Research presented at the recent American College of Rheumatology Annual Scientific Meeting examined whether a shift from nonopioid analgesics toward the use of opioids to treat arthritis pain in senior citizens also incurred an increase in falls and fractures. While, overall, there was a marked increase in the percentage of elderly patients who suffered a fall or fracture, a cause-effect relationship solely implicating opioid analgesics should not be inferred from this sort of research.
In the past, a number of analgesic alternatives, including selective COX-2 inhibitors, have been used to treat pain in the elderly. However, with the removal of rofecoxib from the market in 2004 and valdecoxib in 2005 — both due to adverse cardiovascular effects — and guidelines for treating chronic pain in the elderly from the American Geriatrics Society [AGS, document here], opioid analgesics have become important therapy for managing chronic pain in this population. Therefore, lead author Lydia Rolita, MD, of New York University School of Medicine, and her team conducted an investigation to determine whether prescriptions for opioid analgesics in elderly patients increased after rofecoxib/valdecoxib were taken off the market and if the incidence of falls/fractures changed in these patients as a result [Rolita et al. 2011].
For their study, records of all patients >65 years old with a diagnosis of osteoarthritis during 2001 to 2009 (N= >10,000) were extracted from the Geisinger Health System electronic medical records “data warehouse” for analysis. Diagnoses of falls and fractures were identified by ICD 9 codes, and 3 prescription analgesic groups were identified: (a) opioids with or without other analgesics, (b) COX-2 inhibitors alone or with other analgesics, and (c) NSAIDs and/or others. Additional factors analyzed included age, gender, and the Charlson Index Score of physical comorbidities.
The researchers found that, from 2002 to 2004, patients receiving opioid prescriptions increased from 8% to 20% of the study population and doubled again to 40% by 2009. COX-2 usage was low in this population, peaking at 8% in 2004 and declining during subsequent years. While almost all patients were receiving prescribed NSAIDs and/or other analgesics in 2002, this declined to about 70% by 2009.
Meanwhile, the incidence of falls/fractures increased from less than 1% of all study patients in 2001 to more than 3% in 2009 (figure at left, adapted from Rolita et al.). The researchers propose that this appears to be primarily associated with the increased use of opioid analgesics, as shown in the top line.
Across all groups, patients with falls were older (age 78.1±6.6 vs 73.8±6.3), and opioid-group patients with falls had higher Charlson Index Scores. The influence of age and comorbidities on falls was adjusted using conditional logistic regression; no-fall patients were matched 3:1 to fall patients according to age and Charlson Index Score at the time of fall.
In this adjusted analysis, falls risk increased with opioid use in both study periods (2001-2004 and 2005-2009). During 2005 to 2009, compared with COX-2 inhibitors, opioid use was associated with nearly a 4-fold increase in falls (Odds Ratio=3.7; 95% Confidence Interval, 2.6, 5.4; P<0.001). And, compared with NSAIDs/Other, opioid use incurred more than a 4-fold increase (OR=4.4; 95% CI, 3.9, 4.9; P<0.001). [Relative and absolute risks cannot be calculated from the data they provide.]
The authors conclude that, after rofecoxib/valdecoxib were taken off the market there was a marked increase in the prescription of opioid analgesics in the elderly population with osteoarthritis. Subsequently, falls and fractures increased sharply and all of the increase in falls were in patients prescribed opioid analgesics. They propose that these findings strongly indicate that recommendations of opioids for the treatment of chronic pain in the elderly, as in the AGS guidelines, should be re-evaluated; however, a closer look at their data is warranted.
COMMENTARY: It is important to note that this research is from a conference presentation and was not peer reviewed or officially published in more complete form, as yet. Cause-effect relationships of opioids and falls/fractures should be very cautiously inferred from data such as these. As we have recently noted for other trend-data [here], just because two factors appear to increase in unison does not necessarily mean one is directly affected by or causing the other.
In fact, buried within a retrospective, data-mining study such as this, there could be other, unknown, factors accounting for either (or both) increased opioid prescribing and falls/fractures. For one thing, we do not know the “background incidence rate” of falls/fractures; that is, the extent of these mishaps naturally occurring each year in the total population, including persons without chronic pain conditions. Clearly, from the figure above, there is an increased incidence among persons receiving analgesics; however, this may coincide with normally expected occurrences of these events in a growing and aging health system population.
Furthermore, it is interesting and important to observe in the figure above that falls/fractures associated with COX-2 inhibitors and “Other” analgesics (including NSAIDs) were increasing through the years, albeit somewhat eratically for coxibs, even as the prescribing of these agents was decreasing. So, although the researchers adjusted for age and comorbidity, these trends might suggest that there are other factors influencing falls/fractures besides or in addition to analgesic use.
We have previously reported [UPDATE here] on observational investigations of opioid use in the elderly and increased risks of adverse events, as compared with COX-2 inhibitors and NSAIDs. Among other potentially confounding factors, a history of falls/fractures was more common in opioid-prescribed patients, prior to their receiving opioids; therefore, based on history alone, it might be expected that falls/factures could be more prevalent in these patients. However, patient history of such adverse events was not reported in the study by Rolita et al.
Data-mining research, such as this present study, is a low level of evidence, but has the advantage of examining large reservoirs of patient data and high statistical power. However, even the largest “data warehouses,” like that of the Geisinger Health System, could have deficiencies that limit their external validity. For example, in this study we do not know what opioids were typically prescribed for elderly patients, their dosages or frequency, and the adjunctive use of over-the-counter analgesics. It may be that analgesic-prescribing practices in this particular healthcare system were in certain ways unique and/or suboptimal.
Other studies coming from Geisinger — a well-established physician-led healthcare system serving 43 counties and 2.6 million people in Pennsylvania — have reported some unusual outcomes that may not be typical of other healthcare organizations or the overall U.S. population. For example, in published research relying on the Geisinger database the authors reported a prevalence of addiction in a quarter [UDPATE here] to a third [abstract here] of patients with chronic noncancer pain being treated with opioid analgesics. However, there is no indication of why opioid-use problems were so highly prevalent, why they were not detected prior to prescribing opioids and, if detected, why these patients were not being treated for active opioid addiction.
Anyway, based on the conference presentation by Rolita and colleagues, it could be presumptuous to conclude that opioid analgesics are a sole or primary factor influencing falls/factures in elderly patients, or that the AGS guidelines are in error. In fact, unrelieved pain in these patients due to inadequate analgesia might be a greater precipitating influence on falls and attendant fractures or other morbidity.
Readers should be alert to the possibility that there may be biases against opioids reflected in reports of retrospective data that are potentially confounded by unmeasured or unknown variables. Which is not to dismiss the fact that there are still unanswered questions about optimal approaches for maximizing the safety and efficacy of opioid analgesics in clinical practice and the elderly in particular.
REFERENCE: Rolita L, Spegman A, Cronstein BN. Unintended Consequences; Increased Prescription of Opioid Analgesics for OA in the Elderly Is Associated with Increased Falls and Fractures in the Post-Vioxx Era. Presentation at American College of Rheumatology Annual Scientific Meeting, November 7, 2011, Chicago, IL. Presentation #911 [press release and abstract here].