While medications are often prescribed for all types of chronic pain, research has consistently shown that several classes have proven efficacy for the treatment of neuropathic pain. Ideally, pharmacotherapy of pain would be specifically selected on the basis of considerations of etiology (e.g., ischemic, neuropathic), pathophysiology (e.g., demyelination, central pain), and anatomy (e.g., C fibers, sympathetic nerves). No experimental data exist to support or refute this clinical approach, and a number of drug classes have been found to improve many different kinds of pain. Unfortunately, medications are often underutilized and underdosed. In one study of patients with neuropathic pain, 73% complained of inadequate pain control, but 72% had never received anticonvulsants, 60% TCAs, or 41% opioids, and 25% had never received any of the above. Physicians still attempt to alleviate pain with simple analgesics and fail to appreciate the subtleties of the “adjuvant” medications, which possess multiple pharmacological actions. These medications offer a sophisticated and multifaceted approach to antinociception that is usually required in the treatment of patients with chronic pain.
Comprehensive reviews describe opioid pharmacology and opioid peptide systems. The analgesic effects of opioids typically decrease the distressing affective component of pain more than the sensation of pain. This effect may be more pronounced in women who reported lower levels of affective distress despite higher levels of pain compared with men while being treated with opioids. The treatment of nonmalignant chronic pain with opioids remains a subject of considerable debate, with fears of regulatory pressure, medication abuse, and the development of tolerance creating reluctance to prescribe opioids. Nevertheless, the prescription of long-term opioids for the treatment of chronic nonmalignant pain has increased.
Opioids are effective in the treatment of chronic nonmalignant pain, as demonstrated in randomized, placebo-controlled trials, in reducing pain, pain-related disability, depression, insomnia, and physical dysfunction. Studies of neuropathic pain show that opioids provide direct analgesic benefits and do not just counteract the unpleasantness of pain. Levorphanol reduced pain, affective distress, interference with function, and sleep difficulties in adults with neuropathic pain. Continuous-release morphine decreased pain in patients with postherpetic neuralgia significantly more than did tricyclic antidepressants or placebo.
Successful treatment with opioids requires the assessment and documentation of improvements in function and analgesia without accompanying adverse side effects and aberrant behaviors. The Federation of State Medical Boards, American Academy of Pain Medicine, American Pain Society, and American Geriatrics Society have all produced guidelines for the treatment of chronic pain. These efforts, combined with legislation to support these educational and governmental initiatives, are improving attitudes toward, acceptance of, and access to chronic opioid therapy. If opioid therapy is unsuccessful, the medication should be gradually tapered and discontinued. Acute opioid withdrawal is not dangerous except in patients at risk from increased sympathetic tone, such as those with increased intracranial pressure or unstable angina. Intermittent discontinuation or tapering of opioids often results in exacerbation of the patient’s pain (opioid-abstinence hyperalgesia, opioid-induced hyperalgesia), probably involving spinal sensitization.
Generally, a constant rather than intermittent “as needed” schedule for pharmacotherapy should be followed, with the time between dosages and the individual dose amounts kept consistent. In particular, opioids with slow onset and longer duration of action are preferred so as to minimize the initial euphoria and interdose withdrawal symptoms of traditional short-acting opioids, which should be reserved for the treatment of breakthrough pain. Extended-release oral medications and transdermal routes of administration decrease these qualities of opioids that place patients at risk of inadequate treatment and abuse. In the United States, controlled-release formulations of morphine, oxycodone, fentanyl, and potentially hydromorphone and oxymorphone, as well as newer alternatives such as dihydroetorphine, transdermal buprenorphine, slow-release tramadol, and slow-release dihydrocodeine, are now available but still represent the minority of opioid prescriptions. Mixed agonist-antagonist opioids should be avoided because of their propensity to precipitate withdrawal symptoms in patients undergoing chronic opioid therapy.
Most long-acting opioids are expensive. Methadone offers a low-cost alternative with the unique advantage of suppressing withdrawal symptoms for more than 24 hours. Unfortunately, the analgesic properties of methadone are similar to those of immediate-release morphine, necessitating a 6-hour dosing schedule for the treatment of chronic pain. Generic formulations of continuous-release morphine and oxycodone offer affordable options. In a randomized, open-label, crossover trial in patients with chronic noncancer pain treated with opioids, transdermal fentanyl was preferred to sustained-release oral morphine (65% vs. 28%), with the greater preference attributed to better pain relief, an enhanced quality of life, and less constipation. Transdermal fentanyl produced significantly better costutility ratios than continuous-release formulations of morphine and oxycodone for each quality-adjusted life year gained despite higher costs of therapy.
The most common side effect of chronic opioid therapy is decreased gastrointestinal motility, potentially leading to constipation, vomiting, and abdominal pain. In some patients with chronic abdominal pain, the problem of “narcotic bowel” results from the vicious cycle of opioid treatment causing painful constipation, followed by the escalation of opioid dose, resulting in even more pain. This process is further complicated by rebound pain with attempts to taper the opioids, which leads to additional dose increases with no subsequent benefits, as well as the persistence of colonic dysmotility after opioid discontinuation. Oral opioids differ in their propensity to cause symptoms of gastrointestinal dysmotility. Transdermal fentanyl is an effective analgesic with fewer gastrointestinal side effects than oral medications, with over 90% of patients choosing to continue the medication after completion of a study trial. Newer experimental opioid antagonists that do not cross the blood-brain barrier may offer relief of constipation without compromising analgesia or precipitating withdrawal.
Opioids induce centrally mediated hypogonadism with lower production of testosterone, manifested in fatigue, loss of libido, and impaired sexual function. Concerns about cognitive impairment are more often the reason opioids are not prescribed. Studies comparing patients taking opioids with those who are not or patients before and during treatment with opioids have not demonstrated deleterious effects on neuropsychological testing, computerized testing of performance, or electroencephalography (EEG), except in patients prescribed multiple medications, especially sedatives and hypnotics. Although no studies have examined the risk of delirium in chronic pain syndromes treated with opioids, meperidine poses a unique risk for causing an agitated hyperactive delirium.
Long-term administration of opioids predisposes one to tolerance, but chronic pain may actually facilitate its development. While several physiological mechanisms have been described to explain this phenomenon, tolerance is uncommon in clinical practice. The incidence of analgesic tolerance is lower with more potent opioids such as fentanyl, presumably because they are more receptor-specific and fewer receptors are needed to induce an analgesic effect. Although constipation is likely to persist, tolerance to most opioid side effects usually occurs. The loss of preexisting analgesia can have many causes besides tolerance and should be carefully evaluated so as to determine its etiology. Disease progression or other changes in the patient’s chronic pain condition should be considered before this loss is attributed to tolerance. Are-turn of, or even an increase in, pain can be the result of new injury, worsening neurological damage, comorbid psychiatric disorders, or medication effects such as toxicity, withdrawal, or opioid-induced hyperalgesia.
When tolerance to an analgesic agent develops, suggested strategies have included simultaneous administration of other agents (opioid agonists with differing receptor affinities; ultra-low-dose opioid antagonists; calcium channel blockers; alpha2-adrenergic agonists; COX-2 inhibitors; NMDA receptor antagonists such as ketamine, dextromethorphan, memantine, and amantadine); opioid rotation to a more potent agonist; and intermittent cessation of certain agents (e.g., opioids, benzodiazepines). Augmentation of analgesia may occur by using opioids that possess NMDA antagonist action, such as methadone, dextropropoxyphene, and ketobemidone, or those that inhibit monoamine reuptake, such as methadone, tramadol, and levorphanol. Incomplete cross-tolerance of the analgesic effects of opioids probably accounts for the improved pain relief gained through rotating between different long-acting opioids or switching from short-acting to long-acting opioids. Opioid rotation may also improve analgesia if morphine or hydromorphone is discontinued, because these agents’ 3-glucuronide metabolites can accumulate within the ce-rebrospinal fluid and produce neuroexcitatory effects such as allodynia, myoclonus, delirium, and seizures.
The neurobiology of pain suggests potential efficacy for all antidepressants in the treatment of chronic pain. The analgesic effect of antidepressants is thought to be primarily mediated by the blockade of reuptake of nephrine and serotonin, increasing their levels to enhance the activation of descending inhibitory neurons. However, antidepressants may produce antinociceptive effects through a variety of other pharmacological mechanisms. (“Psychopharmacology”)
The effectiveness of antidepressants for the treatment of major depression is well documented, but their analgesic properties are underappreciated. In 1960, the first report of imipramine use for trigeminal neuralgia was published. Since then, antidepressants, particularly the TCAs, have been commonly prescribed for many chronic pain syndromes, including diabetic neuropathy, postherpetic neuralgia, central pain, poststroke pain, tension-type headache, migraine, and orofacial pain. Tricyclic antidepressants have been most effective in relieving neuropathic pain and headache syndromes. A meta-analysis showed that tricyclic antidepressants were more effective than placebo for the treatment of chronic back pain in reducing pain severity but not functional disability. Meta-analyses of randomized, controlled trials concluded that tricyclic antidepressants are the most effective agents for the treatment of postherpetic neuralgia and that nortriptyline is better tolerated than amitriptyline with equivalent efficacy. Protriptyline, compared with placebo, decreased chronic tension-type headache frequency by 86% in a study of women with this condition.
Only 25% of patients in one multidisciplinary pain center were prescribed TCAs, and 73% of treated patients were prescribed only the equivalent of 50 mg or less of amitriptyline, suggesting the potential for additional pain relief. The cost of tricyclic antidepressants for pain treatment is much lower (often less than $5.00/month) than the cost of other antidepressants and most analgesics. A number of treatment studies of postherpetic neuralgia and painful diabetic peripheral neuropathy have used TCAs, with mean daily doses ranging from 100 to 250 mg. Over 60% of patients reported improvement, usually beginning in the third week of treatment, with serum levels at the low end of the therapeutic range for the treatment of depression. Typically, the analgesic effects of antidepressants are independent of the presence of depression or improvement in mood. Analgesia usually occurs at lower doses and with earlier onset of action than expected for the treatment of depression. The results of investigations to determine drug concentrations needed for pain relief support higher serum levels but remain contradictory.
Noradrenergic activity is often associated with better analgesic effects than serotonergic activity alone. The relatively noradrenergic antidepressants (i.e., with a serotonin/norepinephrine ratio of less than 1.0) include amitriptyline, imipramine, doxepin, nortriptyline, desipramine, and maprotiline. Generally, the tertiary tricyclic antidepressants with balanced effects on serotonin and norepinephrine reuptake (imipramine, amitriptyline, doxepin) are considered more effective analgesic agents than the secondary tricyclic antidepressants with more selective norepinephrine reuptake inhibition (desipramine, nortriptyline, maprotiline). While tertiary amines have been used most commonly, the secondary amines have fewer side effects and are less likely to be discontinued. Randomized, controlled trials have not demonstrated consistent differences in efficacy between the TCAs.
Selective Serotonin Reuptake Inhibitors
The selective serotonin reuptake inhibitors (SSRIs) produce weak antinociceptive effects in animal models of acute pain. This antinociception is blocked by serotonin receptor antagonists and is enhanced by opioid receptor agonists. In human clinical trials, the efficacy of SSRIs in chronic pain syndromes has been variable and inconsistent. In patients with chronic LBP without depression, nortriptyline or maprotiline, but not paroxetine, significantly reduced pain intensity. Desipramine was superior to fluoxetine in the treatment of painful diabetic peripheral neuropathy. On the other hand, paroxetine and citalopram were beneficial in studies of patients with diabetic neuropathy. Fluoxetine significantly reduced pain in patients with rheumatoid arthritis and was comparable in efficacy to amitriptyline. A 12-week course of fluoxetine also improved outcome measures in women with fibromyalgia. The SSRIs may be effective in the treatment of some headaches, especially migraine, and are well tolerated by patients. However, citalopram did not significantly reduce the duration of chronic tension headache, headache frequency, and the intake of analgesics. In depressed patients with neuropathic pain, improvements in pain were dependent on improvements in depressive symptoms if patients were treated with fluoxetine but not fluvoxamine, which improved pain independently of antidepressant effects.
Venlafaxine and duloxetine inhibit the presynaptic reuptake of both serotonin and norepinephrine. Duloxetine more potently blocks serotonin and norepinephrine transporters both in vitro and in vivo when compared with venlafaxine. There is evidence of its analgesic efficacy in preclinical models and in clinical populations. Duloxetine is an effective treatment for major depression and significantly reduced pain complaints and time in pain while awake in these patients. Duloxetine has just been approved by the FDA for treatment of diabetic peripheral neuropathy pain. Controlled trials have shown duloxetine to be effective in fibromyalgia and diabetic neuropathy. A small controlled trial of venlafaxine in patients with neuropathic pain following treatment of breast cancer showed pain relief, with improved response at higher doses of venlafaxine that may be attributable to increased reuptake inhibition of norepinephrine. In patients with neuropathic pain but without depression, bupropion decreased pain intensity and interference of pain with quality of life. In a small open-label trial of diabetic neuropathy, nefazodone significantly reduced pain, paresthesias, and numbness. Monoamine oxidase inhibitors decrease the frequency and severity of migraine headaches. Trazodone is commonly prescribed for insomnia, and several reports suggested efficacy for chronic pain. However, in higher-quality studies, trazodone was ineffective in decreasing pain in a double-blind, placebo-controlled study of patients with chronic LBP.
Comparing Relative Efficacy of Antidepressants and Other Agents
Comparing the relative efficacy of antidepressants and other pharmacological agents used in the treatment of pain can be calculated with the number needed to treat (NNT). NNT is defined as the number of patients who would need to receive the specific treatment for one patient to achieve at least 50% pain relief. Antidepressants, especially tricyclic antidepressants with optimized serum levels, are the most effective in the treatment of neuropathic pain, with the majority of clinical trials enrolling patients with postherpetic neuralgia and diabetic peripheral neuropathy. An NNT of 2.5 for TCAs, compared with an NNT of 6.7 for SSRIs, indicates that the difference in response between the active drug treatment and placebo is approximately 40% versus only 15%, respectively. Subsequent meta-analyses of the treatment of functional gastrointestinal disorders, fibromyalgia, and chronic headache, including both migraine and tension headaches, found no differences in outcome between types of antidepressants with a pooled NNT of 3.2-4.0.
Phenytoin was first reported as a successful treatment for trigeminal neuralgia in 1942. Carbamazepine is the most widely studied anticonvulsant effective for neuropathic pain. Anticonvulsants are effective for trigeminal neuralgia, diabetic neuropathy, postherpetic neuralgia, and migraine recurrence. The NNT ranges from less than 2 to approximately 4 for anticonvulsants, with better compliance when compared with tricyclic antidepressants because of fewer adverse effects. Therapeutic serum levels have not been clearly established, but some evidence suggests lower levels than for seizures may be effective in decreasing pain. (“Psychopharmacology”).
Valproic acid is most commonly used in the prophylaxis of migraine but is also effective in the treatment of neuropathic pain. Valproate was an effective prophylactic treatment in over two-thirds of patients with migraine and almost three-quarters of those with cluster headache. Improvement occurred in frequency of headache, duration or headache days per month, intensity of headache, use of other medications for acute treatment of headache, the patient’s opinion of treatment, and ratings of depression and anxiety.
Gabapentin has been reported to reduce neuropathic pain in multiple sclerosis, migraine, postherpetic neuralgia, spinal cord injury, HIV-related neuropathy, and reflex sympathetic dystrophy. Randomized, double-blind, placebo-controlled clinical trials have confirmed the efficacy of gabapentin in the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, and postamputation phantom limb pain. A retrospective analysis found that patients were more likely to benefit from gabapentin if they had experienced allodynia as a feature of their neuropathic pain. Gabapentin significantly decreased the pain associated with Guillain-Barre syndrome as well as the concomitant consumption of fentanyl.
Lamotrigine may be effective in reducing the pain of phantom limbs, neuroma hypersensitivity, trigeminal neuralgia, causalgia, poststroke pain, and postherpetic neuralgia. Lamotrigine decreased the pain of diabetic neuropathy without associated improvements in mood or pain-related disability. Lamotrigine produced analgesia that was correlated with serum drug concentrations and comparable to that obtained with phenytoin and dihydrocodeine.
Combinations of anticonvulsants with complementary mechanisms of action may increase effectiveness and decrease adverse effects of treatment. Patients with multiple sclerosis or trigeminal neuralgia who had failed treatment with carbamazepine or lamotrigine at therapeutic doses because of intolerable side effects were given gabapentin as an augmentation agent. Gabapentin was titrated to pain relief, with no new side effects up to a maximum dosage of 1,200 mg/day, at which time either carbamazepine or lamotrigine was tapered until side effects were no longer present. Ten of 11 patients achieved pain control with no side effects.
Topiramate, tiagabine, pregabalin, vigabatrin, retigabine, levetiracetam, and zonisamide are new anticonvulsants with a spectrum of pharmacological actions and antinociceptive effects in animal models, but few clinical studies exist to support their use as a first-line therapy for patients with chronic pain. Pregabalin is similar to gabapentin but with greater potency. Topiramate offers the advantages of low protein binding, minimal hepatic metabolism and unchanged renal excretion, few drug interactions, long half-life, and the unusual side effect of weight loss. A pilot study found that tiagabine improved pain symptoms and neuronal function assessed with quantitative sensory testing in patients with painful neuropathy.
Topical lidocaine has been approved for the treatment of postherpetic neuralgia and does not produce significant serum levels. Oral mexiletine has been an effective treatment for neuropathic pain in painful diabetic neuropathy, peripheral nerve injury, alcoholic neuropathy, and phantom limb, but not cancer-related pain. Mexiletine not only decreased reports of pain but also the accompanying paresthesias and dysesthesias. Mexiletine also has been shown to decrease pain and sleep disturbances associated with painful diabetic neuropathy. No significant correlations were found with plasma concentrations of mexiletine. Its effectiveness in widespread clinical use has been disappointing despite relatively few adverse effects.
Calcium Channel Blockers
Verapamil is the most commonly prescribed calcium channel blocker for chronic pain and has proven to be effective in the treatment of migraine and cluster headaches. The calcium channel blockers diltiazem and verapamil have also been found to potentiate morphine analgesia, but the results have been inconsistent. Now in clinical trials, the experimental neuronspecific calcium channel blockers ziconotide and related omega-conopeptides possess potent analgesic, antihyperesthetic, and antiallodynic activity, as well as synergistic analgesic effects with morphine without producing tolerance.
Benzodiazepines are commonly prescribed for insomnia and anxiety in patients with chronic pain (“Psychopharmacology”); however, there is little evidence of their utility for relief of pain, and they may even be counterproductive. Only a limited number of chronic pain conditions, such as trigeminal neuralgia, tension headache, and temporomandibular disorder, were found to improve when treated with benzodiazepines. Clonazepam has been reported to provide long-term relief of the episodic lancinating variety of phantom limb pain. A recent extensive review failed to conclude that benzodiazepines significantly improve spasticity following spinal cord injury.
Benzodiazepines also cause cognitive impairment. In patients with chronic pain, benzodiazepines, but not opioids, were associated with decreased activity levels, higher rates of health care visits, increased domestic instability, depression, and more disability days. Combining benzodiazepines with opioids may cause several problems. In methadone-related mortality, almost 75% of deaths were attributable to a combination of drug effects, and benzodiazepines were present in 74% of the deceased. Benzodiazepines have been associated with exacerbation of pain and interference with opioid analgesia. They also increase the rate of developing tolerance to opioids.
Selections from the book: “Textbook of Psychosomatic Medicine”, 2005.