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, here, here, here, here, 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.

Income Inequality is Not a Problem

The problem with identifying “income inequality” as a social problem is that it misses all the real problems and it implicates non-problems as problems. The desire to alleviate poverty is legitimate, but the blaming of rich people isn’t.

Some people have a hard time in life, for a variety of reasons. Some people have serious emotional issues that make them difficult to employ. Some people have serious absentee/tardiness issues, or just general conscientiousness problems, that make them unreliable as employees. Some people, for whatever reason, failed to acquire any kind of relevant education (college or vocational) and thus have no useful job skills. Some people have a relevant education, but for whatever reason refuse to work at a meaningfully remunerative job (I have seen so much of this, and it is almost always baffling to me). Some people are government workers in cozy jobs whose cost-of-living-adjustment suddenly stops because the government goes broke. All of this is merely to observe and explain, not to blame. Sometimes it really *is* the person’s fault, and sometimes it isn’t. Either way, it’s wrong-headed to tell these people, “You’d be doing a lot better if these rich people weren’t hoarding society’s resources!” Or “If only the political system weren’t dominated by rich interests, it would work better for you, and you’d be sharing more of the wealth.” That’s not what these people need to hear. This kind of scapegoating is shameless pandering when a politician does it and self-congratulating escapism when the “underpaid” workers themselves do it. Either way it’s grossly irresponsible. There are usually actions the person can take to improve their circumstances, and we should encourage that. We shouldn’t be telling them, in effect, “Your problem is due to someone else’s greed, and only a massive change in government policy will fix it.” Without casting any moral judgment, I want to point out the causal mechanism proposed within the income inequality framing is simply mistaken. It just isn’t true that the rich are richer *because* the poor are poorer.

If you aren’t careful, it’s easy to take on a zero-sum worldview (inadvertently or explicitly). It’s easy to think “If he had less, we’d all have more.” Or “Society’s income is $16 trillion per year. We just need to dole it out more equitably.” We don’t live in a zero-sum world. “Society’s income” isn’t something that belongs to all of us; it’s not something that is wrongly and arbitrarily doled out unequally to make a few random winners rich. There really are people whose annual productivity is in the millions of dollars. If large companies didn’t shell out to place the most talented possible individual in their executive roles, they could lose out on millions or even billions of dollars. And without an appropriate incentive to perform, that talented executive might make avoidable million dollar errors. It’s easily possible that the *very* best person for the job of, say, running Microsoft will contribute $10 million more a year to the expected bottom line than the second best person. Getting that person for $5 million would be a steal for the shareholders and for the software users who are using the improved product and the employees of Microsoft who are made more productive by the CEO’s actions. Getting that very best person to put in their very best effort could easily be worth another $10 million. If the difference between a motivated and an unmotivated executive is $10 million to the company’s bottom line, then a generous bonus in the millions of dollars is economically justified. Perhaps the very best executive has a 1% chance of totally destroying the value of a large company over their tenure (say Microsoft, with a market cap of $450 billion), but the second best has a 2% chance of totally destroying the company. This consideration alone makes that top executive worth ([2%-1%] * $450 B = )  $4.5 billion. If Microsoft can acquire this person by making them a billionaire once or twice or even thrice over, it’s worth it. Sorry to burst anyone’s populist bubble, but those very large executive compensation packages make economic sense. You’re *richer* because of them, not poorer. I think it’s not hard to understand that an executive’s productivity should scale up with the total value of the company, and that their take-home pay should reflect this productivity. People react with outrage to these big compensation packages, but economically speaking they are justified.

Consider now a more modest form of inequality: those salary differentials between the professions. These are a feature, not a bug. They are a market signal directing people to where work is most dearly needed. Very high salaries for doctors, lawyers and actuaries are signals that “The world needs one more doctor/lawyer/actuary more than it needs one more teacher/secretary/cashier.” If the pay differential were too small, you wouldn’t have enough people who are willing to undergo the long years of training necessary to enter these professions, and you wouldn’t find enough people to do the often thankless, boring, or even dirty tasks that these jobs entail (and while working longer hours than an average worker).  More to the point, people aren’t being assigned these professions at birth; they choose their profession *knowing* that these salary differentials exist. It’s extremely churlish to choose a low-paying profession while complaining that a higher-paying profession earns more. People don’t just fall into these positions. They end up there after having followed a long and arduous path. Your current profession is a sum of many past choices and your past effort. 

Some people make the mistake of interpreting salary differentials in terms of value judgments, as in “Isn’t education just as important as medicine?” It’s the wrong question, and answering it doesn’t tell you anything useful about how much doctors should be paid vs how much educators should be paid. The actual question is more like, “What is the social value of *one additional doctor* vs *one additional teacher*?” And more to the point, “What salary will attract the extra doctor we need, and what salary will attract the extra teacher we need?” It’s not as though there are a fixed number of slots to fill, and we can just fill them all with any arbitrarily chosen salary figures. The actual number of people willing to enter the profession changes, moves up and down, in response to the salaries offered, and in turn those salaries adjust up or down with the number of people willing to enter the profession. (This is the standard intersecting-supply-and-demand-curves stuff from econ 101.) Inserting your own moralistic value judgment into this consideration would be arbitrary and wouldn’t help you answer the question “What *should* these relative salaries be?”

I have no doubt that there are some people who make an undeserved fortune by adjusting the rules to favor themselves. Perhaps an auto producer or textile company profits from an import quota or tariff. Or perhaps a mega-farm gets paid by the government to leave thousands of useful acres of farmland fallow. Or onerous regulations make it hard for small start-ups to challenge incumbents. It’s often the case that the companies benefiting from these market restrictions are the same companies that actively lobbied for those policies. These gains are ill-gotten. But it’s the “ill-gotten” part that’s the problem, *not* the “gains” part. By fixating wrongly on inequality, we would falsely impugn the honest business owners who earn their fortunes honorably through voluntary transactions. And we might wrongly overlook these kinds of ill-gotten gains if the thief fails to enrich himself compared to his competitors. In both cases, “inequality” is a terrible proxy for the real problem. For both kinds of errors, the inequality framing *completely misses* the problem. 

Countervailing Forces

I think it’s very likely that under drug legalization, the mix of drugs people are taking could change, but total drug-related harms wouldn’t increase. It’s far more likely these harms would decrease substantially. There are countervailing forces here, so we have to be clear about what these forces are and somehow estimate their magnitudes. (I’ll give an incomplete list what those forces are below, but this won’t be a thorough, rigorous cost-benefit analysis.)

Consider the forces that would decrease drug-related harms:

1)      Some currently illegal drugs are extremely non-toxic, contrary to popular belief. Their legal status, while not exactly making them “unavailable”, does raise their relative cost. Legalization, at least for these drugs, would shift consumption toward these and away from the current legal drugs (alcohol, tobacco, and pharmaceuticals), which are more toxic and more prone to addiction problems.

2)      Related to 1), but the same point for drugs that are potentially harmful. Someone might satisfy their need to get intoxicated on a low dose of cocaine or heroin, while needing a very much larger (and overall more harmful) dose of alcohol to achieve the same satisfaction. Don’t scoff at the notion that substituting from alcohol to heroin or from nicotine to methamphetamine could have net positive health and social effects. These drugs are not harmful if properly administered, and some of them (particularly opioids) don’t cause cumulative organ damage.

3)      Currently illegal drugs are made *far more* dangerous by prohibition than they would be in a legal market. Drug interdiction causes the dosage to fluctuate wildly, which is the cause of a lot of overdoses. Often the active ingredient is a completely different chemical than the user realizes (fentanyl sold as heroin, or experimental designer drugs sold as MDMA). Impurities and adulterants are hard to control in a black market. Dealers have a preference for very concentrated doses of the drugs, because they are easier to transfer and smuggle, so these higher-concentration versions of drugs dominate the market.

4)      It’s easier to advise people against self-harming behaviors in a legal market. Warning labels against specific harmful behaviors can be put on the packaging and purchasing the substance puts the buyer in front of a pharmacist who can advise them. Someone who buys two drugs that interact can be told “Don’t mix those.” (Considering that most drug poisoningsare multi-substance interactions, this would be a very important behavioral tweak.) Relatedly, it becomes easier to usher someone into drug rehab if their habit doesn’t make them a criminal. More people are likely to seek necessary help if doing so doesn’t risk legal sanctions.

5)      The legal sanctions are themselves harmful to people’s lives, and these would obviously disappear under full legalization. These include decades in prison, low-level harassment of millions of innocent people, and the occasional beating or shooting of a drug suspect. We’d do away with this class of social harms entirely.

6)      Black market violence is a huge driver of our overall crime rates. Estimates vary, but by all accounts are big. Read “Drug War Crimes” by Jeffrey Miron for the full story, but something like ¼ to ¾ of our murders can be blamed on the drug war, and that’s not even the entire class of black-market social costs.

Now consider the force that would lead to an increase in drug-related harms:

1)      Someone who otherwise wouldn’t have tried cocaine (or some other illegal addictive substance) now tries it and develops a self-harming habit. This is the opposite of 2) above. These people require a large, harmful quantity of illegal drugs to become satisfied. In other words, they are willing to undergo the self-harm for cocaine (and heroin, etc.), but not for the effects of alcohol or something else that is relatively inexpensive under our current regime.

For drug legalization to be a bad idea, the one harm-increasing force would have to dominate all the harm-reducing forces. I find this implausible. Don’t interpret this as a “This list is longer than that list, therefore…” argument. It’s possible in principle for the one harm to overwhelm all the benefits, even though it’s one item. I could arbitrarily express it as four items with some clever manipulation, or compress my list of benefits. We have to weight these things somehow, not simply count them. Still, I think drug legalization comes out ahead. The one “harm-increasing” force is almost surely small. There just aren’t that many people who 1) are willing to endure enormous amounts of self-harm and 2) are deterred significantly by weak legal sanctions. (Here is a more rigorous treatment of the problem, stated in terms of demand curves and total costs.)

Prohibition probably causes people to substitute some drugs in place of others, but it doesn’t alter their underlying willingness to undergo self-harm. If you look at evidence from alcohol and tobacco, it appears that the self-harm dominates the dollar price. No doubt this result generalizes to other addictive substances.  The goal of drug policy should be to reduce the social harms of drugs, not to reduce drug use *per se*. This goal can be achieved by allowing people to achieve their desired state of intoxication in the least harmful way possible. If we had a wider array of intoxicants (some of them almost entirely non-toxic) available to us, this would be a lot easier.

The fear is that light dabbling in these other kinds of drugs will inevitably lead to full-fledged addiction, with all the overdoses and other health problems. But this “try it once and you’re hooked” story is a myth. It doesn’t describe the vast majority of illegal drug use. Normal, well-adjusted people have nothing to worry about. It’s the impulsive people with self-control problems that we need to worry about, and these people are mostly already hurting themselves. Drugs don’t dominate the will and turn the former type of person into the latter. There is just an enormous amount to gain here and very little to lose. Legalizing drugs is the lowest of the low-hanging fruit. It's long past due that we pluck it already.