Mu-Opioid Receptor Genetic Polymorphism and the Duration of Intrathecal Fentanyl Labor Analgesia. Mu-Opioid Receptor Genetic Polymorphism and the Efficacy of Postoperative Intrathecal Morphine Analgesia

Study 1 (intrathecal fentanyl): The primary outcome variable is duration of intrathecal fentanyl analgesia. A two-sided log rank test with an overall sample size of 152 subjects (wild type OPRM1 = 106, variant OPRM1 = 46) achieves 80% power at α = 0.05 to detect a difference of 0.2 between 0.5 and 0.3 (the proportion of subjects with continuing intrathecal fentanyl analgesia after 70 min). This assumes that 70% of subjects will have the wild-type MUOR1 phenotype, and 30% the variant phenotype. To account for anticipated subject dropout, 175 subjects will be enrolled in the study.

Study 2 (intrathecal morphine): The primary outcome variable is amount of rescue analgesia (morphine equivalents) necessary for 24 h after the intrathecal morphine injection. An overall sample size of 71 subjects (wild type OPRM1 = 50, variant OPRM1 = 21) achieves 81% power to detect a difference of 15 mg morphine equivalents between the null hypothesis that both group means are 40 mg morphine equivalents and the alternative hypothesis that the mean of one group is 25 mg morphine equivalents. The estimated group standard deviations are 20 mg morphine equivalents with alpha = 0.05 using a two-side Mann-Whitney test assuming that the actual distribution is uniform. This assumes that 70% of subjects will have the wild-type OPRM1 phenotype, and 30% the variant phenotype. To account for anticipated subject dropout, 90 subjects will be enrolled in the study.

Protocol specific methods:

Study 1: Eligible parturients admitted to the Labor and Delivery Unit of Prentice Women's Hospital will be approached for study participation immediately after the routine preanesthetic evaluation. This occurs shortly after admission to the Labor and Delivery Unit. Women who agree to participate will give written, informed consent at this time.

Venous blood will be obtained for genetic analysis of the 118 position of the µ-opioid receptor gene shortly after the subject consents to study participation, either through an intravenous catheter placed for routine intravenous access for labor and delivery, or through a fresh venipuncture. A total of 10 mL blood will be collected into two 5 mL EDTA tubes. The tubes will be batched, coded and stored in a 40C refrigerator until they will be send (1x/month) to the laboratory of Dr. J. L. Blouin, care of Dr. Landau, at the Hopitaux Universitaires de Geneve. Genetic analysis will be performed as described below. When the subject first requests analgesia, her cervix will be examined (this is routine procedure prior to initiating analgesia). If the cervix is dilated between 2 and 5 cm, the parturient will be included in the study. Visual analogue score (VAS) for pain (100 mm line where 0 mm = no pain and 100 mm = worst possible pain) will be determined immediately before initiation of analgesia. Combined spinal-epidural analgesia will be initiated in the sitting position per routine with intrathecal fentanyl 25 microgram. An epidural catheter will be sited. No drug will be injected through the epidural catheter until the parturient requests analgesia again. The parturient will be placed in the lateral position after the epidural catheter is secured. A VAS will be determined 10 min after the intrathecal injection.