Alprazolam use and related harm among opioid substitution treatment clients – 12 months follow up after regulatory rescheduling

doi:10.1016/j.drugpo.2016.06.006

International Journal of Drug Policy

Volume 36, October 2016, Pages 104-111

https://doi.org/10.1016/j.drugpo.2016.06.006 Get rights and content

Abstract

Background

Alprazolam, has been associated with disproportionate harms compared to other benzodiazepines, especially among people in opioid substitution treatment (OST). We examine the effect of the rescheduling of alprazolam in Australia, from Schedule 4 to Schedule 8 in February 2014 amongst a high-risk population of clients in OST.

Methods

OST participants who reported recent (last month) alprazolam use were recruited from three Sydney clinics. Participants (n = 57) were interviewed immediately prior to rescheduling and again three months and 12 months after rescheduling. We examined self-reported patterns of drug use, drug availability, mental and physical health. A linear mixed models approach was used to analyse changes in alprazolam and other benzodiazepine use.

Results

Mean days of alprazolam use in the past 28 days decreased from 13.7 to 7.1 days, and mean weekly alprazolam dose decreased from 15.1 mg to 6.1 mg at 12 months follow-up (p = 0.001). Total weekly benzodiazepine use also reduced from a mean of 222 mg diazepam equivalent to 157 mg (p = 0.044). Other substance use did not change significantly. Reported mode of cost price of street alprazolam doubled from $5 to $10 over the 12-month period.

Conclusion

Alprazolam rescheduling resulted in an overall reduction in alprazolam and total benzodiazepine use, without substitution with other drugs, in the short term. Unintended harms were not observed. Rescheduling appears to have been effective in reducing alprazolam use in this high-risk population.

Section snippets

Background

Benzodiazepine misuse among opioid-substitution treatment (OST) clients is both highly prevalent (Chen et al., 2011, Darke et al., 2010, Iguchi et al., 1993, Lavie et al., 2009, Nielsen et al., 2007, Peles et al., 2010) and associated with a number of adverse outcomes (Ashton, 2005, Lintzeris and Nielsen, 2010). These include reduced likelihood of opioid abstinence (Kamal et al., 2007), early withdrawal from treatment (Meiler et al., 2005, Peles et al., 2010), increased use of other

Study design

The study used a longitudinal cohort design to examine a range of outcomes in a group of alprazolam using OST clients immediately before, three months and 12 months after the rescheduling of alprazolam on 1st February 2014. Participants were recruited from three public specialist OST clinics in Sydney: The Langton Centre, St George Drug and Alcohol Service (both services of Drug and Alcohol Services, South East Sydney Local Health District) and Rankin Court (Alcohol and Drug Service, St

Baseline demographics

A flow diagram illustrating the number of participants at each wave is shown in Fig. 1. From an estimated pool of 750 OST clients across 3 clinics of which an estimated 285 or 38% (Deacon et al., 2014) would have used benzodiazepines (not necessarily alprazolam) in the last month, the total number of participants recruited was 57. Sixty one participants were screened for eligibility, with three of them not meeting eligibility criteria (no reported alprazolam use in the last 28 days). Of the 58

Conclusions

Using a longitudinal study design with within subject analyses, we were able to examine the effect of a change in the scheduling of alprazolam in a population of OST clients who report regular benzodiazepine use. To the authors knowledge this is the first prospectively conducted cohort study examining the impact of benzodiazepine up-scheduling. We found that alprazolam use reduced significantly in this population at three months follow up which was maintained at 12 months follow up but not

Implications

Regulatory changes in pharmaceutical medications can impact upon the accessibility and patterns of use of medications. This study indicates that the regulatory change of rescheduling alprazolam from S4 to S8 was associated with reduced levels of alprazolam and total benzodiazepine use in a high-risk population of OST clients.

Acknowledgements

Thank you to the study participants for their contributions, and to staff at the Langton Centre, St George and Rankin Court OSTs for facilitating recruitment. We also thank Associate Professor Timothy Dobbins for his assistance with statistical analyses. This study was funded by a grant from the Mental Health and Drug and Alcohol Office, NSW Health.
Conflict of interest: None declared.

References (45)

C.H. Bastien et al.
Validation of the Insomnia Severity Index as an outcome measure for insomnia research
Sleep Medicine
(2001)
P. Buykx et al.
Medications used in overdose and how they are acquired – An investigation of cases attending an inner Melbourne emergency department
Australian and New Zealand Journal of Public Health
(2010)
S. Darke et al.
Benzodiazepine use and HIV risk-taking behaviour among injecting drug users
Drug and Alcohol Dependence
(1992)
C.R. Hjorthøj et al.
Validity of Timeline Follow-Back for self-reported use of cannabis and other illicit substances – Systematic review and meta-analysis
Addictive Behaviors
(2012)
M. Iguchi et al.
Benzodiazepine and sedative use/abuse by methadone maintenance clients
Drug and Alcohol Dependence
(1993)
E. Lavie et al.
Benzodiazepine use among opiate-dependent subjects in buprenorphine maintenance treatment: Correlates of use, abuse and dependence
Drug and Alcohol Dependence
(2009)
E. Peles et al.
15-Year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel
Drug and Alcohol Dependence
(2010)
B. Wolf et al.
Physical dependence on benzodiazepines: Differences within the class
Drug and Alcohol Dependence
(1991)
H. Ashton
The diagnosis and management of benzodiazepine dependence
Current Opinion in Psychiatry
(2005)
Australian Institute of Health and Welfare
National opioid pharmacotherapy statistics 2013. Drug treatment series no. 23. Cat. no. HSE 147
(2014)

M.J. Barker et al.

Cognitive effects of long-term benzodiazepine use: A meta-analysis

CNS Drugs

(2004)

B. Brands et al.

The impact of benzodiazepine use on methadone maintenance treatment outcomes

Journal of Addictive Diseases

(2008)

C.L. Breen et al.

The effects of restricting publicly subsidised temazepam capsules on benzodiazepine use among injecting drug users in Australia

Medical Journal of Australia

(2004)

K. Chen et al.

Benzodiazepine use and misuse among patients in a methadone program

BMC Psychiatry

(2011)

S. Darke et al.

Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome

Drug and Alcohol Review

(2010)

R.M. Deacon et al.

Drug use trends among opioid treatment program clients in south-eastern Sydney

Drug and Alcohol Review

(2014)

L. Degenhardt et al.

The effects of the market withdrawal of temazepam gel capsules on benzodiazepine injecting in Sydney, Australia

Drug and Alcohol Review

(2008)

P. Heikman et al.

New psychoactive substances as part of polydrug abuse within opioid maintenance treatment revealed by comprehensive high-resolution mass spectrometric urine drug screening

Human Psychopharmacology: Clinical and Experimental

(2016)

D. Horyniak et al.

The use of alprazolam by people who inject drugs in Melbourne, Australia

Drug and Alcohol Review

(2012)

IMS Institute for Healthcare Informatics

Medicines use and spending shifts: A review of the use of medicines in the U.S. in 2014

(2015)

G.K. Isbister et al.

Alprazolam is relatively more toxic than other benzodiazepines in overdose

British Journal of Clinical Pharmacology

(2004)

M.M. Islam et al.

Twenty-year trends in benzodiazepine dispensing in the Australian population

Internal Medicine Journal

(2014)

Cited by (12)

Not what the doctor ordered: Motivations for nonmedical prescription drug use among people who use illegal drugs
2020, International Journal of Drug Policy
Citation Excerpt :
In England and Wales, a recent example is the rescheduling of gabapentinoids as Schedule 3 controlled substances under the Misuse of Drugs Regulations 2001 and Class C substances under the Misuse of Drugs Act 1971. Whilst supply-side initiatives aimed at restricting access to medications, either through re-classification or strengthened law enforcement, can lead to sustained reductions in the use of medications among opioid dependent individuals (e.g. in response to the up-scheduling of alprazolam (Deacon et al., 2016; Sutherland, Peacock, Nielsen, & Bruno, 2020) and codeine (Middleton & Nielsen, 2019) in Australia), there are concerns of unintended consequences resulting from regulatory changes, including replacement with other drug types and/or the use of non-prescribed or counterfeit medications (Horyniak, Reddel, Quinn, & Dietze, 2012; Mateu-Gelabert et al., 2017; McLean & Kavanaugh, 2019; Silverstein, Daniulaityte, Miller, Martins, & Carlson, 2020). Our findings align with this body of qualitative work and suggest that stricter prescribing practices can inadvertently result in NMPDU.
Nonmedical Prescription Drug Use (NMPDU) is common among people who use illegal drugs. NMPDU is particularly problematic among this population however, as medications such as benzodiazepines and gabapentinoids can potentiate the harmful effects of opioids. Despite these harms, there is some evidence that NMPDU can have harm reducing and therapeutic potential for some people who use illegal drugs. This study provides further evidence of the harm reducing motives for NMPDU among people who use illegal drugs in community and prison settings in Wales, UK.
In depth, semi-structured interviews were conducted with 60 interviewees recruited from statutory and third sector drug treatment providers operating in five towns and cities in Wales, and from two Welsh prisons. Eligibility was based primarily on whether the person was currently (or previously) a user of illegal drugs and had recent experience of NMPDU.
NMPDU was found to be largely driven by insufficient access to certain prescription medications and treatment. In this context, NMPDU played an important role in alleviating legitimate medical concerns and overcoming logistical and regulatory barriers associated with Opioid Substitution Therapy. NMPDU also had everyday practicality and mitigated many of the everyday harms experienced by people who use drugs, including opioid withdrawal and stimulant comedowns.
Results suggest that NMPDU has the potential to mitigate a number of legitimate medical concerns in the absence of treatment. Finding nuanced ways of responding to patient need whilst reducing the potential for NMPDU are therefore needed, and harm reduction strategies that harness the knowledge and expertise of people who use drugs should be encouraged. Additional policy measures that attend to the inequities and social-structural factors that produce and maintain the need to consume prescription medications in ways that are not intended are also required.
Alprazolam use among a sample of Australians who inject drugs: Trends up to six years post regulatory changes
2020, International Journal of Drug Policy
Citation Excerpt :
Schaffer, Buckley, Cairns and Pearson (2016) found a significant decrease in alprazolam prescriptions, dispensing and calls to Poison Information Centres from 2010–2015 after the introduction of the regulatory change, coupled with an increase in diazepam, oxazepam, antidepressant and antipsychotic dispensing. Deacon et al. (2016) found an overall reduction in self-reported alprazolam and total benzodiazepine use among people receiving opioid agonist therapy in the 12 months post-rescheduling, with no evidence of displacement to other drugs. Finally, an analysis of mortality data (2009–2015) in Victoria reported a decline in the frequency of overdose deaths involving alprazolam, particularly after 2013 (Lloyd, Dwyer, Bugeja & Jamieson, 2017).
Alprazolam is a high potency triazolobenzodiazepine that is associated with a disproportionate amount of harm compared to other benzodiazepines. In Australia, amid growing concerns of extra-medical use and harms, alprazolam was up-scheduled from Schedule 4 (prescription only) to Schedule 8 (controlled drug) on 1 February 2014, with further restrictions introduced on 1 February 2017. This study aims to examine the impact of these regulatory changes among cross-sectional samples of people who inject drugs (PWID), from 2011–2019.
Data were obtained from the 2011–2019 Illicit Drug Reporting System, comprising cross-sectional samples of PWID recruited annually from Australian capital cities (approximately ~900 per year).
By 2019, the proportion of PWID who reported past six-month use of non-prescribed (17%) and prescribed (4%) alprazolam had halved compared to 2011 (39% and 13%, respectively), with no evidence of an increase in use of other sedative substances. Following the up-scheduling of alprazolam in 2014, there was an increase in the median last price paid for 2 mg of diverted alprazolam ($5AUD pre-rescheduling versus $7AUD post rescheduling), with 61% of those able to answer reporting that diverted alprazolam had become ‘more difficult’ to obtain post versus pre-rescheduling. The correlates associated with non-prescribed alprazolam use remained relatively consistent pre- and post-regulatory change, with past-month criminal activity, past six-month opioid agonist therapy and past six-month use of non-prescribed other benzodiazepines associated with non-prescribed alprazolam use in both the 2013 and 2018 samples.
Regulatory changes appear to have resulted in sustained reductions in alprazolam use amongst our annual cross-sectional sentinel samples of PWID, although a considerable minority (17%) continued to report non-prescribed use in 2019. To achieve further reductions in non-prescribed use and associated harms, these regulatory changes need to be coupled with other interventions, such as direct consumer engagement and harm reduction messaging. Our findings suggest that people receiving opioid agonist therapy remain a key target population for such interventions.
The epidemiology of benzodiazepine misuse: A systematic review
2019, Drug and Alcohol Dependence
Benzodiazepine misuse is a growing public health problem, with increases in benzodiazepine-related overdose deaths and emergency room visits in recent years. However, relatively little attention has been paid to this emergent problem. We systematically reviewed epidemiological studies on benzodiazepine misuse to identify key findings, limitations, and future directions for research.
PubMed and PsychINFO databases were searched through February 2019 for peer-reviewed publications on benzodiazepine misuse (e.g., use without a prescription; at a higher frequency or dose than prescribed). Eligibility criteria included human studies that focused on the prevalence, trends, correlates, motives, patterns, sources, and consequences of benzodiazepine misuse.
The search identified 1970 publications, and 351 articles were eligible for data extraction and inclusion. In 2017, benzodiazepines and other tranquilizers were the third most commonly misused illicit or prescription drug in the U.S. (approximately 2.2% of the population). Worldwide rates of misuse appear to be similar to those reported in the U.S. Factors associated with misuse include other substance use, receipt of a benzodiazepine prescription, and psychiatric symptoms and disorders. Benzodiazepine misuse encompasses heterogeneous presentations of motives, patterns, and sources. Moreover, misuse is associated with myriad poor outcomes, including mortality, HIV/HCV risk behaviors, poor self-reported quality of life, criminality, and continued substance use during treatment.
Benzodiazepine misuse is a worldwide public health concern that is associated with a number of concerning consequences. Findings from the present review have implications for identifying subgroups who could benefit from prevention and treatment efforts, critical points for intervention, and treatment targets.
Alprazolam in fatal overdose following regulatory rescheduling: A response to Deacon et al.
2017, International Journal of Drug Policy
A narrative review of evidence to guide deprescribing among older adults
2021, Journal of General and Family Medicine
Mice with GNAO1 R209H movement disorder variant display hyperlocomotion alleviated by risperidones
2020, Journal of Pharmacology and Experimental Therapeutics

View all citing articles on Scopus

View full text

Research paperAlprazolam use and related harm among opioid substitution treatment clients – 12 months follow up after regulatory rescheduling

Abstract

Background

Methods

Results

Conclusion

Section snippets

Background

Study design

Baseline demographics

Conclusions

Implications

Acknowledgements

Sleep Medicine

Australian and New Zealand Journal of Public Health

Drug and Alcohol Dependence

Addictive Behaviors

Drug and Alcohol Dependence

Drug and Alcohol Dependence

Drug and Alcohol Dependence

Drug and Alcohol Dependence

The diagnosis and management of benzodiazepine dependence

Current Opinion in Psychiatry

National opioid pharmacotherapy statistics 2013. Drug treatment series no. 23. Cat. no. HSE 147

Cognitive effects of long-term benzodiazepine use: A meta-analysis

CNS Drugs

The impact of benzodiazepine use on methadone maintenance treatment outcomes

Journal of Addictive Diseases

The effects of restricting publicly subsidised temazepam capsules on benzodiazepine use among injecting drug users in Australia

Medical Journal of Australia

Benzodiazepine use and misuse among patients in a methadone program

BMC Psychiatry

Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome

Drug and Alcohol Review

Drug use trends among opioid treatment program clients in south-eastern Sydney

Drug and Alcohol Review

The effects of the market withdrawal of temazepam gel capsules on benzodiazepine injecting in Sydney, Australia

Drug and Alcohol Review

New psychoactive substances as part of polydrug abuse within opioid maintenance treatment revealed by comprehensive high-resolution mass spectrometric urine drug screening

Human Psychopharmacology: Clinical and Experimental

The use of alprazolam by people who inject drugs in Melbourne, Australia

Drug and Alcohol Review

Medicines use and spending shifts: A review of the use of medicines in the U.S. in 2014

Alprazolam is relatively more toxic than other benzodiazepines in overdose

British Journal of Clinical Pharmacology

Twenty-year trends in benzodiazepine dispensing in the Australian population

Internal Medicine Journal

Research paper
Alprazolam use and related harm among opioid substitution treatment clients – 12 months follow up after regulatory rescheduling