Treatment of Neuropathic Pain

Kristen Jefferies, Pharm.D.


Semin Neurol. 2010;30(4):425-432. 

In This Article

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) inhibit presynaptic reuptake of serotonin and norepinephrine and block cholinergic, adrenergic, histaminergic, and sodium channels.[3] Several TCAs, including amitriptyline, nortriptyline, desipramine, and imipramine, have been studied for the treatment of neuropathic pain.[6] This class of medications has shown positive results in the treatment of painful diabetic neuropathy, postherpetic neuralgia (PHN), painful polyneuropathy, and postmastectomy pain. Efficacy was shown in patients with and without comorbid depression. However, not all types of neuropathic pain respond to TCAs. Trials in phantom limb pain, neuropathic cancer pain, chronic lumbar root pain, chemotherapy-induced neuropathy, and human immunodeficiency virus (HIV) neuropathy had negative results.[6]

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) recommends secondary amine TCAs (nortriptyline and desipramine) as first-line treatment for neuropathic pain and tertiary amines (amitriptyline and imipramine) if a secondary amine is not available.[5] The secondary amines are typically better tolerated with similar efficacy. The European Federation of Neurological Societies (EFNS) task force recommends TCAs as first-line treatment for painful polyneuropathy, postherpetic neuralgia, and central neuropathic pain.[2] The Canadian Pain Society (CPS) recommends TCAs as first-line treatment for neuropathic pain due to diabetes, herpes zoster, and traumatic nerve injury or stroke.[4]

The typical starting dose of any TCA for the treatment of neuropathic pain is 10 to 25 mg nightly. This can be increased by 10 to 25 mg every 3 to 7 days as tolerated up to a usual maximum of 150 mg nightly. A trial of 6 to 8 weeks at the maximum tolerated dose is necessary to assess the benefit of the medication.[6] It may take several weeks to see improvement in pain.

The advantages of TCAs include their effect on common comorbidities such as insomnia and depression. They are inexpensive and dosed once daily.[6] Anticholinergic side effects occur frequently and may be dose limiting. These include dry mouth and eyes, urinary retention, excess sedation, orthostatic hypotension, constipation, and blurry vision. Starting at a lower dose and titrating very slowly may reduce these side effects.[6] Rare, but serious side effects include decreased seizure threshold and cardiac toxicity. Due to reports of tachycardia, myocardial infarction, and sudden cardiac death (at doses greater than 100 mg per day) the NeuPSIG recommends a baseline echocardiogram for patients over 40 years of age and avoiding TCAs in patients at risk for sudden cardiac death or with a history of cardiovascular disease.[5] TCAs have a high risk of mortality in an overdose and should be avoided in patients at risk for suicide attempts.[6] In elderly patients, TCAs can exacerbate cognitive problems and increase the risk of falls.[5]

A Cochrane review[7] of 13 placebo controlled trials that included patients with a variety of neuropathic pain conditions concluded that TCAs were more effective than placebo. From an additional 12 studies that compared one TCA to another, there was no significant difference in efficacy among TCAs. The number needed to treat (NNT) to achieve moderate pain relief was 3.6 (95% CI 3–4.5) for all TCAs, 3.1 (95% CI 2.5–4.2) for amitriptyline <150 mg, 2.6 (95% CI 1.9–4.5) for desipramine, and 2.2 (95% CI 1.7–3.2) for imipramine. The number needed to harm (NNH), defined as causing side effects that led to discontinuation of the medications, was 28 (95% CI 17–68).


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