Full length articleCircumstances and toxicology of sudden or unnatural deaths involving alprazolam
Introduction
Alprazolam is a rapid onset, high potency triazolobenzodiazepine with a an average half-life of 11 h, widely used in the treatment of anxiety and panic disorders (Baselt, 2011, Márquez et al., 2011, Verster and Volkerts, 2004). The toxicity of alprazolam is considered to be greater than that of other commonly used benzodiazepines, such as diazepam, and is exacerbated by concomitant central nervous system (CNS) depressant use (Isbister et al., 2004, Jones and Holgrem, 2013, Lee et al., 2012).
There has been a great deal of concern in recent times regarding alprazolam, relating to increased prescribing rates, abuse, and drug-related mortality. Significant increases in the number of emergency room presentations and fatal toxicity cases involving alprazolam have been reported, most commonly in combination with other drugs (Jones and Holgrem, 2013, Maxwell, 2011, Rintoul et al., 2013, Shah et al., 2012, Wolf et al., 2005, Wunsch et al., 2009). Much of the increase in toxicity cases involving alprazolam appears due to its widespread use by injecting drug users (IDU), among whom benzodiazepines (and rapid onset benzodiazepines in particular) have long been popular (Darke et al., 2010, Forrester, 2006, Horyniak et al., 2012, Lee et al., 2012, Shah et al., 2012). It is worthy of note that while widely popular amongst IDU, benzodiazepines are not prescribed for the long-term management of drug problems such opioid dependence (NSW Health, 2006).
Few large scale case series have reported on the circumstances, toxicology and disease profile of alprazolam-related death (Jenkins et al., 1997, Jones and Holgrem, 2013, Shah et al., 2012, Wolf et al., 2005). As noted recently by Jones and Holmgren (2013), the forensic toxicology of alprazolam-related death is not well documented. Therapeutic, toxic and fatal ranges vary widely and overlap, although concentrations greater than 0.10 mg/L are generally considered toxic (Baselt, 2011, Jones and Holgrem, 2013, Shah et al., 2012). Moreover, blood concentrations of toxicity cases involving alprazolam have been shown to overlap with non-toxicity deaths, as well as with those of impaired drivers (Jones and Holgrem, 2013, Wolf et al., 2005). Concomitant drug use is almost universally reported, most notably CNS depressants such as diazepam, opioids and alcohol, and psychostimulants such as cocaine and methamphetamine (Jones and Holgrem, 2013, Maxwell, 2011, Shah et al., 2012, Wolf et al., 2005). The role of alprazolam in such polydrug deaths is unclear. In cases involving opioids and/or alcohol alprazolam, as a respiratory depressant itself, is likely to further contribute to the respiratory depression that these drugs engender (Baselt, 2011). While the depressant effects of each drug individually may not be toxic, their combined effects may produce substantial respiratory depression. Indeed, it was recently reported that alprazolam concentrations were significantly lower in toxicity cases involving other drugs than those involving alprazolam alone (Maxwell, 2011, Shah et al., 2012). To our knowledge, only one study has reported on the disease profile, or possible role of disease, in cases of alprazolam-related death (Shah et al., 2012). The authors reported noting a significantly greater degree of cardiovascular disease than seen in drug-related deaths not involving alprazolam.
The current study aimed to provide new data on trends, characteristics and clinical presentation sudden or unnatural death involving alprazolam across a 15 year period. We examined all cases presenting to the New South Wales Department of Forensic Medicine (DOFM) between 1997 and 2012 in which the alprazolam was detected in standard toxicological tests conducted as part of the medico-legal process. The DOFM is located in central Sydney, and is the primary forensic pathology centre in New South Wales (NSW), conducting between 2000 and 2500 autopsies per year. Specifically the study aimed to: 1.) determine the characteristics, circumstances and causes of death of sudden or unnatural deaths involving alprazolam; and 2.) determine the toxicology of sudden or unnatural deaths involving alprazolam.
Section snippets
Case identification
Autopsy reports and police summaries of all cases in which blood alprazolam was detected and who underwent autopsy at the DOFM between 1 January, 1997 and 31 December, 2012 were retrieved. Permission to inspect the files was received from the Sydney Local Health District human research ethics committee. All cases were reviewed by the authors.
In NSW a case must be reported to the Coroner in a range of circumstances, including principally where a person dies a violent or unnatural death or where
Cases and circumstances of death
A total of 412 cases were identified. There was a large increase in annual cases, from 3 in 1997 to 86 in 2012 (Table 1). Cases increased sharply from 2009, and 81.6% of all cases occurred between 2009 and 2012. Overall, 1.3% of all case presentations to the DOFM across the study period involved alprazolam, rising from 0.1% in 1997 to 4.5% by 2012. There were no significant variance in cases by day of the week (p = .92), or month (p = .17).
The most common circumstance of death was drug toxicity
Discussion
Clinical concerns regarding increased prescribing and abuse of alprazolam appeared to be substantiated by the results of this study. Across the study period, the number of sudden or unnatural deaths involving alprazolam presenting to DOFM increased dramatically. By 2012, nearly 5% of all cases presenting to DOFM had alprazolam present. Of course, a rise in presentations per se might simply be a marker for the increased prescribing rates seen in Australia (Rintoul et al., 2013). These increases
Role of funding source
This research was funded by the National Drug and Alcohol Research Centre.The National Drug and Alcohol Research Centre had no role in study design; the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
Professor Darke designed the study, aided in data collection and conducted the statistical analyses and write-up of the paper. Ms Torok participated in data collection, data entry, analysis and review of the manuscript. Associate Professor Duflou aided in study design, conducted case searches and generated the case list, provided specialist medical comment, and reviewed the manuscript.All authors contributed to and have approved the final manuscript.
Conflict of interest
None to declare.
Acknowledgement
The National Drug and Alcohol Research Centre at the University of NSW is supported by funding from the Australian Government. We wish to thank Vera Aldertonand Michael Farrell for their assistance.
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