Alternate strategies for postmortem drug testing.

During the last decade, our ability to extract, and reliably quantitate, drugs from blood and tissue has increased drastically. Yet in spite of these advances, it is increasingly apparent that toxicologic measurements, taken in isolation, cannot be used to discriminate between individuals who died as a consequence of drug use and those who did not. The situation is not much better in the living; it is still not possible to relate specific plasma drug concentrations and impairment. Given that subnanogram drug quantitation is already possible, further increases in measurement precision are unlikely to provide the answers needed by pathologists, judges, and juries. Fortunately, the picture is not so bleak as these observations would suggest. Alternate testing strategies employing multiple tissue measurements may provide the needed answers. Fifteen years ago, at the beginning of the current cocaine pandemic, Smart and Anglin (1) were the first to suggest that the lethal dose of cocaine might never be known. Their doubts were prompted by the observation that reported postmortem blood cocaine concentrations, in both man and animal, could sometimes vary by more than an order of magnitude. Fewer than five years ago, their worries were confirmed when the first large postmortem toxicologic studies of methamphetamine and cocaine users were published; blood concentrations in those clearly dying of drug toxicity completely overlapped concentrations seen in decedents where the presence of drug was an incidental finding (2--4). Although no comparable analyses of heroin/morphine-related deaths have been published, it has been the experience of most Medical Examiners that postmortem blood morphine concentrations measured in drug-related deaths are not significantly different from cases where the presence of morphine is an incidental finding, completely unrelated to the cause of death. It is tempting to attribute this overlap to postmortem drug redistribution, the movement of drugs between tissues and body fluids that occurs after death. A long list of factors can affect postmortem drug concentration measurements; the more obvious include postmortem interval, method of collection, site sampled, ambient temperature, physical properties of the drug, preservative used, position of the body, and the amount of unabsorbed drug present at the time of death. But even taking all these variables into account, there is still no assurance that drug concentrations measured after death bear any relationship at all to concentrations measured in life. This long list of confounding variable is acknowledged by pathologists and toxicologists, but until very recently, few realized that even if postmortem measurements were valid indicators of antemortem concentrations, they would still be useless for identifying cases of drug toxicity. The explanation has to do with the phenomenon of drug tolerance. Chronic exposure to opiates and stimulants sets in motion a series of neurochemical and anatomic changes that make drug users less sensitive not only to the drugs psychological effects--with chronic use it takes increasing amounts of drug to produce the same desired mental effect--but also to drug-induced changes in pulse, blood pressure, and respiration (5-7). The development of tolerance explains why otherwise healthy addicts receiving heroin-maintenance therapy have higher plasma morphine concentrations than others dying of heroin overdoses (8). It also explains why plasma cocaine concentrations cannot be related to symptoms or outcome. A case report published in 1990 described an otherwise healthy cocaine abuser who died instantaneously of a gunshot wound to the head; the blood cocaine concentration was 30 mg/L (9). In a prospective study of 101 cocaine users seeking emergency room treatment, Blaho et al. (10) found there was absolutely no correlation between plasma concentrations of cocaine (and all of its major metabolites) and outcome. In fact, the patient with the highest plasma cocaine concentration (3.4 mg/L) was discharged into police custody just 2 h after arrival at the hospital. Not so long ago, cocaine concentrations of that magnitude were thought to be uniformly fatal. Fortunately, it is now both possible and relatively simple to identify tolerant opiate users after death. The solution is to measure hair morphine concentrations (11). Morphine concentrations in the hair of active heroin users are much higher than those in abstinent users, and hair concentrations in overdose deaths are comparable to those seen in abstinent users. Obviously, this situation does not apply in every case, but the observation is consistent with the experience of Medical Examiners everywhere; most heroin overdoses involve chronic heroin users who, for whatever reason, have been abstinent for days or weeks and have lost their opiate tolerance (12). The longer the period of abstinence, the lower the hair morphine concentration is likely to be. As was successfully argued at the trial of serial murderer Dr. Harold Shipman, this inverse relationship can be diagnostic. Shipman killed his victims with lethal injections of heroin. Exhumed victims were found to have high tissue morphine concentrations, but except for one individual with picogram quantities of morphine detected in her hair roots, morphine was not found in the hair of any of the