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

Educational Objective
To review if tramadol prescription associated with a higher risk of all-cause mortality than other pain relief medications among patients with osteoarthritis?
1 Credit CME
Key Points

Question  Is tramadol prescription associated with a higher risk of all-cause mortality than other pain relief medications among patients with osteoarthritis?

Findings  In this cohort study that included 88 902 patients with osteoarthritis, initial prescription of tramadol was associated with a significantly increased risk of mortality over 1 year compared with initial prescription of naproxen (hazard ratio [HR], 1.71), diclofenac (HR, 1.88), celecoxib (HR, 1.70), and etoricoxib (HR, 2.04), but not compared with codeine (HR, 0.94).

Meaning  Tramadol prescription may be associated with increased all-cause mortality compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but further research is needed to determine if this relationship is causal.


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.

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Article Information

Corresponding Authors: Guanghua Lei, MD, PhD, Department of Orthopaedics, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan 410008, China (lei_guanghua@csu.edu.cn); Yuqing Zhang, DSc, Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114 (yzhang108@mgh.harvard.edu).

Accepted for Publication: February 5, 2019.

Author Contributions: Dr Zhang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lei and Zhang are joint corresponding authors.

Concept and design: Zeng, Dubreuil, Lu, Choi, Lei, Zhang.

Acquisition, analysis, or interpretation of data: Zeng, Dubreuil, Larochelle, Lu, Wei, Lei, Zhang.

Drafting of the manuscript: Zeng, Lu, Choi, Lei, Zhang.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lu, Wei, Choi, Zhang.

Obtained funding: Zeng, Wei, Choi, Lei, Zhang.

Administrative, technical, or material support: Zeng, Wei, Choi, Lei, Zhang.

Supervision: Choi, Lei, Zhang.

Conflict of Interest Disclosures: Dr Larochelle reported receiving grants from National Institute on Drug Abuse (K23 DA042168) during the conduct of the study and grants from Optum Labs outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR069127, P60 AR047785), and the National Natural Science Foundation of China (81772413, 81702207, 81702206).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The interpretation of these data is the sole responsibility of the authors.

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