Mu-Opioid Receptor Genetic Polymorphism and Intrathecal Analgesia

NCT00418015 | Completed Results

• 1 other identifier: 0524-025
• Study Type: observational
• Target: 293
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Labor Pain; Post-cesarean Delivery

Keywords

µ-opioid receptor; neuraxial labor analgesia; pharmacogenetics

Outcome Measures

Primary Outcomes (3)

• Duration of Intrathecal Fentanyl Analgesia

  Time from intrathecal drug administration to request for analgesia either in laboring women of after cesarean delivery

  Time (0-1440 minutes) to first analgesia request

• Duration of Intrathecal Analgesia Following Cesarean Delivery

  Time until request for supplemental analgesia following intrathecal morphine/fentanyl for cesarean delivery

  0 to 72 hours following cesarean delivery

• Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention

  Visual analog pain scale (0 to 100) at 1st request for supplemental analgesia

  VAS at analgesia request

Secondary Outcomes (2)

• Severity of Pruritus Following Fentanyl

  Labor analgesia

• Subjects With Pruritus at 24 Hours Post Morphine

  24 hours post cesarean delivery

Study Arms (2)

Labor analgesia

Labor analgesia receiving fentanyl labor analgesia

Procedure: Blood Draw

Cesarean delivery analgesia

Cesarean delivery analgesia consisting of spinal fentanyl and morphine

Procedure: Blood Draw

Interventions

Blood Draw PROCEDURE

Blood for OPRM1 analysis

Cesarean delivery analgesia; Labor analgesia

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Pregnant women

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Related Publications (21)

• 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. doi: 10.1097/00000542-200503000-00028.

  PMID: 15731608 BACKGROUND

• 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. doi: 10.1074/jbc.M006352200. Epub 2000 Nov 6.

  PMID: 11067846 BACKGROUND

• 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. doi: 10.1073/pnas.95.16.9608.

  PMID: 9689128 BACKGROUND

• 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. doi: 10.1046/j.0306-5251.2001.01504.x.

  PMID: 11736886 BACKGROUND

• 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. doi: 10.1097/00008571-200201000-00001. No abstract available.

  PMID: 11773858 BACKGROUND

• 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. doi: 10.1097/00008571-200201000-00002.

  PMID: 11773859 BACKGROUND

• 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. doi: 10.1002/1096-8628(20001009)96:53.0.co;2-f.

  PMID: 11054767 BACKGROUND

• 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. doi: 10.1074/jbc.M104083200. Epub 2001 Jul 16.

  PMID: 11457836 BACKGROUND

• 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.

  PMID: 10490697 BACKGROUND

• 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. doi: 10.1002/humu.9026.

  PMID: 11933204 BACKGROUND

• 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. doi: 10.1038/sj.mp.4000951.

  PMID: 11840318 BACKGROUND

• 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.

  PMID: 9884158 BACKGROUND

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

  BACKGROUND

• 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. doi: 10.1097/00000542-199802000-00014.

  PMID: 9477056 BACKGROUND

• 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. doi: 10.1097/00000542-200205000-00007.

  PMID: 11981144 BACKGROUND

• 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. doi: 10.1097/00000542-199410000-00041. No abstract available.

  PMID: 7943823 BACKGROUND

• 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. doi: 10.1097/00000542-200404000-00042. No abstract available.

  PMID: 15087647 BACKGROUND

• Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology. 1999 Feb;90(2):437-44. doi: 10.1097/00000542-199902000-00018.

  PMID: 9952150 BACKGROUND

• Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate. Science. 1998 Jul 17;281(5375):363, 365. doi: 10.1126/science.281.5375.363. No abstract available.

  PMID: 9705713 BACKGROUND

• 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. doi: 10.2144/02325dd04.

  PMID: 12019788 BACKGROUND

• 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. doi: 10.2144/02325dd03.

  PMID: 12019787 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood Samples

MeSH Terms

Conditions

Labor Pain

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Limitations and Caveats

A limitation to the finding of this study was the relatively low number of OPRM1 heterozygous subjects.

Results Point of Contact

• Title: Dr. Robert J. McCarthy
• Organization: Northwestern University Feinberg School of Medicine

r-mccarthy@northwestern.edu

3129269015

Study Officials

• Cynthia A Wong, M.D.

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Anesthesiology

Study Record Dates

• First Submitted: December 31, 2006
• First Posted: January 4, 2007
• Study Start: October 1, 2005
• Primary Completion: May 1, 2007
• Study Completion: June 1, 2007
• Last Updated: April 14, 2014
• Results First Posted: April 18, 2011

Record last verified: 2014-03

Locations

US (1)