Fentanyl Overdose Deaths: Underlying Mechanisms

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Over the past 5 years acute opioid overdose deaths have risen both in the UK and the USA. A new danger is the emergence on the drug scene of illicit fentanyls (fentanyl and its structural analogues). In the USA deaths due to fentanyls have reached epidemic levels (over 20,000 in 2016) and now exceed those involving either heroin or prescription opioids such as oxycodone. In the UK and Europe there have recently been several alarming outbreaks of fentanyl-related deaths. The purpose of our research is to determine why fentanyls are such deadly drugs. Opioid overdose deaths are due primarily to respiratory depression. In the brain fentanyl interacts with the mu opioid receptor (MOPr) to produce respiratory depression and is an extremely potent opioid, being 50 - 100 times more potent than morphine. Factors that likely contribute to fentanyl overdose deaths are- being highly potent drugs, even a small error in the amount taken could lead to profound respiratory depression. - respiratory depression by fentanyls is less readily reversible by the antagonist naloxone.- on intravenous administration fentanyl can induce respiratory muscle rigidity (referred to as 'wooden chest' syndrome) making it even more difficult to breathe.To facilitate the development of effective interventions to combat fentanyl overdose we need to understand fully why these drugs are so potent, how they depress respiration, why they are resistant to naloxone reversal and whether fentanyls exhibit less cross tolerance to other opioid drugs.We propose to study several novel facets of the interactions of fentanyls with MOPr.(i) How fentanyls bind to and activate MOPrWe hypothesise that - higher lipophilicity results in greater plasma membrane association of fentanyls, - on unbinding fentanyls can very rapidly re-associate with MOPr to reactivate it whereas other opioid agonists do not rapidly re-bind to the receptor but diffuse away from the vicinity of the receptors before re-binding can occur. - fentanyls can access the binding pocket of MOPr directly from the membrane lipid through a hydrophobic pathway as well as via a hydrophilic aqueous pathway.Such novel properties would enhance the in vivo agonist potency of fentanyls to depress respiration and render them less susceptible to reversal by naloxone. We will determine the partition coefficient of fentanyls into phospholipid monolayers, utilise novel fluorescence technologies to study rapid drug-receptor association and dissociation kinetics, and perform advanced molecular dynamic simulations of ligand-receptor interaction using the crystal structure of the MOPr protein. (ii) Contribution of muscle rigidity to respiratory depression by fentanyls. We will use a mouse model of opioid-induced respiratory depression to examine the contribution of respiratory muscle rigidity to respiratory depression by fentanyl derivatives.(iii) Reversal of fentanyls by lipophilic antagonists. We will examine whether highly lipophilic MOPr antagonists more readily reverse fentanyl respiratory depression than naloxone.(iv) Tolerance breakthrough. We will determine whether 'on top' use of the fentanyls can break through the tolerance to respiratory depression that has been induced by prolonged heroin use or from prolonged opioid substitution therapy with methadone or buprenorphine. We hypothesise that the processes which make the fentanyls more potent and their abilities to induce respiratory muscle rigidity may reduce the degree of cross tolerance they exhibit to other opioids.The importance of our research is that it addresses a current major international health problem - the rise in overdose deaths due to the fentanyl class of opioid drugs.