Friday, April 15, 2011

NSAIDs, Opioids, & Fracture Risk in the Elderly

Palliative New research concludes that older persons with painful arthritis who initiate analgesic therapy with opioids are more likely to experience a bone fracture than those taking NSAIDs. However, this is yet another study that goes against established evidence-based guidelines regarding analgesia in the elderly, and there are many flaws and methodological biases that are worthy of close inspection.

Writing in the March 2011 edition of the Journal of the American Geriatrics Society (JAGS), researchers conducted a retrospective cohort study to examine the relative risks of fracture associated with starting opioid analgesics compared with nonsteroidal anti-inflammatory drugs (NSAIDs) in elderly patients [Miller et al. 2011]. Searching data spanning 8 years (1/1/99 – 12/31/06) from 2 statewide pharmaceutical benefit programs, 12,436 initiators of opioids and 4,874 initiators of NSAIDs were identified; mean age of all subjects was 81, 85% were female, and all had osteoarthritis. The primary outcome of interest was fracture of the hip, humerus or ulna, or wrist.

There were 587 fracture events among the participants initiating opioids (120/1,000 person-years) and 38 among those initiating NSAIDs (25/1,000 person-years). Fracture risk was greater with higher opioid doses, and for short-acting rather than long-acting opioids, even in participants taking equianalgesic doses of long- vs short-acting agents. The authors conclude that older persons with arthritis who initiate analgesic therapy with opioids are more likely to experience a bone fracture than those who initiate NSAIDs.

COMMENTARY: This research is the latest to favor NSAIDs over opioid analgesia in the elderly, even though evidence-based guidelines from the American Geriatrics Society (AGS) caution against the use of NSAIDs and COX-2 selective inhibitors in this population. In a previous UPDATE [here] and subsequent journal article [here] we described a pair of investigations claiming that elderly patients taking opioid analgesics had higher risks of serious adverse events (AEs) compared with those taking NSAIDs or coxibs, and the opioids varied among themselves in AE potential.

However, those two studies were seriously flawed by a data-mining approach that was biased by numerous confounding factors and unmeasured variables that unduly slanted outcomes against opioid analgesics. This current investigation in JAGS has similar flaws, which have been assessed by Eric Widera, MD, [here] in the blog GeriPal (Geriatrics and Palliative care). Widera is Assistant Professor of Medicine, Department of Medicine, Division of Geriatrics, University of California, San Francisco, and GeriPal [here] is an excellent resource for professionals in the pain field. Widera describes several important concerns with the JAGS study…

  1. The most common opioid initiated in the study was propoxyphene (45% of cases), followed by hydrocodone (31%), oxycodone (20%), codeine (3%), and fentanyl (2%). As Widera notes, “Propoxyphene is a very bad actor as it is metabolized to a toxic compound – norpropoxyphene. It can cause seizures and cardiotoxicity. The FDA also has recently removed propoxyphene from the market. It does make you think that this study is more a study of poor opioid selection considering 45% of patients in this study were taking this drug.”

  2. Secondly, he observes that the NSAID and opioid groups were very different. “Opioid initiators were more likely to be taking benzodiazepines, antidepressants, PPIs [proton pump inhibitors], steroids, thiazides, and osteoporosis medications,” he notes. Those on opioids also were more likely to have previously fallen and to have been sicker patients — eg, to have taken more medications, made more outpatient visits, have more frequently hospitalizations, more likely to have renal impairment, and to have higher comorbidity scores.

    The study authors made statistical adjustments for a long list of potentially confounding factors; however, “it does make you think what else was different about these populations that may have made the NSAID group look better,” Widera observes. For instance, level of pain and functional impairment due to arthritis were unaccounted for as confounders and these are critically important when it comes to risks of falls and fractures.

  3. Finally, to evaluate possible effects of opioid dose and to control for such doses in the analyses, all opioid use was converted to milligram equivalents of codeine. The dose distribution was divided into three categories — 0–75; 76–225; and >225 mg equivalents of codeine per day — based on the initial prescription. “I guess I'm confused on who would start an elderly patient who has not taken any opioids in the last 6 months on >225 mg of oral codeine equivalents a day (that's greater than 37 mg of oral morphine a day),” Widera says. “Is the problem here an issue with study design, or more that when physicians don’t know how to dose opioids, patients are likely to fall and fracture?”

In our opinion, studies like this are of interest, but mainly because they illustrate flaws in research designs intended to “stack the deck” as it were against opioids and perpetuate misunderstandings about opioid prescribing in elderly patients. As with the prior studies we had critiqued, the opioid-initiating patients in the JAGS study were sicker than those starting NSAIDs and had a prior history of falls. In some cases, a problem with opioids might be that they work too well; that is, elderly patients with debilitating chronic pain may achieve better analgesia with opioids, allowing them to become much more active and, hence, more prone to falls and broken bones. On the other hand, sicker patients, including those with renal impairment and taking comedications — as was evident in the opioid group — may have problems with metabolism, incurring opioid overmedication that could foster falls.

Widera concludes: “Will this study change my practice? It does give me some pause when prescribing opioids in the elderly. There is a very plausible link to falls and fractures, and we should all be more careful in the elderly. …. This study though should not be taken as an endorsement for NSAIDs. The numerous other adverse drug reactions of NSAIDs are not evaluated in this study and should not be under-emphasized.”

REFERENCE: Miller M, Stürmer T, Azrael D, et al. Opioid Analgesics and the Risk of Fractures in Older Adults with Arthritis. J Amer Geriatrics Soc. 2011(Mar);59(3):430-438 [abstract here].