch have little risk of adverse effects; they should be considered for many types of pain.

Neural Blockade

Interrupting nerve transmission in peripheral or central pain pathways via drugs or physical methods provides short-term and sometimes long-term relief. Neuroablation (pathway destruction) is used rarely; it is typically reserved for patients with an advanced disorder and a short life expectancy.

Local anesthetic drugs (eg, lidocaine) can be given IV, intrathecally, intrapleurally, transdermally, subcutaneously, or epidurally. Epidural analgesia using local anesthetics or opioids is particularly useful for some types of postoperative pain. Long-term epidural drug administration is occasionally used for patients with localized pain and a short life expectancy. Generally, for long-term neuraxial infusion, an intrathecal route via an implanted pump is preferred.

Neuroablation involves interrupting a nociceptive pathway surgically or using radiofrequency or microwave energy, cryoablation, or caustic substances (eg, phenol or high-concentration alcohol) to produce a lesion. The procedure is used as follows:

  • Radioablation: To ablate the medial branches of the dorsal spinal root rami, which innervate zygapophyseal (facet) joints, for mechanical axial spine pain

  • To treat cancer pain

Somatic pain is more responsive than visceral pain. Neuroablation of the ascending spinothalamic tract (cordotomy) is usually used; it provides relief for several years, although numbness and dysesthesias develop. Neuroablation of the dorsal roots (rhizotomy) is used when a specific dermatome can be identified.


Stimulation of neural tissues may decrease pain, presumably by activating endogenous pain modulatory pathways. Evidence supports treatment of certain types of neuropathic pain (eg, failed back surgery syndrome with chronic leg pain after spine surgery, complex regional pain syndrome [CRPS]) using an electrode placed epidurally to stimulate the spinal cord (spinal cord stimulation).

Advances in electrical stimulation paradigms have improved the efficacy and applicability of neuromodulation techniques. Use of neuromodulation techniques in pain management has increased significantly. With the shift to limit use of opioids for nonterminal pain, neuromodulation techniques are now considered earlier as treatment options for neuropathic pain.

Advances in neuromodulation techniques and technologies include

  • High-frequency stimulation

  • Dorsal root ganglion stimulation

  • Burst spinal cord stimulation waveforms

  • Small flexible peripheral nerve stimulators

  • Improved MRI compatibility, which has greatly expanded the clinical situations in which neuromodulation can be used

High-frequency stimulation is efficacious for neuropathic limb pain. Efficacy is similar to that of traditional neuromodulation techniques, but evidence suggests that it may also be efficacious for axial spine pain, which is not effectively treated with traditional neuromodulation techniques.

Dorsal root ganglion stimulation is a more focused neuromodulation treatment; it targets localized neuropathic pain within limited dermatomes.

Peripheral nerve stimulators, placed under the skin next to a peripheral nerve can be useful for neuropathic pain when a single nerve is involved (eg, postherniorrhaphy pain syndrome, meralgia paresthetica [pain in the outer part of the thigh due to compression of the lateral femoral cutaneous nerve], some headache syndromes). Stimulation of brain structures (deep brain stimulation, motor cortex stimulation) has been used for refractory neuropathic pain syndromes, but evidence is limited.

Geriatrics Essentials

In older patients, the most common causes of pain are musculoskeletal disorders. However, pain is often chronic and multifactorial, and the causes may not be clear.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Risk of ulcers and gastrointestinal (GI) bleeding due to NSAIDs for people > 65 is 3 to 4 times higher than that for middle-aged people. Risk depends on drug dose and duration of therapy. Older patients at high risk of GI adverse effects may benefit from concomitant use of cytoprotective drugs (usually, a proton pump inhibitor; occasionally, the prostaglandin misoprostol).

The risk of cardiovascular toxicity, which presumably occurs with nonselective COX-1 and COX-2 inhibitors and with selective COX-2 inhibitors (coxibs), is particularly relevant to older patients, who are more likely to have cardiovascular risk factors (eg, a history of myocardial infarction (MI) or cerebrovascular or peripheral vascular disease).

Both nonselective and selective NSAIDs can impair renal function and cause sodium and water retention; they should be used cautiously in older patients, particularly in those who have a renal or hepatic disorder, heart failure, or hypovolemia.

Rarely, NSAIDs cause cognitive impairment and personality changes in older patients. Indomethacin causes more confusion in older patients than other NSAIDs and should be avoided.

Given the overall greater risk of serious toxicity in older patients, long-term NSAID therapy should be used with caution, if at all, and only for pain likely to be responsive. NSAIDS are most likely to relieve pain resulting from inflammation.

Low doses of NSAIDs should be used if possible, and using short-term therapy or interrupted therapy to confirm effectiveness should be considered. Naproxen may be preferred because it appears to have a lower risk of cardiovascular adverse effects than other commonly prescribed NSAIDs.


In older patients, opioids have a longer half-life and possibly a greater analgesic effect than in younger patients. In older patients with chronic pain, short-term use of opioids appears to reduce pain and improve physical functioning but to impair cognitive function. As recognition of overdosage risks with opioids is increasing, practitioners should consider whether cognitive impairment in older patients might interfere with a patient's use of opioids and whether a caregiver can responsibly co-manage the patient's drug therapy.

Opioid-related constipation and urinary retention tend to be more problematic in older patients.

Risk of falls and fracture during the first 2 weeks of treatment is higher with opioids than with NSAIDs in older patients, presumably because of the opioid's sedative, cognitive, and balance adverse effects. Long-term opioid therapy can also lead to osteoporosis, partly because opioids inhibit the hypothalamic-pituitary-gonadal axis, causing androgen (testosterone) and estrogen deficiency. The long-term fracture risk due to osteoporosis is a concern in older patients taking long-term opioid therapy.

Compared with other opioids, transdermal buprenorphine, an opioid agonist/antagonist, has a more favorable risk:benefit profile in older patients with renal insufficiency.

Drugs Mentioned In This Article

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Numbness is defined as loss of sensation, either partial or complete. Numbness can occur from dysfunction anywhere along the pathway from the sensory receptors up to the cerebral cortex. A patient with dysfunction in which of the following CNS areas is most likely to present with facial and body numbness on the same side, plus an inability to perceive multiple stimuli of the same type simultaneously?
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