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

Zeng, Chao; Dubreuil, Maureen; Larochelle, Marc R.; Lu, Na; Wei, Jie; Choi, Hyon K.; Lei, Guanghua; Zhang, Yuqing

doi:10.1001/jama.2019.1347

Cited by 163 publications

(190 citation statements)

References 42 publications

(91 reference statements)

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“…Increased mortality associated with prescriptions of opioids for chronic non‐cancer pain is one component of the North American opioid epidemic (Asbhurn & Fleisher, ). Prescription of tramadol for osteoarthritis pain in persons aged 50 years or more was associated with all‐cause mortality in an UK database of general practitioners between 2000 and 2015 (Zeng et al, ). In contrast, this systematic review found no increased mortality in the opioid group in the context of RCTs.…”

Section: Discussionmentioning

confidence: 99%

Opioids for chronic osteoarthritis pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks double‐blind duration

Welsch

Petzke

Klose

et al. 2020

European Journal of Pain

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Background and Objective This updated systematic review evaluated the efficacy and safety of opioids compared with placebo for chronic osteoarthritis pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to July 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences or standardized mean differences with 95% confidence intervals. We added two new studies with 397 participants for a total of 22 studies with 8,942 participants. Study duration ranged between 4 and 24 weeks. Studies with a parallel and cross‐over design: Based on very low– to low‐quality evidence, opioids provided no clinically relevant pain relief of 50% or greater and no clinically relevant reduction in disability compared with placebo. There was a clinically relevant harm related to the dropout rate due to adverse events. The frequency of serious adverse events did not differ from placebo. Enriched enrolment randomized withdrawal design: Based on very low– to low‐quality evidence, opioids provided no clinically relevant pain relief of 50% or greater and no clinically relevant reduction in disability compared with placebo. Dropout rates due to adverse events and frequency of serious adverse events did not differ from placebo. Conclusions Tolerability of opioids is low and efficacy is not clinically relevant in controlled studies from 4 to 24 weeks for osteoarthritis pain. Significance Within the context of randomized controlled trials (4–24 weeks), opioids provided no clinically relevant pain relief and no clinically relevant reduction in disability compared with placebo in chronic osteoarthritis pain (hip, knee). Number needed to treat for an additional dropout due to side effects was 5 (95% confidence interval 4–7). Two studies found no signals of abuse and addiction. The frequency of serious adverse events including deaths did not differ from placebo.

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Section: Discussionmentioning

confidence: 99%

Opioids for chronic osteoarthritis pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks double‐blind duration

Welsch

Petzke

Klose

et al. 2020

European Journal of Pain

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Section: Introductionmentioning

confidence: 99%

“…Tramadol, a commonly used weak opioid for the treatment of pain, has been considered an analgesic alternative, since its perceived risk of serious cardiovascular and gastrointestinal adverse effects was lower than that of nonsteroidal anti‐inflammatory drugs (NSAIDs), and its risk of addiction and respiratory depression was lower than that of traditional opioids . As a result, tramadol use has been increasing rapidly worldwide over the past decades . For example, data from Truven Health Analytics MarketScan in the United States showed that prescriptions of tramadol increased by 22.8% between 2012 and 2015, and tramadol dispensing rates increased in each of the provinces in Canada, with the highest in Nova Scotia increasing from 0.50/defined daily doses (DDD) in 2007 to 2.64/DDD in 2016 …”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, a recently published population‐based cohort study reported a significantly higher all‐cause mortality rate with tramadol use than with commonly used NSAIDs among patients with osteoarthritis; however, the specific mechanisms linking tramadol use to an increased risk of mortality remains unclear. To date, several studies have reported that tramadol use might increase the risk of falls (a strong risk factor for fracture), but only a few studies have addressed the potential relationship between tramadol use and the risk of fracture, and the results are inconclusive .…”

Section: Introductionmentioning

confidence: 99%

“…(3)(4)(5) Polypharmacy is common among elderly patients due to multiple comorbidities, and some medications may intensify the risk of fracture, either through their effect on increasing fall risk and/or through an effect on bone metabolism. (6)(7)(8)(9) Tramadol, a commonly used weak opioid for the treatment of pain, (10)(11)(12)(13)(14) has been considered an analgesic alternative, since its perceived risk of serious cardiovascular and gastrointestinal adverse effects was lower than that of nonsteroidal antiinflammatory drugs (NSAIDs), (15,16) and its risk of addiction and respiratory depression was lower than that of traditional opioids. (17,18) As a result, tramadol use has been increasing rapidly worldwide over the past decades.…”

Section: Introductionmentioning

confidence: 99%

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Association of Tramadol Use With Risk of Hip Fracture

Wei

Lane²,

Bolster

et al. 2020

Journal of Bone and Mineral Research

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Several professional organizations have recommended tramadol as one of the first‐line or second‐line therapies for patients with chronic noncancer pain and its prescription has been increasing rapidly worldwide; however, the safety profile of tramadol, such as risk of fracture, remains unclear. This study aimed to examine the association of tramadol with risk of hip fracture. Among individuals age 50 years or older without a history of hip fracture, cancer, or opioid use disorder in The Health Improvement Network (THIN) database in the United Kingdom general practice (2000–2017), five sequential propensity score–matched cohort studies were assembled, ie, participants who initiated tramadol or those who initiated one of the following medications: codeine (n = 146,956) (another commonly used weak opioid), naproxen (n = 115,109) or ibuprofen (n = 107,438) (commonly used nonselective nonsteroidal anti‐inflammatory drugs [NSAIDs]), celecoxib (n = 43,130), or etoricoxib (n = 27,689) (cyclooxygenase‐2 inhibitors). The outcome was incident hip fracture over 1 year. After propensity‐score matching, the included participants had a mean age of 65.7 years and 56.9% were women. During the 1‐year follow‐up, 518 hip fracture (3.7/1000 person‐years) occurred in the tramadol cohort and 401 (2.9/1000 person‐years) occurred in the codeine cohort. Compared with codeine, hazard ratio (HR) of hip fracture for tramadol was 1.28 (95% confidence interval [CI] 1.13 to 1.46). Risk of hip fracture was also higher in the tramadol cohort than in the naproxen (2.9/1000 person‐years for tramadol, 1.7/1000 person‐years for naproxen; HR = 1.69, 95% CI 1.41 to 2.03), ibuprofen (3.4/1000 person‐years for tramadol, 2.0/1000 person‐years for ibuprofen; HR = 1.65, 95% CI 1.39 to 1.96), celecoxib (3.4/1000 person‐years for tramadol, 1.8/1000 person‐years for celecoxib; HR = 1.85, 95% CI 1.40 to 2.44), or etoricoxib (2.9/1000 person‐years for tramadol, 1.5/1000 person‐years for etoricoxib; HR = 1.96, 95% CI 1.34 to 2.87) cohort. In this population‐based cohort study, the initiation of tramadol was associated with a higher risk of hip fracture than initiation of codeine and commonly used NSAIDs, suggesting a need to revisit several guidelines on tramadol use in clinical practice. © 2020 American Society for Bone and Mineral Research.

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Using Propensity Score Methods to Create Target Populations in Observational Clinical Research

Thomas

Pencina

2020

JAMA

121

125

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In a propensity score-matched cohort study published in the March 12, 2019, issue of JAMA, Zeng et al 1 found that prescription tramadol was associated with significantly greater 1-year mortality compared with nonsteroidal anti-inflammatory alternatives in adults with osteoarthritis. At baseline, patients receiving tramadol were different than those who received other analgesics in terms of demographics, medical comorbidities, medications, and prior hospital resource utilization. Zeng et al 1 used propensity score matching in an effort to account for differences between groups. 2 This matched sample corresponds to a unique target population. Explanation of the ConceptWhat Is a Target Population?

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

Cited by 163 publications

References 42 publications

Opioids for chronic osteoarthritis pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks double‐blind duration

Opioids for chronic osteoarthritis pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks double‐blind duration

Association of Tramadol Use With Risk of Hip Fracture

Using Propensity Score Methods to Create Target Populations in Observational Clinical Research

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