Risks of Tramadol Likely Outweigh Benefit for Chronic Pain

https://www.medpagetoday.com/neurology/painmanagement/117842

Drug didn’t meet efficacy threshold and doubled serious adverse event risk, analysis suggests

The opioid analgesic tramadol reduced chronic pain levels compared with placebo, but appeared to double the risk of harm, a review of 19 clinical trials suggested.

In a meta-analysis and trial sequential analysis, tramadol improved chronic pain on the numerical rating scale (NRS) with low certainty of evidence (mean NRS difference -0.93 points, 97.5% CI -1.26 to -0.60, P<0.0001), said Jehad Ahmad Barakji, MD, of the Centre for Clinical Intervention Research at Rigshospitalet in Copenhagen, Denmark, and co-authors.

The effect size was below the predefined minimal important difference of 1.0 point, Barakji and colleagues wrote in BMJ Evidence-Based Medicine. The NRS evaluates pain on a scale of 0 (no pain) to 10 (worst pain imaginable).

Tramadol also raised the risk of serious adverse events (OR 2.13, 97.5% CI 1.29-3.51, P=0.001) with moderate-certainty evidence, driven mainly by a higher proportion of cardiac events and neoplasms, the researchers reported. Non-serious adverse events like nausea, dizziness, constipation, and somnolence were higher with tramadol.

“Approximately 60 million individuals worldwide experience the addictive effects of opioids,” observed co-author Janus Christian Jakobsen, MD, PhD, also of the Centre for Clinical Intervention Research.

“Tramadol continues to be widely prescribed for the management of chronic pain and is often perceived as safer than other opioids, although this perception lacks supporting evidence,” Jakobsen told MedPage Today.

“The use of tramadol and other opioids should be minimized as much as possible,” he added. “Our study provides evidence in support of this recommendation.”

Tramadol selectively binds to various opiate receptors in the central nervous system, similar to other opioids. It was first approved as a non-controlled analgesic in 1995 under the brand name Ultram.

In 2014, the Drug Enforcement Administration classified tramadol as a schedule IV controlled substance, indicating it had a lower risk of abuse and dependence than schedule II opioids like oxycodone and hydrocodone.

Tramadol is approved to treat pain severe enough to require an opioid analgesic and carries a boxed warning for addiction and abuse, life-threatening respiratory depression, and other potential harms. Total prescriptions for tramadol-containing products in the U.S. totaled 27.1 million in 2024.

“Tramadol is an interesting drug because there is a sense among many clinicians that it isn’t really an opioid,” noted Molly Jeffery, PhD, of the Mayo Clinic in Rochester, Minnesota, who wasn’t involved with the analysis.

In 2019, Jeffery led a large U.S. insurance claims study that showed patients who used tramadol alone after surgery had a higher risk of prolonged opioid use than expected.

“If tramadol really is very different from other opioids we give people for acute pain, we might expect to see differences in long-term use of opioids in people who are prescribed tramadol versus other opioids after surgery,” Jeffery pointed out.

“We found the opposite was true; people who got tramadol rather than oxycodone or hydrocodone after their surgery were actually more likely to continue using opioids long-term,” she told MedPage Today.

Barakji and colleagues assessed data from 19 clinical trials involving 6,506 participants with chronic pain in their systematic review with meta-analysis and trial sequential analysis. Five trials evaluated tramadol for neuropathic pain, nine focused on osteoarthritis, four assessed chronic low back pain, and one involved fibromyalgia.

Participants were ages 47 to 69; their mean age was 58. All trials involved oral tramadol except one osteoarthritis trial that used topical administration.

Treatment duration ranged from 2 to 16 weeks, and follow-up spanned from 3 to 15 weeks. Eight trials assessed serious adverse events after follow-up periods that ranged from 7 to 16 weeks.

Serious adverse events in the tramadol groups included chest pain, coronary artery disease, congestive heart failure, prostate cancer, breast cancer, and thyroid neoplasm. The follow-up period for neoplasms was short, making a causal link between tramadol and new cancer disease “questionable at this point,” the researchers noted.

Five trials that evaluated tramadol’s effect on quality of life had mixed results; two found improvements, and three reported no significant differences between tramadol and placebo.

The study had several limitations, Barakji and co-authors acknowledged. “All included trials were at high risk of bias except two, which increases the likelihood that our findings overestimate the beneficial effects and underestimate the harmful effects of tramadol,” they wrote.

Several trials did not report the specific types of serious adverse events, and follow-up length varied across trials.

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