Opioids for nonmalignant pain have different adverse event profiles

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Adverse events among older adults using opioids for nonmalignant pain vary significantly by agent, contrary to the commonly held belief that all opioids are associated with a similar risk, a study found.

Researchers devised a propensity-matched cohort analysis that used health care utilization data collected from the years 1996 to 2005 among Medicare beneficiaries from Pennsylvania and New Jersey who started opioid therapy for nonmalignant pain. The five studied opioids were codeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride and tramadol hydrochloride. No patients had a cancer diagnosis, and none were using hospice or nursing home care.

Main outcome measures were incidence rates and rate ratios (RRs) with 95% CIs for cardiovascular events, fractures, gastrointestinal events, and several composite end points. Results appeared in the Dec. 13/27 Archives of Internal Medicine alongside a study derived from the same population and done by many of the same authors. (See the previous story, “For arthritis, opioids present increased relative risk compared to NSAIDs.”)

In the study, 143,482 (26.5%) potentially eligible subjects were available for matching. The study looked at 6,275 subjects in each of the five opioid groups. Their mean age was 79 years; 80.9% were women; 91.0% were white.

Researchers looked at fractures (including hip, pelvis, wrist, and humerus fractures, but not spine fractures), cardiovascular events (myocardial infarction, stroke, heart failure, revascularization and out-of-hospital cardiac death) and gastrointestinal bleeding or bowel obstruction.

Results showed that the risk of cardiovascular events was elevated for codeine (RR, 1.62; 95% CI, 1.27 to 2.06) after 180 days. Compared with hydrocodone, after 30 days of opioid exposure, the risk of fracture was significantly reduced for tramadol (RR, 0.21; 95% CI, 0.16 to 0.28) and propoxyphene (RR, 0.54; 95% CI, 0.44 to 0.66) users. Gastrointestinal safety events did not differ across opioid groups. All-cause mortality was elevated after 30 days for oxycodone (RR, 2.43; 95% CI, 1.47 to 4.00) and codeine (RR, 2.05; 95% CI, 1.22 to 3.45) users compared with hydrocodone users.

Limitations include that the study analyzed typical, nonrandomized practice data, leading to potential residual confounding, and the study was unable to assess causality. Secondly, the study database consisted of health care and pharmacy data without corroboration from death certificates, or other details such as pain levels, functional status, aspirin or tobacco use, or over-the-counter medication use. Third, the study occurred among older, low-income adults, limiting generalizability, and fourth, the study looked at a limited number of events in several outcome-exposure relationships, limiting the ability to prove the safety of an opioid for a specific outcome.

Editorialists commented that there is now a need to re-examine the widespread use of codeine. “If codeine is of middling efficacy for pain and is more risky than other opioids, there would be little reason to use it. ... [T]his large observational study revealing a previously unknown risk makes further research imperative,” they wrote.

Also, the editorial said, elevated fracture risk with opioid use is suspected from increased fall risk and the drugs' effects on bone metabolism. Starting opioids at low doses, monitoring for side effects, and avoiding polypharmacy have been used to prevent adverse events. But, said the editorial, “[T]hese studies strongly suggest that implementation of these basic safety measures is suboptimal for patients taking opioids.”