A new pooled analysis of clinical trials, published online in BMJ Evidence-Based Medicine, has raised serious concerns about the commonly prescribed opioid painkiller tramadol, suggesting that it provides only modest relief for chronic pain while increasing the risk of potentially serious side effects. The study concludes that the harms of tramadol likely outweigh its benefits, and urges healthcare providers to minimize its use wherever possible.
Tramadol is a centrally acting analgesic that functions as both a μ-opioid receptor agonist and a serotonin/norepinephrine reuptake inhibitor (SNRI). Its active metabolite, (+)-O-desmethyl-tramadol (M1), is more potent than the parent drug and enhances its pain-relieving effects. Beyond its opioid activity, tramadol modulates several neuronal and inflammatory pathways, contributing to its complex mechanisms of action. Despite these properties, its real-world effectiveness in chronic pain management has remained uncertain.
The researchers reviewed randomized clinical trials published up to February 2025 that compared tramadol with placebo in patients with chronic pain, including cancer-related pain. A total of 19 trials involving 6,506 participants met the inclusion criteria. The studies focused on a range of conditions, including neuropathic pain (5 trials), osteoarthritis (9 trials), chronic low back pain (4 trials), and fibromyalgia (1 trial). The participants had an average age of 58 years (range 47–69), most trials used oral tablets with one testing a topical formulation, and treatment lasted 2–16 weeks with follow-up periods of 3–15 weeks.
The pooled analysis revealed that tramadol did provide pain relief, but the effect was small and fell below the threshold generally considered clinically meaningful. Eight of the trials reported serious adverse events, including cardiac complications such as chest pain, coronary artery disease, and congestive heart failure. Statistical analysis indicated that tramadol doubled the risk of serious harms compared with placebo. Some trials also suggested a possible elevated risk of certain cancers, though short follow-up periods made this finding uncertain.
In addition to serious complications, tramadol use was associated with milder side effects such as nausea, dizziness, constipation, and sleepiness. The authors noted that many trial outcomes were at high risk of bias, which could overestimate benefits while underestimating harms. Supporting these findings, a large observational study by Musich et al. found that older adults with osteoarthritis using tramadol had higher risks of emergency room visits, falls, fractures, cardiovascular hospitalizations, and mortality compared with non-users.
The findings come amid growing global concern over opioid use. Researchers highlighted that approximately 60 million individuals worldwide suffer from opioid addiction. In 2019, drug-related deaths reached roughly 600,000, with nearly 80% linked to opioids and about 25% caused by overdose. In the United States, opioid-related overdose deaths rose from 49,860 in 2019 to 81,806 in 2022. The current study highlights that while tramadol may provide slight pain relief for chronic conditions, the risk of serious and non-serious adverse events likely outweighs its limited benefits, and healthcare providers should exercise caution when prescribing it.
Reference
- Barakji JA, Maagaard M, Petersen JJ, Barakji YA, Ipsen EØ, Gluud C, et al. Tramadol versus placebo for chronic pain: a systematic review with meta-analysis and trial sequential analysis. BMJ Evidence-Based Medicine [Internet]. 2025 Oct 7 [cited 2025 Oct 14]; Available from: https://ebm.bmj.com/content/early/2025/09/26/bmjebm-2025-114101
- Tramadol [Internet]. [cited 2025 Oct 14]. Available from: https://go.drugbank.com/drugs/DB00193
- Musich S, Wang SS, Schaeffer JA, Slindee L, Kraemer S, Yeh CS. Safety Events Associated with Tramadol Use Among Older Adults with Osteoarthritis. Popul Health Manag. 2021 Feb;24(1):122-132. doi: 10.1089/pop.2019.0220. Epub 2020 Mar 2. PMID: 32119805; PMCID: PMC7875128.