Monday, September 5, 2016

When a "Drug Overdose" Isn’t

Below are some passages I highlighted in my copy of Karch’s Pathology of Drug Abuse, 5th edition, specifically from the chapter on cocaine. I’ll give away the punchline: this is another post arguing that drug overdose death statistics are probably overstated. I wrote about that here with some passages from the chapter on opioids. Without too much throat-clearing, let's dig in:

[A] handful of important pharmacokinetic studies have been published. In one of these, an uncontrolled clinical study, plasma cocaine concentrations in 111 symptomatic cocaine users were studied and an attempt made at correlation of plasma concentrations with clinical symptoms (Blaho et al., 2000). The study was unsuccessful to the extent that no correlation between dose and effect in real cocaine abusers was demonstrated. Failing to find a difference is, presumably, a result of cocaine tolerance, a process that begins to emerge after the first dose (Howell and Ezell, 1990; Mendelson et al., 1998). Using human volunteers, Van Dyke et al. (1982) showed many years ago that tachyphylaxis occurs after even single dose of cocaine.

In other words, cocaine users rapidly develop a tolerance to the drug, so it’s impossible to specify a threshold for “overdose.” (Tachyphylaxis is a fancy word for diminishing responses to successive doses of a drug.)

The results of these studies suggest that (1) chronic users may consume multigram quantities of cocaine with relative impunity; (2) a variety of cocaine metabolites previously thought to be insignificant (EME, norcocaine) are, in fact, formed in fairly substantial quantities; and finally, (3) the half-life of cocaine may be much variable than had previously been thought. All of these variables are partly a function of the route of administration. 

This would make it impossible to tell if a dead body with very high blood levels of cocaine are actually overdoses or heavy users who die of unrelated causes.

Although the plasma cocaine level approximately doubled following the second cocaine administration, the ratings of positive drug effects, heart rate, and blood pressure did not increase after the second cocaine administration. Clearly, acute within-session tolerance develops during repeated administration of intranasal cocaine (Foltin and Haney, 2004).

This passage illustrates just how rapidly cocaine tolerance forms in a user. You might have the image of a coke-fiend chasing a high and consuming a Tony Montana-esque quantity of cocaine. I’ve heard such descriptions of cocaine users, although I suspect these are mostly exaggerations. At any rate, if the users are rapidly developing a tolerance to the drug’s physiological effects, they are also developing a tolerance to the toxic effects.

[H]ighly accurate measurements are seldom of any help in differentiating deaths due to drugs from those deaths where the presence of drugs is simply an incidental finding or, as is increasingly recognized, an interaction between two drugs to produce a third and even more toxic drug. Why are such precise measurements of so little value? Because, except for episodes of massive overdose (as might occur in a drug mule) where the mechanism of death is perfectly clear, most cocaine-related deaths occur in chronic drug users in whom death is a consequence of neurochemical and anatomic changes induced over a period of months or even years.

So here he just comes out and says that the tissue concentrations of cocaine can’t be used to determine the cause of death. I wonder how many medical examiners understand this point, and how many just mark the cause of death a cocaine overdose when it’s a handy and convenient answer? The number of cocaine-related deaths in 2014 was 5,992, according to CDC figures. (It actually went up, from 4,494 in 1999 to a peak of 8,591 in 2006, then back down to 5,992 in 2014, just to give you a sense of what it’s done over the past 15 years.) I’m curious if most of these are really cocaine overdoses, or if most of these are mislabeled and the numbers are tracking with usage but not necessarily with mortality?  As in, “There are more corpses with cocaine in them in 2006, fewer in 2014, but we really have no idea if cocaine was the cause of death in the vast majority of these deaths.” Then again:

Long-term cocaine users have changes in their hearts (Karch et al., 1998) and in their brains (Volkow et al., 1993) that favor the occurrence of sudden death. If the abuser is truly unlucky, he or she may be heterogeneous for one of several abnormal hERG ion channels (Guo et al., 2006) or polymorphic catecholamine receptors (Ghimire et al., 2012). These changes explain why, in both the living and the dead, it is absolutely impossible to correlate a specific blood or plasma concentration with a specific type of toxicity or even speculate whether cocaine-related toxicity occurred at all (Jenkins and Goldberger, 1997; Karch et al., 1998; Blaho et al., 2000).

So there is a countervailing force here that can lead to *understating* the number of cocaine deaths. Someone could have cumulative organ damage from a cocaine habit, but have no cocaine in their system at all. They could have gotten totally clean after a long period of cocaine abuse, but the damage to their hearts and brains can still kill them later. I suspect this is a small countervailing force because the number of long-term cocaine abusers is so small, but obviously this is a giant question mark.

Given these realities, the accurate certification of a drug-related death requires knowledge of (1) the decedent’s past medical history, (2) an account of what happened at the scene, (3) a thorough postmortem examination, and (4) the results of DNA testing to rule out hereditary forms of heart disease or even myocarditis; the cost of such testing is rapidly decreasing to affordable levels. Though it will still be some time until it becomes widely available.

My impression is that most autopsies aren’t this thorough, and Karch reinforces this impression with the following passage:

The definition of just what constitutes a “complete” autopsy is not as simple or clear as it once was. Does the examination of one section of myocardium constitute a “complete” examination of the heart? When a young person dies suddenly, is it proper to refer to their heart as normal when cardiac ion channels have not been measured? In unexplained cases of drug death, should the examination be considered complete if the P450 metabolizer status is not determined? The answer to all of these questions is “no.” As a consequence, cause of death determinations are often based solely on toxicologic measurements, significantly raising the chances for a missed or incorrect diagnosis. Because cocaine is so widely used, cocaine-related deaths present a special set of problems.

Clearly the author thinks that typical autopsies are not adequate to determine the cause of death in a suspected cocaine overdose.

I thought the following passage was a good explanation of why cocaine users feel compelled to keep taking massive doses of the drug, “chasing the high” as it were:

There is seldom any reason for clinicians to measure plasma concentrations of cocaine or its metabolites. Unlike alcohol intoxication, where specific blood concentrations can generally be related to specific physiologic and psychological states, cocaine blood concentrations do not relate to symptoms (Karch et al., 1998; Blaho et al., 2000), not even in the laboratory setting. Accordingly, treatment must be based on the patient’s symptoms, not on the plasma level of cocaine.

When cocaine is given to volunteers, correlations can be drawn between the degree of mood elevation and peak blood levels, but only when cocaine concentrations are rising. If blood concentrations are falling, the exact same concentration that resulted in a “high” when concentrations were rising can be associated with a dysphoric reaction when concentrations are falling. Cardiovascular effects and feelings of euphoria decline more rapidly than do cocaine blood concentrations (Javaid et al., 1978), but the “rush” experienced by cocaine users follows a different time course than the cardiovascular changes.

Emphasis added. Given this, you can easily imagine someone taking more and more cocaine during one session, chasing the state of rising blood concentrations. Given the rapid onset of cocaine tolerance, it’s not clear that this is necessarily dangerous, unless the user takes a truly massive dose.

At one time, cocaine blood concentrations of more than 5 mg/L were thought to be uniformly fatal (Wetli and Mittlemann, 1981). With more experience, it has become apparent that isolated postmortem blood concentrations cannot be used to determine the cause of death at all. Tolerance on a massive scale occurs, and cocaine concentrations well in excess of 5 mg/L can be encountered in traumarelated deaths where the presence of cocaine is clearly an unrelated finding (Pagel et al., 1994; Shannon et al., 1996). For example, one case report described a man who was shot while drinking in a bar. Prior to being shot, the man’s behavior was said to have been normal. When he was autopsied several hours later, after having undergone extensive attempts at resuscitation, including aggressive fluid replacement, multiple blood specimens showed a blood cocaine concentration of 30 mg/L (Howell and Ezell, 1990).

Further driving home the point that blood concentrations can’t be used to determine the cause of death.

The following is good to keep in mind when thinking about the topic of overdose deaths:

Most cocaine-related deaths can be attributed to the occurrence of a lethal arrhythmia.

Unfortunately, lethal arrhythmias happen for reasons unrelated to cocaine. So it’s hard to tell if cocaine was the cause or just incidental.

The last section of this chapter is actually titled “When Is Cocaine the Cause of Death?” and it reiterates the point, repeated throughout the chapter, that it’s a hard question to answer.

It is distressing to see how often deaths caused by cocaine are misclassified. Misconceptions about cocaine-related deaths persist, partly because death certification practices are not standardized and partly because there is no reproducible method by which to make the decision.

I wish this was better quantified, some thing like “50% of ‘drug related’ deaths are misclassified.” Obviously nobody knows what the real number is. But it would be nice if the CDC, when reporting on drug-related fatalities, adjusted for this misclassification problem, or at least acknowledged it.

The following is mentioned in the footnote of a figure:

Except in the case of massive overdose, cocaine-related deaths are always multifactorial.

In other words, it’s never *just* cocaine. It’s always some combination of cocaine and other drugs, or cocaine interacting with a heart condition.

Consider the example of a young cocaine abuser who dies from smoldering myocarditis that has been present for many weeks. If microscopic examination is not performed, or, even worse, if no autopsy was performed except to draw blood for toxicology testing with “a blind stick,” even if the level of cocaine present is trivial, there is a very good chance that death will be attributed to the drug.

Read “smoldering myocarditis” to mean “an unrelated heart issue.” (It’s just a random condition he chose to make his point, as far as I can tell.)  The author is pointing out that sometimes the toxicology is the sole piece of evidence that medical examiners use to determine the cause of death, even though this is completely inappropriate.

In a 2014 study of 245 U.S. college athletes who had died suddenly, with no abnormalities detected at autopsy, nearly a third of the individuals had fully normal autopsies. At about the same time, researchers in Denmark reviewed nearly 439 cases where the decedent was aged 1–49 years (Bjarke et al., 201). As might be expected, nearly 70% of the deaths were the result of coronary artery disease. But in 135 of the U.S. cases, complete autopsy disclosed no anatomic abnormality, very strongly suggesting an underlying mutation (Maron et al., 2014).

In other words, people drop dead for no apparent reason, and sometimes even a thorough autopsy can’t find any underlying anatomical problems. I was glad to see the authors reference some actual studies of this phenomenon, because this is exactly what I suspect is happening in a large number of so-called “drug overdose” cases. This is precisely what I suspect is overstating the overdose numbers.

Suppose a person with a heritable cardiac channelopathy is found dead and a modest amount of [cocaine metabolite] BZE is found in autopsy blood. For many, the temptation to classify the death as drug related may be too strong to resist if they are unaware that a potentially lethal mutation is present.

All of this together reaffirms something I've suspected for a while now. When it’s hard to determine the cause of death, toxicology offers up an easy answer. The medical examiner can fill out the death certificate and go to lunch. I don't know how big a deal this is, but a serious effort should be made to correct for this problem.

There is much, much more in this chapter. It confirms my suspicion that drug overdose deaths are inaccurately measured, and probably are overstated. I hope that the authors don’t mind my generously quoting from their book. Certainly these passages are relevant to a very important public discussion about the drug overdose problem, and certainly these considerations should inform any policy response. 

(If the authors of Karch's Pathology of Drug Abuse see this blog post and want me to cut some of the quotes, I’d be happy to paraphrase instead of quoting. But I insist that the basic point underlying these quotes is relevant to a public discussion, so some form of the above needs to be publicly available. Karch was interviewed for Radley Balko's series on the opioid epidemic at the Huffington Post, where he is quoted as making the above pionts. So surely his intention is to inform the public on this point.) 

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