title: Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women.
abstract: Labor initiates one of the most intensely painful episodes in a woman's life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. mu-Opioid receptor (muOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED(50)) of intrathecal fentanyl via combined spinal-epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n=224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double-blinded trials: up-down sequential allocation (SA, n=50) and a separate confirmatory random-dose allocation trial (RA, n=97). Effective analgesia from intrathecal fentanyl was defined by >or=60 min analgesia with verbal rating score <or=1 (scale 0-10) and was compared between mu OR 304A homozygotes (Group A) and women carrying at least one 304G allele (Group G). OPRM1 304G allele frequency f(-) was 0.18. Using SA, intrathecal fentanyl ED(50) was 26.8 microg (95% CI 22.7-30.9) in Group A and 17.7 microg (95% CI 13.4-21.9) in Group G (p<0.001; 304A homozygosity increased the ED(50) 1.5-fold). RA confirmed that 304A homozygosity significantly increases intrathecal fentanyl ED(50) (27.4 microg in Group A and 12.8 microg in Group G [p<0.002; 2.1-fold]). We demonstrate for the first time that the muOR 304G variant significantly reduces intrathecal fentanyl ED(50) for labor analgesia, suggesting women with the G variant may be more responsive to opioids and require less analgesic drugs. These findings for intrathecal fentanyl pharmacogenetics may have implications for patients receiving opioids in other settings.
authors.affiliation: Department of Anesthesia, University Hospital of Geneva, Geneva, Switzerland Department of Anesthesiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Department of Anaesthesia, University Hospital of South Manchester Wythenshawe, UK Department of Genetic Medicine and Laboratory, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Landau
authors.forename: Christian
authors.initials: C
authors.lastname: Kern
authors.forename: Malachy O
authors.initials: MO
authors.lastname: Columb
authors.forename: Richard M
authors.initials: RM
authors.lastname: Smiley
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Blouin
mesh_terms: D000328:Adult; D016362:Analgesia, Obstetrical / Q000379:methods*; D004311:Double-Blind Method; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage*; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007278:Injections, Spinal; D007743:Labor, Obstetric / Q000187:drug effects / Q000235:genetics*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011247:Pregnancy; D011446:Prospective Studies; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics* / Q000502:physiology
chemical_list: D017450:Receptors, Opioid, mu; D005283:Fentanyl