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, and neural blockade can help selected patients.
Cognitive-behavioral interventions may reduce pain and pain-related disability and help patients cope. These interventions include counseling to refocus a patient's thoughts from the effects and limitations of pain to the development of personal coping strategies and may include counseling to help patients and their family work together to manage pain.
Some integrative (complementary and alternative) medicine techniques (eg, acupuncture, biofeedback, exercise, hypnosis, relaxation techniques) are sometimes used, especially to treat chronic pain.
(See also Overview of Pain.)
Nonopioid Analgesics
Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are often effective for mild to moderate pain (see table Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are often effective for mild to moderate pain (see tableNonopioid Analgesics). These drugs are given orally; ibuprofen, ketorolac, diclofenac, and acetaminophen can be given parenterally. Nonopioids do not cause physical dependence or tolerance.). These drugs are given orally; ibuprofen, ketorolac, diclofenac, and acetaminophen can be given parenterally. Nonopioids do not cause physical dependence or tolerance.
Nonopioid Analgesics
Class | Drug | Usual Dosage Range* |
|---|---|---|
Indoles | DiclofenacDiclofenac | 50–100 mg, followed by 50 mg every 8 hours 75 mg every 12 hours IV or IM |
EtodolacEtodolac | 200–400 mg every 6–8 hours | |
IndomethacinIndomethacin | 25–50 mg every 6–8 hours | |
SulindacSulindac | 150–200 mg every 12 hours | |
TolmetinTolmetin | 200–400 mg every 6–8 hours | |
Naphthylalkanone | NabumetoneNabumetone | 1000–2000 mg every 24 hours |
Oxicam | PiroxicamPiroxicam | 20–40 mg every 24 hours |
Para-aminophenol derivative | AcetaminophenAcetaminophen | 650–1000 mg every 6–8 hours |
Propionic acids | FenoprofenFenoprofen | 200–600 mg every 6 hours |
FlurbiprofenFlurbiprofen | 50–200 mg every 12 hours | |
Ibuprofen†Ibuprofen† | 400 mg every 4 hours to 800 mg every 8 hours (maximum: 3200 mg/day†) | |
KetoprofenKetoprofen | 25–50 mg every 6–8 hours | |
NaproxenNaproxen | 250–500 mg every 12 hours | |
Naproxen sodiumNaproxen sodium | 275–550 mg every 12 hours | |
OxaprozinOxaprozin | 600–1200 mg every 24 hours | |
Salicylates | AspirinAspirin | 650–1000 mg every 4–6 hours |
Choline magnesium trisalicylate | 870 mg every 12 hours | |
DiflunisalDiflunisal | 250–500 mg every 8–12 hours | |
SalsalateSalsalate | 750–2000 mg every 12 hours | |
Fenamates | Meclofenamate | 50–100 mg every 6–8 hours |
Mefenamic acidMefenamic acid | 250 mg every 6 hours | |
Pyrazole | Phenylbutazone | 100 mg every 6–8 hours up to 7 days |
Pyrrolo-pyrrolo derivative | KetorolacKetorolac | 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 | CelecoxibCelecoxib | 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.* 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.† 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.Acetaminophen has no anti-inflammatory or antiplatelet effects and does not cause gastric irritation.
Aspirin is the least expensive NSAID, but it has irreversible antiplatelet effects and increases the risk of gastrointestinal (GI) bleeding.Aspirin is the least expensive NSAID, but it has irreversible antiplatelet effects and increases the risk of gastrointestinal (GI) bleeding.
NSAIDs have analgesic, anti-inflammatory, and antiplatelet effects. They inhibit cyclooxygenase (COX) enzymes and thus decrease production of prostaglandins. There are several classes of NSAIDs, which have different mechanisms and adverse effects:
Nonselective COX inhibitors (eg, ibuprofen, naproxen)Nonselective COX inhibitors (eg, ibuprofen, naproxen)
Selective COX-2 inhibitors (coxibs; eg, celecoxib)Selective COX-2 inhibitors (coxibs; eg, celecoxib)
Both COX inhibitors are effective analgesics. Coxibs have the 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 vary by specific drug, as well as by dose and duration. Some evidence suggests the risk is very low with some of nonselective COX inhibitors (eg, ibuprofen, naproxen, coxibs [celecoxib]). However, clinicians should consider the potential for prothrombotic effects as a risk with all NSAIDs; thus, all NSAIDs should be used cautiously in patients with clinically significant atherosclerosis or multiple cardiovascular risk factors.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 vary by specific drug, as well as by dose and duration. Some evidence suggests the risk is very low with some of nonselective COX inhibitors (eg, ibuprofen, naproxen, coxibs [celecoxib]). However, clinicians should consider the potential for prothrombotic effects as a risk with all NSAIDs; thus, 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 with other NSAIDs) and to 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). 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
“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 (eg, buprenorphine, butorphanol) than with pure agonists (eg, morphine, oxycodone, hydromorphone), but agonist-antagonist drugs have a ceiling effect for analgesia and induce a withdrawal syndrome in patients already physically dependent on opioids. 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 (eg, buprenorphine, butorphanol) than with pure agonists (eg, morphine, oxycodone, hydromorphone), but agonist-antagonist drugs have a ceiling effect for analgesia and induce a withdrawal syndrome in patients already physically dependent on opioids.
Opioid Analgesics
Drug | Adult Dose* | Pediatric Dose† | Comments | |||
|---|---|---|---|---|---|---|
Opioid agonists in combination products‡ for moderate pain | ||||||
CodeineCodeine | Oral: 30–60 mg every 4–6 hours as needed | — | Less potent than morphineLess potent than morphine | |||
HydrocodoneHydrocodone | Oral: 5–10 mg every 4–6 hours as needed | — | More potent than codeineMore potent than codeine | |||
Opioid agonists for moderate-to-severe pain | ||||||
FentanylFentanyl | 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 | Parenteral: 1–2 mcg/kg/dose IV; may be repeated in 2–4 hours as needed | May trigger less histamine release and thus may cause less hypotension than other opioids Transdermal: When used in cachectic 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 | |||
HydromorphoneHydromorphone | Oral immediate release: 2–4 mg every 4–6 hours Oral extended-release: 8–32 mg every 24 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 Rectal: 3 mg every 6–8 hours | — | Short half-life Rectal form: Used at bedtime | |||
LevorphanolLevorphanol | Oral: 2 mg every 6–8 hours Parenteral: 1–2 mg IM or subcutaneously every 6–8 hours; 1 mg IV every 3–6 hours | — | Long half-life | |||
MeperidineMeperidine | Oral: 50–300 mg every 4 hours Parenteral: 50–150 mg IV or IM every 4 hours as needed | — | 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 Because of these risks, use of meperidine for pain management discouraged and meperidine no longer used in some practicesBecause of these risks, use of meperidine for pain management discouraged and meperidine no longer used in some practices | |||
MethadoneMethadone | Oral: 2.5–10 mg every 8–12 hours Parenteral: 2.5–10 mg IM or IV every 8–12 hours | — | Used for treatment of heroin withdrawal, long-term maintenance treatment of opioid use disorder, 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 | |||
MorphineMorphine | Oral immediate-release: 5–30 mg every 4 hours Oral controlled-release: 15 mg every 12 hours Oral sustained-release: 30 mg every 24 hours Parenteral: 2–5 mg IV or IM every 2–4 hours as needed | > 6 months old and < 50 kg:
> 6 months old and ≥ 50 kg:
| Standard of comparison Triggers histamine release more often than other opioids, causing itching | |||
Oxycodone‡Oxycodone‡ | Oral: 5–10 mg every 6 hours Oral controlled-release: 10–20 mg every 12 hours | — | Also in combination products containing acetaminophen or aspirinAlso in combination products containing acetaminophen or aspirin | |||
OxymorphoneOxymorphone | Oral: 5 mg every 4 hours Oral controlled-release: 5–10 mg every 12 hours IM : 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§ | ||||||
BuprenorphineBuprenorphine | IV or IM: 0.3 mg every 6 hours Sublingual: 75 mcg once a day or, if tolerated, every 12 hours for ≥ 4 days, then increased to 150 mcg every 12 hours Transdermal patch: initially 5mcg/hour applied once a week; may be titrated to 20 mcg/hour once a week | 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 naloxoneLower 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 buprenorphineAnalgesic effect of traditional analgesics possibly limited when they are added to long-term therapy with buprenorphine Sublingual and transdermal buprenorphine used occasionally for Sublingual and transdermal buprenorphine used occasionally forchronic pain May be used as agonist therapy in opioid use disorder but requires special licensure | |||
ButorphanolButorphanol | IV: Initially 1 mg, may be repeated every 3–4 hours as needed; usual range: 0.52 mg every 3–4 hours as needed IM: Initially 2 mg, may be repeated every 3–4 hours as needed; usual range: 1–4 mg every 3–4 hours as needed. Nasal: Initially1 mg (1 spray in one nostril); if adequate relief is not achieved, may be repeated in 60–90 minutes; after the second dose, may be repeated every 3–4 hours as needed | Not recommended | — | |||
NalbuphineNalbuphine | Parenteral: 10 mg IM, IV, subcutaneous 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 opioid-induced pruritus (may repeat dose once)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 opioid-induced pruritus (may repeat dose once) | |||
Pentazocine | Oral: 50–100 mg every 3–4 hours Parenteral: 30 mg IV, IM, every 3–4 hours (not to exceed 360 mg/day) | Not recommended | Usefulness limited by the following:
Available in tablets combined with naloxone, aspirin, or acetaminophenAvailable in tablets combined with naloxone, aspirin, or acetaminophen Can cause confusion and anxiety, especially in older patients | |||
Mu-opioid agonists/norepinephrine reuptake inhibitorsMu-opioid agonists/norepinephrine reuptake inhibitors | ||||||
TapentadolTapentadol | Oral immediate-release: 50–100 mg every 4–6 hours, a second dose ≥ 1 hour later (≤ 700 mg total dose on 1st day); after 1st day, 50–100 mg every 4–6 hours (≤ 600 mg total daily dose) Oral extended-release: 50 mg every 12 hours (usual therapeutic dose of 100–250 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 Reported to have fewer frequent adverse effects (eg, constipation) than other opioids, | |||
TramadolTramadol | Oral immediate-release: 50–100 mg every 4–6 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.‡ 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. Appropriate evaluation of the patient and consideration of other treatment options and the risk of opioid misuse are part of the decision-making process to balance between risk of abuse and undertreatment of pain.
Opioids 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.
Generally, for acute pain, short-acting (immediate-release) pure agonist drugs are used 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. Using opioids at higher doses and/or for a longer time increases the risk of needing long-term opioid therapy, adverse effects, and opioid misuse. 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.
Generally, opioids should not be withheld when treating cancer pain; in such cases, adverse effects can be prevented or managed, and addiction is less of a concern.
There is insufficient evidence to support opioid therapy for long-term management of chronic pain due to non-terminal disorders. Also, long-term opioid therapy may result in serious adverse effects (eg, opioid use disorder [addiction], overdose, respiratory depression, death). Thus, in patients with chronic pain due to non-terminal disorders, lower-risk nonopioid therapies should be tried before opioids; these therapies include
Nonopioid drugs
Integrative (complementary and alternative) medicine techniques (eg, acupuncture, massage, transcutaneous electrical stimulation [TENS])
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 non-terminal 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 helps clarify the goals, expectations, and risks of treatment and facilitate education and counseling about misuse.
When appropriate to treat with opioids, chronic pain may be treated with long-acting formulations (see tables Opioid Analgesics and Equianalgesic Doses of Opioid Analgesics). Long-acting formulations should not be used for opioid-naive patients because they have a higher risk of serious adverse effects (eg, death due to respiratory depression).
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. Similarly, tolerance (decreased response to the same dose of a drug that is used repeatedly) develops in all patients treated with opioids. Thus, opioids should be used as briefly as possible. In dependent patients, the dose should be tapered to control withdrawal symptoms when opioids are no longer necessary. Dependence is distinct from opioid use disorder, which typically involves compulsive use and overwhelming involvement with the drug, including craving, loss of control over use, and use despite harm. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides specific criteria to diagnose opioid use disorder.
Opioids have different potencies based on their ability to bind to opioid receptors and the efficiency of oral absorption of the opioid versus direct injection into the vasculature. Understanding the interrelationship of these potencies is essential if patients need to be transitioned from one opioid to another or from and an oral to an IV form. For example, 30 mg of oral morphine is equivalent toOpioids have different potencies based on their ability to bind to opioid receptors and the efficiency of oral absorption of the opioid versus direct injection into the vasculature. Understanding the interrelationship of these potencies is essential if patients need to be transitioned from one opioid to another or from and an oral to an IV form. For example, 30 mg of oral morphine is equivalent to
10 mg of IV morphine (a 3:1 oral-to-IV ratio)10 mg of IV morphine (a 3:1 oral-to-IV ratio)
20 mg of oral oxycodone 20 mg of oral oxycodone
7.5 mg of oral hydromorphone7.5 mg of oral hydromorphone
To allow comparison of opioid use and risk, clinicians should consider the overall dosage of different forms as a uniform variable. The Centers for Disease Control and Prevention (CDC) structured its guidelines for opioid use and risk around the daily oral morphine milligram equivalents (OMME) taken by a patient. For example, a patient taking 10 mg of oral oxycodone 4 times a day is taking 40 mg of oral oxycodone a day. Based on the equianalgesic dosage conversion in the table below (20 mg oral oxycodone equals 30 mg of oral morphine), 40 mg of oral oxycodone is equivalent to 60 mg of oral morphine a day (60 mg OMME). A patient taking 4 mg of oral hydromorphone 4 times a day (16 mg a day) is taking an OMME of 64 mg (from the table below); 7.5 mg of oral hydromorphone equals 30 mg of oral morphine (simplified to 1 mg of oral hydromorphone equals 4 mg of oral morphine).milligram equivalents (OMME) taken by a patient. For example, a patient taking 10 mg of oral oxycodone 4 times a day is taking 40 mg of oral oxycodone a day. Based on the equianalgesic dosage conversion in the table below (20 mg oral oxycodone equals 30 mg of oral morphine), 40 mg of oral oxycodone is equivalent to 60 mg of oral morphine a day (60 mg OMME). A patient taking 4 mg of oral hydromorphone 4 times a day (16 mg a day) is taking an OMME of 64 mg (from the table below); 7.5 mg of oral hydromorphone equals 30 mg of oral morphine (simplified to 1 mg of oral hydromorphone equals 4 mg of oral morphine).
Equianalgesic Doses of Opioid Analgesics*,†
Drug | Parenteral (mg) | Oral (mg) |
|---|---|---|
ButorphanolButorphanol | 2 | — |
CodeineCodeine | 130 | 200 |
HydromorphoneHydromorphone | 1.5 | 7.5 |
LevorphanolLevorphanol | 2 | 4 |
MeperidineMeperidine | 75 | 300 |
MethadoneMethadone | 10 | 20 |
MorphineMorphine | 10 | 30 |
NalbuphineNalbuphine | 10 | — |
OxycodoneOxycodone | 15‡ | 20 |
OxymorphoneOxymorphone | 1 | 15 |
Pentazocine | 60 | 180 |
* 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:* 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:
Methadone dosage should still be reduced by 75–90% even when this more conservative equivalence calculation is used.Methadone dosage should still be reduced by 75–90% even when this more conservative equivalence calculation is used. | ||
† See also Kreutzwiser D, Tawfic QA and Pain Guidelines (based on Quill TE: Primer of Palliative Care, ed. 7. Chicago, Academy of Hospice and Palliative Medicine, 2019). | ||
‡ Parental oxycodone is available in Europe but not in the US.‡ Parental oxycodone is available in Europe but not in the US. | ||
OMME = oral morphine milligram equivalents. | ||
Route of administration
The oral route for opioids may be used for treatment of acute pain if the patient is able to tolerate oral drugs.
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.
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.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.
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 except when a single dosage is anticipated and a patient does not have IV access.
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).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).
Long-term continuous subcutaneous infusion can be used, particularly for cancer pain.
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.
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.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.
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.
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.
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. 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.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.
Treatment of chronic pain with opioids should be done only when other options have been tried and are not effective. 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.
MethadoneMethadone has the highest rate of opioid-induced deaths (per prescription) of all prescribed opioids. It should be prescribed only by practitioners trained in its use. Methadone's pharmacokinetics are variable; has the highest rate of opioid-induced deaths (per prescription) of all prescribed opioids. 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.
If a previously adequate dose becomes inadequate, that dose must usually be increased to control pain.
Adverse effects
In opioid-naive patients, common adverse effects 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.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.
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)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 excessive or persistent 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 (5 to 10 mg orally once or twice a day, titrated by 5 mg every 3 days to a maximum dose of 40 mg a day)Methylphenidate (5 to 10 mg orally once or twice a day, titrated by 5 mg every 3 days to a maximum dose of 40 mg a day)
Dextroamphetamine (initially, 2.5 mg orally once or twice a day)Dextroamphetamine (initially, 2.5 mg orally once or twice a day)
Modafinil (initially, 100 mg orally for 3 to 7 days, then 200 mg orally once a day)Modafinil (initially, 100 mg orally for 3 to 7 days, then 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.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.
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)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 methadoneUse 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 profilePrescribing 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 through an informed consent process.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 through an informed consent process.
Nausea can be treated with one of the following:
Hydroxyzine 25 to 50 mg orally every 6 hoursHydroxyzine 25 to 50 mg orally every 6 hours
Metoclopramide 10 to 20 mg orally every 6 hoursMetoclopramide 10 to 20 mg orally every 6 hours
An antiemetic phenothiazine (eg, prochlorperazine 10 mg orally or 25 mg rectally every 6 hours)An antiemetic phenothiazine (eg, prochlorperazine 10 mg orally or 25 mg rectally every 6 hours)
Ondansetron 4 mg orally or IV every 8 hoursOndansetron 4 mg orally or IV every 8 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.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 ((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 dayPeripherally 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 dayChloride 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.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.
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.
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)., 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.
Opioid misuse, diversion, and abuse
(See also Centers for Disease Control and Prevention: 2019 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.)
Opioids are 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 criteria for diagnosing this disorder. Opioid use disorder is diagnosed if the pattern of use causes clinically significant impairment or distress and if ≥ 2 of the following are observed over a 12-month period:
Taking opioids in larger amounts or for a longer time than intended
Persistently desiring or unsuccessfully attempting to decrease or control opioid use
Spending a great deal of time trying to obtain or use the opioid or recover from its effects
Craving or having a strong desire or urge to use opioids
Using opioids repeatedly resulting in failing to meet obligations at work, home, or school
Continuing to use opioids despite having persistent or recurrent social or interpersonal problems caused or exacerbated by opioid use
Giving up or reducing important social, work, or recreational activities because of opioids
Continuing to use opioids in physically hazardous situations
Continuing to use opioids despite having a persistent or recurrent physical or psychologic disorder caused or worsened by opioids
Having tolerance to opioids
Having opioid withdrawal symptoms
Tolerance and withdrawal (secondary to the development of physical dependence) are expected in patients who take opioids under appropriate medical supervision. Thus, these findings in a patient being medically managed with opioid therapy do not count as part of the criteria of opioid use disorder.
Risk of opioid use disorder depends on frequency of use and dose (3):
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 (4). 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 disorderConsideration 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 also ask patients to sign a contract that specifies 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). Clinicians should go over the contract with patients to make sure they understand what is required. Signing and thus agreeing to the contract is required before patients can take opioids. 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).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.
NaloxoneNaloxone 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 necessaryrepeated 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.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).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).
NalmefeneNalmefene is similar to naloxone, but its duration of action is about 4 to 8 hours. Nalmefene is occasionally used to ensure prolonged opioid reversal.is similar to naloxone, but its duration of action is about 4 to 8 hours. Nalmefene is occasionally used to ensure prolonged opioid reversal.
NaltrexoneNaltrexone, 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. Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain--United States, 2016. JAMA 315 (15):1624–1645, 2016. doi: 10.1001/jama.2016.1464
4. 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 Many drugs are used as adjuvant analgesics, including antiseizure drugs (eg, gabapentin, pregabalin), antidepressants (eg, tricyclics, duloxetine, venlafaxine, bupropion), and many others (see tableDrugs for Neuropathic Pain). These drugs have many uses, most notably to relieve pain with a neuropathic component.
GabapentinGabapentin is widely used for neuropathic pain and headache syndromes.
PregabalinPregabalin 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. Pregabalin is effective for neuropathic pain (including central pain due to spinal cord injury) and 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. Pregabalin is effective for neuropathic pain (including central pain due to spinal cord injury) andfibromyalgia; 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 (amitriptyline, nortriptyline, desipramine), the primary mechanism of action is blocking the reuptake ofserotonin and norepinephrine. Tricyclic antidepressants are effective for neuropathic pain, myofascial pain syndromes, some central neuropathic pain syndromes, visceral pain syndromes, and headache syndromes.
DuloxetineDuloxetine 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'sVenlafaxine's effects and mechanism of action are similar to those of duloxetine.effects and mechanism of action are similar to those of duloxetine.
Drugs for Neuropathic Pain
Class/Drug | Dose* | Comments |
|---|---|---|
Antiseizure drugs† | ||
CarbamazepineCarbamazepine | 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 |
GabapentinGabapentin | 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 |
OxcarbazepineOxcarbazepine | 600–1200 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 painConsidered 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 necessaryUnlike carbamazepine, no CBC or liver function monitoring necessary |
PhenytoinPhenytoin | 300 mg once a day | Limited data; 2nd-line drug |
PregabalinPregabalin | 150–300 mg twice a day Starting dose usually 75 mg twice a day, increased by the same dosage weekly as necessary to a maximum of 300 mg orally twice a day | Mechanism similar to gabapentin but more stable pharmacokineticsMechanism similar to gabapentin but more stable pharmacokinetics Adjust dose in patients with renal insufficiency |
Valproate | 250–500 mg twice a day | Limited data, but strong support for treatment of migraine |
Antidepressants | ||
AmitriptylineAmitriptyline | 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 nortriptylineDesipramine 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 nortriptylineBetter 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 |
DuloxetineDuloxetine | 20–60 mg once a day (starting dose) 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 twice 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 |
MilnacipranMilnacipran | 12.5 mg once a day on day 1, then increased to 12.5 mg twice a day on days 2 and 3, increased further to 25 mg twice a day on days 4 to 7, then 25 mg up to 4 times a day, not to exceed 200 mg/day | Effective for fibromyalgia; not used for neuropathic pain states |
VenlafaxineVenlafaxine | Extended-release (easiest to use): 37.5–75 mg once a day, increased to a target dose of 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 duloxetineSimilar mechanism of action as duloxetine Effective for pain, depression, and anxiety at this dose |
Central alpha-2 adrenergic agonists | ||
ClonidineClonidine | 0.1 mg once a day | Also can be used transdermally or intrathecally |
TizanidineTizanidine | 2 mg every 6–8 hours (maximum 3 doses a day), increased by 2–4 mg every 1–4 days as needed (maximum: 36 mg a day) | Less likely to cause hypotension than clonidineLess likely to cause hypotension than clonidine |
Corticosteroids | ||
DexamethasoneDexamethasone | 0.5–4 mg 4 times a day | Used only for pain with an inflammatory component |
PrednisonePrednisone | 5–60 mg once a day | Used only for pain with an inflammatory component |
NMDA-receptor antagonists | ||
MemantineMemantine | 10–30 mg once a day | Limited evidence of efficacy |
DextromethorphanDextromethorphan | 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 quinidineMetabolism of dextromethorphan blocked by quinidine Combination dextromethorphan/quinidine available for pseudobulbar affect in patients with amyotrophic lateral sclerosis Combination dextromethorphan/quinidine available for pseudobulbar affect in patients with amyotrophic lateral sclerosis |
Oral sodium channel blockers | ||
MexiletineMexiletine | 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 |
Topical | ||
Capsaicin 0.025–0.075% (eg, cream, lotion)Capsaicin 0.025–0.075% (eg, cream, lotion) | Apply 3 times a day | Some evidence of efficacy in neuropathic pain and arthritis |
Capsaicin 8% patchCapsaicin 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 painCauses 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 |
EMLA | Apply 3 times a day, under occlusive dressing if possible | Usually considered for a trial if a lidocaine patch is ineffective; expensiveUsually considered for a trial if a lidocaine patch is ineffective; expensive |
Lidocaine 5%Lidocaine 5% | Daily | Available as patch |
Other | ||
BaclofenBaclofen | Initially 5–10 mg 3 times a day; titrated to 60–120 mg in 3 divided doses | May act via GABA-B receptor Helpful in trigeminal neuralgia; used in other types of neuropathic pain |
Pamidronate (injection)Pamidronate (injection) | 60–90 mg/month IV | Evidence of efficacy in complex regional pain syndrome |
* Route is oral unless otherwise indicated. | ||
† Topical lidocaine 4–5% applied 1 hour before applying capsaicin can help limit irritation.† 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.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.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. Neuroablation is more effective for somatic pain than for visceral pain. 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. Neuroablation is more effective for somatic pain than for visceral pain.
The most common neuroablation procedures are used to treat mechanical axial spine pain: these procedures involve radiofrequency ablation of the medial branches of the dorsal spinal root rami (which innervate zygapophyseal [facet] joints) or ablation of the lateral branches (which innervate the sacroiliac joint). This technology is also being increasingly used to treat refractory pain in the knee (genicular nerve), hip ([articular sensory] branches of the obturator and femoral nerves), and shoulder ([articular sensory] branches of the suprascapular, axillary and lateral pectoral nerves).
Neuroablation in the spinal cord has been rarely used; it is difficult to predict its effectiveness. Neuroablation of the ascending spinothalamic tract (cordotomy) can be used to disrupt pain from an area of the body (eg. whole limb); it may provide relief for several years, although numbness and dysesthesias develop. Neuroablation of the dorsal roots (rhizotomy) is used when a specific dermatome can be identified.
Neuromodulation
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).
Transcutaneous electrical nerve stimulation (TENS) uses low current at low-frequency oscillation to help manage pain.
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 stimulation is being increasingly used to treat intractable neuropathic pain when a single peripheral nerve is involved (eg, postherniorrhaphy pain syndrome, some headache syndromes such as occipital neuralgia, meralgia paresthetica [pain in the outer part of the thigh due to compression of the lateral femoral cutaneous nerve]). It has also been used to stimulate branches of the axillary nerve to treat hemiplegic shoulder pain after stroke. Proof-of-concept studies have reported that peripheral nerve stimulation may be useful in treating postoperative pain during the first several weeks after total knee replacement, anterior cruciate ligament surgery, and foot surgery. Peripheral nerve stimulation involves inserting small, thin, flexible electrode leads percutaneously next to the affected nerve, often using ultrasound guidance. The leads are connected to a stimulator, which is fixed to the skin adjacent to the leads with a replaceable adhesive. Pain in certain areas cannot be treated with peripheral nerve stimulation because the stimulator would interfere with moving or sitting.
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) or substitution of a selective COX-2 inhibitor (coxib; eg, celecoxib). Risk of GI adverse effects is significantly reduced in patients who are taking a selective COX-2 inhibitor (coxib) compared with those taking a nonselective NSAID (eg, ibuprofen).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) or substitution of a selective COX-2 inhibitor (coxib; eg, celecoxib). Risk of GI adverse effects is significantly reduced in patients who are taking a selective COX-2 inhibitor (coxib) compared with those taking a nonselective NSAID (eg, ibuprofen).
The risk of cardiovascular toxicity, which occurs with nonselective NSAIDs and with 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 NSAIDs and coxibs 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.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.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.
Opioids
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 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) andestrogen deficiency. The long-term fracture risk due to osteoporosis is a concern in older patients taking long-term opioid therapy.
Compared with other opioids, buprenorphine, an opioid agonist/antagonist, has a more favorable risk:benefit profile in older patients with renal insufficiency.Compared with other opioids, buprenorphine, an opioid agonist/antagonist, has a more favorable risk:benefit profile in older patients with renal insufficiency.
