Mu-Opioid Receptor Genetic Polymorphism and Intrathecal Analgesia - Study Results

Study Type:	Observational
Study Design:	Observational Model: Cohort; Time Perspective: Prospective
Conditions:	Labor Pain Post-cesarean Delivery
Intervention:	Procedure: Blood Draw

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Laboring subject recruited from 10/2005 to 9/2006 Post cesarean delivery subjects recruited from 10/2005 to 5/2007

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were excluded from the labor analgesia group if they had received an opioid analgesic before initiation of intrathecal analgesia or if they received neuraxial analgesia before 2cm of cervical dilation.

Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G

Participant Flow: Overall Study

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G
STARTED	144	46	78	25
COMPLETED	144	46	78	25
NOT COMPLETED	0	0	0	0

Baseline Characteristics

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Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G
Total	Total of all reporting groups

Baseline Measures

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G	Total
Number of Participants [units: participants]	144	46	78	25	293
Age [units: participants]
<=18 years	0	0	0	0	0
Between 18 and 65 years	144	46	78	25	293
>=65 years	0	0	0	0	0
Age [units: years] Median ( Inter-Quartile Range )	30 ( 28 to 34 )	32 ( 30 to 34 )	34 ( 31 to 37 )	32 ( 29 to 35 )	32 ( 28 to 34 )
Gender [units: participants]
Female	144	46	78	25	293
Male	0	0	0	0	0
Region of Enrollment [units: participants]
United States	144	46	78	25	293

Outcome Measures

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1. Primary:

Duration of Intrathecal Fentanyl Analgesia [ Time Frame: Time (0-1440 minutes) to first analgesia request ]

Measure Type	Primary
Measure Title	Duration of Intrathecal Fentanyl Analgesia
Measure Description	Time from intrathecal drug administration to request for analgesia either in laboring women of after cesarean delivery
Time Frame	Time (0-1440 minutes) to first analgesia request
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Laboring parturients that received intrathecal fentanyl (25 micrograms) for initiation of labor analgesia were evaluated for this outcome per protocol.

Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G

Measured Values

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G
Number of Participants Analyzed [units: participants]	144	46	0	0
Duration of Intrathecal Fentanyl Analgesia [units: Minutes] Median ( 95% Confidence Interval )	70 ( 62 to 78 )	63 ( 50 to 76 )

Statistical Analysis 1 for Duration of Intrathecal Fentanyl Analgesia

Groups ^[1]	Labor Analgesia OPRM1 c304A vs. Labor Analgesia OPRM1 c304A>G
Method ^[2]	Log Rank
P Value ^[3]	0.54

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Log rank test
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

2. Primary:

Duration of Intrathecal Analgesia Following Cesarean Delivery [ Time Frame: 0 to 72 hours following cesarean delivery ]

Measure Type	Primary
Measure Title	Duration of Intrathecal Analgesia Following Cesarean Delivery
Measure Description	Time until request for supplemental analgesia following intrathecal morphine/fentanyl for cesarean delivery
Time Frame	0 to 72 hours following cesarean delivery
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects that received fentanyl and morphine for postpartum analgesia after planned cesarean delivery were analyzed per protocol.

Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G

Measured Values

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G
Number of Participants Analyzed [units: participants]	0	0	78	25
Duration of Intrathecal Analgesia Following Cesarean Delivery [units: Hours] Median ( Inter-Quartile Range )			26 ( 0 to 47 )	40 ( 0 to 60 )

Statistical Analysis 1 for Duration of Intrathecal Analgesia Following Cesarean Delivery

Groups ^[1]	Cesarean Delivery OPRM1 c304A vs. Cesarean Delivery OPRM1 c304A>G
Method ^[2]	Log Rank
P Value ^[3]	0.15

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

3. Primary:

Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention [ Time Frame: VAS at analgesia request ]

Measure Type	Primary
Measure Title	Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention
Measure Description	Visual analog pain scale (0 to 100) at 1st request for supplemental analgesia
Time Frame	VAS at analgesia request
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analysis population per protocol.

Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G

Measured Values

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G
Number of Participants Analyzed [units: participants]	144	46	78	25
Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention [units: Units on a scale] Median ( Inter-Quartile Range )	33 ( 21 to 50 )	38 ( 23 to 51 )	26 ( 0 to 47 )	40 ( 0 to 60 )

Statistical Analysis 1 for Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention

Groups ^[1]	Labor Analgesia OPRM1 c304A vs. Labor Analgesia OPRM1 c304A>G
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.23

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Visual Analog Pain Scale (0 to 100) at Analgesia Request Following Intrathecal Intervention

Groups ^[1]	Cesarean Delivery OPRM1 c304A vs. Cesarean Delivery OPRM1 c304A>G
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.84

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

4. Secondary:

Severity of Pruritus Following Fentanyl [ Time Frame: Labor analgesia ]

Measure Type	Secondary
Measure Title	Severity of Pruritus Following Fentanyl
Measure Description	Severity of pruritus during labor analgesia
Time Frame	Labor analgesia
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G

Measured Values

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G
Number of Participants Analyzed [units: participants]	144	46	0	0
Severity of Pruritus Following Fentanyl [units: participants]
None	9	13
Mild	48	59
Moderate	35	26
Severe	8	2

Statistical Analysis 1 for Severity of Pruritus Following Fentanyl

Groups ^[1]	Labor Analgesia OPRM1 c304A vs. Labor Analgesia OPRM1 c304A>G
Method ^[2]	Chi-squared, Corrected
P Value ^[3]	0.06

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

5. Secondary:

Subjects With Pruritus at 24 Hours Post Morphine [ Time Frame: 24 hours post cesarean delivery ]

Measure Type	Secondary
Measure Title	Subjects With Pruritus at 24 Hours Post Morphine
Measure Description	Subjects reporting pruritus in the first 24 hours post cesarean delivery
Time Frame	24 hours post cesarean delivery
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
Labor Analgesia OPRM1 c304A	Parturients that received spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia who were homozygous for OPRM1 c304
Labor Analgesia OPRM1 c304A>G	Parturients receiving spinal fentanyl 15 micrograms and epidural fentanyl labor analgesia that were heterozygous or homozygous for OPRM1 c304A>G
Cesarean Delivery OPRM1 c304A	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were homozygous for OPRM1 c304A
Cesarean Delivery OPRM1 c304A>G	Cesarean delivery subjects receiving morphine 150 micrograms with spinal bupivacaine 12mg and fentanyl 15 micrograms that were heterozygous for OPRM1 c304A>G

Measured Values

	Labor Analgesia OPRM1 c304A	Labor Analgesia OPRM1 c304A>G	Cesarean Delivery OPRM1 c304A	Cesarean Delivery OPRM1 c304A>G
Number of Participants Analyzed [units: participants]	0	0	78	25
Subjects With Pruritus at 24 Hours Post Morphine [units: participants]			33	3

Statistical Analysis 1 for Subjects With Pruritus at 24 Hours Post Morphine

Groups ^[1]	Cesarean Delivery OPRM1 c304A vs. Cesarean Delivery OPRM1 c304A>G
Method ^[2]	Chi-squared, Corrected
P Value ^[3]	0.02

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
A limitation to the finding of this study was the relatively low number of OPRM1 heterozygous subjects.

Results Point of Contact:

Name/Title: Dr. Robert J. McCarthy
Organization: Northwestern University Feinberg School of Medicine
phone: 3129269015
e-mail: r-mccarthy@northwestern.edu

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