Clinician Article

Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes.

  • Xie J
  • Strauss VY
  • Martinez-Laguna D
  • Carbonell-Abella C
  • Diez-Perez A
  • Nogues X, et al.
JAMA. 2021 Oct 19;326(15):1504-1515. doi: 10.1001/jama.2021.15255. (Original)
PMID: 34665205
Read abstract
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Special Interest - Pain -- Physician
    Relevance - 6/7
    Newsworthiness - 6/7
  • Rheumatology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Neurology
    Relevance - 5/7
    Newsworthiness - 5/7
  • Oncology - General
    Relevance - 4/7
    Newsworthiness - 6/7


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.

Clinical Comments

General Internal Medicine-Primary Care(US)

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

Internal Medicine

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


Another nail in the coffin for tramadol.


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.


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.

Oncology - General

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.


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

Register for free access to all Professional content

Want the latest in aging research? Sign up for our email alerts.

Support for the Portal is largely provided by the Labarge Optimal Aging Initiative. AGE-WELL is a contributing partner. Help us to continue to provide direct and easy access to evidence-based information on health and social conditions to help you stay healthy, active and engaged as you grow older. Donate Today.

© 2012 - 2020 McMaster University | 1280 Main Street West | Hamilton, Ontario L8S4L8 | +1 905-525-9140 | Terms Of Use