Does a Single Intravenous Dose of Ketamine Reduce the Need for Supplemental Opioids in Post-Cesarean Section Patients?

March 17, 2014 updated by: Cynthia Wong, Northwestern University

Pain control after cesarean delivery is associated with improved breastfeeding and infant rooming-in times. In addition, inadequate analgesia leads to elevated plasma catecholamine concentrations, which negatively affect every organ system. There is growing evidence that ketamine, N-methyl-D-aspartate receptor antagonist, is efficacious when used as an adjuvant in postoperative pain control. A 2006 Cochrane Collaboration systemic review and meta-analysis concluded, "Ketamine in subanesthetic doses….is effective in reducing morphine requirements in the first 24 hours after surgery."

Ketamine's prolonged analgesic effect, despite its short half-life and its use in low doses, is theorized to be due to blockade of spinal cord central sensitization. Central sensitization is a phenomenon whereby repeated painful stimulus leads to more severe pain perception over time despite no change in the intensity of the painful stimulus.Ketamine may also prevent the development of acute opioid tolerance. Ketamine's analgesic effects have also demonstrated in the obstetric population. Post-cesarean delivery morphine requirements in women who received ketamine as part of a general anesthesia technique were decreased. Similary, low-dose ketamine in conjunction with bupivacaine-only spinal anesthesia reduced postoperative analgesic requirements compared to bupivacaine-only spinal anesthesia and bupivacaine-fentanyl spinal anesthesia.

In the United States, healthy women scheduled for elective cesarean delivery commonly receive spinal anesthesia with bupivacaine-fentanyl-morphine. To our knowledge, IV ketamine has not been studied as an adjuvant to this regimen in the analgesic management in post-cesarean delivery patients. Multimodal therapy for postoperative pain control is widely practiced due to the advantage it provides in blocking multiple pain pathways while minimizing side effects of each individual pain medication. We hypothesize that low dose intravenous ketamine will improve multi-modal post-cesarean analgesia compared to placebo. The purpose of this study is to evaluate this hypothesis and study the possible side effects of this regimen in combination with bupivacaine-fentanyl-morphine spinal anesthesia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Eligible women for elective cesarean section 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.

Subjects will be prepared preoperatively in the usual fashion with intravenous (IV) access, aspiration prophylaxis and intraoperative monitoring. Preincision antibiotics will be given and uterotonic medications will be used as per usual practice after delivery.

The anesthesiologist will perform a spinal anesthetic per routine with the subject in the sitting position using sterile technique at the L3-4 interspace (± one vertebral interspace). The spinal anesthetic will consist of 12 mg of hyperbaric bupivacaine + 15 μg fentanyl + 150 μg of morphine. The subject will be placed supine with left lateral tilt to alleviate aortocaval compression. Cesarean section will commence after adequate anesthesia is assured to a T4 sensory level to pinprick. Vasopressors and IV fluids will be administered at the anesthesiologist's discretion per usual practice.

At the time of delivery, subjects will be randomized to one of two groups using a computer generated random number table. Randomization will be blocked based on whether the cesarean procedure is a primary or a repeat procedure. Randomization assignments will be kept in sequentially numbered opaque envelopes. The envelope will be opened by a research nurse who will prepare a 20 mL syringe labeled "study drug". The syringe will be given to the anesthesiologist blinded to the treatment group who will subsequently administer the study drug. Subjects randomized to the treatment group will receive ketamine 10 mg (ketamine 10 mg/mL) diluted to 20 mL with 0.9% preservative free saline. Subjects randomized to the placebo group will receive 20 mL preservative free saline.

The study drug will be administered into the intravenous line via an infusion pump over 10 minutes. Five minutes after placebo or drug administration, the anesthesiologist will ask the subject if she has nausea, vomiting and pruritus. Nausea and pruritus will be graded as none, mild, moderate or severe; and vomiting as present or absent. Any spontaneous complaints of psychedelic effects will be noted at this time. Sedation will be assessed via the Richmond agitation-sedation scale (RASS [see Appendix 1]).

Upon completion of the cesarean section, the subject will be transported to the post anesthesia recovery unit. Patients will receive ketorolac 30 mg every 6 hours time 4 doses beginning shortly after admission to the PACU.

At 1 h, 4 h, 8 h, 12 h and at 24 h after administration of the study drug, the subject's pain will be assessed using the numeric rating scale for pain NRS 0-10 (see Appendix 2). Patients may request rescue analgesia if they are experiencing discomfort. The time of first rescue analgesia request will be noted, and the NRS will be determined at the time of request for rescue analgesia.

Rescue medication will consist of hydrocodone 10 mg plus acetaminophen 325 mg per os. An additional dose of hydrocodone 10 mg plus acetaminophen 325 mg will be provided after 1 hour if the pain is not relieved to the subject's satisfaction. These are routine oral analgesic medications for postoperative cesarean delivery analgesia. Standard orders will be written for monitoring sedation and respiratory rate, and treatment of side effects (nausea, vomiting, pruritus and respiratory depression). The total amount of rescue medication will be determined for each subject after 24, 48 and 72 hours.

The presence of nausea, vomiting, and pruritus will be assessed at the same time intervals as the NRS for pain: 1 h, 4 h, 8 h, 12 h and 24 h after IV infusion of ketamine or placebo. The subjective psychedelic effects of ketamine and morphine will be assessed using a set of true/false questions from the LSD and morphine short form of the Addiction Research Center Inventory, ARCI (Appendix 3). These questions will be administered verbally by the anesthesiologist or researcher blinded to the treatment group upon admission to the PACU and at 4 h.

The following data will be collected in addition to the primary and secondary outcome data: maternal age, height, weight, prepregnancy weight, gestational age and IV fluids administered during cesarean section. In addition, all intraoperative and postoperative medications will be recorded, including those administered for the treatment of side effects listed above.

Protocol specific analgesia assessment ends 24 hours after administration of the study drug. At 72 hours the subject will be asked about her satisfaction with postoperative analgesia (100 mm scale, 0 mm = not satisfied at all, 100 mm = very satisfied). One telephone follow-up evaluation 2 weeks after delivery will again, assess for satisfaction with analgesia and average pain (NRS) since the procedure.

Study Type

Interventional

Enrollment (Actual)

188

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Eligible women are at term (≥37 week gestation),
  • Healthy,
  • ASA class 1-2,
  • Scheduled for elective cesarean section whose anesthetic plan is for spinal anesthesia with intrathecal morphine and intravenous ketorolac analgesia for post operative analgesia

Exclusion Criteria:

  • Women with American Society of Anesthesiologists physical status >2,
  • Body mass index ≥40 kg/m2,
  • Known allergy to any of the study medications,
  • Contraindication to the spinal anesthesia,
  • History of substance abuse,
  • History of hallucinations,
  • Chronic opioid therapy,
  • Chronic pain.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ketamine
Subjects receive IV ketamine 10 mg 5 minutes after infant delivery.
Drug: Ketamine
Ketamine 10 mg diluted to 20 mL delivered over 10 minutes via an infusion pump set at 2ml/minute
Other Names:
  • N-methyl-D-aspartate (NMDA)
Placebo Comparator: Placebo
Subjects receive IV Saline 20 mL 5 minutes after infant delivery
Drug: Placebo
Saline 20 mL IV infusion delivered over 10 minutes via an infusion pump set at 2ml/minute
Other Names:
  • 0.9% Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Subjects Requiring Supplemental Analgesia in the First 24 Hours Following Cesarean Delivery
Time Frame: 24 hours
Request for oral hydrocodone/acetaminophen for pain not controlled by around the clock non-steroidal antiflammatory drugs in the first 24 hours following cesarean delivery.
24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Verbal Pain Scores (0 to 10) at First Analgesia Request
Time Frame: 24 hours
Numeric rating of pain scores (NRS) scale (0 to 10) at time of supplemental analgesia request. Zero is no pain and 10 is worst pain imaginable.
24 hours
Cumulative Hydrocodone/Acetaminophen for Supplemental Analgesia to Treat Breakthrough Pain
Time Frame: 72 hours
Cumulative hydrocodone/acetaminophen for supplemental analgesia to treat breakthrough pain for 72 hours following cesarean delivery
72 hours
Postoperative Nausea
Time Frame: 24 hours
Number of subjects reporting nausea in first 24 hours following cesarean delivery
24 hours
Postoperative Vomiting
Time Frame: 24 hours
Number of subjects that vomited in the first 24 hours following cesarean delivery
24 hours
Postperative Pruritus
Time Frame: 24 hours
Number of subjects with pruritus in the first 24 hours following cesarean delivery
24 hours
Disturbing Dreams
Time Frame: 72 hours
Number of subject reporting disturbing dreams at 72 hours post cesarean delivery
72 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northwestern University

Investigators

  • Principal Investigator: Cynthia A Wong, M.D., Northwestern University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2006

Primary Completion (Actual)

October 1, 2008

Study Completion (Actual)

October 1, 2008

Study Registration Dates

First Submitted

June 13, 2007

First Submitted That Met QC Criteria

June 14, 2007

First Posted (Estimate)

June 15, 2007

Study Record Updates

Last Update Posted (Estimate)

April 14, 2014

Last Update Submitted That Met QC Criteria

March 17, 2014

Last Verified

March 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0524-030

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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