A 70-year-old man with a long-standing history of poorly controlled type 2 diabetes presents with increasing burning and tingling in his feet.
Should antidepressants be used for the treatment of neuropathic pain?
Tricyclic antidepressants, particularly amitriptyline, are effective for the treatment of painful diabetic neuropathy and post herpetic neuralgia, and may be beneficial in other neuropathic pain syndromes, but they should be used with caution in patients at increased risk of adverse events.1
Neuropathic pain typically is a burning or “shock-like” pain caused by damage to the peripheral or central nervous system or both. It can be constant or can occur intermittently with paroxysmal attacks, and also may be associated with significant hypersensitivity. Painful diabetic neuropathy affects up to 3 million Americans, and postherpetic neuralgia affects another 1 million.2 Other causes of neuropathic pain include trigeminal neuralgia, central neuropathic pain, and human immunodeficiency virus (HIV) neuropathy. Treatment can be difficult, because neuropathic pain often responds poorly to nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates, but antidepressants3 and the anticonvulsants gabapentin (Neurontin) and carbamazepine (Tegretol) have shown promise.4–6
This Cochrane review1 found that the majority of studies of antidepressants for neuropathic pain focused on tricyclic anti-depressants, most commonly amitriptyline. When the tricyclic antidepressants amitriptyline and desipramine (Norpramin) were compared with placebo, one of every two patients treated experienced at least moderate relief of neuropathic pain (number needed to treat = 2). However, multiple studies comparing tricyclic antidepressants found no evidence that one was superior to another. No high-quality evidence comparing tricyclic antidepressants with anticonvulsants was found.
The Cochrane review also evaluated studies with respect to specific causes of neuropathic pain. There was good evidence for the effect of tricyclic antidepressants for diabetic neuropathy, but only limited evidence of effectiveness was available regarding the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac), citalopram (Celexa), and paroxetine (Paxil). There also was evidence that tricyclic antidepressants are effective for postherpetic neuralgia. There was some evidence of benefit from tricyclic antidepressants for central neuropathic pain, but tricyclic antidepressants were not effective in HIV neuropathy.
Treatment recommendations from the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain, published in the Archives of Neurology, advocate five options for the initial treatment of neuropathic pain: tricyclic antidepressants, gabapentin, 5% lidocaine patch (Lidoderm), opioids, and tramadol (Ultram).2 This conference was sponsored by the manufacturer of the 5% lidocaine patch. The recommendations cite evidence supporting the use of gabapentin for postherpetic neuralgia, diabetic neuropathy, and mixed neuropathic pain syndromes; the lidocaine patch for postherpetic neuralgia; opioids for postherpetic neuralgia and diabetic neuropathy; and tramadol for diabetic neuropathy and painful polyneuropathy. They also note that although tricyclic anti-depressants were the first medications to be demonstrated effective for neuropathic pain in placebo-controlled trials, they must be used cautiously because of the potential for adverse effects.2
The best evidence on antidepressants for neuropathic pain supports the use of tricyclic antidepressants for painful diabetic neuropathy and postherpetic neuralgia. Tricyclic antidepressants should be used with caution in older persons because of the potential for adverse effects including drowsiness, dry mouth, blurred vision, constipation, and urinary retention,1 and caution also is required in patients with underlying cardiovascular disease, glaucoma, or autonomic neuropathy.2 Although anticonvulsants also have been demonstrated effective for neuropathic pain, there is no good evidence comparing the relative safety and effectiveness of tricyclic antidepressants with anticonvulsants or other agents for neuropathic pain. Selection of an agent for treating neuropathic pain should be guided by the underlying diagnosis, an awareness of any comorbid conditions or risk factors, and patient preference.
Background. For many years, antidepressant drugs have been used to manage neuropathic pain, and often are the first-choice treatment. It is not clear, however, which antidepressant is more effective, what role the newer antidepressants can play in treating neuropathic pain, and what adverse effects are experienced by patients.
Objectives. To determine the analgesic effectiveness and safety of antidepressant drugs in neuropathic pain. Migraine and headache studies were not considered.
Search Strategy. Randomized trials of antidepressants in neuropathic pain were identified in MEDLINE (1966 to December 2003); EMBASE (1980 to December 2003); the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2004, issue 1; and the Cochrane Pain, Palliative and Supportive Care Trials Register (May 2002). Additional reports were identified from the reference list of the retrieved papers and by contacting investigators.
Selection Criteria. Randomized trials reporting the analgesic effects of antidepressant drugs in adult patients with subjective assessment of pain of neuropathic origin. Studies that included patients with chronic headache and migraine were excluded.
Data Collection and Analysis. Two reviewers agreed on the included studies, extracted data, and assessed methodologic quality independently. Fifty trials of 19 antidepressants were considered eligible (2,515 patients) for inclusion. Relative risk (RR) estimates and numbers needed to treat (NNTs) were calculated from dichotomous data for effectiveness and adverse effects.
Primary Results. Tricyclic antidepressants are effective treatments for neuropathic pain.
Amitriptyline has an NNT of 2 (95% confidence interval [CI], 1.7 to 2.5), RR 4.1 (95% CI, 2.9 to 5.9), for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. There were insufficient data for an assessment of evidence of effectiveness for other antidepressants such as St. John's wort, venlafaxine (Effexor), and L-tryptophan. For diabetic neuropathy, the NNT was 1.3 (95% CI, 1.2 to 1.5), RR 12.4 (95% CI, 5.2 to 29.2 [five studies]); for postherpetic neuralgia, 2.2 (95% CI, 1.7 to 3.1), RR 4.8 (95% CI, 2.5 to 9.5 [three studies]). There was evidence that tricyclic antidepressants are not effective in human immunodeficiency virus–related neuropathies.
The number needed to harm (NNH) for major adverse effects, defined as an event leading to withdrawal from a study, was 16 (95% CI, 10 to 45). The NNH for minor adverse effects was 4.6 (95% CI, 3.3 to 6.7).
Reviewers' Conclusions. Antidepressants are effective for a variety of neuropathic pains. The best evidence available is for amitriptyline. There are only limited data for the effectiveness of SSRIs. It is not possible to identify the most effective antidepressant until more studies of SSRIs are conducted.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).