Is a New Tramadol Prescription Linked to Increased Risk for Mortality and CV Events?

This population-based cohort study found an association between new tramadol prescription and increased risk for mortality, cardiovascular events, and fractures.

A retrospective, population-based study found that tramadol dispensation was associated with an increased risk for all-cause mortality, cardiovascular events, and fractures compared with codeine in first time users. These findings were published in JAMA.

Data were sourced from the System for the Development of Research in Primary Care (SIDIAP) which comprised routine clinical data covering >80% of the Catalan region in Spain. All patients who had a new prescription of tramadol and/or codeine between 2007 and 2017 were assessed for clinical outcomes among a propensity-matched subset of individuals.

A total of 240,261 and 599,228 individuals had a new prescription of tramadol and codeine and were 57.4% and 54.7% women, 53.9% and 30.8% had back pain, 32.9% and 18.5% neck or shoulder pain, and 18.9% and 6.8% osteoarthritis, respectively. A subset of 184,480 individuals were selected from both cohorts for the propensity-matched subsets.

Tramadol was associated with increased 1-year cumulative incidence of all-cause mortality (12.86 vs 5.59 per 1000 participants), cardiovascular disease (9.97 vs 8.62 per 1000 participants), and fractures (12.07 vs 8.08 per 1000 participants).

These incidence rates corresponded with increased risk for mortality (hazard ratio [HR], 2.31; 95% CI, 2.08-2.56), cardiovascular events (HR, 1.15; 95% CI, 1.05-1.27), and fractures (HR, 1.50; 95% CI, 1.37-1.65) among tramadol users.

Stratified by subgroups, the associated increased risk for mortality was greater among younger (HR, 3.14) than older (HR, 2.39) participants; women (HR, 1.32) were at greater risk than men (HR, 1.03) for cardiovascular events; and fractures were more likely among those with more comorbidities (HR, 2.20) compared with those who had the least comorbidities (HR, 1.47).

There was no risk associated with tramadol for opioid abuse or dependence (HR, 1.91; 95% CI, 0.72-5.08), falls (HR, 1.18; 95% CI, 0.98-1.42), constipation (HR, 1.08; 95% CI, 0.97-1.21), sleep disorder (HR, 1.06; 95% CI, 0.87-1.29), or delirium (HR, 1.02; 95% CI, 0.54-1.93).

These findings may have been biased by the differences in indication for the 2 drugs. For instance, codeine is indicated for managing cough and tramadol is often prescribed to more severely ill patients.

In summary, this population-based cohort study found an association between new tramadol prescription with increased risk for mortality, cardiovascular events, and fractures. The study authors cautioned that these findings should be interpreted with caution given the risk for residual confounding factors.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of 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. 2021;326(15):1504-1515.