Saturday, March 24, 2012

Long-Term Analgesic Misuse After Short-Term Rx?

Acute Pain New research reports an alarmingly high likelihood of briefly prescribed analgesics — whether opioids or NSAIDs — following minor surgery in older persons leading to long-term dependence on these drugs. An implication is that the analgesics are potentially being misused; however, as much as anything, this study seems to portray a fallacy of scientific evidence called post hoc, ergo propter hoc, as well as other flaws that raise questions about its validity.

Writing in the March 12, 2012 issue of Archives of Internal Medicine, a research group from Ontario, Canada, reports on an investigation to determine whether newly prescribed (de novo) analgesics to elderly patients after relatively minor operations influenced the long-term use of those medications [Alam et al. 2012]. Their retrospective cohort study used a population-based administrative database spanning 1997 through 2008 to identify Ontario residents 66 years of age and older who were dispensed either an opioid analgesic or nonsteroidal anti-inflammatory drug (NSAID) within 7 days of a short-stay surgery (eg, cataract surgery, laparoscopic cholecystectomy, transurethral resection of the prostate, or varicose vein stripping).

The risk of long-term opioid use was defined as further prescription of an opioid or NSAID within 60 days of the 1-year anniversary of the surgery. Alam et al. used multivariate logistic regression to examine associations between postsurgical prescription of analgesics and long-term use, adjusting outcomes for such factors as age, sex, comorbidity, and socioeconomic status. Following are the results:

  • Among approximately 391,000 opioid-naïve patients undergoing short-stay surgery, opioids were newly prescribed to 28,000 of them (7.1%) within 7 days of being discharged from the hospital, and 2,850 (10.3%) of those patient were still receiving opioids at 1 year. In contrast, only 7.5% of patients not receiving opioids postsurgically were taking opioid medications at 1 year following surgery. Therefore, the researchers estimate there was a 44% greater likelihood of long-term opioid use at 1 year associated with postsurgical prescription (adjusted odds ratio [OR], 1.44; 95% Confidence Interval [CI], 1.39-1.50).

    Almost all patients receiving opioids following surgery (93.4%) were prescribed codeine, which decreased to 87.5% at 1 year. During this same timeframe, there was roughly a 3-fold increase in the use of oxycodone (from 5.4% within 7 days to 15.9% at 1 year), as well as smaller but multifold increases in the use of morphine, hydromorphone, and fentanyl patch.

  • In a second analysis, among approximately 383,000 NSAID-naïve patients undergoing short-stay surgery, NSAIDs were prescribed to 1,200 of them (0.3%) within 7 days of discharge, and 285, or 24%, of those patients continued to receive the medications at 1 year. In contrast, only 7.8% of all patients who had not received post-surgical NSAIDs were taking them at 1 year (30,000 of 383,000). Therefore, patients who began taking NSAIDs within 7 days of surgery were almost 4 times more likely to become long-term NSAID users compared with patients with no such prescription (adjusted OR, 3.74; 95% CI, 3.27-4.28). The specific NSAIDs prescribed were not discussed.

Alam and colleagues conclude that the prescription of analgesics immediately after ambulatory surgery occurs frequently in older adults and is associated with long-term use. In particular, they express concern that the initial prescription of low-potency opioids may contribute to the frequent later use of stronger opioids that have been shown to influence increased morbidity and mortality, as well as physical dependence and addiction.

COMMENTARY: The researchers’ novel finding that early postoperative analgesic prescription may influence long-term use was the subject of a press release from the journal and of great interest to the news media, which in typical fashion misconstrued the outcomes. One news story even featured the headline, “Older Patients More at Risk of Painkiller Addiction After Surgery” [article here].

In actuality, this study — supported by the Institute for Clinical Evaluative Sciences, which is funded by the Ontario Ministry of Health and Long-Term Care — does not convincingly demonstrate outcomes of major clinical significance from an evidence-based perspective. A common problem of data-mining research such as this is that there are many unmeasured variables, unknown factors, and unanswered questions that can distort results. Any assumption that being prescribed analgesics following minor surgery has a direct influence on continuing to take them 1 year later is most likely erroneous and exemplifies the common fallacy of association called post hoc, ergo proper hoc, or “after this, therefore because of this.”

This fallacy occurs when seemingly related events follow each other and it is wrongly presumed that the first event causes the second to occur. In this study, Alam et al. are proposing that the brief prescription of analgesics for acute postoperative pain often leads to their long term use, and potential dependence, but there is no evidence that there is a direct link between the two events — other explainations are just as likely. [Another example of this type of fallacy was described in an earlier UPDATE here.]

The researchers themselves concede that, “we do not know why analgesics were prescribed in both the early and late postoperative phases of our study.” Among other possibilities, they note, some patients might have had a poorly managed preexisting pain condition that improved with continued use of analgesics long after surgery. Additionally, they suggest, some patients having undermanaged acute postoperative pain can have a greater likelihood of developing chronic pain requiring prolonged analgesic therapy.

Alam and colleagues do not discuss the possibility of defective surgery leading to long-lasting, painful complications. Nor do they consider that many patients in this elderly population (mean age approximately 76 years) might have developed new pain disorders during the postsurgical year of observation that required analgesic therapy.

There are a few additional concerns with this research worth mentioning…

  1. Almost all patients receiving opioid analgesics — both postoperatively and later — were prescribed codeine, which the researchers acknowledge possesses “unpredictable pharmacokinetics and analgesic properties.” Furthermore, a Cochran Review of analgesics for acute pain found that codeine was ranked worst, at the very bottom in a long list of both opioid and NSAID agents [described in UPDATE here]; so, a first concern of this new research by Alam et al. might have been to examine why such an ineffective analgesic was being used so extensively in these patients and whether ineffective acute analgesia may foster longer-term pain.

  2. The researchers express concern that “many individuals prescribed low-potency opioids had transitioned to more potent opioids, such as oxycodone, within 1 year of the surgery.” An implication is that this represented some sort of medication misuse, abuse, or even addiction. However, no data were available to confirm this and it is just as likely that reasons for strong opioid use at 1 year were entirely unrelated to what patients were prescribed following surgery.

  3. The 1.44 odds ratio portraying the greater opioid use at 1 year among patients prescribed those agents postoperatively actually represents a small effect size that, while statistically significant (as indicated by the confidence interval), may not be clinically important. Of much greater concern is the robust 4-fold relative increase with NSAIDs (OR=3.74), with their risks of gastrointestinal and cardiac complications, particularly in an older population. A recent list from the American Geriatrics Society specifically warned against the use of NSAIDs in seniors, favoring opioids instead [see UPDATE here].

    This is of special importance because the researchers say they specifically focused on elders due to greater risks of adverse reactions to pain medicines in this group. However, they do not discuss concerns about NSAID use, even while admitting that their data did not capture over-the-counter NSAID use either perioperatively or at 1 year; so, the full extent of exposure to these agents might be understated in their research.

In sum, the message of this research is confusing at best and misleading at worst. It tells us nothing about why analgesics might have been used long-term to a greater extent among persons receiving them postoperatively, and there is probably no cause-effect relationship in that regard whatsoever. The focus on risks of opioid analgesics, while glancing over the substantive harms of NSAIDs in this population, displays a significant lack of fair balance.

This article was published as part of a “Less is More” series by the Archives of Internal Medicine, and the editors apparently believed it portrayed newly discovered risks of opioid analgesics. In this regard, an editor of the journal states, “We believe that when it comes to opioid administration for minor surgery, among older persons, less is more” [Editor’s note, MH Katz, p. 430, here]. Nothing is mentioned about NSAID risks.

It would be good if the editors could revisit the article and reassess the evidence with more open minds and less biased perspectives. What they actually might want to focus on when it comes to any type of analgesia is not less being more, but “How much is truly enough?”

REFERENCE: Alam A, Gomes T, Zheng H, et al. Long-term Analgesic Use After Low-Risk Surgery: A Retrospective Cohort Study. Arch Intern Med. 2012;172:425-430: [abstract here].

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