Are Opioids More Harmful Than NSAIDs for Elderly Patients?
A pair of investigations recently published in the Archives of Internal Medicine report that elderly patients with chronic noncancer pain taking opioid analgesics have higher risks of serious adverse events (AEs) than those taking NSAIDs; plus, the opioids varied among themselves in AE potential.1,2 These studies appear to contradict current guidelines and caution against opioid use in these patients; however, a closer examination of the research evidence casts doubt on its validity and clinical relevance.
NSAIDs Not Recommended in the Elderly
Acute and chronic pain are prevalent conditions in older persons3 yet they are less likely to receive strong analgesics than younger individuals with comparable pain.4 Guidelines from the American Geriatrics Society (AGS) recommend that nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and the more selective COX-2 inhibitors should be rarely administered in older populations.5 Rather, the AGS proposes that all elderly patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life due to pain should be considered for opioid therapy.
The guidelines state, “… evidence that use of NSAIDs and COX-2 inhibitors may result in serious and life-threatening gastrointestinal and cardiovascular adverse events or gastrointestinal bleeding has shifted attention to opioids, especially for older patients who may be at particular risk for NSAID-related adverse effects.” AGS concerns regarding the potential harms of NSAIDs and COX-2 inhibitors have been confirmed by recent evidence.6-9
The Case Against Opioids
Therefore, it was surprising when the outcomes of 2 recent research investigations1,2 suggested that opioid analgesics are a poor choice for chronic noncancer pain in older adults, and are associated with more AEs than either NSAIDs or COX-2 inhibitors. Data for both studies were derived from medical records of Medicare beneficiaries in 2 states, Pennsylvania and New Jersey, diagnosed with conditions requiring prescribed analgesics. This provided a vast pool of subjects older than age 65 and, using computerized methods, the researchers were able to artificially generate large, well-matched cohorts of subjects in different treatment groups for a retrospective exploratory data analysis.
In the first report,1 researchers examined the comparative safety of NSAIDs, COX-2 inhibitors, and opioids during the period from 1999-2005 among 12,840 Medicare beneficiaries diagnosed with osteoarthritis (roughly 90% of subjects) or rheumatoid arthritis (10%), who were prescribed one of those 3 types of analgesics (4,280 subjects per group).
Overall, persons taking opioids experienced 68% higher rates of serious AEs. For example, the risk of fractures among opioid users was 5 times greater than with COX-2 inhibitors and 4 times greater than with NSAIDs. Opioids and COX-2 inhibitors appeared to be associated with greater cardiac risks than NSAIDs, and opioid use was associated with a higher incidence rate of hospitalization due to AEs and greater all-cause mortality than either COX-2 inhibitors or NSAIDs. Unexpectedly, opioids and NSAIDs exhibited equivalent incidence rates of gastrointestinal AEs, and these rates were nearly twice that of COX-2 inhibitors.
In the second report,2 the same research team focused on those Medicare beneficiaries who specifically received opioids for any type of noncancer pain between 1996 and 2005. They compared the rates of adverse events after 30 and 180 days among 31,375 patients taking either codeine, hydrocodone, oxycodone, propoxyphene, or tramadol (n=6,275 in each group). At 30 days after beginning opioid therapy the risks of gastrointestinal and cardiovascular AEs were similar across the 5 agents.
However, after 180 days, the risk of cardiovascular AEs was increased in those taking codeine. Using hydrocodone as the reference point, the researchers found that the risk of fracture was 79% lower in subjects taking tramadol and 46% lower with propoxyphene. In further comparisons with hydrocodone, hospitalization due to an opioid-related AE was greatest with codeine, and death from any cause was more than twice as likely among those taking codeine or oxycodone. Of interest, the observed risks for any opioid were not explained by the dosage levels being prescribed and, curiously, there actually were some decreases in relative risks at the highest opioid doses.
Findings of these 2 studies appear to provide new evidence supporting the relative safety of NSAIDs, contradicting other research and recommendations in this regard, while raising safety concerns about opioid analgesic therapy in older patients with nonmalignant pain conditions. Furthermore, the authors concede that the data “do not agree with a commonly held belief that all opioids are associated with similar risk.”2 Of particular concern were unexpectedly increased AE risks with codeine.
EBPM Perspectives Reveal Research Flaws
These 2 studies bode poorly for opioids and muddle recommendations for what is safest to prescribe for pain in elderly patients. However, upon closer examination from evidence-based pain management (EBPM) perspectives, this line of research is interesting but also may be misleading.
Retrospective exploratory studies of this sort have the advantage of tapping into vast reservoirs of data that lend robust statistical power to analyses. At the same time, however, the Medicare beneficiary database was not designed to answer the specific questions (hypotheses) asked by the researchers; so, the subsequent “data mining” process to extract seemingly pertinent information for drawing conclusions about subgroups raises questions of validity.10
The authors themselves concede that their research produced strong statistical associations of selected AEs with the opioid analgesics examined, but the data cannot be used to infer causation. They correctly acknowledge that prospective, randomized, controlled trials would be needed to more validly assess relative analgesic harms in the elderly, but this approach would be difficult and probably unethical.
There are a number of other reasons for questioning the validity, biases, and clinical relevance of the findings and conclusions: