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 Oct 19;326(15):1504-1515. doi: 10.1001/jama.2021.15255. (Original study)

Importance: Although tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids.

Objective: To assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings.

Design, Setting, and Participants: Retrospective, population-based, propensity score-matched cohort study using a primary care database with routinely collected medical records and pharmacy dispensations covering more than 80% of the population of Catalonia, Spain (˜6 million people). Patients 18 years or older with 1 or more year of available data and dispensation of tramadol or codeine (2007-2017) were included and followed up to December 31, 2017.

Exposures: New prescription dispensation of tramadol or codeine (no dispensation in the previous year).

Main Outcomes and Measures: 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. Absolute rate differences (ARDs) and hazard ratios (HRs) with 95% confidence intervals were calculated using cause-specific Cox models.

Results: Of the 1?093?064 patients with a tramadol or codeine dispensation during the study period (326?921 for tramadol, 762?492 for codeine, 3651 for both drugs concomitantly), a total of 368?960 patients (184?480 propensity score-matched pairs) were included after study exclusions and propensity score matching (mean age, 53.1 [SD, 16.1] years; 57.3% women). Compared with codeine, tramadol dispensation was significantly associated with a higher risk of all-cause mortality (incidence, 13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08-2.56]; ARD, 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (incidence, 10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05-1.27]; ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (incidence, 12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37-1.65]; ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years). No significant difference was observed for the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders.

Conclusions and Relevance: 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. The findings should be interpreted cautiously, given the potential for residual confounding.

Discipline Area Score
Nurse 6 / 7
Physician 6 / 7
Comments from MORE raters

Physician rater

Tramadol is not such a benign choice. This well done study demonstrates that Tramadol has significant risks.

Physician rater

Codeine and tramadol are on the second rung of the WHO analgesic ladder but codeine is the prototypical weak opioid and is recommended for use first. This retrospective cohort study using a primary care database lacks a homogeneous control group to compare the two opioids. At least in my setting, tramadol is prescribed to patients in severe pain and probably in poorer health than those receiving codeine as an analgesic. This could explain the worse side effects associated with tramadol.

Physician rater

This is outside my area of expertise to some extent, but there are interesting results that are certainly provocative.

Physician rater

This is a very important study showing the danger of tramadol apart from its known side effects.

Physician rater

There is a substantial likelihood of unmeasured confounders contributing to the degree of difference seen in all-cause mortality for tramadol vs codeine. I would be cautious about incorporating this information into my practice.

Physician rater

Another nail in the coffin for tramadol.

Physician rater

The comparative cohort study was well conducted, controlling possible confounders as well as was possible. The differences in all-cause mortality, cardiovascular events and fractures are impressive and should lead to more careful prescribing of tramadol. I realize that there were some earlier studies showing an increased mortality with tramadol compared to codeine, but this was not generally known and needed confirmation.
Comments from PAIN+ CPN subscribers

Mrs. Lee Gardiner (11/23/2021 8:19 PM)

You have to wonder how they can show no increased risk of falls but cite increased risk of fractures. How else are they getting the fractures if not from falling?