Clinician Article

Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis.

  • Zeng C
  • Dubreuil M
  • LaRochelle MR
  • Lu N
  • Wei J
  • Choi HK, et al.
JAMA. 2019 Mar 12;321(10):969-982. doi: 10.1001/jama.2019.1347. (Original)
PMID: 30860559
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 - 5/7
    Newsworthiness - 5/7
  • Rheumatology
    Relevance - 5/7
    Newsworthiness - 5/7


Importance: An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs.

Objective: To examine the association of tramadol prescription with all-cause mortality among patients with osteoarthritis.

Design, Setting, and Participants: Sequential, propensity score-matched cohort study at a general practice in the United Kingdom. Individuals aged at least 50 years with a diagnosis of osteoarthritis in the Health Improvement Network database from January 2000 to December 2015, with follow-up to December 2016.

Exposures: Initial prescription of tramadol (n = 44 451), naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922).

Main Outcomes and Measures: All-cause mortality within 1 year after initial tramadol prescription, compared with 5 other pain relief medications.

Results: After propensity score matching, 88 902 patients were included (mean [SD] age, 70.1 [9.5] years; 61.2% were women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred in the tramadol cohort and 164 (13.8/1000 person-years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1000 person-years [95% CI, 6.3-13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1000 vs 19.2/1000 person-years; HR, 1.88 [95% CI, 1.51-2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1000 vs 18.4/1000 person-years; HR, 1.70 [95% CI, 1.33-2.17]) and etoricoxib (25.7/1000 vs 12.8/1000 person-years; HR, 2.04 [95% CI, 1.37-3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1000 vs 34.6/1000 person-years; HR, 0.94 [95% CI, 0.83-1.05]).

Conclusions and Relevance: Among patients aged 50 years and older with osteoarthritis, initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but not compared with codeine. However, these findings may be susceptible to confounding by indication, and further research is needed to determine if this association is causal.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

Tramadol is associated with increased mortality compared to naproxen or diclofenac when used in osteoarthritis. The mechanism is unknown and further research is needed. However it should ring alarm bells.

General Internal Medicine-Primary Care(US)

This paper is very much subject to confounding but it is an important article for discussion considering how much these medications are prescribed.


Using data from a UK GP practice database, the authors found that tramadol, when prescribed for osteoarthritis, leads to a significantly higher all cause mortality compared to NSAIDs like diclofenac, celecoxib and etoricoxib. Confounding by indication may not allow a causal relationship to be read into these results. It's a little surprising that though the data have been drawn from a UK GP database, none of the authors is from the UK!

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