Liver damage indices as a tool for modifying methadone maintenance treatment: a cross-sectional study

Abstract

AimTo assess the effect of liver damage on methadone metabolism in opiate addicts undergoing methadone maintenance treatment (MMT).MethodsThis cross-sectional study recruited 74 patients treated at the outpatient clinic of Public Health Institute of Split-Dalmatia County from 2013-2016. Concentrations of methadone and its main inactive metabolite were measured in participants’ biological samples on regular check-ups. Urine samples obtained before oral methadone intake, and blood and urine samples obtained 90 minutes after methadone intake were analyzed using gas chromatography/mass spectrometry. Participants were divided into groups according to liver damage criteria: hepatitis C virus status (positive, negative, or clinical remission); aspartate aminotransferase to platelet ratio (APRI) index (<0.7 and ≥0.7); and fibrosis-4 score (<1.45, 1.45-3.25, >3.25).ResultsMetabolic ratio and methadone metabolite concentration in plasma decreased linearly with HCV infection status by the factor of 1.67 (P = 0.001) and 2.2 (P = 0.043), respectively. Metabolic ratio in plasma decreased in patients with APRI index ≥0.7 by the average factor of 2.12 (P = 0.01) and methadone metabolite concentration in plasma decreased by the factor of 6.16 (P = 0.009). Metabolic ratio in urine decreased with the severity of fibrosis-4 score by the average factor of 1.63 (P = 0.008), whereas methadone metabolite concentration decreased by the factor of 3.53 (P = 0.007).ConclusionLiver damage decreases methadone metabolism. Indices of liver function should be calculated regularly during MMT for methadone dose titration.

Toward precision prescribing for methadone: Determinants of methadone deposition

“…This study is limited since HCV status was only determined based upon antibody testing, which does not differentiate between active and resolved infections. Despite these limitations, both studies are in agreement that HCV influences plasma methadone concentration in OUD patients on methadone [67,68]. In contrast to the above-mentioned studies, we did not observe a significant effect of fibrosis stage on methadone metabolism.…”

“…Therefore, the authors concluded that liver damage decreases methadone metabolism. However, this investigation has several weaknesses including lack of clarity as to how HCV status was defined and determined, measurements limited to peak methadone concentration, a homogeneous participant population consisting of males of limited racial and ethnic diversity, and absence of cirrhotic participants [67]. In a Taiwanese population, Wu et al [68] found that total plasma methadone and (R)-methadone concentrations were significantly higher in HCV seropositive compared with HCV seronegative participants.…”

“…The relationship between HCV infection, liver fibrosis, and methadone metabolism has been evaluated in Eastern European and Taiwanese populations. Kljucevic et al [67] observed in a Croatian population with HCV infection that the urine EDDP/methadone ratio and plasma EDDP concentration significantly decreased in a linear fashion with increasing fibrosis stage. Therefore, the authors concluded that liver damage decreases methadone metabolism.…”

ABCB1, CYP2B6, and CYP3A4 genetic polymorphisms do not affect methadone maintenance treatment in HCV-positive patients

“…We took two urine samples per check-up; one immediately before and the other 90 min after oral methadone administration, which totalled six samples per participant. The samples were stored at 4 °C and analysed within 1–4 days as described in detail in our previous reports ( 8 , 11 ). Methadone and EDDP concentrations were used to calculate their ratio ( Table 1 ).…”

“…The risk may be even greater in patients with liver damage caused by hepatitis C virus (HCV) infection, which is common in opioid dependency. Our earlier studies ( 7 , 8 ) have shown that chronic overdose and liver insufficiency (damage) increase the amount of unmetabolised methadone and its toxicity, but we did not consider the influence of the ABCB1 , CYP2B6 , and CYP3A4 genes on methadone metabolism as one of the numerous factors that influence inter-individual variability in that respect. The aim of this study was therefore to address this gap and see if the ABCB1 , CYP2B6 , and CYP3A4 genetic polymorphisms affect methadone metabolism in patients on MMT.…”