Association of tramadol with all-cause mortality, cardiovascular diseases, venous thromboembolism, and hip fractures among patients with osteoarthritis: a population-based study

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Major adverse cardiovascular events and mortality with opioids versus NSAIDs initiation in patients with rheumatoid arthritis

“…As for VTE, although opioid use disorders were associated with increased VTE risk, particularly postoperatively,39 40 there is very limited data on VTE risk with prescription opioids. One recent study comparing tramadol with different NSAIDs in patients with osteoarthritis found an increased risk of VTE with tramadol against diclofenac and cyclo-oxygenase-2 inhibitors 41. Like ours, the VTE risk increase with opioids was higher against nsNSAIDs as diclofenac than cyclo-oxygenase-2 inhibitors.…”

Prevalence of Nonsteroidal Antiinflammatory Drugs Prescribed for Osteoarthritis: A Systematic Review and Meta‐Analysis of Observational Studies

“…We conducted a sensitivity analysis to explore heterogeneity related to risk of bias. When studies scored as having a high risk of bias were removed (n = 5 studies) (46–48,67,69), the pooled prescribing estimate remained similar (43.8% [95% CI 36.8, 51.1], n = 46 studies, high quality of evidence I 2 = 5.1%) (11,12,25,26,28–46,49–56,58–61,58–64,65,66,68,70–73) compared to the original estimate with high heterogeneity (43.1% [95% CI 36.3, 50.1], n = 51 studies, I 2 = 99.9%, low quality of evidence). A post hoc sensitivity analysis was conducted to explore the primary analyses using an alternative statistical approach (see Supplementary Figure 1, available on the Arthritis Care & Research website at https://doi.org/10.1002/acr.25157), which resulted in less conservative estimates than our original model.…”

“…The included studies were published between 1989 and 2022 and were all in English except 1 study published in Croatian (56). Studies were from 31 countries across the globe, including South Asia (n = 4 studies) (37,47,49,57), Middle East and North Africa (n = 1 study) (33), East Asia and Pacific (n = 10 studies) (12,25,32,38,40,51,53,58–60), Europe and Central Asia (n = 23 studies) (26–29,39,42,43,45,46,48,50,52,54–56,61–68), Latin America and Caribbean (n = 1 study) (44), and North America (n = 12 studies) (11,30,31,34–36,41,69–73). Most studies (90.2%) were from high‐income countries with 1 study from an upper‐middle income country (44), and 4 studies were from lower‐middle income countries (37,47,49,57).…”

“…Most studies (90.2%) were from high‐income countries with 1 study from an upper‐middle income country (44), and 4 studies were from lower‐middle income countries (37,47,49,57). Half the studies (52.9%) were from clinical settings, with 20 studies from primary care (26,28,29,34,39,42,46,48–50,52,54,55,58,60,64,65–68), 7 studies from tertiary care clinics (37,43,44,47,56,57,72), and 5 studies from multiple care (30,31,41,45,62); 18 studies (35%) provided prevalence data from a database (11,12,25,27,32,33,35,36,38,40,51,53,59,63,69–71,73), and 1 was a population‐based study (61). Characteristics of included studies are shown in Table 1.…”

Correction: Association of tramadol with all-cause mortality, cardiovascular diseases, venous thromboembolism, and hip fractures among patients with osteoarthritis: a population-based study

“…Upon publication of the original article [ 1 ], it was noticed that final sentence in the Abstract's Results section was incorrect. The correct sentence is: "No differences were observed between tramadol and codeine for all events."…”