Effect of Mu-opioid Receptor Genetics on 3 Doses of Spinal Morphine for Postoperative Analgesia After Cesarean Section

Effect of OPRM1 Genotype on the Dose Response to Spinal Morphine for Post-Cesarean Analgesia

HYPOTHESIS: The response to a given dose of morphine given via a spinal anesthetic for cesarean section will be affected by the genetics of the woman's mu-opioid receptor

Most women undergoing elective cesarean section (CS) receive spinal anesthesia, and most receive a dose of preservative free morphine with the spinal anesthetic. Spinally-administered morphine provides 16-24 hours of high quality pain relief. The dose administered is usually 75-200 micrograms, but surprisingly few dose-response studies exist.

The mu-opioid receptor (OPRM1 gene)is the site of action of endogenous opioid peptides and opioid analgesic drugs like morphine. There is a common genetic variant of this receptor at the 40th amino acid of the protein, with asparagine and asparate being present in different people. The less common variant (aspartate), present in 25-30% of the overall American population (higher in Asian populations, lower in Blacks) at codon 40 that has been shown in many studies to affect opioid analgesia.

This will be a randomized, blinded study of 3 doses of spinal morphine (50, 100, 150 micrograms) given to women undergoing elective cesarean section at term pregnancy. 300 women will be studied (100 per dose). Blood will be obtained for genotyping of OPRM1 and other genes that may affect pain and analgesic responses. The primary outcome will be the amount of intravenous morphine patients self-administer in the 24 hours postsurgery.

The primary outcome (use of intravenous morphine) will be analyzed by dose, and within each dose group by genotype of OPRM1. Secondary outcomes will include pain scores every 6 hours, satisfaction with analgesia, side effects (itching, nausea/vomiting) by dose and genotype.

It is anticipated that there will be an interim data analysis at 150 evaluable subjects for assessment of the dose response to morphine in the overall population; then a final analysis at 300 subjects for the genetic effect assessment.

Study Overview

• Status: Completed
• Conditions: Postoperative Pain
• Intervention / Treatment: Drug: Morphine

• Study Type: Interventional
• Enrollment (Actual): 169
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• healthy women undergoing elective cesarean

Exclusion Criteria:

• cardiovascular disease
• analgesic medications
• complications of pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 50 micrograms (mcg) spinal morphine; Subjects will receive 50 mcg morphine in their spinal anesthetic for cesarean section	Drug: Morphine; Morphine will be given via spinal injection at doses of 50, 100, 150 micrograms as part of a spinal anesthetic for cesarean section
Experimental: 100 micrograms spinal morphine; Subjects will receive 100 mcg morphine in their spinal anesthetic for cesarean section	Drug: Morphine; Morphine will be given via spinal injection at doses of 50, 100, 150 micrograms as part of a spinal anesthetic for cesarean section
Experimental: 150 micrograms spinal morphine; Subjects will receive 150 mcg morphine in their spinal anesthetic for cesarean section	Drug: Morphine; Morphine will be given via spinal injection at doses of 50, 100, 150 micrograms as part of a spinal anesthetic for cesarean section

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Milligrams of Intravenous Morphine Used by Participant in First 24 Hours Postoperatively	IV morphine use in milligrams, by participant-controlled analgesia will be assessed every 6 hours for 24 hours postoperatively.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Scale (VAS) Pain at 6 Hours	Visual analog pain scale measures pain on a 100 millimeter (mm) scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst pain imaginable" (100mm). Pain measured at rest and with movement.	6 hours post-operatively
Visual Analog Scale (VAS) Pain at 12 Hours	Visual analog pain scale measures pain on a 100 millimeter (mm) scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst pain imaginable" (100mm). Pain measured at rest and with movement.	12 hours post-operatively
Visual Analog Scale (VAS) Pain at 18 Hours	Visual analog pain scale measures pain on a 100 millimeter (mm) scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst pain imaginable" (100mm). Pain measured at rest and with movement.	18 hours post-operatively
Visual Analog Scale (VAS) Pain at 24 Hours	Visual analog pain scale measures pain on a 100 millimeter (mm) scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst pain imaginable" (100mm). Pain measured at rest and with movement.	24 hours post-operatively
Visual Analog Scale- Nausea/Vomiting at 6 Hours	Visual analog nausea/vomiting scale measures nausea and vomiting on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Nausea/Vomiting Imaginable" (100mm).	6 hours post-operatively
Visual Analog Scale- Nausea/Vomiting at 12 Hours	Visual analog nausea/vomiting scale measures nausea and vomiting on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Nausea/Vomiting Imaginable" (100mm).	12 hours post-operatively
Visual Analog Scale- Nausea/Vomiting at 18 Hours	Visual analog nausea/vomiting scale measures nausea and vomiting on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Nausea/Vomiting Imaginable" (100mm).	18 hours post-operatively
Visual Analog Scale- Nausea/Vomiting at 24 Hours	Visual analog nausea/vomiting scale measures nausea and vomiting on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Nausea/Vomiting Imaginable" (100mm).	24 hours post-operatively
Visual Analog Scale Pruritus (Itching) at 6 Hours	Visual analog pruritus scale measures itching on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Itching Imaginable" (100mm).	6 hours post-operatively
Visual Analog Scale Pruritus (Itching) at 12 Hours	Visual analog pruritus scale measures itching on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Itching Imaginable" (100mm).	12 hours post-operatively
Visual Analog Scale Pruritus (Itching) at 18 Hours	Visual analog pruritus scale measures itching on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Itching Imaginable" (100mm).	18 hours post-operatively
Visual Analog Scale Pruritus (Itching) at 24 Hours	Visual analog pruritus scale measures itching on a 100mm scale. Participants make a mark on the scale with one end labeled "None" (0mm) and the other labeled "Worst Itching Imaginable" (100mm).	24 hours post-operatively
Visual Analog Patient Satisfaction With Analgesia at 24 Hours	Visual analog patient satisfaction scale measures satisfaction with analgesia on a 100mm scale. Participants make a mark on the scale with one end labeled "Completely Dissatisfied" (0mm) and the other labeled "Completely Satisfied" (100mm).	24 hours postoperatively

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Richard M Smiley, MD, PhD, Columbia University

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: November 2, 2011
• First Submitted That Met QC Criteria: November 2, 2011
• First Posted (Estimate): November 4, 2011

Study Record Updates

• Last Update Posted (Actual): December 10, 2020
• Last Update Submitted That Met QC Criteria: November 16, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: opioid; genetics; morphine; postoperative; cesarean
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Morphine
• Other Study ID Numbers: AAAI2804

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No