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8 Articles in Volume 11, Issue #2
Preventive Therapies for Cluster Headaches
The Pain of Multiple Sclerosis: Is it Real and Is it Treatable?
Antidepressants in the Treatment of Chronic Pain
Genetic Screening for Defects in Opioid Metabolism: Historical Characteristics and Blood Levels
Post-operative Patient-controlled Analgesia in Pediatric Patients
Pharmacogenetics in Pain Care: Consideration of Economic Impediments and Ethical Imperatives
Are Opioids More Harmful Than NSAIDs for Elderly Patients?
How Genetics Can Complicate Pain Treatment

Are Opioids More Harmful Than NSAIDs for Elderly Patients?

Pain Treatment Topics and Opioids 911-Safety are supported in part by medical education grants from Purdue Pharma L.P. and Endo Pharmaceuticals, manufacturers of analgesic products. Neither organization had any role in the initiation or development of this article.

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:

  • The cohorts in both studies (8 groups in all) were well-matched; however, all subjects were roughly 80 years of age on average, predominantly female (generally over 80%), and white race (87%-92%). A majority of subjects in each group also had pre-existing cardiovascular disease (hypertension in 59% to 71%). Furthermore, the subjects were drawn from a limited geographic area—two adjacent eastern states. Therefore, it is doubtful that these groups are representative of elderly patients across the U.S. or in most clinical practices.
  • In both studies, data was unavailable regarding critical variables for inclusion in the analyses, such as: concurrent over-the-counter (OTC) analgesic or other medication use, body mass index, alcohol and/or tobacco use, pain levels and functional status of the subjects, or cause of death in the mortality cases. Any of these could be confounding factors that may not have been equally distributed across groups and, thereby, biased the results—a deficiency that the report authors duly acknowledge.
  • In the case of opioids, the authors further concede that “sicker patients”—having worse pain for longer periods of time—may have been selectively prescribed the stronger analgesics. This greater morbidity itself may have contributed to increased risks for AEs.
  • Furthermore, a companion editorial to the articles11 observes that is it highly likely that many subjects in the opioid groups also were taking OTC NSAIDs, since these are often recommended to some extent along with opioids; hence, the opioid cohort was essentially “contaminated” in the study comparing opioids with NSAIDs and COX-2 inhibitors, and this may have been an unknown confounding factor across opioid groups in the second study as well.
  • Even known factors may have been unevenly distributed across groups and inadequately controlled. For example, in the first study, the authors observe that a history of falls and fractures was more common in persons prescribed opioids than among those taking COX-2 inhibitors or NSAIDs. Therefore, based on history alone, it might be expected that falls/factures would be more prevalent in the opioid-using group—which, indeed, was reflected in the data.
  • The editorial authors raise the further question of biologic plausibility when considering differential effects of opioids on AEs.11 For example, there is no known unique biologic effect of codeine that would account for increased cardiotoxicity, as was found in the second study. On the other hand, propoxyphene products were recently removed from the U.S. market due to cardiac concerns; however, it is interesting to observe that the incidence rates of cardiovascular AEs with propoxyphene were not remarkably different from the other opioids examined.2
  • Neither of the investigations present normative data; that is, how would findings in the study groups compare with a similar cohort of patients who were not taking any opioids, NSAIDs, or coxibs during the time periods in question? While locating an “analgesic-free” group of elderly patients might be difficult, without such comparisons it is unknown if the use of certain analgesics might actually reduce incidences of certain morbidity or mortality that normally occur in elderly patients.

In sum, the findings and conclusions presented in these 2 studies appear to be unhelpful for healthcare providers or their elderly patients in determining which type of analgesic might be the safest choice for chronic noncancer pain. Additionally, there may have been an unintended bias against opioids reflected by data that were confounded by unmeasured variables. While there are still unanswered questions about optimal approaches for minimizing opioid-analgesic safety risks in elderly patients, it seems unfounded at present that NSAIDs or coxibs would be safer or more effective alternatives; therefore, the AGS guidelines still have merit.

Last updated on: March 7, 2011
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