Treatment of Pain
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, 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.
Acetaminophen and NSAIDs are often effective for mild to moderate pain (see Table: Nonopioid Analgesics). Of these, only ketorolac and diclofenac 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.
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 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) and although data are still limited, it is prudent to consider the potential for prothrombotic effects as a risk of all NSAID therapy, suggesting that all NSAIDs should be used cautiously in patients with clinically significant atherosclerosis or multiple cardiovascular risk factors.
If an NSAID is likely to be used only short-term, significant adverse effects are unlikely, regardless of the drug used. Some clinicians use a coxib first whenever therapy is likely to be long-term (eg, months) because the risk of GI adverse effects is lower; others limit coxib use to patients predisposed to GI adverse effects (eg, 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.
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.
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 qid to each affected knee. Other topical diclofenac formulations that may be useful for local pain relief include a patch (applied bid over the affected area) or a 1% gel (2 g qid for the upper extremities or 4 g qid for the lower extremities).
“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—a term originally used to refer to any psychoactive substance that induces sleep. Opioids have both analgesic and sleep-inducing effects, but the 2 effects are distinct from each other.
Some opioids used for analgesia have both agonist and antagonist actions. Potential for abuse among those with a known history of abuse or addiction may be lower with agonist-antagonists than with pure agonists, but agonist-antagonist drugs have a ceiling effect for analgesia and induce a withdrawal syndrome in patients already physically dependent on opioids.
In general, acute pain is best treated with short-acting pure agonist drugs, and chronic pain, when treated with opioids, should be treated with long-acting opioids (see Table: Opioid Analgesicsand Equianalgesic Doses of Opioid Analgesics*). Because of the higher doses in many long-acting formulations, these drugs have a higher risk of serious adverse effects (eg, death due to respiratory depression) in opioid-naive patients.
Opioid analgesics are useful in managing acute and chronic pain. They are sometimes underused in patients with severe acute pain or with pain and a terminal disorder such as cancer, resulting in needless pain and suffering. Reasons for undertreatment include
Generally, opioids should not be withheld when treating acute, severe pain; however, simultaneous treatment of the condition causing the pain usually limits the duration of severe pain and the need for opioids to a few days or less. Also, opioids should generally not be withheld when treating cancer pain; in such cases, adverse effects can be prevented or managed, and addiction is less of a concern.
In patients with chronic noncancer pain, nonopioid therapy should be tried first (see Chronic Pain : Treatment). Opioids should be used when the benefit of pain reduction outweighs the risk of adverse effects and of drug misuse. If nonopioid therapy has been unsuccessful, opioid therapy should be considered. In such cases, obtaining informed consent may help clarify the goals, expectations, and risks of treatment and facilitate education and counseling about misuse. Patients receiving chronic (> 3 mo) opioid therapy should be regularly assessed for pain control, adverse effects, and signs of misuse. If patients have persistent severe pain despite increasing opioid doses, do not adhere to the terms of treatment, or have deteriorating physical or mental function, opioid therapy should be tapered and stopped.
Physical dependence (development of withdrawal symptoms when a drug is stopped) should be assumed to exist in all patients treated with opioids for more than a few days. Thus, opioids should be used as briefly as possible, and in dependent patients, the dose should be tapered to control withdrawal symptoms when opioids are no longer necessary. Patients with pain due to an acute, transient disorder (eg, fracture, burn, surgical procedure) should be switched to a nonopioid drug as soon as possible. Dependence is distinct from addiction, which, although it does not have a universally accepted definition, typically involves compulsive use and overwhelming involvement with the drug including craving, loss of control over use, and use despite harm.
Equianalgesic Doses of Opioid Analgesics*
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.
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.
Transmucosal (sublingual) formulations of fentanyl are now available. Lozenges are used for sedation in children and as treatment of breakthrough pain in patients with cancer.
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 postoperatively. Implanted infusion devices can provide long-term neuraxial infusion. These devices can also be used with other drugs (eg, local anesthetics, clonidine, ziconotide).
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. For opioid-naive patients in particular, opioid therapy should start with a short-acting drug because many longer-acting opioids are more potent.
Because of methadone's variable pharmacokinetics, this drug should be started at a low dose, and the dose should not be increased more often than once/wk.
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 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.
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.
In opioid-naive patients, adverse effects common at the start of therapy include
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). Falls are a particular risk in the elderly. Opioids may cause urinary retention in men with benign prostatic hyperplasia.
Although tolerance to opioid-induced sedation, mental clouding, and nausea usually develops within days, tolerance to opioid-induced constipation and urinary retention usually occurs much more slowly. Any adverse effect may be persistent in some patients; constipation is particularly likely to persist.
Opioids should be used cautiously in patients with certain disorders:
Hepatic disorders because drug metabolism is delayed, particularly with modified-release preparations
COPD because respiratory depression is a risk
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
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 Constipation : 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. If patients receiving palliative care have constipation refractory to fluids, fiber, and laxatives, methylnaltrexone 8 to 12 mg sc every other day may help by antagonizing opioid receptors only in the bowel.
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. Patients and family members should be instructed to contact the physician if patients experience sedation. If sedation impairs quality of life, certain stimulant drugs may be given intermittently (eg, before a family gathering or other event that requires alertness) or, to some patients, regularly. Drugs that can be effective are methylphenidate (initially, 5 to 10 mg 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).
Itching is caused by histamine release and may be relieved by an antihistamine (eg, diphenhydramine, 25 to 50 mg po or IV).
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. Long-term use of opioids may lead to sleep-related breathing disorders including obstructive sleep apnea and, less commonly, central sleep apnea, irregular respiration, and periods of sustained hypoventilation.
For urinary retention, double voiding or using the Credé 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.
Some drugs have unique risks. For example, rapid-acting fentanyl preparations (eg, lozenge, effervescent oral tablet, intranasal spray) have a high risk of dose-related adverse effects in opioid-naive patients with chronic noncancer pain such as migraine; these drugs should not be started until patients require a 24-h morphine dose with analgesic potency equal to 60 mg of oral morphine. Methadone should not be used in patients at risk of QT-interval prolongation.
Opioids are now the leading cause of accidental death and fatal drug overdose in the US. Risk of fatal drug overdose increases significantly when opioid analgesics are used with benzodiazepines. Also, rates of misuse, diversion, and abuse (aberrant drug-taking behaviors—see Opioid Use Disorder and Rehabilitation) 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).
Addiction, typically marked by impaired control and craving, refers to compulsive use despite harm and negative consequences.
When considering prescribing opioid therapy, particularly chronic therapy, clinicians should evaluate patients for risk factors for abuse and diversion and counsel them against intentional and inadvertent misuse. Risk factors include
If risk factors are present, treatment may still be appropriate; however, clinicians should use more stringent measures to prevent abuse and addiction. 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, and use of tamper-resistant opioid formulations that have been developed to deter abuse by chewing or by crushing and injecting oral preparations. Clinicians may need to refer problematic patients to a pain specialist or an addiction medicine specialist experienced in pain management.
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 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.
Many drugs are used as adjuvant analgesics, including anticonvulsants (eg, gabapentin, pregabalin), antidepressants (eg, tricyclics, duloxetine, venlafaxine, bupropion), and many others (see Table: Drugs for Neuropathic Pain). These drugs have many uses, most notably to relieve pain with a neuropathic component.
Gabapentin is the most widely used drug for such purposes. For effective analgesia, the dose should usually be > 600 mg tid, and many patients need a higher dose.
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 mixed mechanism (serotonin and norepinephrine) reuptake inhibitor, which appears to be effective for diabetic neuropathic pain, fibromyalgia, chronic low back pain, and chemotherapy-induced neuropathy.
Drugs for Neuropathic 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.
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, 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.
Stimulation of neural tissues may decrease pain, presumably by activating endogenous pain modulatory pathways. The most commonly used noninvasive method is transcutaneous electrical nerve stimulation (TENS), which applies a small current to the skin. Evidence supports treatment of certain types of neuropathic pain (eg, chronic leg pain after spine surgery) using an electrode placed epidurally to stimulate the spinal cord. Also, electrodes may be implanted along peripheral nerves and ganglia in patients with certain headache syndromes or chronic neuralgia. Stimulation of brain structures (deep brain stimulation, motor cortex stimulation) has also been used, but evidence of benefit is slight.