Is it the prescription or the lifestyle that kills?

Although this study1 analyses a vast amount of data it gives insufficient detail to draw sound conclusions on the safety of co-prescribing benzodiazepines in Opiate Substitution Treatment (OST). Information on why, and how benzodiazepines were prescribed is absent. This is relevant because benzodiazepine treatment is invariably targeted at a higher risk group.
We already know from other studies that many opiate dependent patients also abuse benzodiazepines. This remains a problem when they enter OST2. Methadone maintained benzodiazepine abusers have higher levels of psychopathology2, more frequent contact with the police3, shorter retention in treatment 10 and are less likely to achieve opiate abstinence4. They are more likely to suffer chronic pain5, to inject their drugs, to share needles6, to have unsafe sex, to have used cocaine recently and to be alcohol dependent7. They are known to have a poorer prognosis and a higher mortality8. To ascribe this increased mortality to respiratory depression from an interaction of prescribed medications seems unwise, especially because the paper demonstrates that the increased mortality is present even if benzodiazepines and OST are not prescribed concurrently.
Many addiction clinics try to help patients with problematic benzodiazepine use by offering them benzodiazepine detoxification, using a gradually reducing benzodiazepine dose. We are not aware of any death being reported during this process but most of these detoxifications have no lasting benefit because patients often resume illicit benzodiazepines when they experience withdrawal symptoms. This high-risk group will continue to show all the associated risk behaviours described above.
Alcohol problems should be addressed in OST and benzodiazepines cannot easily be avoided in alcohol detoxification. Not to address them represents poor harm reduction.
Benzodiazepines are also used in opiate detoxification and can actually increase completion and abstinence rates9. Inevitably a successful opiate detox results in loss of opiate tolerance and increased mortality from overdose following detox is universally recognised. Interestingly, the paper shows an increased all-cause and non-drug-related mortality for concurrent prescriptions (table 6). This can be explained by the benzodiazepine-using patients being the higher risk group, whereas for patients prescribed benzodiazepines up to 12 months after OST was discontinued (referred to as ‘co-prescribed’ in the paper), only drug-related deaths increased significantly, and the associations with all-cause and non-drug related mortality disappeared (table 5). This suggests that lack of OST is more likely the cause of the increased mortality, rather than benzodiazepine prescribing.
The paper notes that drug-related deaths have increased in recent years while prescribing benzodiazepine to OST patients has fallen. This indicates that there are bigger factors at play than co-prescribing. Addicts can now order industrial quantities of benzodiazepines (and many other drugs) at the click of a mouse and can take even bigger risks. In view of these increased risks, research into harm-reduction with carefully titrated instalment-dispensed benzodiazepine maintenance treatment seems more appropriate than ever. A cohort study10 confirms that non-prescribed benzodiazepine use reduces treatment retention, whereas those prescribed benzodiazepines had similar retention to the non-benzodiazepine using group. The only RCT11 on this seriously under-researched topic demonstrated that illicit benzodiazepine use was rare during benzodiazepine maintenance, while a retrospective case-note review7 showed that mortality of opiate addicts with problematic benzodiazepine co-addiction carried the same mortality as other addicts in treatment, only if their treatment included benzodiazepine maintenance.
In conclusion, it cannot be claimed on the basis of the current evidence that prescribing benzodiazepines to opioid dependent individuals is itself a cause of increased drug-related deaths in this higher risk group. There is some evidence that prescribing closely monitored benzodiazepine maintenance therapy can improve outcomes in terms of retention in treatment and reduced mortality. Further research should identify patient subgroups where the benefit of prescribing could outweigh the risk.

1 Macleod J, Steer C, et al. 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) 16 (11): e1002965. https://doi.org/10.1371/j.... pmed.1002965
2 Brands B, Blake J et al. The impact of benzodiazepine use on methadone maintenance treatment outcomes. J Addict Dis 27 (2008) 37-48
3 Loxley W, Benzodiazepine use and harms among police detainees in Australia. Trends and issues in crime and criminal justice (2007), Australian Institute of Criminology, Canberra, p336
4 Kamal F, Flavin S, et al. Factors affecting the outcome of methadone maintenance treatment in opiate dependence. Irish Med J (2007) 100, 393-397
5 Higgins C, Smith BH, Matthews K. Substance misuse in patients who have comorbid chronic pain in a clinical population receiving methadone maintenance therapy for the treatment of opioid dependence. Drug Alcohol Depend. 2018 Dec 1;193:131-136
6 Drake S, Swift W, et al. HIV risk-taking and psychosocial correlates of benzodiazepine use among methadone maintenance clients. Drug Alcohol Depend (1993) 34;76-70
7 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
8 Charlson F, Degenhardt L, et al. A systemic review of research examining benzodiazepine related mortality. Pharmacoepidemiol Drug Saf (2009) 18:93-103
9 Gerra G, Zaimovic A, etal. Rapid opiate detoxication in outpatient treatment: relationship with naltrexone compliance. J Subst Abuse Treat. 2000 Mar;18(2):185-91
10 Eibl JK, Wilton AS, et al. Evaluating the Impact of Prescribed Versus Nonprescribed Benzodiazepine Use in Methadone Maintenance Therapy: Results From a Population-based Retrospective Cohort Study. J Addict Med. 2019 May/Jun;13(3):182-187.
11 Weizman T, Gelkopf M et al. Treatment of benzodiazepine dependence in methadone maintenance treatment patients: A comparison of two therapeutic modalities and the role of psychiatric comorbidity. Aust N Z J Psychiatry (2003) 37: 458-463