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.
Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is the third most used illicit drug, after cannabis and amphetamines. There has been considerable interest in the adverse effects of use, with particular attention given to a small number of deaths related to ecstasy use, and the neurotoxic effects of MDMA. This paper reviews case reports of adverse effects attributed to ecstasy use, and the findings of animal and human studies, so as to identify the health effects of ecstasy use, and factors contributing to their occurrence. The incidence of serious acute adverse events related to ecstasy is low. It is the unpredictability of those adverse events and the risk of mortality and substantial morbidity that makes the health consequences of ecstasy significant. Hyperthermia and hyponatraemia are the most significant acute adverse effects, and can occur even when MDMA is the only drug used. Ecstasy users should be aware of the importance of controlling body temperature and fluid intake, early signs of adverse effects, and the need to seek medical assistance promptly. Neurotoxicity is potentially the most significant long-term effect of ecstasy. The clinical implications of neurotoxicity are uncertain at this time, but short-term memory impairment may be significant.
Accurate information on drug use in communities is essential if health, social and economic harms associated with illicit drug use are to be addressed efficiently. In most countries population drug use is estimated indirectly via surveys, medical presentations and police and custom seizures. All of these methods have at least some problems due to bias, small samples and/or long time delays between collecting the information and analysing the results. Recently the direct quantification of drug residues in wastewater has shown promise as a means of monitoring drug use in defined geographical areas. In this study we measured 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine and benzoylecgonine in sewage inflows in metropolitan and regional areas of Australia and compared these data with published European data. Cocaine use was small compared to European cities (p < 0.001) but was compensated for by much greater consumption of methamphetamine (p < 0.001) and MDMA (p < 0.05). MDMA was 2 more popular in regional areas (p < 0.05) whereas methamphetamine and cocaine were mainly consumed in the city (p < 0.05). Greater than 5-fold increases in MDMA use were detected on weekends (p < 0.001). This approach has the potential to improve our understanding of drug use in populations and should be further developed to improve prevention and treatment programs.
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