Title: Evaluating the impact of opiate substitution treatment on drug related deaths in the population: a natural experiment using primary care other drug treatment databases & model projections
Funder: Department of Health (England)

Abstract: Background:- Opiate substitution treatment (OST) is the key treatment for heroin dependence and has been shown to reduce drug related deaths during treatment and has multiple benefits including reductions in drug related crime blood borne virus transmission and improvements in social functioning(1-10). Prescribed OST is mainly delivered in primary care and includes methadone buprenorphine and dihydrocodeine(11;12). OST has been shown to be cost effective in reducing drug related crime and health harms(13). Buprenorphine has been shown to be as good as methadone at treatment retention(14) and hypothetically is less likely to cause fatal overdose than methadone(15). In France ecological analyses suggest that trends in overdose deaths are negatively associated with buprenorphine prescription(16). However direct comparative evidence on the risk of death during buprenorphine vs. methadone is scarce and exclusively from the US. The evidence base on the impact of other drug treatments (residential rehabilitation detoxification and psychological treatments) is more limited; but a few studies also suggest that the risk of mortality is reduced during treatment and elevated after treatment (9;17). In the UK OST has expanded 5-fold in the last 10 years to >1800kg per year (roughly equivalent to 33.3 million doses per year)(18). The rate of methadone deaths per gram of methadone prescribed has fallen this fall coinciding with the implementation of clinical guidelines recommending greater supervised consumption(18). Prescribing of Buprenorphine has also increased in the UK however trends in the overall number of opiate related deaths have not declined and Government targets to reduce the number of drug related deaths have not been met(19). This apparent paradox of expansion of a treatment shown to be effective alongside an increase in mortality from the target condition for this treatment in a situation where the incidence of the condition appears stable remains unexplained. Aim:- We aim to conduct a “natural experiment” to consider the question of whether the benefits of OST and other drug treatments are being outweighed by other factors that influence and increase the risk of death(20). Method:- We will extract and analyse an open observational cohort from the Clinical Practice Research Datalink (CPRD) primary care database. We will extend increase the power and test hypotheses raised by previous analyses on the relationship between drug treatment and mortality (1;18;21;22). Complementary analyses of Drug Data Warehouse (DDW) which cannot assess OST precisely but incorporates National Drug Treatment Monitoring System (NDTMS) linked to mortality file and will investigate the effect of other drug treatments (residential detoxification and non-pharmacological) on the risk of mortality. The evidence generated will be incorporated into mathematical models that link drug treatment coverage and the number of overdose deaths in the population in order to assess how changes in the way treatments are delivered might reduce the number of drug related deaths. The main intervention is OST (methadone buprenorphine or dihydrocodeine) and other drug non-pharmacological treatments (residential and psychological therapies). Control or comparator periods constitute different periods “on” or “off” specialist drug treatment e.g. 1st 2 weeks of treatment 1st 4 weeks after treatment and rest of time out of treatment - vs. baseline (from two weeks until treatment cessation). The latter baseline period has been shown to have the lowest mortality risk. Additional exposures include type of OST co-prescription of benzodiazepines and planned discharge. The main outcomes are overdose and drug related mortality during drug treatment or follow-up period up to one year after date of last OST prescription/treatment discharge(23). Additional outcomes include:- annual measures of treatment duration and OST performance (optimal dosing tapered/planned discharge supervised consumption)(18;24). Follow-up will be from date of first OST within risk period beginning 1990 to end December 2011. We will censor follow-up twelve months after last prescription date in order to reduce potential bias. Key confounders include age gender co-morbidity (measured by Charlson Index(25)) mental illness diagnosis alcohol problems treatment episode number calendar year. We expect there will be 20000 OST patients in CPRD from 1990 to 2011 linked to NHS central registry and mortality data that will generate approximately 67000 person years (pys) follow-up (~32000 on treatment and ~35000 off if censored 12 months after last OST) and over 700 deaths of which ~500 will be due to overdose. This will be the largest study in the UK with precise data on treatment exposure (including ~ 12000 pys on buprenorphine and 30000pys on methadone). In addition the DDW has approximately 50000 patients (and 44000 person years) exposed to other drug treatments from 2005 to 2009.Analyses:-We will use a range of statistical methods to investigate the relationship between periods on and off OST/drug treatment and mortality risk in order to assess both the intervention effects and potential influence of selection bias and confounding. These include standard poisson regression models incorporating time-varying covariates; an adaptation of self-controlled case-series methodology which uses patients as their own controls and has high statistical power(26-29); propensity score methods which aim to weight confounders or match subjects between exposure groups in order to adjust for confounding(30-33); and marginal structural models(34;35).OST and other drug treatment effect estimates derived from analyses of CPRD and DDW will be used in differential equation models that consider the flow of people into and out of drug treatment fitted against estimates of the annual number of drug related deaths in the population. The models will project and examine the impact of drug treatment on drug related deaths in the population(1;36). The model also incorporates information on treatment duration and coverage of interventions provided by CPRD and DDW.Segmented regression techniques will be used to test whether there have been changes in treatment patterns and delivery over time(18;37).The study is an example of applied epidemiological research with the potential to lead to immediate patient benefit.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE