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Benzodiazepines in Opiate Replacement Therapy (BENZORT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04622995
Recruitment Status : Completed
First Posted : November 10, 2020
Last Update Posted : March 9, 2023
Sponsor:
Collaborator:
NHS Research Scotland
Information provided by (Responsible Party):
Joe Schofield, University of Stirling

Study Description
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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.


Condition or disease Intervention/treatment
Substance-Related Disorders Drug: Benzodiazepine

Detailed Description:

Scotland is experiencing a 'public health emergency' of escalating drug-related deaths (DRD) in which benzodiazepine (BZD) are increasingly implicated, often in combination with other substances (National Records of Scotland, 2019; Scottish Government, 2019).

In 2008 BZD were implicated in 26% (n=149) of DRD and were exclusively prescribable drugs such as diazepam, although the source is not known. By 2018 BZD and BZD-type drugs were implicated in 67% (792) of DRD, predominately substances not available on prescription in the United Kingdom (UK) such as etizolam and alprazolam (Xanax). We refer to these as illicit BZD.

People who use illicit BZD, of unknown constituents and potency, can inadvertently or deliberately consume megadoses of BZD many times in excess of safe therapeutic doses, often with alcohol and other drugs, which combine to increase the risk of harm and death. Rights, Respect and Recovery, the current drug and alcohol strategy, expressed Scottish Government concern regarding the increased prevalence and potency of BZD-type drugs.

People presenting to addiction services for initial assessment frequently report illicit BZD use in the month prior to assessment, an average of 2,561 (29%) per year in the past five years for which data are available. The prevalence of illicit BZD use is known to be higher among people with other substance use disorders, especially problematic opiate and/or alcohol dependence. A systematic review identified a high prevalence (typically >40%) among people on Opiate Replacement Therapy (ORT).

The picture of BZD prescribing among people on ORT is complex and evolving. Previous work shows that BZD prescribing among ORT patients is associated with increased harms including mortality, but conversely protective factors such as increased engagement in care. Scottish addiction specialists have confirmed that some addiction services are exploring maintenance prescribing to reduce the risks associated with illicit BZD use among ORT patients. However clinical guidance does not currently provide a framework for this. Evidence of patient safety and other outcomes from BZD prescribing in the context of ORT is sparse and conflicting. A 2018 Cochrane review concluded "it is not possible to draw firm conclusions regarding pharmacological interventions to facilitate BZD discontinuation in chronic BZD users". Recent UK public health alerts have highlighted the need for caution and additional monitoring when co-prescribing BZD and ORT, and the need for improved harm reduction advice regarding the risk of illicit BZD. Addiction clinicians have indicated there has been disagreement among certifying pathologists regarding the role of benzodiazepines in DRD.

There is a need to understand patterns of, and outcomes from, BZD prescribing among ORT patients in Scotland to inform safe and effective clinical practice, address problematic BZD use in the content of poly-drug use, and reduce the risk of harms including mortality among people who use drugs (PWUD).

Study Design
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Study Type : Observational
Actual Enrollment : 46899 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Exploring the Utility and Safety of Benzodiazepine Prescribing Among People Receiving Opiate Replacement Therapy in Scotland (the BENZORT Study).
Actual Study Start Date : August 1, 2021
Actual Primary Completion Date : March 31, 2022
Actual Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Diazepam

Groups and Cohorts
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Group/Cohort Intervention/treatment
Exposed
Patients prescribed opiate replacement therapy plus a benzodiazepine.
 Drug: Benzodiazepine
Benzodiazepine prescribing
Other Names:
  • Valium
  • Diazepam
Unexposed
Patients prescribed opiate replacement therapy with no benzodiazepine prescribing.


Outcome Measures
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Primary Outcome Measures :
  1. All-cause mortality [ Time Frame: From enrollment to end December 2020 ]
    Death from any cause


Secondary Outcome Measures :
  1. Drug-related death [ Time Frame: From enrollment to end December 2020 ]
    Fatal drug overdose

  2. Drug overdose (non-fatal) [ Time Frame: From enrollment to end December 2020 ]
    Non-fatal drug overdose

  3. Hospitalisation [ Time Frame: From enrollment to end December 2020 ]
    Admission to hospital from any cause

  4. Evidence of illicit drug use during Opiate Substitution Therapy [ Time Frame: From enrollment to end December 2020 ]
    Evidence of illicit drug use during Opiate Substitution Therapy

  5. Retention in care [ Time Frame: From enrollment to end December 2020 ]
    Retention in specialist addiction care for substance use disorder(s)


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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').
Criteria

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)

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04622995


Locations
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United Kingdom
NHS Scotland
Edinburgh, Scotland, United Kingdom, EH12 9EB
Sponsors and Collaborators
University of Stirling
NHS Research Scotland
Investigators
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Principal Investigator: Joe Schofield, MPH University of Stirling
More Information
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
Publications:
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
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
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
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
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
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
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/
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

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Responsible Party: Joe Schofield, Research Fellow, University of Stirling
ClinicalTrials.gov Identifier: NCT04622995    
Other Study ID Numbers: BENZORT
First Posted: November 10, 2020    Key Record Dates
Last Update Posted: March 9, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Joe Schofield, University of Stirling:
Benzodiazepine
Opiate Replacement Treatment
Drug-Related Death
Overdose
Additional relevant MeSH terms:
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Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Diazepam
Adjuvants, Anesthesia
Anticonvulsants
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hypnotics and Sedatives
Central Nervous System Depressants
 Muscle Relaxants, Central
Neuromuscular Agents
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action