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

Purpose

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.

Condition	Intervention
Ketamine Adverse Reaction Effects of; Anesthesia, Spinal and Epidural, in Pregnancy Complication of Labor and/or Delivery	Drug: Ketamine Drug: Placebo

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Does a Single Intravenous Dose of Ketamine Reduce the Need for Supplemental Opioids in Post-Cesarean Section Patients?

Resource links provided by NLM:

MedlinePlus related topics: Cesarean Section Nausea and Vomiting

Drug Information available for: Aspartic acid Ketamine hydrochloride Ketamine

U.S. FDA Resources

Further study details as provided by Northwestern University:

Primary Outcome Measures:

Number of Subjects Requiring Supplemental Analgesia in the First 24 Hours Following Cesarean Delivery [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Verbal Pain Scores (0 to 10) at First Analgesia Request [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
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.
Cumulative Hydrocodone/Acetaminophen for Supplemental Analgesia to Treat Breakthrough Pain [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
Cumulative hydrocodone/acetaminophen for supplemental analgesia to treat breakthrough pain for 72 hours following cesarean delivery
Postoperative Nausea [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
Number of subjects reporting nausea in first 24 hours following cesarean delivery
Postoperative Vomiting [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
Number of subjects that vomited in the first 24 hours following cesarean delivery
Postperative Pruritus [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
Number of subjects with pruritus in the first 24 hours following cesarean delivery
Disturbing Dreams [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
Number of subject reporting disturbing dreams at 72 hours post cesarean delivery

Enrollment:	188
Study Start Date:	July 2006
Study Completion Date:	October 2008
Primary Completion Date:	October 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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 Name: 0.9% Saline

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00486902

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:

Yost NP, Bloom SL, Sibley MK, Lo JY, McIntire DD, Leveno KJ. A hospital-sponsored quality improvement study of pain management after cesarean delivery. Am J Obstet Gynecol. 2004 May;190(5):1341-6.

Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004 Aug;99(2):482-95, table of contents. Review.

Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004603. Review.

Menigaux C, Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg. 2000 Jan;90(1):129-35.

Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg. 2001 Sep;93(3):606-12.

Kwok RF, Lim J, Chan MT, Gin T, Chiu WK. Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Anesth Analg. 2004 Apr;98(4):1044-9, table of contents.

Argiriadou H, Himmelseher S, Papagiannopoulou P, Georgiou M, Kanakoudis F, Giala M, Kochs E. Improvement of pain treatment after major abdominal surgery by intravenous S+-ketamine. Anesth Analg. 2004 May;98(5):1413-8, table of contents.

Guillou N, Tanguy M, Seguin P, Branger B, Campion JP, Malledant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003 Sep;97(3):843-7.

Guignard B, Coste C, Costes H, Sessler DI, Lebrault C, Morris W, Simonnet G, Chauvin M. Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Anesth Analg. 2002 Jul;95(1):103-8, table of contents.

Xie H, Wang X, Liu G, Wang G. Analgesic effects and pharmacokinetics of a low dose of ketamine preoperatively administered epidurally or intravenously. Clin J Pain. 2003 Sep-Oct;19(5):317-22.

Suzuki M, Tsueda K, Lansing PS, Tolan MM, Fuhrman TM, Ignacio CI, Sheppard RA. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg. 1999 Jul;89(1):98-103.

Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K. Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology. 2000 Jun;92(6):1624-30.

Kararmaz A, Kaya S, Karaman H, Turhanoglu S, Ozyilmaz MA. Intraoperative intravenous ketamine in combination with epidural analgesia: postoperative analgesia after renal surgery. Anesth Analg. 2003 Oct;97(4):1092-6, table of contents.

Ilkjaer S, Nikolajsen L, Hansen TM, Wernberg M, Brennum J, Dahl JB. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth. 1998 Nov;81(5):707-12.

Woolf CJ, Chong MS. Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg. 1993 Aug;77(2):362-79. Review. No abstract available.

Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995 Sep;62(3):259-74. Review.

Ngan Kee WD, Khaw KS, Ma ML, Mainland PA, Gin T. Postoperative analgesic requirement after cesarean section: a comparison of anesthetic induction with ketamine or thiopental. Anesth Analg. 1997 Dec;85(6):1294-8.

Kashefi P. The benefits of intraoperative small-dose ketamine on postoperative pain after cesarean section. Anesthesiology 2006;104, Supp 1.

Sen S, Ozmert G, Aydin ON, Baran N, Caliskan E. The persisting analgesic effect of low-dose intravenous ketamine after spinal anaesthesia for caesarean section. Eur J Anaesthesiol. 2005 Jul;22(7):518-23.

Downing JW, Mahomedy MC, Jeal DE, Allen PJ. Anaesthesia for cesarean section with ketamine. Anaesthesia 1976;31:883-92.

Dich-Nielsen J, Holasek J. Ketamine as induction agent for caesarean section. Acta Anaesthesiol Scand. 1982 Apr;26(2):139-42.

Maduska AL, Hajghassemali M. Arterial blood gases in mothers and infants during ketamine anesthesia for vaginal delivery. Anesth Analg. 1978 Jan-Feb;57(1):121-3. No abstract available.

Bar-Oz B, Bulkowstein M, Benyamini L, Greenberg R, Soriano I, Zimmerman D, Bortnik O, Berkovitch M. Use of antibiotic and analgesic drugs during lactation. Drug Saf. 2003;26(13):925-35. Review.

Responsible Party:	Cynthia A. Wong, MD, Northwestern University
ClinicalTrials.gov Identifier:	NCT00486902 History of Changes
Other Study ID Numbers:	0524-030
Study First Received:	June 13, 2007
Results First Received:	March 15, 2011
Last Updated:	April 11, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Northwestern University:

Ketamine
Spinal Anesthesia
C-section

Additional relevant MeSH terms:

Obstetric Labor Complications
Pregnancy Complications
N-Methylaspartate
Ketamine
Analgesics, Opioid
Excitatory Amino Acid Agonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses
Excitatory Amino Acid Antagonists
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on May 19, 2013