Duehmke RM, Derry S, Wiffen PJ, et al. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017 Jun 15;6:CD003726. doi: 10.1002/14651858.CD003726.pub4.
Discipline Area Score
Nurse 5 / 7
Physician 5 / 7

BACKGROUND: This review is an update of a review of tramadol for neuropathic pain, published in 2006; updating was to bring the review in line with current standards. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Peripheral neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the peripheral nervous system.

OBJECTIVES: To assess the analgesic efficacy of tramadol compared with placebo or other active interventions for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials.

SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.

SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing tramadol (any route of administration) with placebo or another active treatment for neuropathic pain, with subjective pain assessment by the participant.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH), using standard methods. We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.

MAIN RESULTS: We identified six randomised, double-blind studies involving 438 participants with suitably characterised neuropathic pain. In each, tramadol was started at a dose of about 100 mg daily and increased over one to two weeks to a maximum of 400 mg daily or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months due to cancer, cancer treatment, postherpetic neuralgia, peripheral diabetic neuropathy, spinal cord injury, or polyneuropathy. The mean age was 50 to 67 years with approximately equal numbers of men and women. Exclusions were typically people with other significant comorbidity or pain from other causes. Study duration for treatments was four to six weeks, and two studies had a cross-over design.Not all studies reported all the outcomes of interest, and there were limited data for pain outcomes. At least 50% pain intensity reduction was reported in three studies (265 participants, 110 events). Using a random-effects analysis, 70/132 (53%) had at least 50% pain relief with tramadol, and 40/133 (30%) with placebo; the risk ratio (RR) was 2.2 (95% confidence interval (CI) 1.02 to 4.6). The NNT calculated from these data was 4.4 (95% CI 2.9 to 8.8). We downgraded the evidence for this outcome by two levels to low quality because of the small size of studies and of the pooled data set, because there were only 110 actual events, the analysis included different types of neuropathic pain, the studies all had at least one high risk of potential bias, and because of the limited duration of the studies.Participants experienced more adverse events with tramadol than placebo. Report of any adverse event was higher with tramadol (58%) than placebo (34%) (4 studies, 266 participants, 123 events; RR 1.6 (95% CI 1.2 to 2.1); NNH 4.2 (95% CI 2.8 to 8.3)). Adverse event withdrawal was higher with tramadol (16%) than placebo (3%) (6 studies, 485 participants, 45 events; RR 4.1 (95% CI 2.0 to 8.4); NNH 8.2 (95% CI 5.8 to 14)). Only four serious adverse events were reported, without obvious attribution to treatment, and no deaths were reported. We downgraded the evidence for this outcome by two or three levels to low or very low quality because of small study size, because there were few actual events, and because of the limited duration of the studies.

AUTHORS' CONCLUSIONS: There is only modest information about the use of tramadol in neuropathic pain, coming from small, largely inadequate studies with potential risk of bias. That bias would normally increase the apparent benefits of tramadol. The evidence of benefit from tramadol was of low or very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood is very high that the effect will be substantially different from the estimate in this systematic review.

Comments from MORE raters

Nurse rater

An excellent article that uses appropriate metric tools, which decrease the likelihood of biases and subjective judgments. In my area of practice, Tramadol is considered the savior in many cases with chronic pain. I see this study as a potential game changer to my area of practice.

Nurse rater

This is useful information as many colleagues treating neuropathic pain probably do not know the quality/strength of evidence regarding the use of Tramadol for their patients. This article may help some practitioners decide on better courses of treatment and/or understand why a course of treatment may not be working.

Nurse rater

This updated Cochrane review will be very useful to those practitioners who prescribe tramadol and other medications for neuropathic pain.

Nurse rater

I am happy that this article documents the significant side effects of Tramadol.

Physician rater

I never considered using tramadol for neuropathic pain. The article notes limitations in the studies, but I don't think I'll change what I do at this time.

Physician rater

This is a well conducted systematic review of Tramadol in neuropathic pain. Although we do not have full access to the complete manuscript, the authors seem to have taken into account appropriate study selection, criteria, and risk of bias, and conclude that there are insufficient or not good quality studies to support the use of tramadol in neuropathic pain, and rather highlight the risks over benefits.
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