Abstract: We included six studies treating 310 participants (mean or median age 49 to 64 years) with various neuropathic pain conditions. Five studies used a cross-over design, and one used a parallel-group design; 272 participants were randomised to treatment with nortriptyline, 145 to placebo, 94 to gabapentin, 56 to gabapentin plus nortriptyline, 55 to morphine, 55 to morphine plus nortriptyline, 39 to chlorimipramine, and 33 to amitriptyline. Treatment periods lasted from three to eight weeks. All studies had one or more sources of potential major bias. No study provided first or second tier evidence for any outcome. Only one study reported our primary outcome of people with at least 50% reduction in pain. There was no indication that either nortriptyline or gabapentin was more effective in postherpetic neuralgia (very low quality evidence). Two studies reported the number of people with at least moderate pain relief, and one reported the number who were satisfied with their pain relief and had tolerable adverse effects. We considered these outcomes to be equivalent to our other primary outcome of Patient Global Impression of Change (PGIC) much or very much improved. We could not pool data, but third tier evidence in individual studies indicated similar efficacy to other active interventions (gabapentin, morphine, chlorimipramine, and amitriptyline), and to placebo in the conditions studied (very low quality evidence). Adverse event reporting was inconsistent and fragmented. More participants reported adverse events with nortriptyline than with placebo, similar numbers with nortriptyline and other antidepressants (amitriptyline and chlorimipramine) and gabapentin, and slightly more with morphine (very low quality evidence). No study reported any serious adverse events or deaths. We found little evidence to support the use of nortriptyline to treat the neuropathic pain conditions included in this review. There were no studies in the treatment of trigeminal neuralgia. The studies were methodologically flawed, largely due to small size, and potentially subject to major bias. The results of this review do not support the use of nortriptyline as a first line treatment. Effective medicines with much greater supportive evidence are available, such as duloxetine and pregabalin.

Plain-language summary: In January 2015, we performed searches to look for clinical trials where nortriptyline was used to treat neuropathic pain in adults. We found six studies, with 310 participants with various neuropathic pain conditions. Studies were randomised and double-blind, but often with small numbers of participants. It was not possible to combine information from the different studies, but individually most studies indicated equivalent benefit from nortriptyline (usually at a dose between 50 mg and 100 mg daily) when compared with amitriptyline or chlorimipramine (other antidepressants), gabapentin (an antiepileptic), morphine (an opioid), or placebo (very low quality evidence). More people experienced adverse events with nortriptyline than with placebo, but numbers were similar for nortriptyline and other active medicines (very low quality evidence). There was too little information of adequate quality to be sure that nortriptyline works as a pain medicine in the type of neuropathic pain studies in this review. Other medicines have been shown to be effective.