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Figure.
Monthly Time Series of Alprazolam Prescriptions per 100 000 Population, Dispensings, and Calls to Poisons Information Centre
Monthly Time Series of Alprazolam Prescriptions per 100 000 Population, Dispensings, and Calls to Poisons Information Centre

The rescheduling was announced on June 28, 2013, whereas the rescheduling took effect on February 1, 2014.

Table.  
Use Among Individuals Dispensed Alprazolam the Year Before the Announcement of the Rescheduling and the Year After the Rescheduling
Use Among Individuals Dispensed Alprazolam the Year Before the Announcement of the Rescheduling and the Year After the Rescheduling
1.
Isbister  GK, O’Regan  L, Sibbritt  D, Whyte  IM.  Alprazolam is relatively more toxic than other benzodiazepines in overdose.  Br J Clin Pharmacol. 2004;58(1):88-95.PubMedArticle
2.
Moylan  S, Staples  J, Ward  SA, Rogerson  J, Stein  DJ, Berk  M.  The efficacy and safety of alprazolam versus other benzodiazepines in the treatment of panic disorder.  J Clin Psychopharmacol. 2011;31(5):647-652.PubMed
3.
Rintoul  AC, Dobbin  MD, Nielsen  S, Degenhardt  L, Drummer  OH.  Recent increase in detection of alprazolam in Victorian heroin-related deaths.  Med J Aust. 2013;198(4):206-209.PubMedArticle
4.
Department of Health Therapeutic Goods Administration. Scheduling delegate’s final decisions: ACCS/ACMS, June 2013. 2013; https://www.tga.gov.au/book/part-scheduling-proposals-referred-march-2013-meeting-acms. Accessed May 19, 2016.
5.
Mellish  L, Karanges  EA, Litchfield  MJ,  et al.  The Australian Pharmaceutical Benefits Scheme data collection: a practical guide for researchers.  BMC Res Notes. 2015;8:634.PubMedArticle
6.
Jones  CM, Lurie  PG, Throckmorton  DC.  Effect of US Drug Enforcement Administration’s rescheduling of hydrocodone combination analgesic products on opioid analgesic prescribing.  JAMA Intern Med. 2016;176(3):399-402.PubMedArticle
7.
Fisher  J, Sanyal  C, Frail  D, Sketris  I.  The intended and unintended consequences of benzodiazepine monitoring programmes: a review of the literature.  J Clin Pharm Ther. 2012;37(1):7-21.PubMedArticle
Research Letter
August 2016

Interrupted Time Series Analysis of the Effect of Rescheduling Alprazolam in AustraliaTaking Control of Prescription Drug Use

Author Affiliations
  • 1Centre for Big Data Research in Health, University of New South Wales, Australia
  • 2Pharmacology, University of Sydney, Australia
  • 3New South Wales Poisons Information Centre, Children’s Hospital at Westmead, Australia
JAMA Intern Med. 2016;176(8):1223-1225. doi:10.1001/jamainternmed.2016.2992

Alprazolam is significantly more toxic, has no additional therapeutic benefit, and is increasingly misused compared with other benzodiazepines.13 Due to concerns about the increasing use of alprazolam, in February 2014, the Australian Therapeutic Goods Administration selectively rescheduled alprazolam from Schedule 4 (Prescription Only Medicine) of the Poisons Standard to Schedule 8 (Controlled Drug), equivalent to Schedule II in the United States. This change resulted in increased restrictions for the prescribing and dispensing of alprazolam.4 The objective of this study was to determine the effect of rescheduling alprazolam on benzodiazepine prescribing, dispensing, and intentional poisonings.

Methods

Australia’s Pharmaceutical Benefits Scheme (PBS) subsidizes prescribed medicines for all citizens and permanent residents. We used data from a 10% random sample of PBS data, including authorities to prescribe and pharmacy claims for dispensed medicines.5 From February 2010 to July 2015, we calculated the monthly number of alprazolam prescriptions per 100 000 population; dispensings of PBS-listed benzodiazepines (alprazolam, diazepam, oxazepam, nitrazepam, and temazepam); and switching from alprazolam to a new benzodiazepine, antidepressant, or antipsychotic. We restricted analyses using dispensing claims to individuals for whom we had complete ascertainment of medicines dispensed during the study period.5

From January 2010 to June 2015, we also calculated the monthly number of calls to the New South Wales Poisons Information Centre (NSW PIC) involving recreational or intentional misuse of alprazolam or another benzodiazepine or Z drug. The NSW PIC receives approximately 100 000 calls annually from health care professionals and the public.

We performed an interrupted time series analysis modeled using an autoregressive, integrated moving average approach to assess the effect on prescribing, dispensing, and switching to substitute medicines. We used a segmented negative binomial regression to identify changes in calls to the NSW PIC.

This study was approved by the New South Wales Population and Health Services Ethics Committee and the Sydney Children’s Hospital Network Human Research Ethics Committee.

Results

During the study period, 18 092 people were prescribed alprazolam (median age, 52 years; interquartile range, 39-66 years). After rescheduling, alprazolam prescribing decreased by 14.9/100 000 population per month (95% CI, 5.2-24.5; P = .004), an approximate 22% reduction (Figure). We also observed a decrease in dispensing of alprazolam of 531 per month (95% CI, 404-658; P < .001), an approximate 24% reduction, and an increase in dispensing of diazepam (491 per month; 95% CI, 364-619; P < .001) and oxazepam (274 per month; 95% CI, 113-435; P < .001). After rescheduling, we observed the greatest reduction in alprazolam use among individuals with the largest number of alprazolam dispensings, as well as incident users (Table).

Prior to the rescheduling, a monthly mean of 3.8, 2.5, and 1.1 per 1000 alprazolam users switched to a different benzodiazepine, antidepressant, and antipsychotic, respectively. In the month of the rescheduling, switching to a different benzodiazepine (primarily diazepam and oxazepam) increased by 216% (95% CI, 123%-348%; P < .001). We also observed increased switching to antidepressants (142%; 95% CI, 64%-259%; P < .001) and antipsychotics (129%; 95% CI, 8%-384%; P = .04), but absolute rates were small.

Prior to the rescheduling, there was a mean of 34 calls per month to the Poisons Information Centre involving alprazolam. In the 12 months following the rescheduling of alprazolam, this declined by 50% (95% CI, 31%-68%; P < .001) (Figure). There was no significant change in calls to the Poisons Information Centre involving other benzodiazepines.

Discussion

In Australia, selectively rescheduling alprazolam led to a reduction in overall use and adverse events and increased switching to less toxic benzodiazepines. More important, the greatest decrease in use was in individuals using alprazolam inappropriately in the long term. Rescheduling opioids to address misuse in the United States has similarly resulted in decreased use.6 Although increasing barriers to prescribing benzodiazepines can have unintended consequences,7 we observed no significant change in poisonings associated with other benzodiazepines.

Approximately one-third of alprazolam prescriptions in Australia are private and not captured in PBS claims; whereas private prescriptions are subject to the same regulatory restrictions as PBS prescriptions, further research is needed to determine how the rescheduling has affected the private benzodiazepine market.

Our findings suggest that when one medicine within a class is more toxic and/or more commonly abused, selective rescheduling should be considered to address its misuse.

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Article Information

Corresponding Author: Andrea L. Schaffer, MSc, MBiostat, Centre for Big Data Research in Health, University of New South Wales, AGSM Building, Level 1, Sydney, Australia 2052 (andrea.schaffer@student.unsw.edu.au).

Published Online: July 5, 2016. doi:10.1001/jamainternmed.2016.2992.

Author Contributions: Ms Schaffer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Schaffer, Buckley, Pearson.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Schaffer, Buckley, Pearson.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Schaffer.

Obtained funding: Schaffer.

Study supervision: Schaffer, Pearson.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by the National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Medicines and Ageing (Grant 1060407), by a Cancer Institute New South Wales Career Development Fellowship (Grant 12/CDF/2-25) (Dr Pearson), and by the NHMRC (Grant 1074924) (Ms Schaffer).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The Australian Government Department of Human Services provided the data.

References
1.
Isbister  GK, O’Regan  L, Sibbritt  D, Whyte  IM.  Alprazolam is relatively more toxic than other benzodiazepines in overdose.  Br J Clin Pharmacol. 2004;58(1):88-95.PubMedArticle
2.
Moylan  S, Staples  J, Ward  SA, Rogerson  J, Stein  DJ, Berk  M.  The efficacy and safety of alprazolam versus other benzodiazepines in the treatment of panic disorder.  J Clin Psychopharmacol. 2011;31(5):647-652.PubMed
3.
Rintoul  AC, Dobbin  MD, Nielsen  S, Degenhardt  L, Drummer  OH.  Recent increase in detection of alprazolam in Victorian heroin-related deaths.  Med J Aust. 2013;198(4):206-209.PubMedArticle
4.
Department of Health Therapeutic Goods Administration. Scheduling delegate’s final decisions: ACCS/ACMS, June 2013. 2013; https://www.tga.gov.au/book/part-scheduling-proposals-referred-march-2013-meeting-acms. Accessed May 19, 2016.
5.
Mellish  L, Karanges  EA, Litchfield  MJ,  et al.  The Australian Pharmaceutical Benefits Scheme data collection: a practical guide for researchers.  BMC Res Notes. 2015;8:634.PubMedArticle
6.
Jones  CM, Lurie  PG, Throckmorton  DC.  Effect of US Drug Enforcement Administration’s rescheduling of hydrocodone combination analgesic products on opioid analgesic prescribing.  JAMA Intern Med. 2016;176(3):399-402.PubMedArticle
7.
Fisher  J, Sanyal  C, Frail  D, Sketris  I.  The intended and unintended consequences of benzodiazepine monitoring programmes: a review of the literature.  J Clin Pharm Ther. 2012;37(1):7-21.PubMedArticle
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