The AC/AG Diplotype for the 118A>G and IVS2 + 691G>C Polymorphisms of OPRM1 Gene is Associated with Sleep Quality Among Opioid-Dependent Patients on Methadone Maintenance Therapy.
Ontology highlight
ABSTRACT: Introduction
Methadone is a full agonist of the opioid receptor mu 1 which is encoded by the OPRM1 gene. Sleep disorders were frequently reported by opioid-dependent patients during methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in OPRM1 influence sleep quality among patients on MMT. This study investigated the association of OPRM1 polymorphisms with sleep quality among opioid-dependent patients on MMT.Methods
The sleep quality of 165 male opioid-dependent patients receiving MMT was evaluated using the Pittsburgh Sleep Quality Index (PSQI). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR) genotyping.Results
Patients with IVS2 + 691 CC genotype had higher PSQI scores [mean (SD) = 5.73 (2.89)] compared to those without the IVS2 + 691 CC genotype (IVS2 + 691 GG/GC genotype) [4.92 (2.31)], but the difference did not reach statistical significance (p = 0.081). Patients with combined 118 AA genotype and IVS2 + 691 GC genotype (AC/AG diplotype) had significantly lower PSQI scores [mean (SD) = 4.25 (2.27)] compared to those without the diplotype [5.68 (2.77)] (p = 0.018).Conclusion
Our study indicates that the AC/AG diplotype for the 118A>G and IVS2 + 691G>C polymorphisms of OPRM1 gene is associated with better sleep quality among males with opioid dependence on MMT.
SUBMITTER: Zahari Z
PROVIDER: S-EPMC4912965 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:IntroductionWe recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated that common OPRM1 polymorphisms may be responsible. This study investigated the association between 118A>G (dbSNP rs1799971) and IVS2+691G>C (dbSNP rs2075572) variants on cold pain responses among opioid-dependent Malay males on methadone maintenance therapy.MethodsCold pain responses including pain threshold, pain tolerance, and pain intensity were measured using the cold pressor test. DNA was extracted from the venous blood before polymerase chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes.ResultsA total of 148 participants were recruited. With the recessive model, those with IVS2+691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2+691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A>G and IVS2+691G>C variations despite being analyzed using various models (all P > 0.05).ConclusionThe IVS2+691 CC genotype and AC/AG diplotype of 118A>G and IVS2+691G>C seem to have opposing roles in pain tolerance among opioid-dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity.
| S-EPMC4676768 | biostudies-literature
Project description: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 (C(trough)) 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 C(trough) (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 C(trough) 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 C(trough) 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.
| S-EPMC3513228 | biostudies-literature
Project description:Cancer pain is the most feared symptom at end of life. Methadone has advantages over other opioids but is associated with significant variability in clinical response, making dosing challenging in practice. OPRM1 is the most studied pharmacogene associated with the pharmacodynamics of opioids, however reports on the association of the A118G polymorphism on opioid dose requirements are conflicting, with no reports including methadone as the primary intervention. This association study on OPRM1 A118G and response to methadone for pain management, includes a review of this genetic factor's role in inter-patient variability. Fifty-four adult patients with advanced cancer were recruited in a prospective, multi-centre, open label dose individualization study. Patient characteristics were not shown to influence methadone response, and no significant associations were observed for methadone dose or pain score. The findings of our review of association studies for OPRM1 A118G in advanced cancer pain demonstrate the importance of taking ancestry into account. While our sample size was small, our results were consistent with European populations, but in contrast to studies in Chinese patients, where carriers of the A118G polymorphism were associated with higher opioid dose requirements. Pharmacogenetic studies in palliative care are challenging, continued contribution will support future genotype-based drug dosing guidelines.
| S-EPMC10858860 | biostudies-literature
Project description:Substance misuse is associated with cognitive dysfunction. We used a stop signal task to examine deficits in cognitive control in individuals with opioid dependence (OD). We examined how response inhibition and post-error slowing are compromised and whether methadone maintenance treatment (MMT), abstinence duration, and psychiatric comorbidity are related to these measures in individuals with OD.Two-hundred-and-sixty-four men with OD who were incarcerated at a detention center and abstinent for up to 2 months (n = 108) or at a correctional facility and abstinent for approximately 6 months (n = 156), 65 OD men under MMT at a psychiatric clinic, and 64 age and education matched healthy control (HC) participants were assessed. We computed the stop signal reaction time (SSRT) to index the capacity of response inhibition and post-error slowing (PES) to represent error-related behavioral adjustment, as in our previous work. We examined group effects with analyses of variance and covariance analyses, followed by planned comparisons. Specifically, we compared OD and HC participants to examine the effects of opioid dependence and MMT and compared OD sub-groups to examine the effects of abstinence duration and psychiatric comorbidity.The SSRT was significantly prolonged in OD but not MMT individuals, as compared to HC. The extent of post-error slowing diminished in OD and MMT, as compared to HC (trend; p = 0.061), and there was no difference between the OD and MMT groups. Individuals in longer abstinence were no less impaired in these measures. Furthermore, these results remained when psychiatric comorbidities including misuse of other substances were accounted for.Methadone treatment appears to be associated with relatively intact cognitive control in opioid dependent individuals. MMT may facilitate public health by augmenting cognitive control and thereby mitigating risky behaviors in heroin addicts.
| S-EPMC3984179 | biostudies-other
Project description:Opioid analgesic use and disorders have dramatically increased among the general American population and those receiving methadone maintenance treatment (MMT). Most research among MMT patients focuses on opioid analgesics misuse or disorders; few studies focus on MMT patients prescribed opioid analgesics. We describe demographic, clinical, and substance use characteristics of MMT patients prescribed opioid analgesics and compare them with MMT patients not prescribed opioid analgesics.We conducted a cross-sectional secondary data analysis using screening interviews from a parent study. From 2012 to 2015, we recruited adults from 3 MMT Bronx clinics. Questionnaire data included patterns of opioid analgesic use, substance use, comorbid illnesses, and demographic characteristics. Our main dependent variable was patients' report of currently taking prescribed opioid analgesics. To compare characteristics between MMT patients prescribed and not prescribed opioid analgesics, we conducted chi-square tests, t tests, and Mann-Whitney U tests.Of 611 MMT patients, most reported chronic pain (62.0%), hepatitis C virus (HCV) infection (52.1%), and current use of illicit substances (64.2%). Of the 29.8% who reported currently taking prescribed opioid analgesics, most misused their opioid analgesics (57.5%). Patients prescribed (versus not prescribed) opioid analgesics were more likely to report human immunodeficiency virus (HIV) infection (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 1.1-2.3) and chronic pain (aOR = 7.6, 95% CI: 4.6-12.6).Among MMT patients primarily in 3 Bronx clinics, nearly one third reported taking prescribed opioid analgesics. Compared with patients not prescribed opioid analgesics, those prescribed opioid analgesics were more likely to report chronic pain and HIV infection. However, between these patients, there was no difference in illicit substance use. These findings highlight the complexity of addressing chronic pain in MMT patients.
| S-EPMC4935628 | biostudies-literature
Project description:Methadone maintenance treatment (MMT) patients have a high prevalence of central sleep apnea and ataxic breathing related to damage to central respiratory rhythm control. However, the quantification of sleep apnea indices requires laborious manual scoring, and ataxic breathing pattern is subjectively judged by visual pattern recognition. This study proposes a semi-automated technique to characterize respiratory variability in MMT patients.Polysomnography, blood, and functional outcomes of sleep questionnaire (FOSQ) from 50 MMT patients and 20 healthy subjects with matched age, sex, and body mass index, were analyzed. Inter-breath intervals (IBI) were extracted from the nasal cannula pressure signal. Variability of IBI over 100 breaths was quantified by standard deviation (SD), coefficient of variation (CV), and scaling exponent (?) from detrended fluctuation analysis. The relationships between these variability measures and blood methadone concentration, central sleep apnea index (CAI), apnea-hypopnea index (AHI), and clinical outcome (FOSQ), were then examined.MMT patients had significantly higher SD and CV during all sleep stages. During NREM sleep, SD and CV were correlated with blood methadone concentration (Spearman R = 0.52 and 0.56, respectively; p < 0.01). SD and CV were also correlated with CAI (R = 0.63 and 0.71, p < 0.001, respectively), and AHI (R = 0.45 and 0.58, p < 0.01, respectively). Only ? showed significant correlation with FOSQ (R = -0.33, p < 0.05).MMT patients have a higher respiratory variability during sleep than healthy controls. Semi-automated variability measures are related to apnea indices obtained by manual scoring and may provide a new approach to quantify opioid-related sleep-disordered breathing.
| S-EPMC4795289 | biostudies-literature
Project description:Objective: To explore the association between methadone dosage, plasma drug concentration, SNPs of μ-opioid receptor gene (OPRM1), ATP-binding cassette subfamily B member 1 gene (ABCB1), and methadone maintenance treatment (MMT) response. Method: A total of 240 Chinese Han participants receiving MMT were recruited from Shanghai. Nine single nucleotide polymorphisms (SNPs) of the OPRM1 gene and three SNPs of the ABCB1 gene were genotyped, plasma methadone concentration was detected, and a morphine urine test was taken from all subjects. Results: Methadone dosage, plasma methadone concentration, and negative rate of morphine urine test of retention participants were significantly higher, although the addiction severity index (ASI) was not significantly different between the two groups. A allele and AA genotype carriers of rs562859 (OPRM1 gene) had better compliance of MMT, and AA genotype carriers had a higher negative rate of morphine urine test. However, the difference was not significant after adjusting influence factors (age, sex, and methadone dosage). GG genotype carriers of rs3192723 (OPRM1 gene) had a significantly lower negative rate of morphine urine test, and the difference was still significant after adjusting influence factors. Logistic regression analysis showed that methadone-free trough concentration (OR = 0.910, p = 0.023) and AA genotype of rs526859 (OR = 0.580, p = 0.037) were associated with better compliance of MMT. After Bonferroni correction, only free trough concentration of methadone was negatively correlated with MMT compliance. The SNPs rs6912029 (OR = 0.021, p = 0.066) and rs6902403 (OR = 0.910, p = 0.007) of the OPRM1 gene, age at first use (OR = 1.118, p = 0.005), and average methadone dosage (OR = 1.033, p = 0.045) were associated with MMT effect. After Bonferroni correction, average methadone dosage was no longer correlated with MMT effect. Conclusion: Dosage of methadone, plasma methadone concentration, several SNPs (rs3192723, rs6912029, rs6902403) of the OPRM1 gene, and age of first drug use were associated with better MMT outcomes.
| S-EPMC6216325 | biostudies-literature
Project description:The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.
| S-EPMC5468510 | biostudies-literature
Project description:INTRODUCTION:Treatment of opioid addiction with methadone is effective; however, it is known to produce interindividual variability. This may be influenced in part by genetic variants, which can increase the initial risk of developing opioid addiction as well as explain differences in response to treatment. This pilot study aimed to assess the feasibility of conducting a full-scale genetic analysis to identify genes that predict methadone treatment outcomes in this population. METHODS:This was a cross-sectional observational study of patients admitted to a methadone maintenance treatment program for opioid addiction. We obtained demographic and clinical characteristics in addition to blood and urine samples, for the assessment of treatment outcomes. RESULTS:The recruitment process yielded 252 patients, representing a 20% recruitment rate. We conducted genetic testing based on a 99.6% rate of provision of DNA samples. The average retention in treatment was 3.4 years, and >50% of the participants reported psychiatric and medical comorbidities. BDNF rs6265 and DRD2 rs1799978 were the common single nucleotide polymorphisms (SNPs) selected for the feasibility study. DISCUSSION:This study met our predetermined feasibility criteria; recruitment, response rates, and genetic testing were feasible; treatment duration was sufficient for follow up; and the prevalence of comorbid conditions indicated the need for reliable psychiatric and chronic pain measures. The study strengths included effective collaboration with clinics and the generalizability of sample population. Key learning points show the need for assessment of treatment outcomes on multiple domains, implementation of follow up, and the development of standardized training for the study clinical staff.
| S-EPMC4149396 | biostudies-literature
Project description:Objectives: Opioid dependence has been a threat to public health for hundreds of years. With the increasing number of studies on acupuncture-related therapies for opioid dependence patients receiving methadone maintenance treatment (MMT), its effect of acupuncture therapy in treating MMT patients remains controversial. Therefore, we conducted a multiple-treatments meta-analysis, and incorporated both direct and indirect comparisons, in order to discover the most effective treatment for opioid dependence patients receiving MMT. Methods: Five English databases and three Chinese databases were searched from its inception to August 20, 2020, in order to compare the effects of acupuncture-related therapies and MMT, which was summarized as Western medicine (WM) in the following texts. The quality of studies was assessed according to Cochrane's risk of bias tool 5.1.0, and a pair-wise meta-analysis, cumulative meta-analysis, and the network meta-analysis was performed using the R software (Version 3.6.1) and STATA (Version 14.0). The primary outcome was the effective rate, which was calculated by the ratio of detoxifying patients to the total. The secondary outcome was the Modified Himmelsbach Opiate Withdrawal Scale (MHOWS). Results: A total of 20 trials were included, which consisted of comparisons among WM, traditional Chinese medicine (TCM), and the four types of acupuncture, namely, manual acupuncture (MA), electro-acupuncture (EA), auricular acupuncture (AA), and transcutaneous electrical acupoint stimulation (TEAS). Though none of the trials were at low risk of bias. In the pair-wise meta-analysis, no statistically significant differences were observed in terms of the effective rate. Furthermore, MA was more efficacious than WM, EA, and TEAS in MHOWS, with mean differences (MDs) of (-8.59, 95% CI: -15.96 to -1.23, P < 0.01), (-6.15, 95% CI: -9.45 to -2.85, P < 0.05), and (-10.44, 95% CI: -16.11 to -4.77, P < 0.05), respectively. In the network meta-analysis, MA was more effective than WM (RR: 1.40, 95% CI: 1.05 to 1.99) on the effective rate, and (MD: -5.74, 95% CI: -11.60 to -0.10) on MHOWS. TEAS was more effective than WM (MD: -15.34, 95% CI: -27.34 to -3.46) on MHOWS. Synthetically, MA had the highest probability to rank first in treating opioid dependence. Conclusions: The existing evidence shows that acupuncture related-therapies may effectively be used for treating patients receiving MMT, and that manual acupuncture may be the best choice for opioid dependence among all kinds of acupuncture-related therapies. Nevertheless, reducing the relapse and promoting the recovery of opioid dependence need more efforts from not only the medical industry but also government support, security system, and educational popularization. To strengthen the assurance of acupuncture-related therapies in the treatment of opioid dependence, we expected that clinical trials with high quality would be conducted, to provide more confident evidence.
| S-EPMC8710762 | biostudies-literature