The strong opioid painkiller tramadol is not that effective at easing chronic pain for which it's widely prescribed, finds a pooled data analysis of the available research, led by a team from Copenhagen University Hospital and published online in BMJ Evidence Based Medicine.
It may also increase the risk of serious side effects, including heart disease, the findings indicate, prompting the researchers to conclude that the potential harms of tramadol probably outweigh its benefits, and that its use should be minimised.
News-Medical.net reports that tramadol is a dual action opioid widely prescribed for the treatment of moderate to severe acute and chronic pain.
As such, it’s recommended in several medical guidelines for pain management, note the researchers.
Its use has surged in recent years, possibly because of its perceived lower risk of side effects and the widespread belief that it is safer and less addictive than other short-acting opioids, they add.
Although tramadol has been included in previous systematic reviews, none has provided a comprehensive assessment of its efficacy and safety in a range of chronic pain conditions.
In a bid to plug this knowledge gap, the researchers scoured research databases for randomised clinical trials published up to February 2025 that compared tramadol with placebo for patients with chronic pain, including cancer pain.
A total of 19 clinical trials involving 6 506 participants with chronic pain were eligible for inclusion in the analysis. Five looked at the impact of tramadol on neuropathic pain; nine focused on osteoarthritis; four looked at chronic low back pain; and one focused on fibromyalgia.
The average age of the trial participants was 58, but ranged from 47 to 69. Tablets were the primary formulation used; only one trial included topical cream. Length of treatment ranged from two to 16 weeks while length of follow up ranged from three to 15 weeks.
Pooled data analysis of the trial results showed that while tramadol eased pain, the effect was small and below what would be considered clinically effective.
Eight of the trials reported on the proportion of serious side effects arising after treatment during follow up periods of between seven and 16 weeks.
Statistical analysis of these trials results indicated a doubling in the risk of harms associated with tramadol compared with placebo, mainly driven by a higher proportion of “cardiac events”, such as chest pain, coronary artery disease, and congestive heart failure.
Use of tramadol was also associated with a heightened risk of some cancers, although the follow up period was short, making this finding “questionable”, say the researchers.
Pooled data analysis of all of the trial results indicated that tramadol treatment was associated with a heightened risk of several milder side effects, including nausea, dizziness, constipation, and sleepiness.
The researchers acknowledge that the outcome results were at high risk of bias, but this increases the likelihood that the findings over-estimate the beneficial effects and under-estimate the harmful effects of tramadol, they suggest.
“Approximately 60m individuals worldwide experience the addictive effects of opioids. In 2019, drug use was responsible for 600 000 deaths, with nearly 80% of these associated with opioids and approximately 25% resulting from opioid overdose.
“In the United States, the number of opioid-related overdose deaths increased from 49 860 in 2019 to 81 806 in 2022. Given these trends and the present findings, the use of tramadol and other opioids should be minimised to the greatest extent possible.”
They concluded that tramadol may have a slight effect on reducing chronic pain (low certainty of evidence) while possibly 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 probably outweigh its limited benefits.”
Study details
Tramadol versus placebo for chronic pain: a systematic review with meta-analysis and trial sequential analysis
Barakji, JA, et al
Published in BMJ Evidence-Based Medicine in October 2025
Abstract
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.
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