Association of CYP2B6 and OPRM1 Genotypes with Methadone Dose Requirements and Serum Concentrations in a Vietnamese Cohorts

Buprenorphine/naloxone (BUP-NX) and methadone are used to treat opioid use disorder (OUD), yet there is insufficient evidence on the impact of doses on interventions' effectiveness and safety when treating OUD attributable to other opioids than heroin. We explored associations between methadone and BUP-NX doses and treatment outcomes using data from OPTIMA, a 24-week, pragmatic, open-label, multicenter, pan-Canadian, randomized controlled, two-arm parallel trial with participants (N = 272) with OUD who primarily use opioids other than heroin. Participants were randomized to receive flexible take-home BUP-NX (n = 138) or standard supervised methadone treatment (n = 134). We examined associations between highest BUP-NX and methadone doses, and (1) percentage of opioid-positive urine drug screens (UDS);(2) retention in the assigned treatment; and (3) adverse events (AEs). The mean (SD) highest BUP-NX and methadone dose were 17.31 mg/day (8.59) and 67.70 mg/day (34.70). BUP-NX and methadone doses were not associated with opioid-positive UDS percentages or AEs. Methadone dose was associated with higher retention in treatment (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.010; 1.041), while BUP-NX dose was not (OR: 1.055; 95%CI: 0.990; 1.124). Higher methadone doses (70-110 mg/day) offered higher odds of treatment retention. Methadone dose was associated with higher retention, which may be related to its full µ-opioid receptor agonism. Future research should notably ascertain the effect of pace of titration on a wide range of outcomes. Our results extend previous findings of high doses of methadone increasing retention to be applied in our population using opioids other than heroin, including highly potent opioids.

Methadone maintenance treatment (MMT) has been shown to be an effective therapeutic strategy for opioid users. This study aimed to investigate the predictive effect of clinically predominant sleep disturbance (CPSD) on the dose of methadone among opiate users receiving MMT during a follow-up period of 6 years in Taiwan. This retrospective study included 1,290 individuals with opioid dependence who visited our MMT clinic for the first time. Generalized estimating equations were used to analyze the effect of CPSD on the daily dose of methadone by controlling for the effects of demographic and MMT characteristics. A total of 469 (36.4%) participants were comorbid with CPSD. After controlling for the effects of demographic and MMT characteristics, the participants comorbid with CPSD had a higher dose of daily methadone than those without CPSD (estimate: 7.03, p < .001). Furthermore, younger age (estimate: -1.22, p < .001), older age at initial MMT (estimate: .44, p < .001), lower educational level (estimate: -.90, p = .003) and lower attendance rates (estimate: -.14, p = .033) are significantly related to higher doses of daily methadone. Our study provided a naturalistic observation of the cohort for long period, along with a large sample size which could reflect clinical practice in the real world. We reported that a higher daily dose of methadone was significantly associated with CPSD after controlling for the effects of other factors. CPSD should be routinely surveyed among heroin users receiving MMT. (Am J Addict 2018;27:225-230).

Relapse to Opioid Use After Treatment of Chronic Hepatitis C With Pegylated Interferon and Ribavirin

Divided Doses for Methadone Maintenance

Background:Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment.Methods:Opioid-dependent subjects (n = 119) maintained on methadone (15–300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (Ctrough) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype).Results:Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and Ctrough (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher Ctrough than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or Ctrough without taking into account confounding genetic variability at the other locus. Therefore, two interacting pharmacogenetic determinants of methadone maintenance treatment response were identified, ie, ABCB1, where variants are associated with lower methadone requirements, and OPRM1, where the variant is associated with higher methadone requirements.Conclusion:These opposing pharmacogenetic effects therefore need to be considered in combination when assessing methadone maintenance treatment pharmacogenetics.

Objective:Methadone treatment is effective for managing opioid use disorder (OUD) but raises concerns about its impact on cardiac function. This study aimed to assess the prevalence of cardiac dysfunction among individuals under methadone treatment.Methods:This cross-sectional study involved 200 OUD patients admitted to addiction treatment centers of Kerman, Iran, who were at least 1 year under methadone maintenance therapy. Participants were enrolled using a convenience sampling method. Exclusion criteria included concurrent alcohol or nonopioid drug abuse, underlying diseases affecting cardiac function (diabetes, hypertension, and chronic renal failure), hepatic diseases, or use of drugs affecting methadone metabolism. Data on methadone dose, treatment duration, and cardiac parameters assessed through echocardiography and electrocardiography were collected.Findings:A total of 200 OUD patients aged 46.34 ± 13.93 years (72% male) were included. The average duration of methadone use was 2.17 ± 1.34 years, and the average dose was 52.10 ± 27.46 mg/day. 38% of subjects had QT prolongation, while echocardiographic assessment revealed various cardiac abnormalities: 17.5% with systolic dysfunction, 12.5% with abnormal left ventricular end-diastolic diameter, 66.5% with diastolic dysfunction, and 15.5% with increased systolic pulmonary artery pressure. Significant correlations were observed between methadone dose and duration with all measured cardiac parameters.Conclusion:This study demonstrated an association between methadone treatment characteristics (higher dose and longer duration) and cardiac dysfunction. These findings suggest dose- and time-dependent cardiotoxic effects of methadone. Clinicians should implement cardiac monitoring, dose minimization, and risk-reduction strategies for patients on long-term methadone therapy.

Methadone maintenance treatment (MMT) effectively reduces illicit opioid use and its negative consequences when patients participate in and adhere to treatment. Patients' participation and adherence may relate to their perceptions about methadone doses and dose adjustments and the meanings that patients associate with treatment. This study assessed patient perceptions about methadone dosing and the meanings associated with methadone treatment to better support patient adherence to and success in MMT. We conducted semistructured interviews with 19 patients in an urban MMT program. Interviews were transcribed verbatim and analyzed through an iterative process. Participants' expressed perceptions about methadone doses related to ideas of "comfort" and "function," suggesting a model for determining dose appropriateness and "ideal" methadone dose based on various factors both intrinsic and extrinsic to MMT. Intrinsic factors included those exerting downward pressure on "ideal" methadone dose such as lack of control in treatment, disdain for getting "high," concerns about methadone dependence, and desire to avoid adverse effects; those exerting upward pressure such as concern about withdrawal; and those exerting mixed pressures such as methadone formulations. Extrinsic factors included those exerting downward pressure such as shame about and stigma around MMT; those exerting upward pressure such as medical conditions and medication interactions; and those exerting mixed pressures such as family and peer relationships. Participants held perceptions about methadone dosing that included considerations beyond typical medical parameters used by physicians and other MMT providers to determine appropriate methadone doses. The model that emerged from our data could help inform MMT providers to support greater patient comfort with methadone doses and dose changes, as well as adherence to and success in MMT.

(295) Potential Targets for Pain Management among Patients with Co-Occurring Opioid Use Disorder and Chronic Pain

Background There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. Objectives We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. Methods We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016–2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. Results When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: −2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (−0.50; −4.59, 3.59; 0.810). Conclusions Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.

To assess CYP2D6 activity and genotype in a group of patients undergoing methadone maintenance treatment (MMT). Blood samples from 34 MMT patients were genotyped by a polymerase chain reaction-based method, and results were compared with CYP2D6 phenotype (n = 28), as measured by the molar metabolic ratio (MR) of dextromethorphan (DEX)/dextrorphan (DOR) in plasma. Whereas 9% of patients (3/34) were poor metabolizers (PM) by genotype, 57% (16/28) were PM by phenotype (P < 0.005). Eight patients, who were genotypically extensive metabolizers (EM), were assigned as PM by their phenotype. The number of CYP2D6*4 alleles and sex were significant determinants of CYP2D6 activity in MMT patients, whereas other covariates (methadone dose, age, weight) did not contribute to variation in CYP2D6 activity. There was a discordance between genotype and in vivo CYP2D6 activity in MMT patients. This finding is consistent with inhibition of CYP2D6 activity by methadone and may have implications for the safety and efficacy of other CYP2D6 substrates taken by MMT patients.

Methadone dose at the time of release from prison significantly influences retention in treatment: Implications from a pilot study of HIV-infected prisoners transitioning to the community in Malaysia

Methadone treatment reduces the use of heroin and withdrawal symptoms; however, methadone is an expensive medication with a narrow safety margin. We compared the retention rates, persistence of heroin use, and quality of life of a group of patients undergoing conventional Methadone Maintenance Treatment (MMT) with a group for whom the CYP2B6 516G>T polymorphism was used in addition to the MMT to calculate the required methadone dose. Over 12 weeks, the retention rate, heroin usage, and quality of life of patients under conventional treatment (n = 34) were compared with those of patients for whom we used genetic markers to calculate methadone dosage (n = 38). At the end of the study, 26.4% of patients abandoned the program, and neither demographic nor clinical variables were associated with treatment adherence. Of the remaining patients, 16% of the control group and 8% of patients in the pharmacogenetic group reported heroin use, while both groups showed a 64% reduction in the use of cocaine/crack (no significant differences between the groups were found). Starting in the second week, the methadone dosage was lower among the patients for whom methadone was prescribed based on genotype. Although there were six individuals in the control group and three in the pharmacogenetic group with QTc intervals > 450 ms (a threshold that is considered dangerous), we did not find a relationship between the QTc interval and methadone dosage. There were no differences in the perception of quality of life between the two groups. The results of this pilot study suggest that concerning methadone therapy, the CYP2B6 genotype contributes to reduced effective doses and treatment costs.

Introduction. Opioid dependence and co-occurring depressive disorders represent a significant clinical challenge within the field of psychiatry, necessitating effective interventions to improve patient outcomes. Antidepressant treatment has emerged as a potential therapeutic approach, yet its efficacy in the context of Methadone Maintenance Treatment (MMT) remains inconclusive. Methods. To address this critical knowledge gap, a comprehensive literature review was conducted. Databases including PubMed, the National Institutes of Health (NIH), Google Scholar, and Cochrane Drugs and Alcohol Reviews were meticulously searched for relevant publications from January 2010 to June 2022, using targeted keywords (“antidepressants,” “opioid addiction,” “methadone”). Results. The review uncovered a complex landscape of studies, highlighting the challenges in evaluating the efficacy of antidepressant treatment in opioid-dependent individuals receiving MMT. While some investigations have reported modest benefits in alleviating depressive symptoms, others remain inconclusive or contradictory. Desvenlafaxine, a dualaction antidepressant, demonstrated some effectiveness in this population, suggesting a potential treatment option. However, these findings necessitate further exploration through large-scale, complex studies with a focus on diverse patient populations. Discussion. The multifaceted nature of opioid dependence, comorbid depressive disorders, and the complexities of MMT underscore the challenges in ascertaining treatment outcomes definitively. Additionally, the potential for adverse effects and drug interactions, particularly in cases of relapse, complicates the therapeutic landscape. Patients often resort to self-medicating depressive symptoms with other substances, further clouding the interpretation of treatment results. Conclusion. The literature review reveals the need for continued research to elucidate the role of antidepressant treatment in opioid-dependent patients undergoing MMT. As patients’ needs vary widely, a comprehensive approach to managing affective symptoms should encompass not only pharmacotherapy but also various psychotherapeutic and social interventions. By addressing these complexities, future research may pave the way for more tailored and effective treatment strategies, ultimately enhancing the well-being of individuals grappling with the dual burdens of opioid dependence and depressive disorders within the MMT context.

The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.

To identify medication adherence and its influencing factors among patients of 14 methadone maintenance treatment (MMT) clinics in Xi'an, China. Data were obtained from the National AIDS Information System-Community Methadone Maintenance Treatment. All patients registered in the system were not permitted to take methadone at home without professionals' supervision. Medication adherence was assessed using categorical (ie, dropout or retained) and continuous (ie, treatment time, methadone use time, and percentage of methadone use days) variables. Percentages of methadone use days of >90%, 50% to 90%, or <50% indicated good, moderate, and poor adherence, respectively. Multivariate Cox stepwise regression analysis was used to identify the influencing factors. Of the 10,398 patients, 52.2% had dropped out of MMT by December 31, 2013, whereas only 11.8% regularly visited the clinic for daily methadone (ie, >90% methadone use days) during a certain period. Protective factors were older age (>30 years); female sex; having no contact with peer drug users over the past month; no needle-sharing experience; a negative initial morphine urine test; and a higher average daily methadone dose (>20 mg) (P < 0.05). Risk factors were answering "others" for marital status; being employed; having a lack of stable income; not living with family; answering "others" for drug use type; frequently engaging in unauthorized drug use during MMT; no readmission; long travel times to the MMT clinic (>30 minutes); having no convenient MMT service time; and being dissatisfied with MMT service (P < 0.05). Based on our findings, multimodal intervention and management programs can be developed to improve poor medication adherence among the MMT patient population.