Tofranil

Chronic pain affects approximately 86 million Americans, substantially reducing their quality of life. (1) The socioeconomic burden also is significant, with chronic pain estimated to cost $90 billion annually in medical expenses and reduced work productivity. (1)

Our understanding of many chronic pain disorders is evolving rapidly, and the development of newer antidepressant drug classes and second-generation antiepileptic drugs has created unprecedented opportunities for the treatment of chronic pain.

Chronic and Acute Pain

Chronic and acute pain differ significantly in several important respects and require different treatment approaches. Acute pain is a protective response to injury, whereas chronic pain may be a maladaptive response. Acute pain most often is nociceptive (i.e., resulting from injury or inflammation of somatic or visceral tissue). Chronic pain may be nociceptive or neuropathic (i.e., resulting from neuronal maintenance of pain either peripherally or in the central nervous system [CNS]).

Nociceptive pain usually is treated with anti-inflammatory or analgesic medications. Neuropathic pain typically is treated with medications that influence neurotransmitters (e.g., antidepressants, antiepileptic drugs), and treatment with opioids is reserved for patients with refractory neuropathic pain.

Peripheral neuropathic pain typically is described as burning, sharp, shooting, or aching, and it may be associated with tingling, dysesthesias, or numbness. Allodynia (i.e., a painful sensation from a normally nonpainful stimulus) is common. Pain often is worse at night and may be exacerbated by activity.

Common non-cancer pain syndromes may be neuropathic (peripheral or central) or non-neuropathic (Table 1). (2) It is likely that both peripheral and central mechanisms con-tribute to the persistence of most types of neuropathic pain. Neuropathic pain also may coexist with non-neuropathic pain (e.g., in some patients with chronic low back pain).

Mechanism of Action of Antidepressants and Antiepileptic Drugs in Pain Syndromes Transmission of painful stimuli through the spinal column and CNS is modulated by excitatory and inhibitory neurotransmitters, as well as actions at sodium and calcium channels. Norepinephrine and serotonin may be excitatory or inhibitory, but they are functionally inhibitory on pain transmission; glutamate is the other important excitatory neurotransmitter. The most important inhibitory neurotransmitter is [gamma]-aminobutyric acid (GABA). Antidepressants and antiepileptic drugs are thought to relieve neuropathic pain through interaction with specific neurotransmitters and ion channels (Table 2). (3)

TRICYCLIC ANTIDEPRESSANTS

Tricyclic antidepressants are thought to affect pain transmission in the spinal cord by inhibiting the reuptake of norepinephrine and serotonin, both of which influence descending pain pathways. In addition, histamine [H.sub.1]-receptor affinity (associated with sedation) may be correlated with the analgesic effect of antidepressants. Amitriptyline (Elavil) also has an analgesic effect in patients with acute pain. (4)

Tricyclic antidepressants may be categorized as secondary or tertiary amines. Secondary amines such as nortriptyline (Pamelor) and desipramine (Norpramin) show relatively selective inhibition of nor-epinephrine reuptake. Tertiary amines such as amitriptyline and imipramine (Tofranil) show more balanced inhibition of norepinephrine and serotonin, but they also have greater anticholinergic side effects.

The novel antidepressants venlafaxine (Effexor) and duloxetine (Cymbalta) have balanced inhibition of serotonin and norepinephrine reuptake without blockade of other neuroreceptors that are responsible for typical tricyclic side effects. The mechanism of action of bupropion (Wellbutrin) is uncertain but involves blockade of dopamine uptake.

ANTIEPILEPTIC DRUGS

Antiepileptic drugs act at several sites that may be relevant to pain, but the precise mechanism of their analgesic effect remains unclear. These agents are thought to limit neuronal excitation and enhance inhibition. Relevant sites of action include voltage-gated ion channels (i.e., sodium and calcium channels), ligand-gated ion channels, the excitatory receptors for glutamate and N-methyl-D-aspartate, and the inhibitory receptors for GABA and glycine (Table 2). (3)

Antiepileptic drugs may be categorized as first or second generation. The second-generation agents are better tolerated, cause less sedation, and have fewer CNS side effects.

Clinical Efficacy

The efficacy of antidepressants and antiepi-leptic drugs varies dramatically in neuropathic and non-neuropathic pain syndromes. Specific agents within each medication class can vary in effectiveness. Table 3 lists typical dosages and side effects of medications commonly used to treat chronic pain. Table 4 (4-19) reviews the levels of evidence for these agents.

NEUROPATHIC PAIN

Antidepressants. Meta-analyses (5,6) have con-firmed the efficacy of tricyclic antidepressants in the treatment of neuropathic pain. Nontricyclic antidepressants show variable degrees of efficacy in patients with neuropathic pain.

Antidepressants with mixed-receptor or noradrenergic activity appear to have the greatest analgesic effect in patients with neuropathic pain. Predominantly serotoninergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), often are ineffective in treating chronic pain. (5,20) Amitriptyline and its metabolite nortriptyline have the best documented efficacy in the treatment of neuropathic and non-neuropathic pain syndromes. (4) The novel antidepressants bupropion, (10) venlafaxine, (11) and duloxetine (12) also have proved effective in patients with neuropathic pain.

The efficacy of tricyclic anti-depressants in the treatment of neuropathic pain appears to be independent of their antidepressant effect, (21) and patients with pain but no depression respond to these agents. Although pain reduction occurs at dosages lower than those typically used to treat depression, a dose response between 25 and 100 mg has been noted. (22) Some experts recommend documenting a therapeutic level of a tricyclic antidepressant before concluding that the drug is clinically ineffective in a patient with chronic pain.

Antiepileptic Drugs. Specific antiepileptic drugs are effective in the treatment of patients with neuropathic pain. (14) Of the first-generation agents, carbamazepine (Tegretol) is indicated for the treatment of trigeminal neuralgia. Carbamazepine also has shown modest efficacy in trials involving patients with diabetic neuropathy or postherpetic neuralgia. (14) Phenytoin (Dilantin) is used infrequently to treat chronic pain.

Of the second-generation antiepileptic drugs, gabapentin (Neurontin) has the best documented efficacy in the treatment of neuropathic pain. Gabapentin has been proved superior to placebo in patients with painful diabetic neuropathy (15) or postherpetic neuralgia. (16) In these trials, (15,16) effective dosages have ranged from 2,400 to 3,600 mg per day.

One study (23) of patients with painful diabetic neuropathy found no significant effect for gabapentin in a dosage of 900 mg per day. The efficacy of this drug in other pain syndromes that may have a neuropathic component (e.g., persistent postoperative pain) has been of borderline statistical significance. (24)

The investigational drug pregabalin (Lyrica) has documented efficacy in the treatment of diabetic neuropathy (18) and postherpetic neuralgia. (19) Approval of pregabalin by the U.S. Food and Drug Administration is pending.

Lamotrigine (Lamictal) has been proved modestly effective in patients with trigeminal neuralgia, (17) neuropathy associated with human immunodeficiency virus infection, (25) and poststroke pain. (26) The drug is ineffective in patients with unspecified refractory neuropathic pain. (27) The use of lamotrigine is limited by potentially life-threatening rashes.

Comparative Efficacies. Antidepressants and antiepileptic drugs have comparable efficacy in patients with neuropathic pain. However, the drug classes (and individual agents within each class) differ in safety, tolerability, and side effect profiles. (28)

In a meta-analysis (28) of trials of antidepressants and anti-epileptic drugs in patients with neuropathic pain, the estimated number needed to treat for significant reduction of pain was 2.6 with tricyclic antidepressants, 6.7 with SSRIs, 2.5 with sodium channel-blocking antiepileptic drugs (i.e., phenytoin and carbamazepine), and 4.1 with gabapentin. Another meta-analysis (5) found no significant difference between antidepressants and antiepileptic drugs in the reduction of neuropathic pain.

A small randomized, double-blind, controlled trial (29) of gabapentin and amitriptyline in patients with diabetic neuropathy found that both agents were effective, with no significant differences. Tolerability also was comparable.

NON-NEUROPATHIC PAIN

The efficacy of tricyclic antidepressants has been documented in a variety of non-neuropathic pain syndromes. Most other anti-depressants and most antiepileptic drugs have little or no documented efficacy in the treatment of non-neuropathic pain.

Fibromyalgia. Analysis of controlled trials on the treatment of fibromyalgia is limited by differences in outcome measures, inconsistent reporting of associated depression, and conflicting results. (30) A meta-analysis (31) found that antidepressants were mildly beneficial in reducing pain severity and improving sleep and overall well-being, and mildly effective in reducing fatigue; treatment with these agents also showed a trend for a beneficial effect on tender points.

In one study, (32) 30 to 47 percent of patients with fibromyalgia who were treated with amitriptyline reported moderate or marked improvement of pain. However, similar efficacy was reported for other antidepressants, tranquilizers, cyclobenzaprine (Flexeril), nonsteroidal anti-inflammatory drugs, exercise, and physical therapy.

Tricyclic antidepressants have the best documented efficacy in patients with fibromyalgia, but the treatment effect is modest and tends to wane over time. (33) Although fluoxetine (Prozac) has shown no efficacy in a conventional dosage (20 mg per day), a study (9) of dosages of up to 80 mg per day showed significant efficacy. Cyclobenzaprine, a muscle relaxant that structurally is a tricyclic agent, also has shown modest efficacy in patients with fibromyalgia. (34)

Recently, duloxetine in a dosage of 60 mg twice daily was shown to improve pain and global measures of fibromyalgia, compared with placebo. (13) The improvement occurred regardless of baseline depression status.

Of the antiepileptic drugs, only pregabalin has demonstrated efficacy in the treatment of fibromyalgia. Patients taking 450 mg per day reported reduced pain and fatigue, and improved sleep. (34)

Low Back Pain. A recent meta-analysis (7) found that patients with chronic back pain who were treated with antidepressants had a small but significant decrease in pain. However, their ability to perform activities of daily living did not improve. Efficacy was less for antidepressants with predominantly serotoninergic activity.

Other Chronic Pain Disorders. One review (8) evaluated the efficacy of antidepressants in the treatment of a variety of pain disorders. The non-neuropathic pain disorders included osteoarthritis and rheumatoid arthritis, chronic low back pain, and other chronic pain disorders (not specified). In the arthritis studies, 26 to 68 percent of patients were noted to have a 50 percent or greater improvement in pain; however, the studies had small sample sizes and methodologic flaws. (8)

Clinical Considerations

Because efficacy in neuropathic pain is similar for antidepressants and antiepileptic drugs, initial drug selection is based on side effects, contraindications, coexisting conditions, and cost (Table 5).2 Patients with associated anxiety, depression, or sleep disturbance may benefit from a tricyclic or novel antidepressant, although gabapentin and pregabalin also appear to reduce anxiety. Tricyclic anti-depressants are significantly less expensive than second-generation antiepileptic drugs.

Sedation and weight gain are common side effects of tricyclic antidepressants and gabapentin. Tricyclic antidepressants should not be used in patients with cardiac conduction abnormalities, recent cardiac events, or narrow-angle glaucoma. Elderly patients should not be treated with tertiary amines because of the greater anticholinergic effects of these agents.

Even when drug therapies for painful neuropathies are successful, there is only a 30 to 50 percent reduction of pain. A combination of drugs that target different sites and receptors may be reasonable, although this approach has not been evaluated. (2) Opiates (2,35) and tramadol (Ultram) (2) have been proved effective in the treatment of neuropathic and non-neuropathic pain.

Nonpharmacologic treatments (e.g., exercise, behavioral therapies) are particularly important in patients with non-neuropathic pain syndromes. Currently available medications have limited benefit in these syndromes.

REFERENCES

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The authors indicate that they do not have any conflicts of interest. Dr. Maizels is on the speakers' bureaus for Merck & Co., Inc., and Pfizer Inc., and has been a consultant for GlaxoSmithKline, Merck & Co., Inc., and Pfizer Inc. Dr. McCarberg is on the speakers' bureaus for Endo Pharmaceuticals, Janssen Pharmaceutica Products, L.P., Ortho-McNeill Pharmaceutical, Pfizer Inc., and the Purdue Frederick Company.

MORRIS MAIZELS, M.D., is a member of the Department of Family Medicine at Kaiser Permanente, Woodland Hills, Calif., as well as founder and director of the Woodland Hills Headache Clinic. Dr. Maizels received his medical degree from the University of Washington School of Medicine, Seattle, and completed residency training at the Antelope Valley Family Practice Residency of the University of California, Los Angeles. Dr. Maizels is a member of the board of directors of the American Headache Society and an associate editor of Headache.

BILL MCCARBERG, M.D., is founder of the Chronic Pain Management Program for Kaiser Permanente, San Diego, and assistant clinical professor in the Department of Family Practice at the University of California, San Diego, School of Medicine. Dr. McCarberg graduated from Northwestern University Medical School, Chicago, and completed a family practice residency at Highland Hospital, Rochester, N.Y. He has served on the board of directors of the American Pain Society and currently is co-president of the Western Pain Society.

Address correspondence to Morris Maizels, Department of Family Practice, Kaiser Permanente, 5601 DeSoto Ave., Woodland Hills, CA 91365 (e-mail: mor-ris.maizels@kp.org). Reprints are not available from the authors.

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