Tramadol use is linked to a higher risk of mortality compared with codeine, according to study results published in JAMA.

Tramadol is considered to be a relatively safe opioid and is widely used to treat patients with chronic noncancer pain. As limited data are available on the safety of tramadol compared with other opioids, the objective of the current study was to compare tramadol with codeine and determine mortality risk and other adverse clinical outcomes in outpatient settings.

The retrospective, population-based, propensity score-matched cohort study used a primary care database with medical data and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The study sample included patients ≥18 years of age who had been prescribed tramadol or codeine between 2007 and 2017 and were followed up to December 31, 2017.

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Outcomes studied were all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within 1 year after the first dispensation.

Following study exclusions and propensity score matching, the final analysis included 368,960 patients (mean age, 53.1 years; 57.3% women), including 184,480 in the tramadol cohort and 184,480 in the codeine cohort. The most common diagnoses were back pain (47.5% vs. 48.5%, respectively), neck/shoulder pain (28.6% vs. 29.5%, respectively), and osteoarthritis (15.3% vs. 15.5%, respectively).

Compared with codeine, tramadol use was significantly associated with an increased risk for mortality (13.00 vs. 5.61 per 1000 person-years; hazard ratio [HR], 2.31; 95% CI, 2.08-2.56), cardiovascular events (10.03 vs. 8.67 per 1000 person-years; HR, 1.15; 95% CI, 1.05-1.27), and fractures (12.26 vs. 8.13 per 1000 person-years; HR, 1.50; 95% CI, 1.37-1.65).

According to subgroup and sensitivity analyses, the increased mortality risk associated with tramadol was greater among young (HR, 3.14; 95% CI, 1.82-5.41) compared with older adults (HR, 2.39; 95% CI, 2.20-2.60). Furthermore, the risk for cardiovascular events was significantly greater among women (HR, 1.32; 95% CI, 1.19-1.46) than men (HR, 1.03; 95% CI, 0.93-1.13).

There were no significant differences between the medications regarding the risk for falls, delirium, constipation, opioid abuse/dependence, or sleep disorders.

The study had several limitations, including potential confounding by indication, unmeasured confounders, lack of data on cause of death, and potential underestimation of some of the study outcomes in routine clinical practice, such as delirium and sleep disorders.

“In this population-based cohort study, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures, but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders,” concluded the researchers.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Xie J, Strauss VY, Martinez-Laguna D, et al. Association of tramadol vs. codeine prescription dispensation with mortality and other adverse clinical outcomes. JAMA. October 19, 2021. doi: 10.1001/jama.2021.15255