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  • Benzodiazepine prescription and mortality among persons in opioid maintenance treatment (OMT)

Systematic review

Benzodiazepine prescription and mortality among persons in opioid maintenance treatment (OMT): a systematic review

Published

The purpose of this systematic review was to investigate the effect on mortality after prescription of benzodazepines to persons in OMT.

Forside dødelighet Benzo LAR.jpg

The purpose of this systematic review was to investigate the effect on mortality after prescription of benzodazepines to persons in OMT.


Downloadable as PDF. In Norwegian. English summary.

About this publication

  • Year: 2021
  • By: Norwegian Institute of Public Health
  • Authors Hestevik CH, Evensen LH.
  • ISBN (digital): 978-82-8406-240-2

Key message

Benzodiazepines are commonly prescribed to persons in opioid maintenance treatment (OMT). 

However, there is a lack of synthesized evidence of the effects on mortality of prescribed benzodiazepines among people in OMT. The purpose of this systematic review was to investigate the effect on mortality after prescription of benzodazepines to persons in OMT. 

We searched for randomized and non-randomized studies in research databases. We screened the references, extracted data and analysed studies that met our inclusion criteria. We included six non-randomised studies: five cohort studies and one case-control study. All the studies had a medium or low methodological quality. There was also a lack of consistency in the results across individual studies, uncertain generalizability to the Norwegian context, and imprecise effect estimates. 

Our main findings: 

Among persons in OMT it is uncertain whether prescription of benzodiazepines leads to 

  • increased risk of all-cause mortality  
  • increased risk of drug-related mortality  
  • Increased risk of mortality related to other causes, that are not overdose-or drug related 

 

Our certainty in these results is very low. The current evidence base is too limited to be certain of the effect of prescription of benzodiazepines on mortality among persons in OMT. 

Summary

Introduction 

Many people with an opioid dependence disorder who enter opioid maintenance treatment (OMT) also have benzodiazepine dependence. Benzodiazepines consists of two groups of drugs: anti-anxiety drugs and sleeping pills. However, the use of benzodiazepines may disturb the stabilizing effect of the OMT and can make it difficult to achieve specific treatment goals. In addition, concurrent use of benzodiazepines with opioids is associated with a greater risk of overdose. Nevertheless, studies show that benzodiazepines are frequently prescribed to persons in OMT. This may be because anxiety and sleeping disorders are common among this population, and cessation of benzodiazepines is challenging. There is a lack of summarised research on the effects on mortality of prescribed benzodiazepines among people in OMT. 

In May 2021, the Norwegian Institute of Public Health (FHI) was commissioned by the Norwegian Directorate of Health to carry out a systematic review on the prescription of benzodiazepines for people in OMT, and the effect on mortality. The purpose of the review is to be included in the evidence base for a recommendation on how to manage benzodiazepine dependence among persons in OMT in the revised national guideline for treatment of opioid dependence. 

 

Objective 

The purpose of this systematic review is to investigate the effect on mortality of prescription of benzodazepines  to persons in OMT. 

 

Method 

We conducted a systematic literature search in electronic databases in June 2021. We screened titles and abstracts to assess whether they meet our inclusion criteria. We obtained references that we considered relevant in full text and made a final assessment of which studies to include. We evaluated the included studies’ risk of bias. We extracted predetermined data from the studies and pooled effect estimates in meta-analyses, when possible. 

We also evaluated our confidence in the results by assessing the certainty of the overall evidence by using the GRADE approach (Recommendations Assessment, Development and Evaluation). 

  

Results 

We included six studies (in eight publications), published between 2009 and 2019, which were relevant to the research question. Five of the studies were retrospective registry-based cohort studies, and one was a registry-based case-control study. 

The studies were conducted in England, Scotland, Sweden, Canada and the USA, and had 84,452 participants in total. The results and our certainty in the results are summarized below.   

 

Summary table of effects of prescription of benzodiazepines on mortality for persons in OMT 

Population: Persons in OMT. Setting: England (n=2), Scotland (n=1), Sweden (n=1), Canada n=1) and USA (n=1) 

Outcomes* 

Anticipated absolute effects** (95% CI)  

Relative effect 
(95% CI)  

№ of participants  
(studies)  

 
(GRADE) 

Risk with no benzodiazepine prescription 

Risk with benzodiazepine prescription  

All-cause mortality – 

 in OMT  

14 per 1 000  

25 per 1 000 
(22 to 29)  

HR 1.83 
(1.59 to 2.11)  

79 964 
(3 observational studies)  

⨁◯◯◯ 
VERY LOW a,b 

Death, other causes –  

in OMT*** 

1.79 per 100 person-years 

1.31 per 100 person-years 

RR 0.73 

(0.21 to 3.18) 

278 
(1 observational study)  

◯◯◯ 
VERY LOW a,b,d 

All-cause mortality – 

 in and outside OMT  

66 per 1 000  

97 per 1,000 
(67 to 138)  

HR 1.49 
(1.02 to 2.18)  

6 879 
(2 observational studies)  

◯◯◯ 
VERY LOW a,b,c 

Drug-related deaths – 

in OMT  

5 per 1 000  

12 per 1 000 
(7 to 21)  

HR 2.36 
(1.38 to 4.05)  

74 952 
(3 observational studies)  

◯◯◯ 
VERY LOW a,b,c, 

Drug-related deaths – 

in OMT*** 

0.90 per 100 person-years 

0.39 per 100 person-years 

RR 0.44 

(0.05 – 5.24) 

278 
(1 observational study) 

◯◯◯ 
VERY LOW a,b,d 

Drug related death – 

in OMT 

Absolute effect could not be estimated because this is a case-control study 

OR 1.6 
(1.1 to 2.5)  

175 cases 873 controls 
(1 observational study)  

◯◯◯ 
VERY LOW b 

Drug-related deaths – 

 in and outside OMT 

34 per 1 000  

72 per 1,000 
(27 to 186)  

HR 2.19 
(0.80 to 6.00)  

6 879 
(2 observational studies)  

◯◯◯ 
VERY LOW a,b,c,d 

Death, other causes – 

 in OMT  

34 per 1 000  

58 per 1 000 
(45 to 75)  

HR 1.73 
(1.33 to 2.25)  

11 607 
(2 observational studies)  

◯◯◯ 
VERY LOW b 

Death, other causes –  

in and outside OMT 

32 per 1 000  

63 per 1 000 
(41 to 98)  

HR 2.02 
(1.29 to 3.18)  

4 501 
(1 observational study)  

◯◯◯ 
VERY LOW b 

*The studies had different observation times; **The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI), based on the mean of the studies includes in the analysis. *** This study did not report hazard ratio and could not be included in the meta-analysis for this outcome. We calculated an unadjusted rate ratio and 95% CI based on the number of deaths and observation time per. group stated in the study 
CI: Confidence interval; OMT: Opioid Maintenance Treatment; HR: Hazard Ratio; OR: Odds ratio; RR, rate ratio  

 

Explanations 

1. Differences between interventions and control groups or a lack of information about comparability of the groups in relation to important background factors, as well as uncertainty or lack of consideration for potential confounders 

b. The studies took place in countries with uncertain generalizability to the Norwegian context 

c. Lack of agreement between the studies 

d. Wide Confidence interval 

 

 

Discussion 

The overall results from the studies indicated that prescription benzodiazepines are associated with higher mortality measured in OMT and throughout the whole observation period. However, for overdose-related deaths assessed throughout the whole observation period, the confidence interval included both positive and negative effects. We have very low certainty in the results, and it is uncertain whether prescription benzodiazepines influence mortality for persons in OMT. 

This systematic overview is based on a thorough and systematic literature search using an explicit search strategy. We have also consulted with experts on whether they have knowledge of relevant studies. We may still have missed studies where OMT drugs, benzodiazepines and mortality are not mentioned in the title or abstract, but we consider it probable that we have identified all relevant studies. 

The six included studies had methodological limitations and half of them were considered to have a high risk of bias. In addition, there was lack of consistency in results across individual studies and imprecise results. It is also uncertain how comparable Norwegian OMT is with OMT in other countries, especially when it comes to how closely the patients are followed up when it comes to substance abuse-related problems and other health and social problemsThe studies took place in Sweden, Scotland, Canada, England, and the USA. Different structure and content in the various OMT programs can affect both benzodiazepine prescription practices and outcomes. The risk of death may vary between OMT programs, depending on the characteristics of the population and organization of the OMT programs.  

All the studies we identified were retrospective observational studies, and there is a lack of randomized studies in the field. Only one of the included studies addressed the requisition of benzodiazepines as maintenance treatment of benzodiazepine dependence, while the others did not specify the status of benzodiazepine dependence. 

Conclusion 

It is uncertain whether prescription of benzodiazepines has an effect on mortality among persons in OMT, regardless of the cause of death, as the current scientific evidence is too scarce to determine the effect.