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T he dramatic increase in use of prescription opioids to treat chronic pain and the subsequent rise in opioid-related overdose and death have become a major focus of public health efforts at the state and national levels. Between 2001 and 2014, the rate of deaths related to prescription opioids rose from 1.9 to 5.9 per 100,000. In response, the CDC has taken the unusual step of proposing clinical guidelines for prescribing opioids to treat chronic pain. On February 2, 2016, President Obama proposed additional funding of 1.1 billion dollars to address prescription opioid and heroin abuse. The problems of prescription opioid overdose and abuse are real and critically important to address. At the same time, the risk of overdose is concentrated among a relatively small proportion of patients who consume high doses (> 100 mg morphine equivalents per day), or who are at high-risk for other reasons (e.g., patients with substance use disorders). The top 10 % of patients taking opioids account for > 60 % of all opioids consumed in the United States. In contrast to growing evidence of a dose–response relationship between opioid consumption and overdose risk, we know relatively little about other risks of long-term opioid use, including risks that are clinically important for the majority of patients on opioids, who are taking low doses of these medications. Falls and fractures are particularly important potential risks because they are major contributors to disability and death among older adults. Older patients with osteoarthritis pain and contraindications to nonsteroidal anti-inflammatory drugs are a clinical population who are at risk for falls and for whom low-dose opioids may sometimes be a reasonable treatment option. The article by Krebs et al. published in this issue of JGIM is a welcome addition to the literature characterizing associations between opioid use and risk of fall or fracture. The authors performed a secondary analysis of data from the Osteoporotic Fractures in Men Study (MrOS), a multisite cohort study that enrolled 5994 ambulatory, community-dwelling men aged 65 years or older between 2000 and 2002. Detailed clinical measures related to pain, bone density, health, and functional status were obtained from participants during one baseline and two subsequent clinic visits over a mean follow-up period of 4.5 years. The primary outcomes of interest, participantreported falls and fracture events, were assessed every 4 months; fractures were confirmed radiographically. The authors analyzed a subset of 2902 patients who reported persistent back, knee, or hip pain at baseline, in order to test their hypothesis that opioid use (defined as taking opioid analgesics daily or near daily) would be associated with increased risk of falls and incident fractures. In their primary analysis, the authors found that, compared to no opioid use, daily or near daily opioid use was not associated with a statistically significant increased risk of either fall (RR 1.10; 95 % CI 0.99-1.24, p=0.08) or incident fracture (HR 1.13, 95 % CI 0.94 -1.36. p=0.07). In secondary analyses, they found no significant difference between these two groups in rates of either hip fracture or decline in physical performance over time. The authors concluded that additional data and research are needed to determine whether opioid use is associated with risk of falls, fractures, and functional impairment among older adults suffering from musculoskeletal pain. The parent study was restricted to men, so these findings do not provide information about the association between opioid use and risk of falls or fractures among older women. This study has several notable strengths. The parent study followed a large number of older men for up to 9 years and had remarkably complete follow-up data. Participants provided detailed clinical information that cannot be obtained from administrative records. The primary outcomes were prospectively and rigorously measured. This study is also one of the few to examine associations between opioid use and falls, which, unlike fractures, do not reliably result in patients seeking formal medical care. The authors’ statistical analyses were rigorous and made efficient use of the parent study’s repeated-measures design. They analyzed opioid use, falls, and even propensity scores as time-varying factors to account for participants whose selfreported opioid use changed during the study. Their results also show the utility of using propensity scores to adjust for differences inmeasured confounders when attempting tomake causal inference from observational data. Participants who reported opioid use at baseline differed substantially from those who did not in several respects: they were less likely to report good or excellent health, were frailer, and were more likely to report back pain. Propensity score techniques attempt to account for these differences and are most useful for studies such as this one that include detailed clinical information on all Published online March 7, 2016

Evaluating the Risks of Opioid Use for Chronic Pain: Moving Beyond Overdose