Mechanisms of fatal opioid overdose

Abstract

There has been increasing recognition of the problem of fatal opioid overdose. This review examines the pharmacological basis of respiratory depression following opioid administration. Respiration is controlled principally through medullary respiratory centres with peripheral input from chemoreceptors and other sources. Opioids produce inhibition at the chemoreceptors via mu opioid receptors and in the medulla via mu and delta receptors. While there are a number of neurotransmitters mediating the control of respiration, glutamate and GABA are the major excitatory and inhibitory neurotransmitters, respectively. This explains the potential for interaction of opioids with benzodiazepines and alcohol: both benzodiazepines and alcohol facilitate the inhibitory effect of GABA at the GABAA receptor, while alcohol also decreases the excitatory effect of glutamate at NMDA receptors. Heroin and methadone are the major opioids implicated in fatal overdose. Heroin has three metabolites with opioid activity. Variation in the formation of these metabolites due to genetic factors and the use of other drugs could explain differential sensitivity to overdose. Metabolites of methadone contribute little to its action. However, variation in rate of metabolism due to genetic factors and other drugs used can modify methadone concentration and hence overdose risk. The degree of tolerance also determines risk. Tolerance to respiratory depression is less than complete, and may be slower than tolerance to euphoric and other effects. One consequence of this may be a relatively high risk of overdose among experienced opioid users. While agonist administration modifies receptor function, changes (usually in the opposite direction) also result from use of antagonists. The potential for supersensitivity to opioids following a period of administration of antagonists such as naltrexone warrants further investigation. While our understanding of the pharmacological basis of opioid-related respiratory depression has advanced, better understanding of the role of heroin metabolites, the metabolism of methadone, drug interactions and tolerance would all be of considerable value in knowing how best to respond to this problem.

Intentional Overdose Among Heroin Overdose Survivors

“…Previous research has shown that there are many factors that contribute to heroin overdose, such as differing metabolic rates, recent changes in patterns of use affecting tolerance, use in combination with other drugs or alcohol, and the purity of the heroin used. 3,4 However, investigation of these factors in the absence of information about the user's state of mind immediately prior to the overdose in question assumes that the event was accidental.…”

The Relationship Between Depressive Symptoms and Nonfatal Overdose Among a Sample of Drug Users in Baltimore, Maryland

“…2 Epidemiologic studies have identified several factors that increase the risk of overdose, including (1) concomitant use of other drugs, such as benzodiazepines and alcohol; (2) low tolerance level; and (3) impaired physical health status of the user. 3 Warner-Smith et al 4 documented that drug users who have experienced a nonfatal overdose suffer from peripheral neuropathy, lung infections, cardiac complications, and cognitive impairment.…”

The extent of and factors associated with self-reported overdose and self-reported receipt of naloxone among people who inject drugs (PWID) in England, Wales and Northern Ireland

“…This increased frequency of overdose in heroin injectors is most likely due to the physiological effects heroin has and the nature of a heroin overdose; there is often a fine line between acute respiratory suppression and when heroin dosage becomes toxic causing respiratory failure, hypoxia and potentially death (Jolley, Bell, Rafferty, Moxham, & Strang, 2015;White & Irvine, 1999).…”