Benzodiazepines in Opiate Replacement Therapy

NCT04622995 | Completed

• 1 other identifier: BENZORT
• Study Type: observational
• Target: 46,899
• Locations: 1 country
• Sites: 1

Brief Summary

Drug-related deaths (DRD) are a significant and increasing public health problem in Scotland. Benzodiazepines and BZD-type substances (BZD) are increasingly implicated in DRD. In 2018, BZDs were implicated in 67% of DRD, often in combination with other illicit and prescribable substances including Opiate Replacement Therapies (ORT) such as methadone and buprenorphine. Illicit BZD use and dependence is higher among people with other substance use disorders. 29% of patients presenting to Scottish addiction services report current illicit BZD use. There is widespread variance in approaches to the clinical management of BZD dependence among people with opioid use disorder in Scotland. Some addiction clinicians are reluctant to prescribe BZD to people on ORT, some will prescribe BZD with the primary aim of dose reduction and detoxification, others will consider longer-term maintenance prescribing whilst patients stabilise on ORT. Previous research has identified increased risks of mortality among people taking BZD and ORT. Other work suggests that co-prescribing BZD and ORT increases patient engagement and retention in addiction treatment. This retrospective cohort study will analyse anonymised, linked data on people who received ORT between 01/01/2010 and 31/12/2020 to explore any relationships between exposure (co-prescribing of BZD and ORT) and harms including: mortality (all-cause and DRD), hospitalisation, illicit drug use during ORT, and reduced retention in addiction care.

Conditions

Substance-Related Disorders

Keywords

Benzodiazepine; Opiate Replacement Treatment; Drug-Related Death; Overdose

Outcome Measures

Primary Outcomes (1)

• All-cause mortality

  Death from any cause

  From enrollment to end December 2020

Secondary Outcomes (5)

• Drug-related death

  From enrollment to end December 2020

• Drug overdose (non-fatal)

  From enrollment to end December 2020

• Hospitalisation

  From enrollment to end December 2020

• Evidence of illicit drug use during Opiate Substitution Therapy

  From enrollment to end December 2020

• Retention in care

  From enrollment to end December 2020

Study Arms (2)

Exposed

Patients prescribed opiate replacement therapy plus a benzodiazepine.

Drug: Benzodiazepine

Unexposed

Patients prescribed opiate replacement therapy with no benzodiazepine prescribing.

Interventions

Benzodiazepine DRUG

Benzodiazepine prescribing

Also known as: Valium, Diazepam

Exposed

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population includes people who received medication assisted treatment for the management of opiate / opioid addiction from community settings (e.g. community-based specialist addiction services and primary care physicians 'General Practitioners').

The cohort will consist of people who were prescribed ORT between 01/01/2010 and 31/12/2020. The definition of ORT is based on the following medications and associated British National Formulary (BNF) codes: Chemical (BNF code): Buprenorphine Hydrochloride/Naloxone Hydrochloride (0410030B0); Buprenorphine Hydrochloride (0410030A0); Methadone Hydrochloride (0410030C0)

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University of Stirling: lead
• NHS Research Scotland: collaborator

Study Sites (1)

NHS Scotland

Edinburgh, Scotland, EH12 9EB, United Kingdom

Location

Related Publications (17)

• Baandrup L, Ebdrup BH, Rasmussen JO, Lindschou J, Gluud C, Glenthoj BY. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database Syst Rev. 2018 Mar 15;3(3):CD011481. doi: 10.1002/14651858.CD011481.pub2.

  PMID: 29543325 BACKGROUND

• Bakker A, Streel E. Benzodiazepine maintenance in opiate substitution treatment: Good or bad? A retrospective primary care case-note review. J Psychopharmacol. 2017 Jan;31(1):62-66. doi: 10.1177/0269881116675508. Epub 2016 Dec 14.

  PMID: 28072037 BACKGROUND

• Chen KW, Berger CC, Forde DP, D'Adamo C, Weintraub E, Gandhi D. Benzodiazepine use and misuse among patients in a methadone program. BMC Psychiatry. 2011 May 19;11:90. doi: 10.1186/1471-244X-11-90.

  PMID: 21595945 BACKGROUND

• Cornish R, Macleod J, Strang J, Vickerman P, Hickman M. Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database. BMJ. 2010 Oct 26;341:c5475. doi: 10.1136/bmj.c5475.

  PMID: 20978062 BACKGROUND

• Macleod J, Steer C, Tilling K, Cornish R, Marsden J, Millar T, Strang J, Hickman M. Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med. 2019 Nov 26;16(11):e1002965. doi: 10.1371/journal.pmed.1002965. eCollection 2019 Nov.

  PMID: 31770388 BACKGROUND

• McCowan C, Kidd B, Fahey T. Factors associated with mortality in Scottish patients receiving methadone in primary care: retrospective cohort study. BMJ. 2009 Jun 16;338:b2225. doi: 10.1136/bmj.b2225.

  PMID: 19535400 BACKGROUND

• Park TW, Larochelle MR, Saitz R, Wang N, Bernson D, Walley AY. Associations between prescribed benzodiazepines, overdose death and buprenorphine discontinuation among people receiving buprenorphine. Addiction. 2020 May;115(5):924-932. doi: 10.1111/add.14886. Epub 2020 Jan 20.

  PMID: 31916306 BACKGROUND

• Votaw VR, Geyer R, Rieselbach MM, McHugh RK. The epidemiology of benzodiazepine misuse: A systematic review. Drug Alcohol Depend. 2019 Jul 1;200:95-114. doi: 10.1016/j.drugalcdep.2019.02.033. Epub 2019 May 7.

  PMID: 31121495 BACKGROUND

• Scottish Government. (2019). Statistics show highest ever level of drug deaths. Scottish Government. Edinburgh. Retrieved from https://news.gov.scot/news/statistics-show-highest-ever-level-of-drug-deaths

  BACKGROUND

• Scottish Government. (2018). Rights, Respect and Recovery. Edinburgh. Retrieved from https://www.gov.scot/binaries/content/documents/govscot/publications/strategy-plan/2018/11/rights-respect-recovery/documents/00543437-pdf/00543437-pdf/govscot%3Adocument/00543437.pdf

  BACKGROUND

• Public Health England; (2020, July 24). Evidence of harm from illicit or fake benzodiazepines. Retrieved October 16, 2020, from https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103075

  BACKGROUND

• National Records of Scotland. (2019). Drug-related Deaths in Scotland in 2018. Edinburgh: National Records of Scotland. Retrieved from https://www.nrscotland.gov.uk/statistics-and-data/statistics/statistics-by-theme/vital-events/deaths/drug-related-deaths-in-scotland/2018

  BACKGROUND

• Medicines and Healthcare products Regulatory Agency. (2020, March 18). Benzodiazepines and opioids: reminder of risk of potentially fatal respiratory depression. Retrieved October 16, 2020, from https://www.gov.uk/drug-safety-update/benzodiazepines-and-opioids-reminder-of-risk-of-potentially-fatal-respiratory-depression

  BACKGROUND

• Johnson, C. F., Barnsdale, L. R., & McAuley, A. (2016). Investigating the role of benzodiazepines in drug-related mortality: a systematic review undertaken on behalf of the Scottish National Forum on Drug-Related Deaths. Retrieved from https://www.scotpho.org.uk/media/1159/scotpho160209-investigating-the-role-of-benzodiazepines-in-drug-related-mortality.pdf

  BACKGROUND

• Information Services Division. (2020). Scottish Drug Misuse Database: Overview of Initial Assessments for Specialist Drug Treatment 2018/19. Edinburgh. Retrieved from https://beta.isdscotland.org/find-publications-and-data/lifestyle-and-behaviours/substance-use/scottish-drug-misuse-database/3-march-2020/

  BACKGROUND

• EMCDDA. The misuse of benzodiazepines among high-risk opioid users in Europe, Perspectives on drugs (2018). Portugal. Retrieved from http://www.emcdda.europa.eu/topics/pods/benzodiazepines_en

  BACKGROUND

• Best CS, Matheson C, Robertson J, Ritchie T, Cowden F, Dumbrell J, Duncan C, Kessavalou K, Woolston C, Schofield J. Association between benzodiazepine coprescription and mortality in people on opioid replacement therapy: a population-based cohort study. BMJ Open. 2024 Mar 14;14(3):e074668. doi: 10.1136/bmjopen-2023-074668.

  PMID: 38485490 DERIVED

MeSH Terms

Conditions

Substance-Related Disorders; Drug Overdose

Interventions

Benzodiazepines; Diazepam

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders; Mental Disorders; Prescription Drug Misuse; Drug Misuse

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzodiazepinones

Study Officials

• Joe Schofield, MPH

  University of Stirling

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Fellow

Study Record Dates

• First Submitted: November 3, 2020
• First Posted: November 10, 2020
• Study Start: August 1, 2021
• Primary Completion: March 31, 2022
• Study Completion: December 31, 2022
• Last Updated: March 9, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)