Academic journal article Hong Kong Journal of Psychiatry

Antidepressants for the Treatment of Neuropathic Pain

Academic journal article Hong Kong Journal of Psychiatry

Antidepressants for the Treatment of Neuropathic Pain

Article excerpt


Tricyclic antidepressants have been the mainstay treatment modality of neuropathic pain. However, use of these agents has been limited by their significant side effects and potential cardiac adverse events, particularly in overdose. Newer antidepressants have been shown to have better safety profiles and tolerability. This article examines current evidence of the use of newer antidepressants in the treatment of neuropathic pain. The proposed mechanisms of action, clinical evidence and tolerability were reviewed. Although tricyclic antidepressants appear to be the most efficacious agents for neuropathic pain, there is inadequate evidence supporting their prolonged use. Paroxetine, trazodone, nefazodone, mirtazapine, and venlafaxine are potentially useful agents, but these drugs can also produce treatment-limiting side effects.

Key words: Antidepressive agents, Diabetic neuropathies, Neuralgia


Neuropathic pain is the pain initiated or caused by a primary lesion or dysfunction in the nervous system. (1,2) The possible aetiologies could be central in cases of stroke, multiple sclerosis, or epilepsy, or peripheral in conditions such as diabetic neuropathy, postherpetic neuralgia, and traumatic nerve injury. (2,3) There is no pathognomonic description for neuropathic pain in the literature, but the combination of burning or electrical pain with numbness and tingling, as well as pins and needles are thought to be highly indicative. (2) Since this pain is usually chronic and responds poorly to analgesics, many non-pharmacological and pharmacological treatments have been proposed. For example, transcutaneous electrical nerve stimulation (TENS) had been shown to be effective in the treatment of diabetic neuropathy. (4)

A large variety of pharmacological agents, topical or oral, are also being used. These include antidepressants (especially the tricyclic antidepressants; TCAs), anticonvulsants, gamma-aminobutyric acid (GABA)-B receptor agonists, N-methyl-D-aspartate (NMDA) antagonists, opioids, levodopa and topical capsaicin creams.

According to the systematic review by Sindrup and Jensen, TCAs are the most efficacious agents for the treatment of neuropathic pain. (5) While newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and venlafaxine share some similar pharmacodynamic properties with TCAs, the former may be potentially useful for the treatment of neuropathic pain, especially for patients with comorbid depression and suicide risk. Newer antidepressants have additional benefits--they are better tolerated and safer in overdose. (6) While the side effects of TCAs may limit the achievement of optimal dose, this problem is less likely with newer antidepressants. In this review, the current evidence for possible underlying mechanisms and side effect profiles of antidepressants commonly used in the treatment of neuropathic pain are examined.

Tricyclic Antidepressants

The efficacy of TCAs in the treatment of depression was originally reported by Kuhn in 1958. (7) Thereafter, TCAs came to be considered the mainstay treatment for depression. Although monoamine reuptake blockade properties seem to be the important initial mediator for their antidepressant action, the main mechanism is thought to be a delayed adaptive downregulation of postsynaptic receptors. (8)

The use of TCAs in the treatment of neuropathic pain can be dated back to a report by Woodforde et al of treatment of postherpetic neuralgia in 1965. (9) However, early studies of tricyclic antidepressants were complicated by the concomitant use of other drugs. (10) In 1982, Watson et al reported one of the earliest randomised, double-blind, placebo-controlled, crossover trials studying the effects of amitriptyline in the treatment of postherpetic neuralgia. (10) The study recruited 24 patients and employed a treatment duration of 3 weeks. The effects on depression, sleep, and untoward reactions were monitored. …

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