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      Risk-factors for methadone-specific deaths in Scotland’s methadone-prescription clients between 2009 and 2013*

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          Highlights

          • Powerful analysis of a national cohort’s 362 methadone-specific deaths.

          • Scottish cohort of 33,128 methadone-prescription clients in 2009–2013.

          • Steeper age-gradient than for all drugs-related deaths.

          • No gender differential in the hazard of methadone-specific deaths.

          • Increased hazard at the highest quintile for quantity of methadone prescribed.

          Abstract

          Aim

          To quantify gender, age-group and quantity of methadone prescribed as risk factors for drugs-related deaths (DRDs), and for methadone-specific DRDs, in Scotland’s methadone-prescription clients.

          Design

          Linkage to death-records for Scotland’s methadone-clients with one or more Community Health Index (CHI)-identified methadone prescriptions during July 2009 to June 2013.

          Setting

          Scotland’s Prescribing Information System and National Records of Scotland.

          Measurements

          Covariates defined at first CHI-identified methadone prescription, and person-years at-risk (pys) thereafter until the earlier of death-date or 31 December 2013. Methadone-specific DRDs were defined as: methadone implicated but neither heroin nor buprenorphine. Hazard ratios (HRs) were assessed using proportional hazards regression.

          Findings

          Scotland’s CHI-identified methadone-prescription cohort comprised 33,128 clients, 121,254 pys, 1,171 non-DRDs and 760 DRDs (6.3 per 1,000 pys), of which 362 were methadone-specific. Irrespective of gender, methadone-specific DRD-rate, per 1,000 pys, was higher in the 35+ age-group (4.2; 95% CI: 3.6–4.7) than for younger clients (1.9; 95% CI: 1.5–2.2). For methadone-specific DRDs, age-related HRs (e.g., 2.9 at 45+ years; 95% CI: 2.1–3.9) were steeper than for all DRDs (1.9; 95% CI: 1.5–2.4); there was no hazard-reduction for females; no gender by age-group interaction; and, unlike for all DRDs, the highest quintile for quantity of prescribed methadone at cohort-entry (>1960 mg) was associated with increased HR (1.8; 95% CI: 1.3–2.5).

          Conclusion

          Higher methadone-specific DRD rates in older clients, irrespective of gender, call for better understanding of methadone’s pharmaco-dynamics in older, opioid-dependent clients, many with progressive physical or mental ill-health.

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          Most cited references46

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          Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence.

          Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.
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            Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs.

            To test the hypothesis that female prevalence is greater than expected among reported cases of torsades de pointes associated with cardiovascular drugs that prolong cardiac repolarization. A MEDLINE search of the English-language literature for the period of 1980 through 1992, using the terms torsade de pointes, polymorphic ventricular tachycardia, atypical ventricular tachycardia, proarrhythmia, and drug-induced ventricular tachycardia, supplemented by pertinent references (dating back to 1964) from the reviewed articles and by personal communications with researchers involved in this field. Ninety-three articles were identified describing at least one case of polymorphic ventricular tachycardia (with gender specified) associated with quinidine, procainamide hydrochloride, disopyramide, amiodarone, sotalol hydrochloride, bepridil hydrochloride, or prenylamine. A total of 332 patients were included in the analysis following application of prospectively defined criteria (eg, corrected QT [QTc] interval of 0.45 second or greater while receiving drug). Clinical and electrocardiographic descriptors were extracted for analysis. Expected female prevalence for torsades de pointes associated with quinidine, procainamide, disopyramide, and aminodarone was conservatively estimated from gender-specific data reported for antiarrhythmic drug prescriptions in 1986, as derived from the National Disease and Therapeutic Index, a large pharmaceutical database; expected female prevalence for torsades de pointes associated with sotalol, bepridil, and prenylamine was assumed to be 50% or less since these agents are prescribed for male-predominant cardiovascular conditions. Women made up 70% (95% confidence interval, 64% to 75%) of the 332 reported cases of cardiovascular-drug-related torsades de pointes, and a female prevalence exceeding 50% was observed in 20 (83%) of 24 studies having at least four included cases. When analyzed according to various descriptors, women still constituted the majority (range, 51% to 94% of torsades de pointes cases), irrespective of the presence or absence of underlying coronary artery or rheumatic heart disease, left ventricular dysfunction, type of underlying arrhythmia, hypokalemia, hypomagnesemia, bradycardia, concomitant digoxin treatment, or level of QTc at baseline or while receiving drug. When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P < .05) for all agents except procainamide. These findings strongly suggest that women are more prone than men to develop torsades de pointes during administration of cardiovascular drugs that prolong cardiac repolarization. The pathophysiological basis for, and therapeutic implications of, this gender disparity should be further investigated.
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              Role of maintenance treatment in opioid dependence.

              Methadone maintenance treatment (MMT) involves the daily administration of the oral opioid agonist methadone as a treatment for opioid dependence-a persistent disorder with a substantial risk of premature death. MMT improves health and reduces illicit heroin use, infectious-disease transmission, and overdose death. However, its effectiveness is compromised if low maintenance doses of methadone (<60 mg) are used and patients are pressured to become prematurely abstinent from methadone. Pregnancy and psychiatric comorbidity are not contraindications for MMT. As an alternative to MMT, other oral opioid agents (eg, naltrexone, buprenorphine) may increase patient choice and avoid some of the more unpleasant aspects of MMT. The public-health challenge for the future is to develop and continue to deliver safe and effective forms of opioid maintenance treatment to as many opioid-dependent individuals as can benefit from them.
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                Author and article information

                Contributors
                Journal
                Drug Alcohol Depend
                Drug Alcohol Depend
                Drug and Alcohol Dependence
                Elsevier
                0376-8716
                1879-0046
                01 October 2016
                01 October 2016
                : 167
                : 214-223
                Affiliations
                [a ]MRC Biostatistics Unit, Cambridge CB2 0SR, United Kingdom
                [b ]Usher Institute of Population Health Sciences and Informatics, Edinburgh University, EDINBURGH EH16 4UX, United Kingdom
                [c ]Information Services Division, NHS National Services Scotland, Edinburgh EH12 9EB, United Kingdom
                [d ]Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom
                [e ]Department of Mathematics and Statistics, Strathclyde University, Glasgow G1 1XH, United Kingdom
                Author notes
                [* ]Corresponding author at: MRC Biostatistics Unit, Cambridge, CB2 0SR, United Kingdom.MRC Biostatistics UnitCambridgeCB2 0SRUnited Kingdom sheila.bird@ 123456mrc-bsu.cam.ac.uk
                Article
                S0376-8716(16)30869-9
                10.1016/j.drugalcdep.2016.08.627
                5047032
                27593969
                87ecf1b3-c125-494d-9e86-6b8c05170cbc
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 June 2016
                : 1 August 2016
                : 22 August 2016
                Categories
                Full Length Article

                Health & Social care
                deaths,drugs-related,methadone-specific,risk-factors,gender,age-group,prescribed-methadone,quantity,daily-dose,quintiles

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