Optimising opioid assisted therapy
: outcomes for opioid use disorder treatment using personalised care and therapeutic drug monitoring

Student thesis: Doctoral ThesisDoctor of Philosophy


Background and aim
This thesis (incorporating three publications in peer-reviewed journals) investigates the clinical effectiveness of Medication Assisted Treatment (MAT) for opioid use disorder (OUD) with buprenorphine/naloxone film (BUP/NX-F) medication (Suboxone®). In a randomised controlled trial, take-home (i.e. unsupervised patient self-administered) prescriptions BUP/NX-F were made available contingent of medication adherence by Therapeutic Drug Monitoring (TDM) and drug use abstinence by Urine Drug Screen (UDS).
MAT with buprenorphine (BUP) containing medications is an evidence-based treatment for OUD. Clinical effectiveness of BUP is affected by several moderators, including medication misuse and diversion, medication non-adherence, sub-optimal clinical care, and poor treatment retention. While Directly Observed Treatment (DOT) can minimise the likelihood of poor medication adherence and limit diversion, this practice is associated with high treatment discontinuation and high cost. Contingency Management (CM) using medication take-home prescriptions is an effective behavioural adjunct to MAT that enhances retention, but there may be a continued risk of medication diversion. In the Middle-East countries, provision of MAT is limited due to concern over diversion. There is a word-wide call to develop sensitive and specific tools to detect misuse and diversion. Therapeutic Drug Monitoring (TDM) has been recommended to monitor adherence with BUP, but there has been no research trials on integrating feasibility of TDM and integration in clinical practice. The aim of the thesis was to determine the effectiveness of a TDM and CM manualised medication management (MM) to enhance the effectiveness of BUP/NX-F for OUD.

Design and method
This was a single-centre pragmatic randomised controlled trial of MAT (BUP/NX-F; buprenorphine/naloxone ratio 4:1) with TDM and CM (in a manual guided medication management (MM) protocol; Incentivised Abstinence and Adherence Monitoring; IAAM) was the experimental condition. This was compared to BUP/NX-F as usual (the control group) using intention-to-treat analysis. Participants (n=141) adults with OUD, all stabilised on BUP/NX-F) were randomised to receive 16-weeks outpatient treatment in the experimental (n = 70) and control (n = 71) groups. The primary outcome measure was the percentage of negative opioid UDS recorded during the 16-week follow-up with missed appointments imputed as positive for opioids). The secondary outcome was the rate of completion of the 16-week outpatient treatment without interruption (retention in treatment) in each condition. On an exploratory basis, the buprenorphine elimination rate (BUP EL. R) was examined for association with the percentage of negative UDS and retention to examine if this would predict outcomes. Several measures of patient characteristics were explored for their associations with outcomes.

The experimental group achieved 76.7% (SD 25.0) negative UDS and the control group achieved 63.5% (SD 34.68) (mean difference = 13.26% [95% CI 3.19−23.31; p = 0.01; effect size [ES] = 0.44 [95% CI 0.09−0.76]). The difference in study completion rate between the experimental and control group was not significant (i.e. 57.14% in the experimental and 46.4% in the control group; odds ratio [OR] 1.54, 95% CI 0.78−2.97). To achieve higher percentage negative UDS, the adjusted Incidence Rate Ratio (IRR) in the experimental group compared to the control group was 1.15 (95% CI 1.01 − 1.30). For the secondary outcome, 40 participants in the experimental group and 33 in the control group completed the trial without significant difference (χ2 = 1.605, p=0.21). Buprenorphine elimination rate (BUP EL. R) was negatively associated with the percentage of UDS (Spearman’s rho = -0.274, p < 0.05) and predicted the primary outcome (R2 0.265, p=0.001). No other sociodemographic factor nor the dose of BUP/NX-F correlated with either the primary or the secondary outcome. 

The clinical effectiveness of BUP/NX-F for OUD can be, enhanced by integrating TDM with medication management applying two contingencies for take home prescriptions. This treatment modality can facilitate access to MAT with minimal concern over diversion and possibly optimize cost-effectiveness. In contrast, BUP EL.R is a promising predictor of response to buprenorphine/naloxone measured by opioid use, and can contribute to implement precision medicine and personalised treatment. 
Date of Award1 Feb 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJohn Marsden (Supervisor) & Abdu Adem (Supervisor)

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