In this population-based study, current use of opioids for chronic non-cancer pain among persons 60 or older was associated with a borderline significant 28% increase in fracture risk. Compared with persons not currently taking opioids, persons taking average daily doses of ≥50 mg/day were at twice the fracture risk (HR 2.00).
Although our finding of a 28% increased risk of fracture associated with opioid use did not reach statistical significance (p
0.06) the point estimate is consistent with findings from several other studies12,20
. A recent meta analysis based on six studies concluded that opioids were associated with a 1.38 (1.15, 1.66)) increased risk of fracture20
. The authors pointed out the need for additional large prospective studies that minimize selection bias and provide more accurate measures of fracture risk.
The current study was designed to address several limitations of prior research. In contrast to some prior studies that compared opioid users to non-users (e.g. persons who may never have used opioids)12,16
, the comparison (non-exposed) group in this study was persons who initiated and then discontinued use of prescribed opioids for chronic non-cancer pain. This comparison group was selected to control for selection bias, because patients receiving prescribed opioids for chronic non-cancer pain are likely to be different from those not prescribed opioids for chronic non-cancer pain. Other study features designed to improve evaluation of opioid risks included time-varying measures of opioid use based on comprehensive, high-quality automated data sources22
, validation of outcome (fractures) through medical record review, and control for potential confounders, including time-varying measures of other medications that may be linked to fracture risk12,27,28
The principal contribution of this study is estimation of time-varying average consumed daily dose based on timing of refills, number of pills and strength of pills in morphine equivalents derived from comprehensive, high quality automated data sources. Few studies have assessed the association of opioid dose with fracture risk among community practice patients. For example, the meta-analysis mentioned above lacked information about the association of fracture risk with opioid dose. In a study among employees included in a Medicare database, researchers found a dose response relationship between propoxyphene use of ≥260 mg /day (60 mg morphine equivalents) and hip fracture risk16
. A case-control study that assessed the association of fracture risk with the cumulative dose of specific opioids, rather than average daily dose, generally did not detect a dose-response effect11
. Other researchers, in the absence of high-quality computerized prescription data, have adopted proxy measures of dose including strength of the pill14
and daily versus less frequent use of opioids over two weeks12
. Based on a measure of average daily dose derived from high quality automated sources, we conclude that there is a clinically and statistically significant increase in fracture risk at doses of ≥50 mg /day MED.
What is less clear is the exact relationship between fracture risk and dose level. The formal test of dose response was borderline significant (p
0.06) and associations between the lower dose subgroups and fractures were not statistically significant. However, failure to reach statistical significance does not necessarily mean that low opioid doses are as safe as non-use. For example, the confidence interval indicates that fracture risk among persons using 20–50 mg of opioids per day could range from 10% lower to 100% greater than the fracture risk observed among persons not using opioids. Confidence intervals for both of the lower dosage categories reflect considerable uncertainty about the association of opioid use with fracture risk at these dosage levels, suggesting the need for analyses in larger cohorts than we were able to assemble in this study.
Several mechanisms have been suggested to explain the putative impact of opioids on fracture risk. Researchers have hypothesized that side effects of opioid use, such as dizziness, sedation, lightheadedness and nausea, increase the risk of falls, and consequently, fractures11,12
. Others, reporting an association between opioid use and reductions in bone mineral density, propose that opioids might interfere with bone formation through suppression of endogenous sex hormone production29
. Ensrud et al. suggested that opioids might directly affect neuromuscular function but acknowledged that such impairments could be caused by other characteristics associated with the opioid users in their study—e.g. a higher prevalence of comorbid medical conditions12
. Whatever the cause, our finding of a twofold increase in fracture risk associated with higher opioid doses has potential public health implications. A recent study estimated that 3% of older Americans used opioids regularly7
. Fractures in older adults are often sentinel health events resulting in long-term reductions in mobility and capacity for independent living30
. Indeed, more than one-third of fractures in this study resulted in hospitalization or other institutional care. One in ten study subjects taking 50 mg/day or more experienced a fracture in a year. Our results suggest that clinicians should consider fracture risk when deciding whether to initiate opioid therapy—particularly at higher dosage levels—in older adults.
Physicians face a dilemma when choosing medications for treating chronic pain among the elderly. The American Geriatrics Society recently recommended opioids as preferable to NSAIDs in the treatment of moderate-severe persistent pain in older adults31
. While there is no ideal pain medication for this sub-population, an appropriate clinical response to pain and suffering is needed32
. Decisions about medication selection and dose should consider each patient’s risk profile and preferences, along with available non-pharmacologic options for managing chronic pain. The results of the current study underscore the need for future research that evaluates how to reduce risks of potential adverse effects of sustained use of opioid medications, particularly at higher dosage levels.
This study has several significant limitations that need to be considered in interpreting results. As in any observational study, it is possible that residual confounding remains although we controlled for many potential confounding variables. Because of our reliance on automated data, we were not able to control for some potential confounders such as bone mineral density, gait, activities of daily living, frailty, family history of fracture, and pain severity. Measures of use and average daily dose were based on timing of refills determined by automated data, but we cannot definitely establish how patients used the medications. We were unable to examine whether the increased risk associated with higher dose opioids is due to how quickly opioid dosage levels were increased. Finally, our study may be subject to bias since only fractures brought to medical attention were included.
In conclusion, this study found that persons age 60 years and older who used opioids at dosages of ≥50 mg/day were at double the fracture risk compared to older persons who had discontinued opioid use. Clinicians should consider this risk when prescribing higher opioid dosage levels to older people. More research is needed to evaluate the association of opioid dose with fracture risk among older adults, and to determine whether enhanced monitoring, modifying opioid doses, and/or non-pharmacologic options for managing chronic pain might reduce fracture risk among older adults while affording pain control acceptable to patients.