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Alprazolam in fatal overdose following regulatory rescheduling: A response to Deacon et al.
International Journal of Drug Policy 39 (2017) 138–139
Contents lists available at ScienceDirect
International Journal of Drug Policy journal homepage: www.elsevier.com/locate/drugpo
Response
Alprazolam in fatal overdose following regulatory rescheduling: A response to Deacon et al. Belinda Lloyda,b,* , Jeremy Dwyerc,d, Lyndal Bugejac, Audrey Jamiesonc a
Turning Point, 54-62 Gertrude Street, Fitzroy, VIC 3065, Australia Eastern Health Clinical School, Monash University, 5 Arnold Street, Box Hill, Australia c Coroners Court of Victoria, 65 Kavanagh Street, Southbank, VIC 3006, Australia d Melbourne School of Population and Global Health, The University of Melbourne, Level 4, 207 Bouverie Street, VIC 3010, Australia b
Deacon et al.’s (2016) finding that the rescheduling of alprazolam was followed by an overall decrease in alprazolam and total benzodiazepine use among a sample of Sydney opioidsubstitution treatment clients, is welcome news for those working to reduce benzodiazepine-related harms in Australia. However, as the authors note, the study examined a very specific population of drug users; information from other sources is needed to establish the range of impacts on drug use and drug-related harms. To this end we present recent data from the Coroners Court of Victoria (CCOV) overdose deaths register, which suggests the rescheduling had mixed effects. The overdose deaths register is implemented consistently with the Substance Abuse and Mental Health Services Administration (SAMHSA) Consensus Panel recommendations for determining and documenting drug poisoning deaths (Goldberger, Maxwell, Campbell, & Wilford, 2013). Regular searches are conducted across coronial databases to identify Victorian deaths where the expert death investigators (the coroner, forensic pathologist and forensic toxicologist) established that the acute toxic effects of a drug or drugs played a causal role. For each such overdose death the individual drugs that the expert death investigators determined were contributory are recorded in the register; information regarding drugs that were detected but not determined to be contributory is not recorded. Early data from the register, showing that benzodiazepines played a contributory role in 49% of Victorian overdose deaths during 2010, informed a Victorian coroner’s recommendation that the Therapeutic Goods Administration (TGA) move all benzodiazepines into Schedule 8 of the Standard for the Uniform Scheduling of Medicines and Poisons (Jamieson, 2012). This recommendation became the initiating application for the consultation and evaluation process that culminated in the TGA’s June 2013 final decision to reschedule alprazolam. Subsequently the coroner expressed concern that recurring issues encountered when
* Corresponding author at: Turning Point, 54-62 Gertrude Street, Fitzroy, VIC 3065, Australia. Fax: +61 3 9416 3420. E-mail address: [email protected] (B. Lloyd). http://dx.doi.org/10.1016/j.drugpo.2016.10.008 0955-3959/ã 2016 Published by Elsevier B.V.
investigating Victorian overdose deaths – including benzodiazepine dependence, misuse, prescription shopping, and poor prescribing practices – are common to all benzodiazepines, so rescheduling only alprazolam is unlikely to result in an overall reduction in benzodiazepine contribution to overdose death (Jamieson, 2014). To examine whether there was early evidence to support this concern, we extracted aggregate data on annual frequencies of Victorian overdose deaths involving relevant drugs from the register for the period 2009–2015. As shown by Schaffer, Buckley, Cairns, & Pearson (2016), alprazolam prescribing reduced following announcement of the rescheduling decision in June 2013, even through implementation of this change did not occur until February 2016. Accordingly, it is important to consider the effect of rescheduling from the point of announcement of any change. Data extraction and reporting did not require any identifying information to be accessed and was determined to present no foreseeable risk of harm, inconvenience or discomfort to a person, and therefore was subject to coronial oversight but not Human Research Ethics Committee review. Table 1 shows that the annual frequency of Victorian fatal overdoses generally rose steadily across the period, from 342 deaths in 2010 to 453 deaths in 2015. The sub-set of these overdose deaths in which one or more benzodiazepines contributed, appeared to follow the same general trend, rising from 160 deaths in 2009 to 238 deaths in 2015 and representing approximately 51.5% of all overdose deaths across the period. In 65.5% of these deaths a single benzodiazepine was contributory; the remaining 34.5% of the deaths involved multiple contributing benzodiazepines (an average of 2.3 contributing benzodiazepines per death). There was a decline in the frequency of overdose deaths involving alprazolam, particularly after 2013; and a steady increase over the course of 2009–2015 in overdose deaths where clonazepam and diazepam contributed. The frequency of overdose deaths involving each of nitrazepam, oxazepam and temazepam fluctuated over time with no clearly discernable trend. Further years of post-rescheduling data are needed before robust statistical analysis can be performed, however these findings together suggest a preliminary conclusion that the rescheduling of
B. Lloyd et al. / International Journal of Drug Policy 39 (2017) 138–139 Table 1 Annual frequency of all overdose deaths, and overdose deaths involving benzodiazepines and other selected drugs, Victoria 2009–2015. Overdose deaths
2009
2010
2011
2012
2013
2014
2015
379
342
362
367
380
387
453
Overdose deaths involving any benzodiazepine 160 169 180 199
212
215
238
Overdose deaths involving specific benzodiazepinesa Alprazolam 62 56 43 57 Clonazepam 7 9 14 18 Diazepam 104 109 124 133 Nitrazepam 17 16 11 24 Oxazepam 18 19 44 41 Temazepam 28 22 48 35
45 19 164 26 17 22
28 25 169 13 19 20
23 33 192 17 34 25
All overdose deaths
a
Multiple specific benzodiazepines may have contributed to a single death.
alprazolam might have reduced alprazolam involvement in Victorian overdose deaths, but it did not appear to interrupt the longer-term upward trend in overdose deaths involving benzodiazepines. Claims regarding the increased toxicity of alprazolam compared with other benzodiazepines are largely based on a much-cited study that found alprazolam overdose was associated with increased length of stay and increased need for medical intervention in a toxicology service compared with other benzodiazepines (Isbister, O’Regan, Sibbritt, & Whyte, 2004). However, the strongest determinant of poorer clinical outcome reported in the study was co-ingestion of other drugs with benzodiazepines, particularly tricyclic antidepressants. This is consistent with literature noting the heightened risk of overdose when benzodiazepines are combined with other drugs (Ashton, 1995; Jones, Mogali, & Comer, 2012). This is also consistent with the CCOV overdose deaths register data, which shows that there were only 28 overdose deaths involving benzodiazepines alone (2%) among the 1373 Victorian overdose deaths involving benzodiazepines between 2009 and 2015. However, benzodiazepines were ubiquitous in overdose deaths involving most other central nervous system depressants. For example, benzodiazepines co-contributed in 899 (69%) of the 1294 Victorian overdose deaths between 2009 and 2015 which involved pharmaceutical opioids; in 675 (74%) of the 910 overdose deaths involving antidepressants; 397 (77%) of 517 deaths involving antipsychotics; 484 (51%) of 948 deaths involving heroin; and 334 (52%) of 641 deaths involving alcohol. These findings indicate that caution should be taken when
139
considering prescribing any benzodiazepine in combination with other drugs. The TGA’s stated reasons for rescheduling alprazolam but not other benzodiazepines included that alprazolam appears to have increased morbidity and mortality in alprazolam overdose compared with other benzodiazepines, possible increased toxicity, and evidence of more prevalent diversion and misuse (Therapeutic Goods Administration, 2013). The initial findings presented here suggest that benzodiazepines as a class are involved in fatal overdose, and tackling individual benzodiazepines might not impact on overall benzodiazepine involvement. If analogous findings emerge from examining how other measures of drug use and drug related harms (such as ambulance attendances for non-fatal overdose and drug use patterns among people who inject drugs) have changed following the rescheduling, the TGA decision should be reviewed with some urgency: first, because it will not have improved overall public health and safety; and second, because of the inaccurate impression it creates among prescribers and patients that Schedule 4 benzodiazepines are somehow ‘safer’ than alprazolam.
References Ashton, H. (1995). Toxicity and adverse consequences of benzodiazepine use. Psychiatric Annals, 25(3), 158–165. Deacon, R. M., Nielsen, S., Leung, S., Rivas, G., Cubitt, T., Monds, L. A., et al. (2016). Alprazolam use and related harm among opioid substitution treatment clients— 12 months follow up after regulatory rescheduling. International Journal of Drug Policy, 36, 104–111. http://dx.doi.org/10.1016/j.drugpo.2016.06.006. Goldberger, B. A., Maxwell, J. C., Campbell, A., & Wilford, B. B. (2013). Uniform standards and case definitions for classifying opioid-related deaths: recommendations by a SAMHSA consensus panel. Journal of Addictive Diseases, 32(3), 231–243. Isbister, G. K., O’Regan, L., Sibbritt, D., & Whyte, I. M. (2004). Alprazolam is relatively more toxic than other benzodiazepines in overdose. British Journal of Clinical Pharmacology, 58(1), 88–95. Jamieson, A. (2012). Finding with inquest into the death of David Andrew Trengrove. . . Retrieved on 5 July 2016 from http://www.coronerscourt.vic.gov.au/home/ coroners+written+findings/findings+-+404208+david+andrew+trengrove. Jamieson, A. (2014). Finding without inquest into the death of Kirk Steven Ardern. . . Retrieved on 5 July 2016 from http://www.coronerscourt.vic.gov.au/home/ coroners+written+findings/findings+225412+kirk+ardern. Jones, D. J., Mogali, S., & Comer, S. D. (2012). Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence, 125, 1–2. http:// dx.doi.org/10.1016/j.drugalcdep.2012.07.004. Schaffer, A. L., Buckley, N. A., Cairns, R., & Pearson, S. (2016). Interrupted time series analysis of the effect of rescheduling alprazolam in Australia: taking control of prescription drug use. JAMA Internal Medicine, 176(8), 1223–1225. Therapeutic Goods Administration (2013). Scheduling delegate’s final decisions: ACCS/ ACMS June 2013. . . Retrieved on 5 July 2016 from https://www.tga.gov.au/book/ part-scheduling-proposals-referred-march-2013-meeting-acms.
Contents lists available at ScienceDirect
International Journal of Drug Policy journal homepage: www.elsevier.com/locate/drugpo
Response
Alprazolam in fatal overdose following regulatory rescheduling: A response to Deacon et al. Belinda Lloyda,b,* , Jeremy Dwyerc,d, Lyndal Bugejac, Audrey Jamiesonc a
Turning Point, 54-62 Gertrude Street, Fitzroy, VIC 3065, Australia Eastern Health Clinical School, Monash University, 5 Arnold Street, Box Hill, Australia c Coroners Court of Victoria, 65 Kavanagh Street, Southbank, VIC 3006, Australia d Melbourne School of Population and Global Health, The University of Melbourne, Level 4, 207 Bouverie Street, VIC 3010, Australia b
Deacon et al.’s (2016) finding that the rescheduling of alprazolam was followed by an overall decrease in alprazolam and total benzodiazepine use among a sample of Sydney opioidsubstitution treatment clients, is welcome news for those working to reduce benzodiazepine-related harms in Australia. However, as the authors note, the study examined a very specific population of drug users; information from other sources is needed to establish the range of impacts on drug use and drug-related harms. To this end we present recent data from the Coroners Court of Victoria (CCOV) overdose deaths register, which suggests the rescheduling had mixed effects. The overdose deaths register is implemented consistently with the Substance Abuse and Mental Health Services Administration (SAMHSA) Consensus Panel recommendations for determining and documenting drug poisoning deaths (Goldberger, Maxwell, Campbell, & Wilford, 2013). Regular searches are conducted across coronial databases to identify Victorian deaths where the expert death investigators (the coroner, forensic pathologist and forensic toxicologist) established that the acute toxic effects of a drug or drugs played a causal role. For each such overdose death the individual drugs that the expert death investigators determined were contributory are recorded in the register; information regarding drugs that were detected but not determined to be contributory is not recorded. Early data from the register, showing that benzodiazepines played a contributory role in 49% of Victorian overdose deaths during 2010, informed a Victorian coroner’s recommendation that the Therapeutic Goods Administration (TGA) move all benzodiazepines into Schedule 8 of the Standard for the Uniform Scheduling of Medicines and Poisons (Jamieson, 2012). This recommendation became the initiating application for the consultation and evaluation process that culminated in the TGA’s June 2013 final decision to reschedule alprazolam. Subsequently the coroner expressed concern that recurring issues encountered when
* Corresponding author at: Turning Point, 54-62 Gertrude Street, Fitzroy, VIC 3065, Australia. Fax: +61 3 9416 3420. E-mail address: [email protected] (B. Lloyd). http://dx.doi.org/10.1016/j.drugpo.2016.10.008 0955-3959/ã 2016 Published by Elsevier B.V.
investigating Victorian overdose deaths – including benzodiazepine dependence, misuse, prescription shopping, and poor prescribing practices – are common to all benzodiazepines, so rescheduling only alprazolam is unlikely to result in an overall reduction in benzodiazepine contribution to overdose death (Jamieson, 2014). To examine whether there was early evidence to support this concern, we extracted aggregate data on annual frequencies of Victorian overdose deaths involving relevant drugs from the register for the period 2009–2015. As shown by Schaffer, Buckley, Cairns, & Pearson (2016), alprazolam prescribing reduced following announcement of the rescheduling decision in June 2013, even through implementation of this change did not occur until February 2016. Accordingly, it is important to consider the effect of rescheduling from the point of announcement of any change. Data extraction and reporting did not require any identifying information to be accessed and was determined to present no foreseeable risk of harm, inconvenience or discomfort to a person, and therefore was subject to coronial oversight but not Human Research Ethics Committee review. Table 1 shows that the annual frequency of Victorian fatal overdoses generally rose steadily across the period, from 342 deaths in 2010 to 453 deaths in 2015. The sub-set of these overdose deaths in which one or more benzodiazepines contributed, appeared to follow the same general trend, rising from 160 deaths in 2009 to 238 deaths in 2015 and representing approximately 51.5% of all overdose deaths across the period. In 65.5% of these deaths a single benzodiazepine was contributory; the remaining 34.5% of the deaths involved multiple contributing benzodiazepines (an average of 2.3 contributing benzodiazepines per death). There was a decline in the frequency of overdose deaths involving alprazolam, particularly after 2013; and a steady increase over the course of 2009–2015 in overdose deaths where clonazepam and diazepam contributed. The frequency of overdose deaths involving each of nitrazepam, oxazepam and temazepam fluctuated over time with no clearly discernable trend. Further years of post-rescheduling data are needed before robust statistical analysis can be performed, however these findings together suggest a preliminary conclusion that the rescheduling of
B. Lloyd et al. / International Journal of Drug Policy 39 (2017) 138–139 Table 1 Annual frequency of all overdose deaths, and overdose deaths involving benzodiazepines and other selected drugs, Victoria 2009–2015. Overdose deaths
2009
2010
2011
2012
2013
2014
2015
379
342
362
367
380
387
453
Overdose deaths involving any benzodiazepine 160 169 180 199
212
215
238
Overdose deaths involving specific benzodiazepinesa Alprazolam 62 56 43 57 Clonazepam 7 9 14 18 Diazepam 104 109 124 133 Nitrazepam 17 16 11 24 Oxazepam 18 19 44 41 Temazepam 28 22 48 35
45 19 164 26 17 22
28 25 169 13 19 20
23 33 192 17 34 25
All overdose deaths
a
Multiple specific benzodiazepines may have contributed to a single death.
alprazolam might have reduced alprazolam involvement in Victorian overdose deaths, but it did not appear to interrupt the longer-term upward trend in overdose deaths involving benzodiazepines. Claims regarding the increased toxicity of alprazolam compared with other benzodiazepines are largely based on a much-cited study that found alprazolam overdose was associated with increased length of stay and increased need for medical intervention in a toxicology service compared with other benzodiazepines (Isbister, O’Regan, Sibbritt, & Whyte, 2004). However, the strongest determinant of poorer clinical outcome reported in the study was co-ingestion of other drugs with benzodiazepines, particularly tricyclic antidepressants. This is consistent with literature noting the heightened risk of overdose when benzodiazepines are combined with other drugs (Ashton, 1995; Jones, Mogali, & Comer, 2012). This is also consistent with the CCOV overdose deaths register data, which shows that there were only 28 overdose deaths involving benzodiazepines alone (2%) among the 1373 Victorian overdose deaths involving benzodiazepines between 2009 and 2015. However, benzodiazepines were ubiquitous in overdose deaths involving most other central nervous system depressants. For example, benzodiazepines co-contributed in 899 (69%) of the 1294 Victorian overdose deaths between 2009 and 2015 which involved pharmaceutical opioids; in 675 (74%) of the 910 overdose deaths involving antidepressants; 397 (77%) of 517 deaths involving antipsychotics; 484 (51%) of 948 deaths involving heroin; and 334 (52%) of 641 deaths involving alcohol. These findings indicate that caution should be taken when
139
considering prescribing any benzodiazepine in combination with other drugs. The TGA’s stated reasons for rescheduling alprazolam but not other benzodiazepines included that alprazolam appears to have increased morbidity and mortality in alprazolam overdose compared with other benzodiazepines, possible increased toxicity, and evidence of more prevalent diversion and misuse (Therapeutic Goods Administration, 2013). The initial findings presented here suggest that benzodiazepines as a class are involved in fatal overdose, and tackling individual benzodiazepines might not impact on overall benzodiazepine involvement. If analogous findings emerge from examining how other measures of drug use and drug related harms (such as ambulance attendances for non-fatal overdose and drug use patterns among people who inject drugs) have changed following the rescheduling, the TGA decision should be reviewed with some urgency: first, because it will not have improved overall public health and safety; and second, because of the inaccurate impression it creates among prescribers and patients that Schedule 4 benzodiazepines are somehow ‘safer’ than alprazolam.
References Ashton, H. (1995). Toxicity and adverse consequences of benzodiazepine use. Psychiatric Annals, 25(3), 158–165. Deacon, R. M., Nielsen, S., Leung, S., Rivas, G., Cubitt, T., Monds, L. A., et al. (2016). Alprazolam use and related harm among opioid substitution treatment clients— 12 months follow up after regulatory rescheduling. International Journal of Drug Policy, 36, 104–111. http://dx.doi.org/10.1016/j.drugpo.2016.06.006. Goldberger, B. A., Maxwell, J. C., Campbell, A., & Wilford, B. B. (2013). Uniform standards and case definitions for classifying opioid-related deaths: recommendations by a SAMHSA consensus panel. Journal of Addictive Diseases, 32(3), 231–243. Isbister, G. K., O’Regan, L., Sibbritt, D., & Whyte, I. M. (2004). Alprazolam is relatively more toxic than other benzodiazepines in overdose. British Journal of Clinical Pharmacology, 58(1), 88–95. Jamieson, A. (2012). Finding with inquest into the death of David Andrew Trengrove. . . Retrieved on 5 July 2016 from http://www.coronerscourt.vic.gov.au/home/ coroners+written+findings/findings+-+404208+david+andrew+trengrove. Jamieson, A. (2014). Finding without inquest into the death of Kirk Steven Ardern. . . Retrieved on 5 July 2016 from http://www.coronerscourt.vic.gov.au/home/ coroners+written+findings/findings+225412+kirk+ardern. Jones, D. J., Mogali, S., & Comer, S. D. (2012). Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence, 125, 1–2. http:// dx.doi.org/10.1016/j.drugalcdep.2012.07.004. Schaffer, A. L., Buckley, N. A., Cairns, R., & Pearson, S. (2016). Interrupted time series analysis of the effect of rescheduling alprazolam in Australia: taking control of prescription drug use. JAMA Internal Medicine, 176(8), 1223–1225. Therapeutic Goods Administration (2013). Scheduling delegate’s final decisions: ACCS/ ACMS June 2013. . . Retrieved on 5 July 2016 from https://www.tga.gov.au/book/ part-scheduling-proposals-referred-march-2013-meeting-acms.