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Association of Tramadol With All-Cause Mortality, Cardiovascular Diseases, Venous Thromboembolism, and Hip Fractures Among Patients With Osteoarthritis
The use of tramadol among osteoarthritis (OA) patients has been increasing rapidly around the world, but population-based studies on its safety profile among OA patients are scarce. We sought to determine if tramadol use in OA patients is associated with increased risks of all-cause mortality, cardiovascular diseases (CVD), venous thromboembolism (VTE), and hip fractures compared with commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) or codeine.
Using administrative health datasets from British Columbia, Canada, we conducted a sequential propensity score-matched cohort study among all OA patients between 2005 and 2013. The tramadol cohort (i.e., tramadol initiation) was matched with four comparator cohorts (i.e., initiation of naproxen, diclofenac, cyclooxygenase-2 [Cox-2] inhibitors, or codeine). Outcomes are all-cause mortality, first-ever CVD, VTE, and hip fractures within the year after the treatment initiation. Patients were followed until they either experienced an event, left the province, or the 1-year follow-up period ended, whichever occurred first. Cox proportional hazard models were used to estimate hazard ratios after adjusting for competing risk of death.
Overall, 100,358 OA patients were included (mean age: 68 years, 63% females). All-cause mortality was higher for tramadol compared to NSAIDs with rate differences (RDs/1000 person-years, 95% CI) ranging from 3.3 (0.0-6.7) to 8.1 (4.9-11.4) and hazard ratios (HRs, 95% CI) ranging from 1.2 (1.0-1.4) to 1.5 (1.3-1.8). For CVD, no differences were observed between tramadol and NSAIDs. Tramadol had a higher risk of VTE compared to diclofenac, with RD/1000 person-years (95% CI) of 2.2 (0.7-3.7) and HR (95% CI) of 1.7 (1.3-2.2). Tramadol also had a higher risk of hip fractures compared to diclofenac and Cox-2 inhibitors with RDs/1000 person-years (95% CI) of 1.9 (0.4-3.4) and 1.7 (0.2-3.3), respectively, and HRs (95% CI) of 1.6 (1.2-2.0) and 1.4 (1.1-1.9), respectively. No differences were observed between tramadol and NSAIDs for all events.
OA patients initiating tramadol have an increased risk of mortality, VTE, and hip fractures within 1 year compared with commonly prescribed NSAIDs, but not with codeine.
Disclosure statements are available on the authors' profiles:
Association of Tramadol With All-Cause Mortality, Cardiovascular Diseases, Venous Thromboembolism, and Hip Fractures Among Patients With Osteoarthritis: a Population-Based StudyArthritis Res. Ther. 2022 Apr 11;24(1)85, L Li, S Marozoff, N Lu, H Xie, JA Kopec, J Cibere, JM Esdaile, JA Aviña-Zubieta
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Tramadol is an analgesic that has had a mixed journey since it was first introduced, with great hope as a non-controlled medication in 1995. It earned this designation due to its actions as a partial opioid agonist (versus full agonists such as morphine or oxycodone). Unfortunately, tramadol was noted to have an abuse potential and in 2014 was reclassified as a schedule IV controlled substance. Over time other concerns have been surfacing, including that early use of tramadol (such as in the post-op setting) may lead to a subsequent higher likelihood of long-term opioid use in comparison with other short-acting opioids and a higher likelihood of seizures and serotonin syndrome potentially related to tramadol’s central actions.1,2
Regardless, tramadol has continued to hold a place for some clinicians for difficult-to-treat arthritis where NSAIDs were not adequately managing the pain. Unfortunately, this perception has also been tarnished due to recent reviews that have noted no additional pain relief versus NSAIDs.3,4 In addition, there have been reports of higher adverse effects in patients with arthritis where tramadol is often utilized to reduce NSAID over-reliance or reduce the initiation of stronger opioids.
Although these reports have been increasing, population-based studies have been lacking. To address this, Canadian researchers examined administrative health datasets from British Columbia for all patients with osteoarthritis (OA) between 2005 and 2013, which resulted in a large group of 100,358 patients (mean age, 68 years; 63% females). Within this group, the cohort using tramadol was compared with those using NSAIDs and codeine.
Over 1 year of follow-up, compared with commonly prescribed NSAIDs, the initiation of tramadol was associated with a higher risk of:
These differences were not observed between the tramadol and codeine cohorts. In addition, no differences in cardiovascular disease outcomes were noted between patients who used tramadol and those who used NSAIDs, which are already well-established to increase these outcomes.5
The authors posed several potential mechanisms for the increased risk with tramadol, including:6
The authors conclude that “OA patients initiating tramadol have an increased risk of mortality, VTE, and hip fractures within 1 year compared with commonly prescribed NSAIDs, but not with codeine.” Further, they argue that, although more analysis is required, “the accumulation of evidence of the risks associated with tramadol use suggests that current guidelines regarding tramadol use in clinical practice might need to be revisited.”
Several limitations are present with population-based trials. This study attempted to overcome this by capturing a more complete picture of medication use through the incorporation of a large national database. In addition, there is the potential confounding that patients already at a higher risk due to more severe OA or contraindication for NSAIDs were mainly receiving tramadol. This limitation was overcome by the authors attempting to adjust for variables that are associated with OA pain (ie, OA duration and comorbidities).
Tramadol continues to demonstrate higher risk in multiple areas than originally thought. Until recommendations are updated, these findings in OA populations should give clinicians pause when considering pharmacotherapy. As with other analgesics, and in line with recent recommendations, this news provides greater motivation to discuss and incorporate non-pharmacological options to the best of our abilities for our patients with OA, especially those who may be at an increased risk for the adverse events noted in this trial.