Author: Carla Cantor
Medscape BMJ Evidence-Based Medicine.
Tramadol, a commonly prescribed opioid often viewed as a safer option for chronic pain, provided limited pain relief while increasing the risk for serious side effects, results of a new analysis showed.
In a systematic review and meta-analysis, investigators found that tramadol offered clinically insignificant pain relief, while doubling the likelihood of serious adverse events, most commonly cardiac complications.
“Given the limited analgesic benefits and increased risk of harm, tramadol use for chronic pain should be reconsidered,” Jehad Ahmad Barakji, MD, of the Centre for Clinical Intervention Research at Rigshospitalet in Copenhagen, Denmark, told Medscape Medical News.
However, the researchers cautioned that the certainty of the evidence was low-to-moderate and that the quality of the underlying trials varied substantially.
Tramadol, a dual-action opioid that modulates serotonin and norepinephrine pathways, has long been promoted as a middle-ground analgesic — less addictive than morphine but stronger than nonopioid medications. It is approved for moderate-to-severe pain, including postoperative and chronic conditions.
Prescriptions have risen sharply worldwide, fueled by perceptions of safety and a belief that tramadol carries a lower risk for dependence. A recent global analysis estimated that nearly 18% of adults have used tramadol in their lifetime, and more than 80% of those users combined it with at least one other substance.
Despite its widespread use, evidence supporting tramadol’s long-term effectiveness and safety in chronic pain has been limited and inconsistent. Previous research has largely focused on short-term or condition-specific outcomes, such as osteoarthritis or neuropathic pain, leaving uncertainty about the drug’s overall risk-benefit profile.
The current study is the first comprehensive systematic review to evaluate tramadol alone for chronic pain using both meta-analysis and trial sequential analysis, providing a broader view of efficacy and safety across pain types.
“We sought to fill this gap by evaluating the totality of evidence to guide clinical practice,” Barakji said.
The analysis included 19 randomized, placebo-controlled trials with 6569 adults. The average participant age was 56 years, and study durations ranged from 4 to 16 weeks. Pain intensity was typically assessed with the 0-10 numeric rating scale (NRS), while function and quality of life were measured with validated patient-reported tools.
Across the pooled analysis, participants receiving tramadol experienced an average pain reduction of 0.9 points on the NRS compared with placebo — a difference below the one-point threshold considered clinically meaningful. About 7% more patients in the tramadol groups achieved noticeable pain relief, but investigators said the benefit was modest and uncertain.
The researchers acknowledged that most included trials were at a high risk for bias due to incomplete outcome reporting, small sample sizes, and inconsistent assessment methods, factors that may have exaggerated benefits and underestimated harms.
Reevaluating Tramadol’s Role
Commenting on the research, Jessica Otte, MD, clinical associate professor in the Department of Family Medicine at The University of British Columbia, Vancouver, British Columbia, Canada, said the new review stands out for examining tramadol’s use across a range of chronic pain conditions, an area where clinicians often struggle to help patients achieve meaningful and sustained relief.
“This review doesn’t change the narrative but strengthens it: Tramadol’s reputation as a safer or uniquely effective opioid is increasingly difficult to defend,” she told Medscape Medical News.
While she believes the study makes an important contribution, Otte said the results should be interpreted with caution because of gaps in the underlying evidence. The Danish authors noted similar concerns, and Otte agreed that many of the included trials had methodological shortcomings.
She added that patients assigned to tramadol were more likely to discontinue early, both overall and because of side effects, raising concern about tolerability and attrition bias.
Also commenting, Houman Danesh, MD, professor and medical director of pain management at the Icahn School of Medicine at Mount Sinai in New York City, said the review provides moderate-certainty evidence that tramadol increases the risk for serious adverse events; but its broad approach — evaluating efficacy and safety across multiple chronic pain conditions — could be a confounding factor.
“Tramadol may benefit some conditions more than others,” he noted, which could alter the overall risk-benefit profile.
Danesh emphasized that clinicians should weigh the study alongside other research and their own experience when deciding whether to prescribe the drug.
“It’s important to take this study into consideration,” he said, “but there are multiple studies that support the use of tramadol, and we have to look at the totality of the evidence.”