Tramadol versus placebo for chronic pain: a systematic review with meta-analysis and trial sequential analysis.

Objectives: The objective of our study was to assess the benefits and harms of tramadol vs placebo in adults with chronic pain.

Design: The research method was a systematic review of randomised clinical trials with meta-analysis. The review followed the Trial Sequential Analysis and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Data sources: The Cochrane Library, MEDLINE, Embase, Science Citation Index and BIOSIS were searched for trials published from inception to 6 February 2025.

Eligibility criteria for selecting studies: Studies were eligible for inclusion if they were published and unpublished randomised clinical trials comparing tramadol vs placebo in adults with any type of chronic pain. Risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions.

Main outcome measures: The main outcome measures were pain level, adverse events, quality of life, dependence, abuse and depressive symptoms.

Results: We included 19 randomised placebo-controlled clinical trials enrolling 6506 participants. All outcome results were at high risk of bias. Meta-analysis and Trial Sequential Analysis showed evidence of a beneficial effect of tramadol on chronic pain (mean difference numerical rating scale (NRS) -0.93 points; 97.5% CI -1.26 to -0.60; p<0.0001; low certainty of evidence). However, the effect size was below our predefined minimal important difference of 1.0 point on NRS. Beta binomial regression showed evidence of a harmful effect of tramadol on serious adverse events (OR 2.13; 97.5% CI 1.29 to 3.51; p=0.001; moderate certainty of evidence), mainly driven by a higher proportion of cardiac events and neoplasms. It was not possible to conduct a meta-analysis of the quality of life due to a lack of data. Meta-analysis and Trial Sequential Analysis showed that tramadol increased the risk of several non-serious adverse events including nausea (number needed to harm (NNH) 7), dizziness (NNH 8), constipation (NNH 9), and somnolence (NNH 13) (all very low certainty of evidence).

Conclusion: Tramadol may have a slight effect on reducing chronic pain levels (low certainty of evidence) while likely increasing the risk of both serious (moderate certainty of evidence) and non-serious adverse events (very low certainty of evidence). The potential harms associated with tramadol use for pain management likely outweigh its limited benefits.