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Nonopioid and opioid analgesics are the main drugs used to treat pain. Antidepressants, anticonvulsants, and other 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, incremental gains in function; 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.
Nonopioid Analgesics
Acetaminophen and NSAIDs are often effective for mild to moderate pain (see Table 1: Pain: Nonopioid Analgesics ). Of these, only ketorolac can be given parenterally. Nonopioids do not cause physical dependence or tolerance.
Acetaminophen has no anti-inflammatory or antiplatelet effects and does not cause gastric irritation.
NSAIDs include nonselective COX (COX-1 and COX-2) inhibitors and selective COX-2 inhibitors (coxibs); all are effective analgesics. Aspirin is the least expensive but has prolonged antiplatelet effects. 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. Recent studies suggest that inhibition of COX-2, which occurs with both nonselective COX inhibitors and coxibs, is associated with a prothrombotic effect that can increase risk of MI, 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), it is prudent to consider the potential for prothrombotic effects as a risk of all NSAID therapy.
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, the elderly, 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. Although data are still limited, the prothrombotic risk suggests that all NSAIDs should be used cautiously in patients with clinically significant atherosclerosis or multiple cardiovascular risk factors. 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 CBC, electrolytes, and hepatic and renal function.
Opioid Analgesics
“Opioid” is a generic term for natural or synthetic substances that bind to specific opioid receptors in the CNS, producing an agonist action. Opioids are also called narcotics. 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 less 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 pure agonist drugs, and chronic pain is best treated with longer-acting pure agonist drugs (see Table 2: Pain: Opioid Analgesics and Table 3: Pain: Equianalgesic Doses of Opioid Analgesics*).
Opioid analgesics are useful in managing severe acute or chronic pain. They are often underused, resulting in needless pain and suffering because clinicians often underestimate the required dosage, overestimate the duration of action and risk of adverse effects, and have unreasonable concerns about addiction (see Drug Use and Dependence: Opioids). 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. However, addiction (loss of control, compulsive use, craving and use despite harm) is very rare in patients with no history of substance abuse. Before opioid therapy is initiated, clinicians should ask about risk factors for abuse and addiction. These risk factors include prior alcohol or drug abuse, a family history of alcohol or drug abuse, and a prior major psychiatric disorder. If risk factors are present, treatment may still be appropriate; however, the clinician should use more controls to prevent abuse (eg, small prescriptions, frequent visits, no refills for “lost” prescriptions) or should refer the patient to a pain specialist or an addiction medicine specialist experienced in pain management.
Route of administration:
Almost any route can be used. 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. Formulations of fentanyl are now available for delivery through the oral mucosa. Lozenges are used for sedation in children and as treatment of breakthrough pain. Effervescent tablets are available for breakthrough pain. Breakthrough pain has been targeted by these formulations because they have a relatively more rapid onset than the oral route; other rapid-onset, transmucosal formulations of fentanyl and other drugs are in development.
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 sc infusion can be used, particularly for cancer pain.
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 like morphine is used; they are typically used postoperatively. Implanted infusion devices can provide long-term neuraxial infusion. These devices can also be used with other drugs (eg, local anesthetics, clonidine, ziconotide).
Dosing and titration:
Initial dose is modified according to the patient's response; it is increased incrementally until analgesia is satisfactory or adverse effects limit treatment. Sedation and respiratory rate are monitored when opioids are given parenterally to relatively opioid-naive patients. The elderly are more sensitive to opioids and are predisposed to adverse effects; opioid-naive elderly 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 prn. For severe or ongoing pain, doses should be given regularly, without waiting for severe pain; supplemental doses are given as needed when treating cancer pain and are typically considered case by case when treating chronic noncancer pain. A common error is prescribing short-acting drugs at long intervals, allowing breakthrough pain.
For patient-controlled analgesia, a bolus dose (in a postoperative setting, typically morphine 1 mg q 6 min) is provided when patients push a button; a baseline infusion (eg, morphine 0.5 to 1 mg/h) may or may not be given. The physician controls the amount and interval of the bolus. Patients with prior opioid exposure or with chronic pain require a higher bolus and baseline infusion dose; the infusion 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). 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 by 30 to 100% 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, mental clouding, constipation, nausea, vomiting, and itching. Respiratory depression is serious but is rare when opioids are given at appropriate doses. 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 the elderly, opioids tend to have more adverse effects (commonly, constipation and sedation or mental clouding). 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 and this is much more likely with constipation.
Opioids should be used cautiously in patients with certain disorders:
Constipation is common among patients who take opioids for more than a few days. For prevention in predisposed patients (eg, the elderly), dietary fiber and fluids should be increased, and a stimulant laxative (eg, senna—see Approach to the Patient With Lower GI Complaints: Types of laxatives) should be given. Persisting constipation can be managed with Mg citrate 90 mL po q 2 to 3 days, lactulose 15 mL po bid, or propylethylene glycol powder (dose is adjusted as needed). Some patients require regular enemas.
While sedated after taking an opioid, patients should not drive and should take precautions to prevent falls and other accidents. 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 po bid), dextroamphetamine (initially, 2.5 to 10 mg po bid), or modafinil (initially, 100 to 200 mg po once/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 hydroxyzine 25 to 50 mg po q 6 h, metoclopramide 10 to 20 mg po q 6 h, or an antiemetic phenothiazine (eg, prochlorperazine 10 mg po or 25 mg rectally q 6 h).
Respiratory depression is rare with conventional doses and with long-term use. If it occurs acutely, ventilatory assistance may be needed until the opioid's effect can be reversed by an opioid antagonist.
For urinary retention, double voiding or using Credé's method during voiding may help; some patients benefit from adding an α-adrenergic blocker such as tamsulosin 0.4 mg po once/day (starting dose).
Opioids can cause neuroendocrine effects, typically reversible hypogonadism. Symptoms may include fatigue, loss of libido, infertility due to low levels of sex hormones, and, in women, amenorrhea.
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 min 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 min. 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 q 2 to 3 min prn. 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. A reasonable regimen is 1 mL of a dilute solution (0.4 mg in 10 mL saline) IV q 1 to 2 min, titrated to adequate respirations (not alertness). Nalmefene is similar to naloxone, but its duration of action is about 4 to 8 h. 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.
Adjuvant Analgesic Drugs
Many drugs are used as adjuvant analgesics, including anticonvulsants (eg, pregabalin, gabapentin) and antidepressants (eg, tricyclics, duloxetine, venlafaxine, bupropion), and many others (see Table 4: Pain: 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. The dose often needs to be high, up to 1200 mg tid or sometimes higher. Pregabalin is similar to gabapentin but has more stable pharmacokinetics; some patients who do not respond well to gabapentin do respond to pregabalin and visa versa. Duloxetine is a new mixed mechanism (serotonin and norepinephrine) reuptake inhibitor, which has good evidence of analgesic efficacy in diabetic neuropathic pain and fibromyalgia.
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Table 4
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| Drugs for Neuropathic Pain |
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Class/Drug
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Dose*
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Comments
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Anticonvulsants†
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Carbamazepine
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200–400 mg bid
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Monitor WBCs when starting treatment
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Gabapentin
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300 mg bid–1200 mg tid
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Preferred drug in this class; starting dose usually 300 mg once/day
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Phenytoin
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300 mg once/day
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Limited data; 2nd-line drug
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Pregabalin
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75–300 mg bid
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Mechanism similar to gabapentin but more stable pharmacokinetics
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Valproate
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250–500 mg bid
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Limited data, but strong support for treatment of headache
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Antidepressants
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Amitriptyline
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10–25 mg at bedtime
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May increase dose to 75–150 mg over 1–2 wk, particularly if significant depression is present; may not need high doses; not recommended for the elderly or patients with a heart disorder because it has strong anticholinergic effects
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Desipramine
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10–25 mg at bedtime
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Better tolerated than amitriptyline
May increase dose to 150 mg or sometimes higher
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Duloxetine
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30 mg bid
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Better tolerated than tricyclic antidepressants
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Central α2-adrenergic agonists
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Clonidine
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0.1 mg once/day
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Also can be used transdermally or intrathecally
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Tizanidine
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2–20 mg bid
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Less likely to cause hypotension than clonidine
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Corticosteroids
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Dexamethasone
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0.5–4 mg qid
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Used only for pain with an inflammatory component
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Prednisone
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5–60 mg once/day
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Used only for pain with an inflammatory component
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NMDA-receptor antagonists
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Memantine
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10–30 mg once/day
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Limited evidence of efficacy
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Dextromethorphan
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30–120 mg qid
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Usually considered 2nd-line
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Oral Na channel blockers
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Mexiletine
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150 mg once/day to 300 mg q 8 h
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Used only for neuropathic pain
For patients with a significant heart disorder, cardiac evaluation considered before the drug is started
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Topical
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Capsaicin 0.025–0.075%
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tid
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Some evidence of efficacy in neuropathic pain and arthritis
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EMLA®
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tid, under occlusive dressing if possible
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Usually considered for a trial if lidocaine patch is ineffective; expensive
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Lidocaine 5%
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Daily
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Available as patch
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Other
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Baclofen
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20–60 mg bid
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May act via GABAB receptor
Helpful in trigeminal neuralgia; used in other types of neuropathic pain
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Pamidronate
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60–90 mg/mo
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Evidence of efficacy in complex regional pain syndrome
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*Route is oral unless otherwise indicated.
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†Newer anticonvulsants have fewer adverse effects.
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EMLA = eutectic mixture of local anesthetics; GABA =
γ-aminobutyric acid; NMDA =
N-methyl-d-aspartate.
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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 disorders and a short life expectancy.
Local anesthetic drugs (eg, lidocaine) can be given IV, intrathecally, intrapleurally, transdermally, sc, 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 energy to produce a lesion. The procedure is used mainly for 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.
Neuromodulation
Stimulation of neural tissues may decrease pain, presumably by activating endogenous pain modulatory pathways. The most common method is transcutaneous electrical nerve stimulation (TENS), which applies a small current to the skin. Also, electrodes may be implanted along peripheral nerves or along the dorsal columns in the epidural space. Stimulation of brain structures (deep brain stimulation and motor cortex stimulation) has also been used, but evidence of benefit is slight.
Last full review/revision February 2007 by Russell K. Portenoy, MD
Content last modified November 2005
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