Evaluation of opioid related deaths associated with opioid utilisation and the impacts of tramadol classification as a Schedule III Controlled Drug in the United Kingdom
Year: 2019

In the past two decades, there has been a marked increase in opioid utilisation paralleled with the rising opioid mortality in many western countries. In contrast to opioid overdose deaths in the United States which were mainly caused by opioid poisoning, the increasing opioid related death in the United Kingdom (UK) involves a complex mechanism, including persistent opioid utilisation, medicines for chronic pain management and illicit drugs. However, no research has evaluated the association between opioid related death, opioid utilisation and other determinants in the UK. In June 2014, tramadol was classified as a Schedule III controlled drug due to the concerns of increasing tramadol utilisation and tramadol related deaths, but no research has evaluated the impact of the tramadol classification. Therefore, this PhD project aimed to identify the association between opioid utilisation and opioid related deaths in the UK primary care setting and to evaluate the impact of policy implementation using tramadol as a case study. This study took a drug utilisation research and pharmacoepidemiology approach to develop and test a hypothesis about the association between opioid related deaths and opioid utilisation. Firstly, a cross sectional study was conducted using the UK Clinical Practice Research Datalink and aggregate level national data to evaluate the impact of tramadol classification on tramadol utilisation, the prevalence of tramadol users and tramadol related deaths by interrupted time series analysis. Secondly, a case cross over study was conducted to identify cases of opioid related death, explore the characteristics and medication utilisation of opioid related deaths and investigate the association between opioid related death and opioid daily dose. Finally, a nested case control study was conducted to analyse the association between opioid related death and persistent opioid utilisation in the three patient years retrospectively followed from the date of opioid related deaths by conditional logistic regression. After tramadol classification, the levels of monthly tramadol utilisation and the prevalence of tramadol users decreased by 12.9 defined daily dose/1000 registrants and 6.4 tramadol users/10000 registrants. In addition, the trends of monthly tramadol utilisation and the prevalence of tramadol users decreased by 1.6 defined daily dose/1000 registrants and 0.37 tramadol users/10000 registrants. The impacts of tramadol classification seems predominantly associated with the reduced accessibility of tramadol to both new and existing users. Of the 232 cases of opioid related deaths, 62 (26.7% cases did not receive any opioid in the one year before opioid related death. Only 48 cases received a daily dose of opioid of more than 120 mg oral morphine equivalent (OMEQ) dose in the final year, and an opioid daily dose more than 120 mg OMEQ dose was not significantly associated with opioid related deaths (adjusted odds ratios [aOR] 1.4; 95% confidence interval [95%CI] 0.52, 3.6) In addition, most of the opioid related deaths were diagnosed with alcohol abuse disorders (25.4% other substance abuse disorder (30.6% had a history of overdose of any medication (26.7% or were regularly prescribed with sedatives (81% Compared to patients who were not prescribed with opioids persistently, persistent opioid use in any of the last three retrospective patient years was associated with an increased risk of opioid related death (aOR: 2.0; 95%CI: 1.3, 3.1) especially in the final retrospective patient year (aOR: 3.6; 95%CI: 1.6, 8.0) In addition, a higher risk of opioid related death was observed when taking a higher dose of benzodiazepines, gabapentin/pregabalin and tricyclic antidepressants. This is the first study applying nationwide individual patient data and aggregate level national data to evaluate the impact of tramadol classification and the association between opioid related deaths and opioid utilisation in the UK. Tramadol classification reduced the increasing tramadol prescribing and tramadol related deaths in a short term, but the impacts on the utilisation of other medications with abuse potential and the effectiveness of chronic pain management among individual patients are still unclear. In addition to substance abuse and concurrent sedatives, opioid related deaths are associated with persistent opioid utilisation. As the effectiveness of persistent opioid utilisation is not supported by published evidence and persistent opioid utilisation is related to opioid related death in this study, an information system longitudinally evaluating the benefits and risks of opioid treatment for individual patients may be beneficial to facilitate opioid deprescribing. Further studies need to investigate the optimisation of opioids for patients with chronic pain and attitude of opioid disposal and diversion from potential prescribing opioid abusers.