Clinical and laboratory investigation into heroin and opioid overdose risk

Background: Globally, more than 100,000 people die annually from opioid overdose, and this number continues to increase. In the UK, opioid-related deaths are at an all-time high. The depressant effects of opioids on breathing centres in the brain cause 'respiratory depression' with effects on regular breathing rhythm and neural respiratory drive (signals coming from brain to breathing muscles), which then impairs the adequately balanced levels of blood oxygen and carbon dioxide. Mechanisms of opioid overdose and the degree of opioid-induced respiratory depression among long-term users are not well understood. Aims: This thesis incorporates retrospective analyses as well as direct clinical investigations to examine risk factors for overdose, as captured through clinical samples and in a clinical research facility, exploring influence of dose, route of administration and pre-existing disease. Methods: Primary and secondary data were collected and analysed. Primary data collection involved two clinical studies utilising novel objective markers of respiratory depression. First, an observational study investigated the severity of respiratory depression in long-term heroin users on an opioid substitution treatment. The second clinical study, in a clinical research facility, examined effects of varying doses of pharmaceutical heroin (diamorphine) on physiological markers of respiratory depression and observed and subjective ratings of drug effect. Secondary data analysis involved physiological data from a previous clinical study, and data extraction from historical literature. Results: Major impairment of respiratory function was identified across a broad clinical sample of dependent opioid users, and particularly following intravenous heroin administration (studied in an experimental clinical laboratory context). Conclusions: Without a practical, 'gold standard' measure of respiratory depression, it is crucial that reliable and sensitive techniques are used to elucidate the complex physiological responses to opioid use. Important next steps are identified for research to inform better understanding and better public response to the opioid overdose crisis.