Saturday, August 13, 2016

Casting More Doubt on the "Prescription Painkiller Epidemic"

When a doctor “certifies” a cause of death, his certification is based upon his evaluation of the evidence available to him, but it is still just his opinion and does not set a precedent for similar cases.

It turns out assigning a cause of death is really hard. 

I’m reading through Karch’s Pathology of Drug Abuse. This is the standard textbook on the topic. It repeatedly makes the point that toxicology results can’t be used to determine the cause of death. I’ve only read a fraction of it so far, but it’s definitely strengthened my belief that the recent rise in overdose deaths is, at least in part, a spurious trend. The book’s authors go into some detail on the mechanisms that make postmortem toxicology unreliable. This is important because there is much ink spilt about the recent supposed rise in prescription painkiller deaths, and much more recently the rise in heroin overdose deaths. It’s true that there are many more prescriptions today than there were 15 years ago; the sheer tonnage of opioids prescribed is easy enough to track, and the government does track these figures. It is far less clear that the rise in opiod-related deaths is real. It could simply be the case that, with more people walking around with opioids in their system, more deaths are being labeled “drug poisonings” even though the drugs are incidental and the real cause of death was actually something else. When a medical examiner labels a death a “drug poisoning,” they are expressing an opinion.

When you see numbers such as “There were 47,000 drug overdose deaths last year” or “There were 18,000 deaths from prescription painkillers last year”, these figures are basically a guess. For each such death, somebody (a coroner or medical examiner) looked over the body and determined it was a drug overdose, and that death went into a big database of all 2.6 million deaths that happened that year. Then later somebody ran a query against that database that counted up all the deaths that matched criteria X, Y, and Z. I sincerely wish that the people and organizations reporting these figures would be a bit more careful about issuing caveats and admitting to uncertainties in their data and methods. I hear a news story once a week or so about the prescription painkiller epidemic, and I'm getting increasingly annoyed that the news outlets aren't doing the slightest bit of vetting on the underlying numbers. Did not a single one of these reporters bother to crack a textbook on the topic? Did nobody bother to ask "How do you know if a death is a drug overdose?" The database and query are actually pretty straightforward, but the whole thing falls apart if you don’t have much confidence that the data reflect the true causes of death. It’s very likely that many of these deaths were due to some other cause, and the drug use was an incidental finding.

From the section on methadone:

Because methadone has a very high volume of distribution, concentrations can be expected to rise after death. Indeed, fourfold increases have been reported (Levine et al., 1995; Milroy and Forrest, 2000). Postmortem methadone concentrations are also site dependent and, for unexplained reasons, the increases appear to be greater in men than women (Caplehorn and Drummer, 2002). In every published series methadone blood concentrations in fatal cases completely overlap those found in methadone maintenance program participants.
So basically the blood concentrations are useless in terms of determining the cause of death. For one thing, drug users develop a tolerance, so what would be a fatal dose to a naïve user is safe to an experienced user. This is particularly true of opioids, although all drugs build some degree of tolerance in their users. The problem of “postmortem redistribution”, diffusion between blood and tissues, exacerbates this problem.

Not one single control study, even in animals, has ever shown that postmortem drug concentrations accurately reflect drug concentrations at the time of death, but a goodly number have shown quite the opposite to be true, chiefly because of the problem of postmortem redistribution (Pounder et al., 1996; Hilberg et al., 1999; Moriya and Hashimoto, 1999; Drummer and Gerostamoulos, 2002; Flanagan et al., 2003; Ferner, 2008). Postmortem redistribution is defined as the movement of a drug down a concentration gradient after death.

In other words, blood concentrations don’t follow a smooth decay curve after death.

The postmortem movement of free morphine out of the tissue, back into the plasma, makes it impossible to estimate the time of ingestion by calculating the ratio of free to conjugated morphine.

[T]he Vss [steady-state blood concentration] for methamphetamine, in healthy volunteers given fixed doses of drug and then living in a locked ward, was found to range from 2 to 11 L/kg (Schepers et al., 2003). This enormous and unpredictable degree of variability, even in the living, makes it impossible to establish any sort of relationship between postmortem drug concentrations and reported dosage, though it would seem reasonable to conclude that if low levels of drug are detected, the drug was consumed.

In other words, people given the same dose may show wildly varying blood levels of the drug, even in healthy living test subjects. This complicates setting any threshold for a toxicology screening, as in “Anything above X is a fatal dose, anything below X is nonfatal.” All the stuff about redistribution after death complicates matters even further.

This next part borders on a philosophy of causation lecture:

Could the death of a cocaine and heroin abuser, with cardiomyopathy, be related to the fact that his cardiologist had just begun treatment with carvedilol, or did the doctor at the methadone maintenance clinic administer the wrong dose of methadone? It may be impossible to say, but these complex issues exist and cannot be ignored. 

The authors even discuss how gut bacteria cause drugs and their metabolites to diffuse through the body after death (if I’m reading them correctly):

It is not uncommon to hear an “expert” offer an opinion on how much time had elapsed between the last dose of heroin/morphine and death. Such speculation is unscientific, not just because of the differences in Vss between parent drug and metabolite, because bacteria translocate. That is, they migrate through the walls of the bowel, invading the rest of the body within a few hours of death (Kellerman et al., 1976).
Two short sentences about how genetic differences between individuals can contribute to different drug metabolism:

Thus, even in the living, without knowing an individual’s ability to conjugate morphine (which would require DNA resequencing), comparing the ratio of bound morphine to free morphine is a meaningless exercise.
Genetic polymorphism is, no doubt, responsible for more than a few cases of drug toxicity, but the true incidence of this problem is not really known.
In other words, people metabolize drugs differently. A fatal dose to one person may be nonfatal to another, even before considering things like acquired tolerance. The authors go on to describe a specific genetic trait and its effect on codeine metabolism:

Individuals entirely lacking CYP2D6 activity (7%–10% of Caucasians) are called PMs and are not likely to get much pain relief from codeine because they cannot convert enough of it into morphine. But it is also possible to have multiple duplications of CYP2D6, making the individual into an ultrametabolizer who can transform abnormally large amounts of codeine into morphine. Thus it is quite conceivable that a person with a gene duplication might experience an overdose even though only a modest dose of codeine had been taken.

The author gives two examples of deaths that might be labeled an “overdose” and explains why the true cause of death isn’t so clear:

If toxicology results cannot be considered in a vacuum, neither can autopsy findings. When a doctor “certifies” a cause of death, his certification is based upon his evaluation of the evidence available to him, but it is still just his opinion and does not set a precedent for similar cases. If the decedent was a known cocaine user, the body was noted to have frothy pulmonary edema, blood cocaine concentration is 1 mg/L, and a crack pipe was found at his side, the decision is not difficult. But what if the blood cocaine concentration had been 0.050 mg/L, there was minimal pulmonary edema, and no other apparent stigmata of drug abuse or anatomic abnormalities were observed, but concentric cardiac hypertrophy was evident? How would the pathologist determine which abnormality was causal—the one he could see and weigh or the hERG channel–cocaine interaction he knows might exist, but cannot measure?
Another example that illustrates how difficult it is to determine the cause of death:

In the same fashion, suppose the pathologist was confronted with a decedent who had a remote history of heroin abuse and only mild pulmonary edema with a blood morphine concentration of 20 ng/mL evident at autopsy. In the absence of other identifiable anatomic changes, the pathologist would, no doubt, determine the manner of death as heroin overdose and an accidental death. But that would be incorrect for at least two reasons. First, unless hair testing had been performed, the pathologist would have no idea whether the decedent was a regular user and therefore tolerant or whether the decedent was naïve and intolerant. Second, the cocaine that was present could have unmasked one of many genetic defects that can interfere with the metabolism of morphine or exaggerate its effects (Oertel et al., 2009). Whether such a death would be classified as natural or accidental could be a matter for debate. What is not debatable is that the autopsy pathologist has no way to look at the body and determine whether or not the decedent suffered from a P-gp variant or an SCN9A mutation, at least not without performing genetic resequencing first.

There is much, much more. In fact, everything above is from the chapter on opioids. Other chapters are full of similar warnings about assigning a cause of death or interpreting blood concentrations of a drug. I’ve written several posts about how the recent rise in drug poisoning deaths could be spurious, herehereherehere, and here . I still think that part of the increase in real, but some large fraction of it is spurious. Those news outlets who are fanning the flames of a moral panic need to cool their jets until we really understand what’s going on. 

I'm still reading this book. More to come if I find more interesting topics.

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