Friday, April 20, 2012

Opium, Opioids & Death: Sophistry vs Science

Editor's Notebook What are we to think of an editorial in this week’s edition of the British Medical Journal with the pithy title, “Opium, Opioids, and an Increased Risk of Death?” The author compares Middle-Eastern opium addicts with patients who have chronic noncancer pain and are prescribed opioid analgesics, claiming that both groups face similarly increased risks of death from their drug use. More than anything, this perspective is a remarkable display of wrong-headed reasoning, or sophistry, found too often in the pain literature these days.

The Demise of “Opium Eaters”

In the brief editorial, Irfan A. Dhalla, MD [Dhalla 2012, ref below] — who is Assistant Professor, Department of Medicine, St. Michael’s Hospital, Toronto, Canada — ostensibly comments on a research report also appearing in this edition of BMJ. This was from Iranian investigators who examined effects of opium use on subsequent risks of death [Khademi et al. 2012, ref below]. The researchers used information collected from more than 50,000 people in northeastern Iran between 2004 and 2008, with many subjects followed until 2011.

Opium Eater Subjects were between the ages of 40 to 75 and 17% were opium users, mostly for recreational purposes rather than for a pre-existing illness. After adjusting for variables that might have influenced health outcomes, such as poverty and cigarette smoking, the researchers found an 86% increased likelihood of death from major causes among opium users. Key drivers of increased mortality risks were cardiovascular disease and cancer, and secondarily asthma, COPD, cirrhosis, tuberculosis, and other infections. The effects were greater in women than men, but comparable in tobacco smokers and non-smokers, and in people who took opium orally or smoked it.

In his editorial, Dhalla states that the authors’ “conclusion of opium increasing risks of death across a variety of diseases is probably true.” However, he does not stress that the research was observational in design, merely revealing possible associations, and not the result of controlled study. Also, Khademi et al. had recorded morbidity and mortality associated with “ever use” of opium, whether such use was a rare or an everyday occurrence. Therefore, the study does not in any way prove that opium was the cause of increased death risks.

The opium study most likely reflects a common fallacy called “Cum Hoc, Ergo Propter Hoc” (With This, Therefore Because of This). That is, wrongly assuming that events occurring together and closely correlated depict cause-effect relationships, without adequate consideration of other explanations. Khademi and colleagues did not discuss alternative causes, but Dhalla concedes that mortality risk might have been mediated more by the “myriad consequences of addiction rather than by opium use itself.”

After his description of this study — which is of questionable relevance for most of the world where pure opium is no longer used medicinally or recreationally — Dhalla turns to the true agenda of his editorial, which relies heavily on sophistry. This is an approach to argumentation or discourse, stemming from Plato’s dialog of sophists in Euthydemus, that seems reasonable on the surface but is actually flawed and oftentimes misleading.

Failures of Reason

Dhalla acknowledges that in “high income” countries encounters with opium users have become rare; in contrast, he notes, millions of patients with chronic noncancer pain (CNCP) are prescribed opioid analgesics. He then reveals his bias with the question, “Are these patients, like opium users, also at increased risk of death?” Furthermore, if this is the case, are the deaths due to increased risks of overdose, “or are patients who are prescribed opioids also at increased risk of dying from cancer, cardiovascular disease, and infection?”

With these questions, Dhalla sets the stage for his narrative fallacy, fabricating an illusory correlation of harms experienced both by opium abusers and by patients with CNCP who are prescribed opioid analgesics. In this way, he equates taking long-term opioids for chronic pain with a dreadful spectre of opium addiction.

In lieu of solid scientific evidence to support his narrative, Dhalla refers to 3 research investigations of dubious quality:

  • First, he refers to a study by Solomon et al. published in 2010, proposing that all-cause mortality is twice as high in older adults with osteoarthritis treated with opioids as in those receiving non-steroidal antiinflammatory drugs (NSAIDs). This study was thoroughly critiqued in an UPDATE [here], which pointed out that this retrospective data-mining exercise was conducted in a select population of elderly patients for whom much critical information was missing to make any valid cause-effect assumptions, or to even conclude reliable associations of opioids and mortality.

  • Next, Dhalla references studies by Dunn et al. (2010) and by Gomes, Dhalla, et al. (2011), discussed in prior UPDATES [here] and [here], respectively. He uses these as evidence that patients prescribed high doses of opioids (considered as >100 mg/day of morphine or equivalent dose, or MED) are at greatly increased risk of fatal overdose and death.

    The study by Dunn et al. — culling a database of patients at a large health maintenance organization in Washington state — was hampered by an array of confounding variables, not the least of which was that most patients were taking comedications with overdose potential. Plus, less than a quarter (22%) were taking higher doses of opioids and the average in all subjects was only 13 mg/d. The absolute numbers of overdoses/deaths were very small, with most occurring in patients taking low to medium doses — in contrast to Dhalla’s assertion about high-dose dangers. Finally, this study was done during a period of time when the state was pressing for the prescription of methadone, with its inherent hazards that probably skewed outcomes in the study.

    The study by Gomes, Dhalla, et al. was a case-control, data-mining exploration conducted in Canada. Outcomes were confounded by the presence of multidrug use among subjects, questionable forensic definitions of opioid-related deaths, and somewhat vague determinations of opioid dosing, among other deficiencies. A close inspection of statistics presented in the report actually indicate that the data do not support the authors’ premise that daily opioid dose significantly influences opioid-related mortality.

Dhalla concludes that the opium study by Khademi et al., plus his purported evidence cited above, “should remind us not only that opium is harmful, but also that opioids have substantial risks that are incompletely understood. For the management of chronic non-cancer pain, a better prescription may be caution.” Thus, lacking any valid evidence as proof, Dhalla’s final entreaty is a vague appeal to ignorance, or “Argumentum ad Ignoratum,” warning of allegedly substantial yet “incompletely understood” risks as being critically important.

Much more detail on the investigations cited as evidence by Dhalla is available in the UPDATES linked above. All of those studies, as does the opium study, suffer from the Cum Hoc, Ergo Proper Hoc fallacy. They carefully select adverse events occurring simultaneously with either opium or opioid administration, ignoring other variables that may alter interpretations, and falsely arrive at conclusions that imply causality.

Researchers/authors are usually careful to avoid overt statements of cause-effect. Sometimes they even concede that the significant statistical associations they find cannot be used to infer causation and, in fact, quite often those findings also represent effect sizes of little if any clinical significance. Yet, they well know that readers will interpret their conclusions as implying causation, and that this is how the outcomes will be described in the literature by future authors. This is sophistry at its best, and most cleverly deceptive.

A Pattern of Faulty Reasoning

This is not the first time that Dhalla has used arguments and evidence similar to the above in a crusade against long-term opioid prescribing for CNCP. For example, in a previous paper for the British Medical Journal, he and two coauthors state, “Many physicians are unaware that there is no evidence from randomized controlled trials to support the popular assertion that the benefits of long-term opioid therapy outweigh the risks” [Dhalla et al. 2011, see ref below]. What they do not make clear in this Argumentum ad Ignoratum is that there also is no substantial evidence directly in opposition to the benefits of such opioid therapy.

In this earlier paper, Dhalla et al. refer to the same 3 studies of questionable validity noted above as “evidence.” And, they criticize how, due to a dearth of high quality evidence, clinical guidelines on opioid prescribing have not come out strongly enough against opioid prescribing for CNCP. Yet, Dhalla and colleagues do not seem hindered by such a lack of solid evidence when stating their own anti-opioid perspectives.

Furthermore, one of the less reported adverse effects among patients with unrelieved chronic pain is suicide risk, often in association with inadequate opioid therapy [eg, see UPDATE here]. This might be an argument in favor of higher adequate opioid dosing, contrary to the position of Dhalla and others. Interestingly, a letter to the journal editor criticized the study by Gomes, Dhalla, and colleagues [2011, as noted above and discussed here] regarding their apparent indifference to suicide risks.

In their rebuttal argument to the letter, Gomes, Dhalla, et al. manage to combine two fallacies in one statement; saying, “…given the absence of evidence that high-dose opioid therapy reduces the risk of suicide, and the presence of evidence that many individuals commit suicide with opioids, the risk of suicide is yet another reason to prescribe opioids particularly cautiously to individuals with chronic pain.” The first part is another Argumentum ad Ignoratum — that the absence of evidence is itself evidence. The second part invokes a Cum Hoc, Ergo Propter Hoc fallacy, suggesting that evidence of opioids associated with suicides is reason to assume that opioids cause suicides and those adverse events can be reduced by limiting the prescription of opioids.

This second fallacy is like saying that many people commit suicide by jumping off tall buildings, so tall buildings are a cause of suicides, and the solution is to reduce the height of buildings. However, going beyond the sophistry in the above statement by Gomes, Dhalla, et al., the entire argument might be viewed as inhumane in its discounting of the suffering by patients with unrelieved pain that might motivate suicide in the first place.

Dhalla also is a member of a group called Physicians for Responsible Prescribing, or PROP — mentioned by investigative reporter Radley Balko in an excellent series for the Huffington Post [described in UPDATE here] — and Dhalla appears to echo the group’s perspectives. In fact, his paper in BMJ noted above — Dhalla et al. 2011 — is featured at the PROP website [here].

Relatively little is known about PROP, except that they are a group of extremely outspoken critics of opioid prescribing for CNCP. They do not reveal their sources of funding or acknowledge the scope of their membership, other than listing at their website a core group, including Dhalla, several healthcare providers from Washington state, and a handful of others. Seemingly bolstered by a rigorous public relations campaign, they manage to espouse their philosophies in frequent journal articles and newspaper interviews, which often reflect the same sort of sophist arguments described above, along with misquotes of information sources or misrepresentations of evidence [described by Balko in his latest article last March 9, 2012].

For example, Andrew Kolodny, MD, an addiction specialist and the highly vocal founder of PROP, has claimed that nearly a third of patients may become addicted to their opioid medications, while some of the evidence suggests that the prevalence is lower or uncertain [see Balko article]. Kolodny also stated, “The people advocating for [long-term opioid therapy] are advocating a treatment with substantial risk. And there's just no data showing that it's effective,” which invokes the Argumentum ad Ignoratum fallacy that absence of evidence is evidence of absence.

He further remarked in the Balko article, “There's no question that the move toward treating chronic pain patients with opioids is leading to overdose and death. …. This treatment is harming far more people than it's helping.” However, while Kolodny and colleagues raise what appears to be reasonable suspicion, they provide no credible and valid scientific evidence to serve as a higher level of proof to support those broad claims.

Is Anyone Being Fooled?

Are healthcare professionals, patients, government officials, and the public being fooled by the sophistry of the arguments against opioids for CNCP, along with the distorted, unbalanced dialog that results? It seems that many, indeed, are being deceived — perhaps, willingly so.

For one thing, besides Balko’s series of articles and just a few others, there has been very little push-back against the questionable claims and distorted perspectives surrounding opioids for chronic pain. And, for some groups and individuals the arguments may actually intersect with their own tacit biases regarding opioid medications, for example:

  • Legislators and regulators may adopt the arguments as a rationale for their Myths of Beneficence [first discussed in UPDATE here]. The stated objective of these narratives is usually something like, “we want to reduce abuse and overdose of prescription opioids while ensuring patients with pain have access to those vital medications.” The statement reflects a fallacy in that it appears to be well-intended, serving the best interests of patients, while at the same time motivating actions or rules and regulations that end up restricting access to opioids in one way or another as an unintended consequence.

  • Antidrug advocates may welcome the arguments as confirmation of their appeals against any and all drugs that can be misused or abused; ignoring the fact that many persons with pain — who could be their relatives, friends, or neighbors — may need certain of those drugs to survive and thrive. Scientific evidence takes second place to their emotional investment in crusades to end substance abuse, overdose, and related deaths — at any cost.

  • Some healthcare providers also may harbor unspoken biases against opioid medications. Some fear regulatory reprisals for opioid prescribing, while others become disgruntled with the ploys of disingenuous “patients” who actually are drug seekers and abusers; even though such miscreants are a very small minority. The sophistry against opioids may help these practitioners to justify false beliefs and negative attitudes that they intuitively know are not science-based or in the best interests of good patient care.

Where will this all end? Certainly, not well for patients with chronic noncancer pain; not unless fair balance can be restored to the dialog surrounding opioid analgesics. Some day, science rather than sophistry may offer more definitive high-quality evidence to resolve critical questions about the relative benefits and harms of long-term opioids for CNCP. Meanwhile, the pain management community and the public should not be tricked into accepting that a lack of evidence, or collections of weak evidence, or conclusions based on fallacious reasoning are sufficient to serve as proof that favors limiting the prescription and/or dosing of these vital medications.

POSTSCRIPT: Levels of proof and assessment of causation in pain research were discussed in part 11 of our series on “Making Sense of Pain Research” [here]. The topic for part 12 of this series will be “Fallacies of Evidence in Pain Research.”

DISCLOSURE: Pain Treatment Topics is supported in part by unrestricted educational grants from manufacturers of opioid analgesics — Purdue Pharma LP and Endo Pharmaceuticals, at present. In full compliance with accepted standards, supporters have absolutely no role in the selection, development, or review of any contents for Pain-Topics UPDATES. The views and opinions expressed are entirely those of the author and do not necessarily reflect those of supporting organizations or Pain Treatment Topics advisors.

> Dhalla IA. Opium, opioids, and an increased risk of death. BMJ. 2012(Apr 17);314:e2617 [
> Dhalla IA, Persaud N, Juurlink DN. Facing up to the prescription opioid crisis. BMJ. 2011;343:d5142 [
> Khademi H, Malekzadeh R, Pourshams A, et al. Opium use and mortality in Golestan Cohort Study: prospective cohort study of 50,000 adults in Iran. BMJ. 2012(Apr 17);344:e2502 [

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