Mu-Opioid Receptor Genetic Polymorphism and Intrathecal Analgesia - Full Text View

Purpose

Pharmacogenetics has allowed clinicians to identify associations between an individual's genetic profile and his/her response to drugs. The A118G (c.188A>G)is a single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1). The mutated protein, N40D, appears to increase the binding affinity and potency of beta-endorphin approximately 3-fold. Individuals carrying the variant receptor gene (A118G) may show differences in some of the functions mediated by beta-endorphin action at the altered OPRM1. Combined spinal-epidural (CSE) analgesia is a commonly utilized technique for labor analgesia. Analgesia is initiated with the intrathecal administration of a lipid-soluble opioid (e.g. fentanyl), sometimes combined with a local anesthetic. The mean (± SD) duration of analgesia after intrathecal fentanyl 25 microgram was 89 ± 43 min. The ED50 of intrathecal fentanyl for labor analgesia varies between 14 microgram to 18.2 microgram. The wide variability in the duration of analgesia, as was well the differences in ED50 may result from differences known to affect labor pain (e.g., ethnicity, parity, stage of labor). Another possible explanation for the differences in opioid requirements and duration, as well as incidence of side effects such as itching and nausea/vomiting, is that opioid responsiveness is determined by genetic variability of the µ-opioid receptor. The ED50 for intrathecal fentanyl labor analgesia was significantly lower for parturients carrying the A118G variant of the mu-opioid receptor, compared to parturients with the A118 wild type receptor. The purpose of this study is to determine whether polymorphism at nucleotide 118 of OPRM1 influences the duration of intrathecal opioid (fentanyl) labor analgesia, and intrathecal opioid (morphine) postoperative analgesia.

Condition	Intervention
Labor Pain Post-cesarean Delivery	Procedure: Blood Draw

Study Type:	Observational
Study Design:	Observational Model: Cohort Time Perspective: Prospective
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Cesarean Section Itching

Drug Information available for: Fentanyl

U.S. FDA Resources

Further study details as provided by Northwestern University:

Primary Outcome Measures:

Duration of Intrathecal Fentanyl Analgesia [ Time Frame: Time (0-1440 minutes) to first analgesia request ] [ Designated as safety issue: No ]
Time from intrathecal drug administration to request for analgesia either in laboring women of after cesarean delivery
Duration of Intrathecal Analgesia Following Cesarean Delivery [ Time Frame: 0 to 72 hours following cesarean delivery ] [ Designated as safety issue: No ]
Time until request for supplemental analgesia following intrathecal morphine/fentanyl for cesarean delivery
Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention [ Time Frame: VAS at analgesia request ] [ Designated as safety issue: No ]
Visual analog pain scale (0 to 100) at 1st request for supplemental analgesia

Secondary Outcome Measures:

Severity of Pruritus Following Fentanyl [ Time Frame: Labor analgesia ] [ Designated as safety issue: No ]
Severity of pruritus during labor analgesia
Subjects With Pruritus at 24 Hours Post Morphine [ Time Frame: 24 hours post cesarean delivery ] [ Designated as safety issue: No ]
Subjects reporting pruritus in the first 24 hours post cesarean delivery

Biospecimen Retention: Samples With DNA

Blood Samples

Enrollment:	293
Study Start Date:	October 2005
Study Completion Date:	June 2007
Primary Completion Date:	May 2007 (Final data collection date for primary outcome measure)

Groups/Cohorts	Assigned Interventions
Labor analgesia Labor analgesia receiving fentanyl labor analgesia	Procedure: Blood Draw Blood for OPRM1 analysis
Cesarean delivery analgesia Cesarean delivery analgesia consisting of spinal fentanyl and morphine	Procedure: Blood Draw Blood for OPRM1 analysis

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes
Sampling Method:	Non-Probability Sample

Study Population

Pregnant women

Criteria

Inclusion Criteria:

Study 1: Laboring Women

Nulliparous women in spontaneous labor or with spontaneous rupture of membranes
Term pregnancy (≥ 37 weeks gestation)
Vertex presentation
Healthy, ASA PS 1-2
Desire neuraxial labor analgesia.

Study 2: Cesarean Delivery

Nulliparous women undergoing elective primary Cesarean delivery (e.g., for breech presentation, macrosomia)
Term pregnancy (≥ 37 weeks gestation)
Healthy, ASA PS 1-2
Desired spinal anesthesia.

Exclusion Criteria:

Study 1: Laboring Women

Chronic or pregnancy induced disease
Chronic opioid use
History of substance abuse
Systemic opioid analgesia before initiation of neuraxial labor analgesia
Cervical dilation < 2 cm or > 5 cm of time of request for neuraxial analgesia
Allergy to fentanyl

Study 2: Cesarean delivery

Chronic or pregnancy induced disease
Chronic opioid use
Previous abdominal or pelvic surgery
Allergy to fentanyl, morphine, or bupivacaine
BMI ≥ 40 kg/m2
History of substance abuse
Failed spinal anesthesia
Requirement for systemic opioid supplementation during Cesarean delivery.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00418015

Locations

United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

Investigators

Principal Investigator:

Cynthia A Wong, M.D.

Northwestern University

More Information

Publications:

Palmer SN, Giesecke NM, Body SC, Shernan SK, Fox AA, Collard CD. Pharmacogenetics of anesthetic and analgesic agents. Anesthesiology. 2005 Mar;102(3):663-71. Review.

Befort K, Filliol D, Decaillot FM, Gaveriaux-Ruff C, Hoehe MR, Kieffer BL. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem. 2001 Feb 2;276(5):3130-7. Epub 2000 Nov 6.

Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek MJ, Yu L. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9608-13.

Grosch S, Niederberger E, Lotsch J, Skarke C, Geisslinger G. A rapid screening method for a single nucleotide polymorphism (SNP) in the human MOR gene. Br J Clin Pharmacol. 2001 Dec;52(6):711-4.

Hollt V. A polymorphism (A118G) in the mu-opioid receptor gene affects the response to morphine-6-glucuronide in humans. Pharmacogenetics. 2002 Jan;12(1):1-2. No abstract available.

Lotsch J, Skarke C, Grosch S, Darimont J, Schmidt H, Geisslinger G. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics. 2002 Jan;12(1):3-9.

LaForge KS, Shick V, Spangler R, Proudnikov D, Yuferov V, Lysov Y, Mirzabekov A, Kreek MJ. Detection of single nucleotide polymorphisms of the human mu opioid receptor gene by hybridization or single nucleotide extension on custom oligonucleotide gelpad microchips: potential in studies of addiction. Am J Med Genet. 2000 Oct 9;96(5):604-15.

Wang D, Quillan JM, Winans K, Lucas JL, Sadee W. Single nucleotide polymorphisms in the human mu opioid receptor gene alter basal G protein coupling and calmodulin binding. J Biol Chem. 2001 Sep 14;276(37):34624-30. Epub 2001 Jul 16.

Town T, Abdullah L, Crawford F, Schinka J, Ordorica PI, Francis E, Hughes P, Duara R, Mullan M. Association of a functional mu-opioid receptor allele (+118A) with alcohol dependency. Am J Med Genet. 1999 Oct 15;88(5):458-61.

Shi J, Hui L, Xu Y, Wang F, Huang W, Hu G. Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat. 2002 Apr;19(4):459-60.

Schinka JA, Town T, Abdullah L, Crawford FC, Ordorica PI, Francis E, Hughes P, Graves AB, Mortimer JA, Mullan M. A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances. Mol Psychiatry. 2002;7(2):224-8.

Sander T, Gscheidel N, Wendel B, Samochowiec J, Smolka M, Rommelspacher H, Schmidt LG, Hoehe MR. Human mu-opioid receptor variation and alcohol dependence. Alcohol Clin Exp Res. 1998 Dec;22(9):2108-10.

Wong CA: Combined spinal-epidural labor analgesia. Techniques in Regional Anesthesia and Pain Management 2003; 7: 181-88

Palmer CM, Cork RC, Hays R, Van Maren G, Alves D. The dose-response relation of intrathecal fentanyl for labor analgesia. Anesthesiology. 1998 Feb;88(2):355-61.

Nelson KE, Rauch T, Terebuh V, D'Angelo R. A comparison of intrathecal fentanyl and sufentanil for labor analgesia. Anesthesiology. 2002 May;96(5):1070-3.

Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after intrathecal injection of fentanyl for analgesia during labor: a cause of fetal bradycardia? Anesthesiology. 1994 Oct;81(4):1083. No abstract available.

Landau R, Cahana A, Smiley RM, Antonarakis SE, Blouin JL. Genetic variability of mu-opioid receptor in an obstetric population. Anesthesiology. 2004 Apr;100(4):1030-3. No abstract available.

Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology. 1999 Feb;90(2):437-44. Erratum in: Anesthesiology 1999 Apr;90(4):1241.

Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate. Science. 1998 Jul 17;281(5375):363, 365. No abstract available.

Wasson J, Skolnick G, Love-Gregory L, Permutt MA. Assessing allele frequencies of single nucleotide polymorphisms in DNA pools by pyrosequencing technology. Biotechniques. 2002 May;32(5):1144-6, 1148, 1150 passim.

Neve B, Froguel P, Corset L, Vaillant E, Vatin V, Boutin P. Rapid SNP allele frequency determination in genomic DNA pools by pyrosequencing. Biotechniques. 2002 May;32(5):1138-42.

Responsible Party:	Cynthia A. Wong, M.D., Northwestern University
ClinicalTrials.gov Identifier:	NCT00418015 History of Changes
Other Study ID Numbers:	0524-025
Study First Received:	December 31, 2006
Results First Received:	February 15, 2011
Last Updated:	April 25, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Northwestern University:

µ-opioid receptor
neuraxial labor analgesia
pharmacogenetics

Additional relevant MeSH terms:

Labor Pain
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Analgesics, Opioid
Analgesics

Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Central Nervous System Depressants

ClinicalTrials.gov processed this record on May 23, 2013