Cardiovascular Safety of Tramadol Not Assured for Osteoarthritis Patients

Tramadol, a weak opioid agonist, is associated with less risk of addiction and respiratory depression than traditional opioids, and it is perceived to have a lower risk of serious cardiovascular adverse effects than nonsteroidal anti-inflammatory drugs. Accordingly, tramadol is often considered a reasonable option for the treatment of osteoarthritis. However, there is little top-level evidence about the cardiovascular safety profile of tramadol.

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In a large population-based retrospective study, Yuqing Zhang, DSc, director of Epidemiological and Biostatistical Methods at the Division of Rheumatology, Allergy and Immunology at Massachusetts General Hospital, and Jie Wei, PhD, research fellow, and colleagues found that the risk of incident myocardial infarction (MI) with tramadol was higher than that of naproxen and comparable to that of diclofenac and codeine, which have been associated with an increased risk of cardiovascular adverse effects. Their report appears in Osteoarthritis and Cartilage.

Study Methods

The research team drew on The Health Improvement Network (THIN), a database of electronic medical records on approximately 17 million patients from 770 general practices in the U.K.

Eligible participants were those ages 50 to 90 who had a diagnosis of osteoarthritis mentioned in their records between January 2000 and December 2016 and were not prescribed any of the study drugs within one year before study entry. Participants with a history of MI, cancer or opioid use disorder before the study entry were ineligible.

The researchers conducted three separate substudies on:

• 33,024 patients who started using tramadol during the study period compared with 33,024 patients who initiated naproxen
• 18,662 tramadol initiators compared with 18,662 diclofenac initiators
• 42,722 tramadol initiators compared with 42,722 codeine initiators

Within each substudy, the two groups were matched by age, sex, standard of living, body mass index, alcohol use, smoking status, site of osteoarthritis, duration of osteoarthritis, prior comorbidities, prior medication use and health care utilization during the past year.

Incident MI

The primary outcome of the study was MI (fatal or non-fatal) within the first six months after initiation of tramadol or the comparator:

Tramadol vs. naproxen

• Number of MI events: 4.8 vs. 2.8 per 1,000 person-years
• Rate difference: 1.9 per 1,000 person-years
• Hazard ratio: 1.68 (95% CI, 1.16–2.41)

Tramadol vs. diclofenac

• Number of MI events: 6.4 vs. 5.1 per 1,000 person-years
• Rate difference: 1.2 per 1,000 person-years
• Hazard ratio: 1.24 (95% CI, 0.84–1.82)

Tramadol vs. codeine

• Number of MI events: 6.1 vs. 5.0 per 1,000 person-years
• Rate difference: 1.1 per 1,000 person-years
• Hazard ratio: 1.23 (95% CI, 0.95–1.60)

The findings were independent of the major confounders and remained consistent in various sensitivity analyses.

Implications for Prescribing

Tramadol may not be as safe with respect to cardiovascular adverse effects as some perceive. Considering that MI is a leading cause of morbidity and mortality, clinicians should carefully consider the risk/benefit ratio before prescribing tramadol to patients with osteoarthritis.

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