Tramadol Linked to Increased Hip Fracture Risk in Older Adults

Nancy Melville

February 11, 2020

Older patients treated with the pain medication tramadol show significant increases in the risk of hip fracture compared with those using codeine or commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), new research shows.

"Considering the significant impact of hip fracture on morbidity, mortality, and healthcare cost, our results point to the need to consider tramadol's associated risk of fracture in clinical practice and treatment guidelines," first author Jie Wei, PhD, an associate professor of epidemiology at Xiangya Hospital, Central South University, China, told Medscape Medical News.

In commenting on the research, Shailendra Singh, MD, noted that the "article clearly reinforces [prior] knowledge…that opiates are associated with an increased risk of falls and fractures."

The American Geriatric Society BEERS criteria for inappropriate drugs for the elderly, for instance, lists tramadol and opiates as drugs to avoid in patients with increased risk of falls and fractures, added Singh, who is rheumatology medical director of the White River Medical Center in Batesville, Arkansas, and was not involved with the current study.

Increased Risk of Hip Fracture With Tramadol Even Compared With Codeine  

The new study, published this month in the Journal of Bone and Mineral Research, involved data on 146,956 patients in the United Kingdom who were age 50 years and older and enrolled in The Health Improvement Network (THIN).

The patients had initiated treatment with tramadol between 2000 and 2017 for noncancer-related pain, and had no history of hip fracture, cancer, or opioid use disorder.

In the propensity-matching analysis, those initiating tramadol were matched 1:1 with well-balanced characteristics to patients identified as initiating codeine during the same period (146,956 in each group).

Equal-numbered groups were also matched between tramadol and naproxen (115,109 in each group) or ibuprofen (107,438 per group), both NSAIDs, or celecoxib (43,130 per group) or etoricoxib (27,689 per group), which are both cyclooxygenase‐2 inhibitors.

Participants in the matched groups had a mean age of 65 and 56.9% were women.

For the primary outcome of the incidence of hip fracture over 1 year, the risk was higher for tramadol compared with codeine (hazard ratio [HR], 1.28), with 518 cases of hip fracture (3.7 per 1000 person-years) in the tramadol cohort and 401 (2.9 per 1000 person-years) in the codeine cohort.

Likewise, the risk was higher with tramadol compared with naproxen (HR, 1.69), ibuprofen (HR, 1.65), celecoxib (HR, 1.85), and etoricoxib (HR, 1.96).

A sensitivity analysis restricted to individuals aged 60 or older showed no major differences in the associations for all of the drug groups.

"The sensitivity analyses had similar results, indicating that the observed associations were robust and raising a concern on the potential risk of hip fracture among initiators of tramadol use," the authors say.

The increased risk compared with the initiation of codeine is particularly notable, as codeine is regarded as a weak opioid and often used in a similar context as tramadol, Wei noted.

"The risk of incident hip fracture among tramadol initiators was not only higher than that among NSAIDs initiators, but also higher than that among codeine initiators, suggesting that the confounding by indication may not substantially account for an increased risk of hip fracture for tramadol," she observed.

She added that "this was further supported by the evidence that risk factor profiles between initial prescription of tramadol and that of codeine were similar even before propensity-matching, except a few (for instance BMI was higher among tramadol than codeine prescriptions)."

"Nevertheless, as in all observational studies, we can't rule out the impact of potential residual confounders when comparing the risk of hip fracture between initial prescription of tramadol and other pain-relief medications," Wei stressed.

Tramadol Seen as Beneficial NSAID Alternative for Pain

Tramadol is seen as a valuable analgesic alternative to NSAIDs, with perceived lower cardiovascular and gastrointestinal effects while providing a reduced risk of addiction and respiratory depression compared with traditional opioids, the authors note.

Guidelines of professional organizations recommend tramadol for pain under various conditions, including the most recent guidelines of the American College of Rheumatology (ACR), which conditionally recommend tramadol for the treatment of knee or hip osteoarthritis, "including when patients may have contraindications to NSAIDs, find other therapies ineffective, or have no available surgical options."

Use of the drug has been on the rise worldwide in recent decades, with one survey showing a 22.8% increase in tramadol prescriptions in the US from 2012 to 2015.

The authors note that important limitations of the study include the fact that the THIN database does not include measures on two potentially important confounders — bone density and frailty.

Singh said it's unknown whether propensity score matching can adjust for important factors, such as the severity of disease: "(For instance), people with severe osteoporosis are at a higher risk of fracture, compared to moderate…the lower the T-score, the higher the risk of fracture."

Link Between Increased Risk of Falls and Tramadol?
Don't Prescribe It First-Line

As reported by Medscape Medical News, Wei and her colleagues showed an association between tramadol use and a higher risk of all-cause mortality among patients in the THIN network in a study published last year.

The specific mechanisms linking tramadol use to an increased risk of mortality remain unclear, however.

And that study, which — as opposed to the current one — was limited to patients with osteoarthritis pain, showed the increased mortality risk did not extend to those treated with codeine.

Although the mechanisms that may explain the increased risk of fracture are not known, Wei and colleagues note previous research suggesting an effect of tramadol in activating mu-opioid receptors while suppressing central serotonin and norepinephrine reuptake, which can be linked to the risk of seizures, dizziness, and/or delirium — all of which could increase the risk of fall.

"In fact, several studies have reported that tramadol use was indeed associated with a higher risk of fall, which is a critical risk factor for fracture," they note.

"All these studies appear to suggest that relation of tramadol to the risk of hip fracture may be, at least partly, through its effect on fall," they surmise.

"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."

Singh agrees. While underscoring that further studies are needed to determine the mechanism of action in the increased hip fracture risk, he concluded that "opiates of any kind, including tramadol, should not be used as a first line drug for pain management in any setting."

The study was supported by the National Institutes of Health, the National Natural Science Foundation of China, and the Postdoctoral Science Foundation of Central South University. The authors and Singh have disclosed no relevant financial relationships.

Journal of Bone and Mineral Research. Published February 5, 2020. Abstract

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