Toxicological studies of opiate-related death

This thesis comprises studies on opiate overdose death, and focuses on evaluation of toxicological characteristics including the possible influence of abstinence and polydrug use for the fatal outcome. In order to identify and classify drug abusers, a screening method for several drugs of abuse was developed and applied on randomly selected autopsy cases. Out of 75 cases, 26 positive results were found in 16 subjects. In two cases, drug abuse was not previously known by relatives or the police. The method developed includes the detection of the most common illicit drug groups in Sweden, and proved feasible for application in the medicolegal routine casework to confirm or exclude previous drug abuse in deceased subjects. In addition, the method may be applied on hair samples collected from living subjects for the same purpose. Although the designation heroin overdose gives the impression that these subjects have taken a high dose, or a dose of high purity, blood morphine concentrations vary widely and many victims actually present with fairly low blood morphine levels. To investigate the importance of abstinence in unexpected death at low opiate concentrations, all screening results were confirmed with segmental hair analysis, allowing for a detailed temporal mapping of the previous drug use. Hair samples were collected from 60 deceased addicts of whom 28 were classified as heroin overdose deaths. Segmental hair analysis revealed that 18 of these subjects had recently discontinued opioid use, suggesting a reduced tolerance to opioids. However, their blood morphine levels were similar to those found in the 10 subjects with a continuous opioid use. Further, hair and blood analysis disclosed an extensive use of additional drugs that directly or indirectly may influence the opioid system and contribute to the overdose. In a larger sample of deceased drug addicts, the possible importance of abstinence and polydrug use in opioid overdose deaths was explored. In 160 of 210 deceased suspected drug addicts, drug abuse was confirmed by hair screening. Of these, 91 were opiate overdose deaths. Hair and blood analysis revealed extensive polydrug use, which was more pronounced among opiate overdose victims than in drug addicts dying of other causes. Blood analysis showed that pure heroin intoxication was very rare; about 60% of the overdose cases had three or more drugs in blood at the time for death. Segmental hair analysis revealed that more than 80% of the opiate overdose cases had not been exposed to opiates during the most recent weeks before their demise. In most cases, the hair opiate concentrations displayed a gradual decrease before the last dose. The toxicological results also showed that opiate overdose death was more likely to occur if opiates were combined with benzodiazepines, but less likely when opiates were combined with stimulants such as amphetamines. An experimental model was developed to address the issue of tolerance and abstinence in opiate overdose death. Rats given a high dose of morphine or heroin showed a reduced mortality if pre-treated for two weeks with morphine. This protection was reduced if the pre-treatment was followed by one week of opiate abstinence. Delayed deaths, similar to those observed in a proportion of human heroin overdose victims, were also seen in the rats. Toxicological results showed that delayed deaths were not due to accumulation of morphine or morphine glucuronides in either blood or other tissues examined. In conclusion, these studies provide support for the notion that polydrug use and recent opiate abstinence are important risk factors for opiate overdose death. LIST OF PUBLICATIONS I. Kronstrand R, Nystrom I, Strandberg J, Druid H. Screening for drugs of abuse in hair with ion spray LC-MS-MS. Forensic Science International 2004;145(2-3):183-90 II. Druid H, Strandberg JJ, Alkass K, Nystrom I, Kugelberg FC, Kronstrand R. Evaluation of the role of abstinence in heroin overdose deaths using segmental hair analysis. Forensic Science International 2006 March 22; [Epub ahead of print] III. Strandberg JJ, Kugelberg FC, Alkass K, Gustavsson A, Zahlsen K, Spigset O, Druid H. Toxicological analysis in rats subjected to heroin and morphine overdose. Toxicology Letters 2006;166(1):11-8. IV. Strandberg JJ, Alkass K, Nystrom I, Kugelberg FC, Kronstrand R, Druid H. Abstinence, polydrug use and changes in abuse pattern are common in fatal opiate overdose. Submitted