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.

This study has provided evidence of a methamphetamine withdrawal syndrome that can be categorized into two phases, the acute phase lasting 7-10 days during which overall symptom severity declined in a linear pattern from a high initial peak, and a subacute phase lasting at least a further 2 weeks.

Buprenorphine did not differ from methadone in its ability to suppress heroin use, but retained approximately 10% fewer patients. This poorer retention was due possibly to too-slow induction onto buprenorphine. For the majority of patients, buprenorphine can be administered on alternate days.

Opioid substitution treatment for dependence may alter sensitivity to pain. Previous studies on pain sensitivity in methadone maintenance patients have yielded contradictory results. This study compared nociceptive responses between 16 patients on stable, once daily, doses of methadone and 16 matched control subjects. Two types of nociceptive stimuli were used: (1) electrical stimulation; and (2) a cold pressor test. Two parameters were measured: detection for onset of pain, and pain tolerance. Methadone patients were tested over an inter-dosing period: at the time of trough plasma methadone concentration (0 h), and 3 h after their daily dose. Control subjects were tested twice 3 h apart. Blood samples were collected to determine plasma methadone concentration. In methadone patients, trough to peak increases in mean R-(-)- and S-(+)-methadone concentrations (118 and 138 ng/ml to 185 and 259 ng/ml, respectively) resulted in significant increases in pain detection and tolerance values for both nociceptive stimuli. Using electrical stimulation, methadone patients' pain tolerance values were lower than controls at 0 h, but higher than controls at 3 h; no significant differences in pain detection values were found. For the cold pressor test, methadone patients detected pain significantly earlier than controls at 0 h, and were also substantially less pain tolerant than controls at both 0 and 3 h. There were no significant differences in pain detection values between the two groups at 3 h. Pain tolerance to pain detection ratios for methadone patients were significantly lower than controls for the cold pressor test at 0 and 3 h, and for electrical stimulation at 0 h only. In summary, the relative pain sensitivity of methadone maintenance patients is determined by the nature of the nociceptive stimulus (e.g. cold pressor test versus electrical stimulation), the plasma methadone concentration (trough versus peak plasma concentration), and whether thresholds are determined for detection of pain or pain tolerance. Although responding to changes in plasma methadone concentration, maintenance patients are markedly hyperalgesic to pain induced by the cold pressor test.

No abstract

Aims To investigate the steady-state pharmacokinetics of (R)-and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultra®ltration, and plasma a 1 -acid glycoprotein concentrations were quanti®ed by radial immunoassay. Results (R)-methadone had a signi®cantly (P<0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were signi®cantly (P<0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were signi®cantly (P<0.01) lower than for (S)-methadone, while AUC ss q u (167%) was signi®cantly (P<0.001) greater. There were no signi®cant (P>0.2) differences between the methadone enantiomers for AUC ss q , steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted signi®cantly (P<0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coef®cients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a signi®cant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokineticpharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

No abstract

We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18–45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test (TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties.