Search

Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). To examine whether certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p-glycoprotein) transporter. Our results did not support this hypothesis, because no statistically significant difference (p = 0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p = 0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p = 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Drugs contributing to overdose deaths are listed on death certificates, but their validity is rarely studied. To assess the accuracy of "morphine" and "codeine" listings on death certificates for unintentional overdose deaths in Allegheny County, PA, investigative and laboratory reports were reviewed. Deaths were reclassified as heroin-related if documentation showed 6-monoacetylmorphine in blood or urine, "stamp bags" or drug paraphernalia at scene, history of heroin use, or track marks. Deaths were considered morphine-related if notes indicated morphine use, prescription, or morphine at scene, or codeine-related if the codeine blood level exceeded morphine. Of 112 deaths with morphine but not heroin listed on the death certificate, 74 met heroin criteria and 21 morphine criteria. Of 20 deaths with both morphine and heroin listed, only one met morphine criteria. Of 34 deaths with codeine listed, only five were attributed to codeine. Consideration of patient history, death scene evidence, and expanded toxicology testing may improve the accuracy of death certificate drug listings., (© 2014 American Academy of Forensic Sciences.)

The codeine to morphine concentration ratio is used in forensic toxicology to assess if codeine has been ingested alone or if morphine and/or heroin have been ingested in addition. In our experience, this interpretation is more difficult in autopsy cases compared with samples from living persons, since high morphine concentrations are observed in cases where only codeine is assumed to have been ingested. We have investigated if codeine and morphine glucuronides are subject to cleavage to the same extent in living and autopsy cases in vitro. We included whole blood samples from eight living subjects and nine forensic autopsy cases, where only codeine ingestion was suspected. All samples were incubated for 2 weeks at 37°C and analyzed for codeine and six codeine metabolites using liquid chromatography tandem mass spectrometry. A reduction in the codeine to morphine concentration ratio was found, both in samples from living subjects (mean 33%, range 22-50%) and autopsy cases (mean 37%, range 13-54%). The increase in the morphine concentrations was greater in the autopsy cases (mean 85%, max 200%) compared with that of the living cases (mean 51%, max 87%). No changes were seen for codeine or codeine-6-glucuronide concentrations. The altered ratios might mislead the forensic toxicologist to suspect morphine or heroin consumption in cases where only codeine has been ingested.

A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is therefore objected.

Background: Substance use disorders have repeatedly been found to lead to premature death, i.e. drug-related death by disease, fatal intoxications, or trauma (accidents, suicide, undetermined suicide, and homicide). The present study examined the relationship between multi-drug substance use and natural and unnatural death., Methods: All consecutive, autopsied patients who had been in contact with the Addiction Centre in Malmö University Hospital from 1993 to 1997 inclusive were investigated. Drug abuse was investigated blindly in the case records and related to the cause of death in 387 subjects., Results: Every substance apart from alcohol used previously in life added to the risk of unnatural death in a linear way. There were independent increased risks of fatal heroin overdoses or undetermined suicide. Death by suicide and violent death were unrelated to additional abuse., Conclusion: The number of drugs used was related to an increased risk of unnatural death by undetermined suicide (mainly fatal intoxications) and heroin overdose.

Introduction: The purpose of this study was to investigate deaths among drug addicts in Eastern Denmark in 2005, partly fatal poisonings, partly deaths where the cause of death not was a poisoning and to compare the results with those reported in studies from 1991, 1997 and 2002., Material and Methods: All deaths among drug addicts investigated at the Institute of Forensic Medicine in Copenhagen., Results: The number of deaths among drug addicts was 160 of which 64% were due to fatal poisoning. The number of drug addict deaths has remained almost constant in the period 1991-2005, but in 2002 and 2005 a decrease of about 10% was seen in the fraction of fatal poisonings. As in 2002, a decrease in the fraction of heroin/morphine poisonings was seen, and an increase in the fraction of methadone poisonings with a proportion of heroin/morphine poisonings of 17% and a proportion of methadone poisonings of 39%. As in the previous studies, the most commonly detected drugs were methadone, heroin/morphine, benzodiazepines and cannabis and, as in 2002, methadone was more frequently detected than heroin/morphine. In the non-poisoning deaths, the most frequent manner of death was natural death (44%). In 12% the manner of the death was suicide, in 14% death was accidental, in 4% homicide was the manner of death and in 26% the manner of death was undetermined., Conclusion: The increase in the number of fatal poisonings with methadone and the decrease in the number of fatal poisonings with heroin/morphine seen in the 2002 study continued in 2005. The poly-drug use had increased in 2005 with more drugs detected in each case than before.

Aims: To analyse the demographic data from fatalities arising directly from illicit drug abuse in the Grampian area and compare the findings with trends in drug seizures in Grampian to ascertain if these reflect the recorded deaths, and to attempt to identify a subgroup of the abusing population which might be at greater danger from overdose of controlled substances., Methods: Cases in which the cause of death was directly attributed to illicit drugs from the beginning of January 1995 until the end of December 1999 were identified, and their epidemiological and toxicological data were analysed. The information regarding drug seizures was gained from Home Office publications for the same time period., Results: One hundred and thirteen cases were retrieved consisting of 93 males and 20 females, aged 16 to 43 years (Median 25). The most commonly isolated substance was morphine followed by benzodiazepines. In 97 cases two or more drugs were involved with five cases showing positive toxicology for four or more drugs. Of the female deaths 75% fell into the 16-25 year age range. Drug seizures rose by 49% from 1995 to 1998 with both heroin and benzodiazepine seizures increasing by more than five fold in the same period., Conclusions: Deaths directly due to illicit drugs showed a significant increase over the study period and were concentrated in the young male population. The drug seizures increased but the extent of this was not mirrored in the deaths. A shift in emphasis to an older age group is also indicated; drug misuse educational programmes should continue to be targeted at all populations but information may also be targeted at the older age groups and at females under 25 years of age.

This study includes all deaths among drug addicts in the years 1991 (n = 219) and 1992 (n = 214) investigated at the three institutes of forensic medicine in Denmark. The results are compared with deaths among drug addicts in 1984-1985. The number of deaths among drug addicts increased by approximately 50% in 1991-1992 compared with 1984-1985. The increase was most significant among drug addicts over 35 years of age. The cause of death was intoxication in three-quarters of the cases in 1991-1992. In half of these cases heroin/morphine had caused death, while intoxications caused by methadone accounted for approximately 30% of the cases. In the metropolitan area the frequency of methadone intoxications increased significantly compared with 1984-1985, whereas the number of heroin/morphine intoxications did not change. Outside the metropolitan area, however, a significant increase in heroin/morphine intoxications was noticed. In all parts of the country the number of propoxyphene intoxications decreased to a few annual cases. The most commonly used drugs of abuse were heroin/morphine, diazepam and methadone, often in combination with alcohol.

Cases of fatal poisoning among drug addicts examined at the institutes of forensic medicine in Aarhus, Denmark (n = 238) and Oslo, Norway (n = 263) are compared and discussed on the basis of the availability of illicit and medical drugs during the 1980s. The annual number of deaths among drug addicts in age groups over 30 years increased, but there was no increase in the number of deaths among younger drug addicts in either country. More than 80% of the drug addicts in both samples were men. Heroin-/morphine-related deaths comprised three-quarters of the Norwegian material compared with one-third of the Danish material. The registered medical drugs propoxyphene, methadone and ketobemidone accounted for half of the Danish cases but only a small number of the Norwegian cases. Amphetamine caused few deaths in either country. Alcohol and benzodiazepines were present in more than one-third of the cases in both countries, indicating frequent use of these substances.

Drug addicts who had died in Copenhagen City and County in 1981 and 1989 were analysed for methadone. In 1981, 94 cases were analysed of which 16% were found positive for methadone, and in 1989, 70 cases were analysed of which 37% were positive. Methadone alone was found to be the cause of death in 50% more cases in 1989 than in 1981. Only half of the drug addicts who were found positive for methadone had been under methadone treatment. Morphine and benzodiazepines were the most frequently occurring other substances in both 1981 and 1989. Alcohol was found in only about 30% of the methadone-positive cases. The median whole blood concentrations of methadone found in addicts where methadone was the cause of death was 0.3 mg/kg where no alcohol was present and 0.2 mg/kg where alcohol was present. In living persons using methadone, the median was 0.1 mg methadone/kg whole blood with or without alcohol present.

Five different strains of mice were investigated for their suitability to serve as models for the study of long-term effects of propoxyphene napsylate (PN) on narcotic-dependent mice. The NIH/Swiss outbred strain proved to be most suitable because of its high liability to manifest physical dependence on morphine. Following removal of subcutaneously-implanted morphine pellets from the mice, the incidence of spontaneous withdrawal jumping was used as a quantifiable criterion of physical dependence. An orally administered suspension of PN suppressed the withdrawal jumping in a dose-dependent manner. However, chronic (daily) administration of PN at doses high enough to prevent withdrawal jumping was characterized by a high degree of toxicity.

From 1918 to 1920, the police department of New Haven, Connecticut, operated a maintenance clinic for morphine addicts. The clinic registered 91 patrons by September 1920, when the facility was closed because of a change in federal narcotics-regulation policies. Death certificates recovered for 40 of the 91 registrants (44 per cent) show that the patrons mean age of death was 55.9 years. Although this age is 13 years younger than the mean age of death of the general population, it is comparable to the death rates for lower socioeconomic groups. The causes of death of the 40 patrons were rarely related to drugs; however, like nonaddicted persons in lower socioeconomic groups, the patrons faced higher risks of alcoholism, infectious diseases, suicide, and accidents. Thus, although many in the group appear to have freed themselves from drug addiction, they continued to face other hazards predisposing them to premature mortality.

Fatal intoxications with morphine derivatives have become increasingly common in Sweden. Toxicologic data and pathologic findings in 34 cases of morphine intoxications from 1966 to 1974 in Sweden are presented. From 1972 on when morphine the black market, lethal intoxications with centrally stimulation amines.

In the period 1968-1986 a total of 1618 fatalities among drug addicts were investigated at the three University Institutes of Forensic Medicine in Denmark. The annual number rose from 5 in 1968 to 163 in 1980, thereafter there has been a gradual fall to 121 in 1986. About 80% were males. The average age has risen from 22/23 years in the early 1970s to 31 years in 1986, and the percentage of addicts with a duration of abuse more than 10 years has increased gradually; both facts indicate a decrease in the recruitment among the quite young. In the whole period morphine was abused, supplemented by various medicines. Amphetamine was abused in the first years and again in 1986. The percentages of addicts with an abuse of alcohol and of addicts dying after a period of abstinence lasting more than 1 year, respectively, have increased. No essential changes were observed regarding distribution of residence or of the cause and manner of death. In the poisoning cases the predominant drug of poisoning was morphine/heroin, in all the years constituting approx. 30-50%. The second most frequent drugs of poisoning in the first half of the period was barbiturate, in the last half dextropropoxyphene and methadone. Only very few cases dying of cocaine poisoning were present and deaths due to so-called designer drugs have not been observed.

300 young morphine addicts in Copenhagen were personally followed up 7 years after their first referral for treatment. The tracking rate was 93.7%. Of the original population, approximately 2% died yearly, i.e. 16%. Each year 5-6% ceased drug abuse, and in 1980, 39% were characterized as being socially well adjusted. In all, 20% remained heavy drug users, though some had changed to other drugs.

The files of the Casualty Branch of the Military Personnel Center, Europe, Seventh Medical Command, and of the U.S. Army's Tenth Medical Lab were used to examine the epidemiology of "overdose" deaths of U.S. Army soldiers in Europe during the calendar years 1978 and 1979. A total of 91 cases were so identified; i.e., death was the direct result of injection, inhalation, or ingestion of an intoxicant, legal or illegal. Not included were deaths caused by trauma or drowning while intoxicated, deaths from disease secondary to chronic drug or alcohol abuse, and deaths due to chemicals not widely viewed as intoxicants. The monthly distribution of cases showed a spring peak similar to that reported by several studies of U.S. civilian drug deaths. No such similarity was apparent in terms of victim characteristics and circumstances, with soldier victims being nearly always male, equally often White as Black, 20-24 years old, very rarely suicides, and nearly always using heroin and/or alcohol. "Control" data from circumscribed subgroups of nonvictim European soldiers, however, show that victims did not differ markedly from the junior enlisted population from which they came, as least on the variables generally available in personnel and medical records.

Two hundred eighty-seven deaths directly related to narcotic abuse occurred in the District of columbia between July 1971 and December 1979. Factors contributing to death in some cases included lack of opiate tolerance as well as the conjoint abuse of ethanol. Free morphine was identified more often in the blood of victims dying rapidly than in the blood of those with longer post-injection survival. A statistically significant correlation between the number of heroin-related fatalities and the purity of heroin available to the user was observed over the 8 1/2-year study period.

Morphine, the active metabolite of heroin, is rapidly inactivated by glucuronidation at the 3 carbon. Unconjugated (pharmacologically active) morphine was measured in postmortem blood by radioimmunoassay using an antibody-coated tube kit. The kit shows less than 0.2% cross-reactivity with codeine and morphine-glucuronide. Unconjugated morphine concentrations were confirmed by gas chromatography/mass spectrometry (GC/MS) using deuterated morphine as the internal standard. The blood was precipitated with 10% trichloroacetic acid (TCA) and concentrated hydrochloric acid (HCl), centrifuged, and decanted. The supernatant was then either diluted (unhydrolyzed) or heated to 100 degrees C, 30 min (hydrolyzed), followed by a wash with 4:1 chloroform:isopropranol. The upper aqueous layer was then saturated with sodium bicarbonate (NaHCO3) and extracted with 4:1 chloroform:isopropranol. The organic layer was evaporated, derivatized with trifluoroacetic anhydride (TFA), and analyzed by selected ion monitoring (SIM) GC/MS. Comparison of the results for unconjugated morphine by radioimmunoassay and unhydrolyzed morphine by GC/MS gave a correlation coefficient of r = 0.98, n = 100. Unconjugated morphine ranged from 0 to 100% of total morphine with a mean of 42%, n = 200, for heroin or morphine involved deaths. Review of 56 putative rapid deaths gave a mean of 68% unconjugated morphine with a range of 26 to 100%. The ratio of unconjugated to total morphine was found to be stable in postmortem blood after more than a year of storage at room temperature, within the precision of the method.