Implications of OPRM1 and CYP2B6 variants on treatment outcomes in methadone-maintained patients in Ontario: Exploring sex differences

Genetic variants in the OPRM1 and CYP2B6 genes, respectively coding for an opioid receptor and methadone metabolizers, have been linked to negative treatment outcomes in patients undergoing methadone maintenance treatment, with little consensus on their effect. This study aims to test the associations between pre-selected SNPs of OPRM1 and CYP2B6 and outcomes of continued opioid use, relapse, and methadone dose. It also aims to observe differences in associations within the sexes. 1,172 participants treated with methadone (nMale = 666, nFemale = 506) were included in this study. SNPs rs73568641 and rs7451325 from OPRM1 and all the tested CYP2B6 SNPs were detected to be in high linkage disequilibrium. Though no associations were found to be significant, noteworthy differences were observed in associations of OPRM1 rs73568641 and CYP2B6 rs3745274 with treatment outcomes between males and females. Further research is needed to determine if sex-specific differences are present.

A systematic review of GWAS identified SNPs associated with outcomes of medications for opioid use disorder

Background Patients with opioid use disorder (OUD) display an interindividual variability in their response to medications for opioid use disorder (MOUD). A genetic basis may explain the variability in this response. However, no consensus has been reached regarding which genetic variants significantly contribute to MOUD outcomes. Objectives This systematic review aims to summarize genome-wide significant findings on MOUD outcomes and critically appraise the quality of the studies involved. Methods Databases searched from inception until August 21st, 2020 include: MEDLINE, Web of Science, EMBASE, CINAHL and Pre-CINAHL, GWAS Catalog and GWAS Central. The included studies had to be GWASs that assessed MOUD in an OUD population. All studies were screened in duplicate. The quality of the included studies was scored and assessed using the Q-Genie tool. Quantitative analysis, as planned in the protocol, was not feasible, so the studies were analyzed qualitatively. Results Our search identified 7292 studies. Five studies meeting the eligibility criteria were included. However, only three studies reported results that met our significance threshold of p ≤ 1.0 × 10–7. In total, 43 genetic variants were identified. Variants corresponding to CNIH3 were reported to be associated with daily heroin injection in Europeans, OPRM1, TRIB2, and ZNF146 with methadone dose in African Americans, EYS with methadone dose in Europeans, and SPON1 and intergenic regions in chromosomes 9 and 3 with plasma concentrations of S-methadone, R-methadone, and R-EDDP, respectively, in Han Chinese. Limitations The limitations of this study include not being able to synthesize the data in a quantitative way and a conservative eligibility and data collection model. Conclusion The results from this systematic review will aid in highlighting significant genetic variants that can be replicated in future OUD pharmacogenetics research to ascertain their role in patient-specific MOUD outcomes. Systematic review registration number CRD42020169121.

1306Methadone dose affects service satisfaction of HIV infected PWIDs treated on methadone in Myanmar

Background HIV prevalence among people who inject drugs (PWIDs) in Myanmar was 34.9%. This analysis identifies how methadone dose affects treatment satisfaction of HIV patients. Method A total of 210 patients on methadone at least 6 months were recruited from five cities using stratified random sampling in Myanmar. Verona Service Satisfaction Scale for Methadone-Treatment (VSSS-MT) was administered to identify service satisfaction and urine samples were collected for identification of illicit drugs. Results More than one-third (36.5%, n = 76) received high-dose (above 80mg/day), while the rest 63.5% received low-dose (less than 80mg/day). Almost half, 47% reported hepatitis C, 37% had reported HIV, and 16% had HIV and HCV. Among HIV cases, 68 (92%) were on antiretroviral therapy (ART). Myanmar’s (ART) regimen: tenofovir, emtricitabine and efavirenz accounted for 86% which need a methadone dose adjustment. The majority, 89% were satisfied with the current methadone service. Specifically, 89.5% for professional skills, 91.9% satisfied for basic intervention and 74.6% satisfied for specific intervention (e.g. individual rehabilitation and psychotherapy) categories. Treatment satisfaction was estimated 2-times higher among HIV negative compared to HIV positive patients after adjusted dosage (IRR=0.49, p = 0.000). Conclusion Significant dose adjustment is required for ART with Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs). High dose adjustment is important for methadone patients on antiretroviral therapy with enzyme inducers. Key message Estimated treatment satisfaction varies with infection status after adjusting for dose. Continuous treatment assessments are vital for HIV/HCV co-infections for effective service delivery.

First-Line Methadone For Cancer Pain. Titration Time Analysis

Background. Methadone is a low-cost, strong opioid that is increasingly used as a first-line treatment for pain in palliative care (PC). Its long and unpredictable half-life and slow elimination phase can make titration challenging. Evidence for titration modalities is scarce.Objective. To describe the titration phase of the treatment with low dose first-line methadone and the use of methadone for breakthrough pain.Methods. Prospective study with strong opioid-naïve patients with moderate to severe cancer pain followed at a tertiary PC unit in Argentina. Starting methadone dose was 2.5-5 mg/day every 8, 12, or 24 hours. Titration allowed daily dose increases from Day 1, and prescription of oral methadone 2.5 mg every 2 hours with a maximum of 3 rescue doses/day for breakthrough pain. Pain control, methadone stabilization dose, and adverse effects, among other variables, were daily assessed over the first 7 days (T0 –T7).Results. 62 patients were included. Initial median (IQR) methadone dose was 5(2.5) mg/day. Pain intensity decreased from a median (IQR) of 8(2.3) at T0 to 4(2.3) at T1 and remained ≤4 until T7 (all p<0.0001 compared to T0). Similar results were obtained through the categorical and tolerability scales for pain. Fifty patients (81%) reached pain control, 66% in the first 48 hours. Methadone daily dose at T2 and T7 were higher than that at T0: 7.5(3) and 6.7(5.5) versus 5(2.5); respectively (all p<0.05). The opioid escalation index at T7 was 1.7%. The median (IQR) number of rescues, stabilization dose and time for stabilization were 0 (1), 5(4.5) mg and 3(2) days, respectively. Two patients were discontinued due to delirium. All the other side effects were mild.Conclusions. First-line, low-dose methadone using rescue methadone resulted in a pronounced and rapid decrease in pain, with minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

Objective The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. Study Design This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100–199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. Results Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14–37] days, intermediate dose 31 [18–45] days, and high dose 35 [20–48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. Conclusion Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. Key Points