Jennifer L. Pilgrim

Involvement of Amphetamines in Sudden and Unexpected Death

Abstract:  In the present study, the effects of amphetamine‐class drugs were examined in cases reported to the Victorian coroner from 2001 to 2005 to determine if death can occur from the use of amphetamine‐class drugs alone. A total of 169 cases were reviewed where a forensic autopsy detected amphetamine(s) in the blood. Pathology, toxicology, and police reports were analyzed in all cases to ascertain the involvement of amphetamine‐class drugs in these deaths. In Victoria, methamphetamine (MA) is the principal abused amphetamine‐class followed by methylenedioxymethamphetamine (MDMA). There were six cases in which a cerebral hemorrhage caused death and three cases in which serotonin syndrome was established as being caused by the interaction of MDMA and moclobemide. There were 19 cases in which long‐term use of amphetamines was associated with heart disease. There were three cases where amphetamine‐class drugs alone were regarded as the cause of death, of which two cases exhibited high levels of MDMA and lesser amounts of MA and/or amphetamine. There were no cases in which significant natural disease was absent and death was regarded as caused by the use of MA. There was no correlation between blood concentration of drug and outcome.

Review: Pharmacogenetic aspects of the effect of cytochrome P450 polymorphisms on serotonergic drug metabolism, response, interactions, and adverse effects

The field of pharmacogenetics contains a wealth of potential for the enhancement of clinical practice by providing a more effective match between patient and drug, consequently reducing the probability of an adverse drug reaction. Although a relatively novel concept in the forensic context, pharmacogenetics has the capability to assist in the interpretation of drug related deaths, particularly in unintentional drug poisonings where the cause of death remains unclear. However, the complex pharmacology of the drugs when subjected to genetic variations in metabolism makes interpretation of the expected response and adverse events difficult. Many possess multiple metabolic pathways, narrow therapeutic indices and active metabolites or enantiomers which may be eliminated via different pathways to the parent drug. A number of these drugs, which are metabolised primarily by the CYP450 system, are also associated with serotonin syndrome, or serotonin toxicity, especially when used concomitantly with other serotonin active drugs which rely on the same metabolic pathways for drug elimination. A comprehensive understanding of polymorphic drug metabolism and its expected outcomes is therefore essential when interpreting the involvement of drugs in adverse reactions. This review examines the genetically variable CYP450-mediated metabolism of a number of serotonin-active drugs that are often implicated in cases of serotonin toxicity, to assess the impact of pharmacogenetics on drug metabolism, response, interactions and adverse effects.

Trends in fentanyl prescriptions and fentanyl‐related mortality in Australia

INTRODUCTION AND AIMS The study aims to quantify trends in fentanyl prescribing and fentanyl mortality in Australia within the context of concern among health professionals concerning increasing accessibility of fentanyl, and the harms that may arise as a result. DESIGN AND METHODS This paper presents data on prescribing patterns of fentanyl by 10 year age group adjusted by population rate, detailed analyses of fentanyl-related deaths from the National Coronial Information System and deaths adjusted for prescribing levels within Australia. RESULTS Fentany prescriptions have increased and are most prevalent among Australians aged over 80 years. One hundred and thirty-six fentanyl-related deaths were recorded during 2000-2011; 54% of decedents had a history of injecting drug use and, among this group, 95% had injected fentanyl at the time of death; 62% of deaths recorded misuse (most notably injection) of fentanyl; 50% recorded a history of drug dependence and 40% a mental health problem; 37% recorded a history of chronic pain; and 36% recorded fentanyl as being prescribed at the time of death. Deaths were primarily among Australians under 47 years of age. DISCUSSION AND CONCLUSIONS There have been significant increases in fentanyl prescribing in Australia. It is unclear what proportion of this increase represents legitimate treatment of pain. Fentanyl deaths have also increased, although mortality is currently low in Australia. A large proportion of the deaths involved the injection of diverted fentanyl, highlighting the need for messages regarding safer injecting practices targeting people who inject drugs, and strategies to minimise the risks of diversion.

Cocaine in sudden and unexpected death: a review of 49 post-mortem cases.

Cocaine is a potent sympathomimetic drug that is associated with cardiotoxicity, including ventricular arrhythmia, systemic hypertension, acute myocardial infarction and left ventricular hypertrophy. The use of cocaine in Australia has risen steadily since the late 1990s. What remains unclear in the literature is whether cocaine-associated death can occur in the absence of other contributing factors, such as concomitant drug use or natural disease. A search was conducted on the National Coroners Information System database, to identify all deaths occurring in Victoria, Australia, between January 2000 and December 2011, where cocaine or its metabolites were detected by post-mortem toxicological analysis. All cases were closed by the Coroner. These cases were examined with regards to case circumstances, pathology and toxicology results, and coronial findings, to determine the prevalence of cardiotoxicity and the involvement of cocaine in the deaths compared with other contributing factors. There were 49 cases where cocaine, benzoylecgonine, ecgonine methyl ester, methylecgonine or cocaethylene, were detected in the 11-year period. The individuals ranged in age from 16 to 70 years (median 30). There were 36 males. In 22 cases the cause of death was determined to be drug toxicity, 22 were external injury and 5 were attributed to natural disease. The concentration of cocaine in the cases was relatively low (range 0.01-3 mg/L, median 0.1 mg/L). Cocaine metabolites were detected frequently in blood and urine: benzoylecgonine (46 cases); ecgonine methyl ester (12 cases); cocaethylene (8 cases); and methylecgonine (9 cases). Opioids were commonly detected (23 cases), in addition to amphetamines (15 cases), ethanol (17 cases) and benzodiazepines (12 cases). Of the 43 cases receiving a full autopsy, there were 14 cases involving significant heart disease. This included coronary artery disease (11 cases), an enlarged heart (5 cases), myocarditis and contraction band necrosis. Cocaine is detected relatively infrequently in Victorian coronial cases. However it appears to be associated with a significant degree of cardiotoxicity, particularly coronary artery disease and ventricular hypertrophy, independent of cocaine concentration.

Deaths involving contraindicated and inappropriate combinations of serotonergic drugs

In the Australian state of Victoria, all fatalities that were recorded from 2002 through to 2008 involving the use of certain serotonin active drugs (tramadol, venlafaxine, fluoxetine, sertraline, citalopram and paroxetine), were reviewed to assess the incidence of contraindicated or ill advised drug combinations. More than 1,000 were identified of which 326 cases formed the basis of this study. These cases involved contraindicated or inappropriate drug combinations that can lead to adverse drug reactions (ADRs) and subsequent fatal toxicity. Of these, 46% were drug-related, 35% were a result of natural disease and 13% were classified as external injury cases. The remaining cases were those where the cause of death (COD) was unascertained. Tramadol was the most common drug, usually detected alongside a serotonergic antidepressant (in 20% of cases). Twenty-five (8%) cases involved contraindicated drug combinations while the remainder (301 cases, 92%) involved drug combinations that are associated with adverse interactions ranging from minor to major severity. Of these 326 cases, the Coroner determined 166 cases (51%) to be acts of intentional self-harm or drug misuse, with the remainder unascertained or attributed to natural disease. Very few post-mortem reports and Coroners’ findings made mention of possible ADRs when such combinations were actually present. The majority of cases comprising contraindicated drug combinations involved the combined use of five drugs (24%) at the time of death. A combination of three to five drugs was most common in cases involving inadvisable drug combinations. Combined drug toxicity was the most common COD, with heart disease the most common co-morbidity.

Deaths involving serotonergic drugs

Serotonin-active drugs are detected relatively frequently in Victorian deaths. During 2002-2008, there were 1123 fatalities where one or more of the serotonin-active drugs tramadol, venlafaxine, fluoxetine, sertraline, citalopram, paroxetine and MDMA, were detected. These deaths were reviewed using pathology, toxicology and police reports, to determine the contribution of these drugs to the cause of death, particularly if serotonin toxicity was the mechanism of death. There were 28 cases of most interest to this research because of the presence of the target drugs and the circumstances suggesting the likelihood of serotonin toxicity involvement in death. There were 5 cases of reported serotonin toxicity and 23 other deaths suspected to have involved this form of toxicity. Tramadol featured most commonly out of the seven target drugs and was frequently detected in combination with serotonergic antidepressants. MDMA was also detected relatively commonly and was associated with moclobemide in 4 cases of confirmed serotonin toxicity. There were an additional 1095 cases where natural disease, external injury or the misuse of other drugs caused death, of which 2 reported the incidental contribution of serotonin toxicity.

Trends and characteristics of accidental and intentional codeine overdose deaths in Australia

Objectives: To examine trends in codeine‐related mortality rates in Australia, and the clinical and toxicological characteristics of codeine‐related deaths.

A review of methadone deaths between 2001 and 2005 in Victoria, Australia.

This study examined methadone-associated deaths reported to the Coroner in Victoria, Australia, between 2001 and 2005. There were 206 deaths involving methadone, attributed predominantly to drug toxicity (137 cases), in addition to natural disease (24 cases), external injuries (44 cases) and one case where the cause was unascertained. The number of deaths each year did not rise significantly. There were 38 cases involving Physeptone(®) for chronic pain, 36 cases (14%) that were regarded as diversion deaths and 9 cases where the source of methadone was unknown. The remainder involved patients in opioid replacement therapy. Diversion deaths were signified by the unprescribed use of methadone by an individual not possessing a valid permit from the Victorian Department of Health. In these cases, the Coroner also described illicit use of the drug in the findings. Fifty-one individuals (25%; 15 female and 36 males) died within 14 days of commencing opioid replacement therapy with methadone administered via syrup. Many of these cases involved rapid dose increases of up to 25mg per day. The median starting dose was 35 mg and the median (mean; range) blood methadone concentration was 0.5mg/L (0.6 mg/L; 0.1-3.0mg/L). A number of cases were identified as having too high a starting dose, with 44% starting on 40 mg or more. The OD4-methadone index indicated a substantial increase in relative methadone toxicity from around 28 per million DDDs in the early 1990 s to over 60 in 2005. Ninety-eight percent of cases involved the use of other CNS depressants including: opioids, antidepressants, antipsychotics and ethanol, with benzodiazepines most common (88% confirmed positive). Improvements in the management of ORT, particularly in the induction period, has the potential to reduce mortality of patients receiving methadone.

The role of toxicology interpretations in prevention of sudden death

Inappropriate combinations of pharmaceutical drugs are often detected in deaths reported to a coroner. However, the involvement of drug combinations in the cause of death can be overlooked in cases when significant natural disease or external injury is also present. This study examined pathology reports and coroner’s findings between January 2002 and December 2008. Cases that included exposure to a selection of serotonergic drugs were examined to determine the role of different death investigators in drug-associated deaths in Victoria, Australia. Of the 326 cases identified, the involvement of drugs in the death was discussed to some degree in 66% of cases. Recommendations by the coroner pertaining to death prevention were made in 12 cases (4%). In 16 cases (5%) the drugs were not mentioned in the findings, including at least 11 cases of probable major adverse drug interactions. Death investigations serve an important public health and safety role, however, the potential involvement of drugs in many cases is not always recognized.

Completed suicide among nursing home residents: a systematic review

The aim of this study is to systematically review published research describing the frequency, nature, and contributing factors of completed suicides among nursing home residents.