Methadone dosing based on testosterone-to-creatinine urine ratio.

ADICCIONES, 2013 · VOL. 25 NÚM. 4 · PÁGS. 358-359 Enviar correspondencia a: José Roberto Lozano Ortiz. C/ Ramón y Cajal, 60, 50004 Zaragoza (Spain) Telf +34876764522. Correo electrónico: [email protected]. Dear editor: Methadone Maintenance Treatment programs (MMT) are the procedures of choice for opioid addiction since the 60`s (Dole & Nyswander, 1965), but the interindividual variability in methadone disposition, resulting in a high variability of methadone dosage, difficults the dosage regimen design in opioid dependence treatment of patients included in MMT programs (Torrens, Castillo & Pérez-Solá, 1996; López, Baño & Guillen , 2000; Crettol et al., 2006). Thus, we aimed to identify a laboratory surrogate marker which, alongside to clinical response data (e.g. dose titration according to patient symptoms), allows us to improve the accuracy of methadone dosing in these MMT programs. Based on disruption of pituitary-gonadal axis, caused by opiates, and on the different “opiate potency”, defined as the lowest concentration of opiate required to produce 50% of maximum effect, which results in a dose-dependent decrease of testosterone plasma levels (Cicero, 1970; Mendelson, Mendelson & Vernon, 1974), we conducted the present work aimed to study the relationship between urinary testosterone-to-creatinine ratio values (U-T/Cr) and methadone doses, and its application to dosing in MMT, as follows: Sample of 62 patients with heroin addiction, age 40.0 (± 6.4) years old, women 32.5%, methadone (given as racemic oral solution at 0.5 %) dose at steady-state 91.8 (± 38.9) mg, addict since the age of 18.2 (± 4.3) years old, remaining in a MMT program for 8.3 (± 4.4) years and no symptoms of withdrawal syndrome for at least 1 month before sample collection. We analized urine samples for testosterone (Testosterone RIA Kit test Coat-A-Count® , limit of detection, 0.4 mcg/L) and creatinine (autoanalyzer Hitachi Modular DPP, Roche®), then we calculated the U-T/Cr ratio for all patients and, finally, we applied the gaussian Kernel density estimation (Kernel`s test) to data series, for population analysis. The following overall results were obtained: creatinine 1.5 (± 0.7) g/L, testosterone 45.4 (± 66.1) mcg/L and U-T/ Cr ratio 31.3 (± 36.1) mcg/g. After applying Kernel’s test to the U-T/Cr data serie, we observed two main subpopulations (Student`s “t” two-tailed test, p = .001), the first and most important with an estimated mean value of 23.4 (± 13.9) mcg/g (n = 58; 93.5% patients) and the second with an estimated mean value of 103.4 (± 15.2) mcg/g (n = 4; 6.5%). After applying Kernel’s test to methadone-dose data serie, we observed two main subpopulations (Student`s “t” two-tailed test, p = .001) with an estimated mean value of 56.4 (± 18.4) mg (n = 29; 47% of patients) and 122.8 (± 21.8) mg (n = 33; 53%) of methadone, respectively. According to the main population from U-T/Cr data, we taken the value of U-T/Cr = 23.4 mcg/g as “clinical surrogate endpoint” for methadone dosing. Accordingly with this target, only 6.5% of patients, those with U-T/Cr = 103.4 (± 15.2) mcg/g, required a 1.5 to 2-fold dose increases, which was made using the relation of Figure 2. There are many different studies showing the reduction of testosterone levels induced by opioid drug. So, this ability to decrease plasma and/or urine testosterone can be used to evaluate the pharmacokinetic constants and reach conclusions about their pharmacological potency and its optimal therapeutic dose (Cicero et al., 1975; Mendelson, Inturrisi, Renault & Sinay, 1976). Methadone dosing based on testosterone-to-creatinine urine ratio Dosificación de metadona basada en el indice urinario testosterona-creatinina