Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone metabolism, dose and treatment response in patients with opioid addiction: a systematic review and meta-analysis.
BACKGROUND
Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse.


OBJECTIVE
To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment).


METHODS
Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms.


RESULTS
We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05-1.00, p = 0.03) with minimal heterogeneity (I(2) = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27-2.61, p = 0.02) however significant heterogeneity was observed (I(2) = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response.


CONCLUSIONS
Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada ; Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada ; Population Genomics Program, McMaster University, Hamilton, Ontario, Canada.
Brittany B
BB
Dennis
Population Genomics Program, McMaster University, Hamilton, Ontario, Canada ; McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program, McMaster University, Hamilton, Ontario, Canada.
Monica
M
Bawor
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada ; Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada ; Population Genomics Program, McMaster University, Hamilton, Ontario, Canada ; Departments of Pediatrics and Anesthesia, McMaster University, Hamilton, Ontario, Canada ; Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Lehana
L
Thabane
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada ; Population Genomics Program, McMaster University, Hamilton, Ontario, Canada ; Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Zahra
Z
Sohani
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada ; Population Genomics Program, McMaster University, Hamilton, Ontario, Canada ; McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program, McMaster University, Hamilton, Ontario, Canada ; Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada ; Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Zainab
Z
Samaan
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D065702:Cytochrome P-450 CYP2B6; D016206:Databases, Bibliographic; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008691:Methadone / Q000097:blood / Q000493:pharmacokinetics*; D009293:Opioid-Related Disorders / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D008691:Methadone