Multimodal Pain Management for Cesarean Delivery

• ClinicalTrials.gov Identifier: NCT02922985
• Recruitment Status: Completed
• First Posted: October 4, 2016
• Results First Posted: July 24, 2018
• Last Update Posted: December 6, 2021
• Sponsor: The University of Texas Medical Branch, Galveston
• Information provided by (Responsible Party): The University of Texas Medical Branch, Galveston

Study Description

Brief Summary:

Opioid use and abuse has become a major medical problem in the United States. Over prescription of opioid medications is a major contributor to this growing problem. Cesarean delivery (CD) is the most commonly performed surgery in the US and women are generally given opioid medications for postoperative pain management. This is not a common practice in other developed countries. We believe that a multimodal pain management strategy is superior to current practices for control of postoperative pain after CD and will lead to a decrease in the use of opioid medications. This will have beneficial effects on patients' recovery and bonding with their newborns, as well as societal effects in reducing the burden of opioid abuse in the US. Our objective is to investigate the use of a multimodal pain regimen in pregnant patients undergoing CD. This is a randomized double-blinded, placebo controlled trial. The multimodal intervention consists of a pre-operative dose of IV acetaminophen (Ofirmev), infiltration of subcutaneous bupivacaine prior to skin incision, and a dose of IM ketorolac at time of fascial closure. These study medications are currently used in our patient population but not in a standardized fashion, not in every patient, and not always in combination with each other. The control group will receive placebo IV infusion preoperatively and an IM injection at fascial closure, and subcutaneous infiltration with normal saline before skin incision. Both groups will receive spinal regional anesthesia as per anesthesia team and then postoperatively, both groups will receive the current standard of care, which consists postoperative hydrocodone/acetaminophen and ibuprofen as needed depending on pain score. Our primary outcome of interest will be the total opioid intake in the first 48 hours after surgery. Secondary outcomes include time to first opioid given, pain scores at 6-12, 24 and 48 hours post op, and total number of opioid tablets left after discharge on post op day number 7. We will also evaluate patient satisfaction scores and total length of hospital stay. We will evaluate neonatal outcomes including Apgar scores, cord blood gases, immediate newborn complications in the first 48 hours after birth, and any infant adverse outcomes related to maternal opioid use up to 4 weeks of life. Our hypothesis is that our multimodal pain regimen will decrease the total opioid requirement in the first 48 hours after surgery.

Condition or disease	Intervention/treatment	Phase
Pain	Drug: Intravenous acetominophen; Drug: Ketorolac, intramuscular; Drug: Bupivacaine, subcutaneous; Drug: Normal saline	Phase 4

Detailed Description:

We are proposing a double-blinded, placebo controlled, randomized trial of patients undergoing elective cesarean delivery. Participants will be randomized to either a control group or study group. This is a double-blinded study, neither participants nor the obstetric or anesthesia team are aware of study assignment. The study group, aka multimodal group, will receive 1 g of IV acetaminophen (ofirmev) within 30 minutes before starting the surgery, regional anesthesia (spinal anesthesia only) with fentanyl, duramorph (morphine) and bupivacaine will be performed as per anesthesia team, the anticipated sight of skin incision will be infiltrated with 20 mL of bupivacaine 0.25% in the subcutaneous space prior to skin incision, and 60 mg of intramuscular (IM) ketorolac (toradol) will be given at the time of fascial closure. The control group will receive a placebo drip within 30 minutes before starting the surgery, regional anesthesia (spinal anesthesia only) with fentanyl, duramorph (morphine) and bupivacaine will be performed as per anesthesia team, the anticipated sight of skin incision will be infiltrated with 20 mL of normal saline in the subcutaneous space prior to skin incision, and an IM dose of placebo at the time of fascial closure. Post-operatively both groups will be managed similarly.

Inclusion Criteria:

• Women who are 18 - 45 years of age at the time of cesarean delivery with the ability to give informed consent
• Elective cesarean delivery
• Gestational age ≥ 34 weeks
• Fluent in either English or Spanish
• Spinal anesthesia

Exclusion Criteria:

Urgent or emergent CD Active labor Epidural or Intrathecal regional anesthesia General anesthesia Patients with a contraindication for regional anesthesia Acute or chronic hepatic disease Acute or chronic renal disease Active asthma Gastrointestinal ulceration Inflammatory bowel disease Allergy to ketorolac, acetaminophen, hydrocodone, codeine, ibuprofen or bupivacaine Opioid dependence Non reassuring fetal or maternal status requiring immediate delivery Placenta previa or accreta Acute or chronic pain disorder Maternal weight <50 kilograms Uncontrolled hypertension Ischemic cardiac disease Congestive heart failure Thrombocytopenia, platelet count <150,000/microliter Preeclampsia including Hemolysis Elevated Liver enzymes Low Platelets syndrome DIC or active hemorrhage before randomization Estimated blood loss > 2000 mL

Primary Outcome: The primary outcome of the study is the total opioid (hydrocodone) use in milligrams in the first 48 hours after cesarean delivery.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multimodal Pain Management for Cesarean Delivery: A Randomized Control Trial
• Study Start Date: October 2016
• Actual Primary Completion Date: June 2017
• Actual Study Completion Date: July 2017

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo Control Group; Patients will receive a placebo dose of all three study medications: Patients will receive the pre-operative dose of IV normal saline placebo within 30 minutes of going to the OR for CD. The patient will receive the subcutaneous infiltration of 20 mL of subcutaneous normal saline placebo after positioning and preparation but prior to skin incision. At the time of fascial closure, the patient will receive an IM dose of normal saline placebo.	Drug: Normal saline; Normal saline will be given intravenously, intra-muscularly, and subcutaneously in the same volume as the study drugs for the patients in the placebo group.
Active Comparator: Multimodal Pain Regimen Group; Patients will receive the actual study medication for all three study medications: Patients will receive the pre-operative dose of IV acetaminophen 1 g within 30 minutes of going to the OR for CD. The patient will receive the subcutaneous infiltration of either 20 mL of bupivacaine 0.25% after positioning and preparation but prior to skin incision. At the time of fascial closure, the patient will receive 60 mg of IM ketorolac.	Drug: Intravenous acetominophen; One dose if 1 gram intravenous to be given pre-surgery; Other Name: Ofirmev; Drug: Ketorolac, intramuscular; One dose of 60 mg Intramuscular to be given at time of skin closure; Other Name: Toradol; Drug: Bupivacaine, subcutaneous; Inject 20 mL of 0.25% bupivacaine at the site of anticipated skin incision.

Outcome Measures

Primary Outcome Measures :

1. Total Opioid Intake in Morphine Milligram Equivalents in the First 48 Hours After Cesarean Delivery (CD) [ Time Frame: 48 hours post cesarean delivery ]
   Every opioid intake by the patient in the first 48 hours after CD will be recorded and quantified in morphine milligram equivalents

Secondary Outcome Measures :

1. Time to First Administration of Opioid Pain Medication Post Operatively [ Time Frame: 48 hours post cesarean delivery ]
   Time, in hours, to first administration of opioid pain medication post operatively
2. Pain Score at 6-12 Hours Post Operatively [ Time Frame: 6-12 hours post-operatively ]
   Pain score at 6-12 hours post-operatively, expressed on a pain scale from 0-10 with the higher score meaning worse pain (outcome).
3. Number of Opioid Pain Tablets Remaining on Post-operative Day #7 From the Discharge Prescription. [ Time Frame: 7 days post delivery ]
   Number of opioid pain tablets remaining on post-operative day #7 from hospital discharge as reported by patients
4. Hospital Length of Stay [ Time Frame: From time of hospital admission to time of discharge home up to 168 hours. ]
   Time to discharge from hospital, measured in hours
5. Pain Score at 24 Hours Post-operatively [ Time Frame: 24 hours post-operatively ]
   Pain Score at 24 Hours Post Operatively, expressed on a pain scale from 0-10 with the higher score meaning worse pain (outcome).
6. Pain Score at 48 Hours Post-operatively [ Time Frame: 48 hours post-operatively ]
   Pain Score at 48 Hours Post-operatively, expressed on a pain scale from 0-10 with the higher score meaning worse pain (outcome).
7. Apgar Score at 5 Minutes [ Time Frame: 5 minutes after birth ]
   This is the Apgar score of the newborn collected at 5 minutes. Range is from 0-10, with the higher scores meaning a better outcome.
8. NICU Admission [ Time Frame: after birth and before hospital discharge ]
   Rate of admission to the neonatal intensive care unit
9. Need for Respiratory Support [ Time Frame: after birth and before hospital discharge ]
   neonate receipt of oxygen by nasal cannula or mechanical ventilation

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Women who are 18 - 45 years of age at the time of cesarean delivery with the ability to give informed consent
• Elective cesarean delivery
• Gestational age ≥ 34 weeks
• Fluent in either English or Spanish
• Spinal anesthesia

Exclusion Criteria:

• Urgent or emergent CD
• Epidural or combined spinal epidural regional anesthesia
• General anesthesia
• Patients with a contraindication for regional anesthesia
• Acute or chronic hepatic disease
• Acute or chronic renal disease
• Active asthma
• Gastrointestinal ulceration
• Inflammatory bowel disease
• Allergy to ketorolac, acetaminophen, hydrocodone, codeine, ibuprofen or bupivacaine
• Opioid dependence
• Non reassuring fetal or maternal status requiring immediate delivery
• Placenta previa or accreta
• Acute or chronic pain disorder
• Maternal weight <50 kilograms
• Uncontrolled hypertension
• Ischemic cardiac disease
• Congestive heart failure
• Thrombocytopenia, platelet count <150,000/microliter
• Preeclampsia including Hemolysis Elevated Liver enzymes Low Platelets syndrome
• Disseminated intravascular coagulation (DIC) or active hemorrhage before randomization
• Estimated blood loss > 2000 mL

Contacts and Locations

Locations

United States, Texas

University of Texas Medical Branch

Galveston, Texas, United States, 77555

Sponsors and Collaborators

The University of Texas Medical Branch, Galveston

Investigators

• Principal Investigator: Emily E Hadley, MD; University of Texas

  Study Documents (Full-Text)

Documents provided by The University of Texas Medical Branch, Galveston:

Study Protocol and Statistical Analysis Plan  [PDF] November 22, 2016

More Information

Publications:

Bartels K, Mayes LM, Dingmann C, Bullard KJ, Hopfer CJ, Binswanger IA. Opioid Use and Storage Patterns by Patients after Hospital Discharge following Surgery. PLoS One. 2016 Jan 29;11(1):e0147972. doi: 10.1371/journal.pone.0147972. eCollection 2016.

Santoso JT, Ulm MA, Jennings PW, Wan JY. Multimodal pain control is associated with reduced hospital stay following open abdominal hysterectomy. Eur J Obstet Gynecol Reprod Biol. 2014 Dec;183:48-51. doi: 10.1016/j.ejogrb.2014.10.007. Epub 2014 Oct 14.

Rosaeg OP, Lui AC, Cicutti NJ, Bragg PR, Crossan ML, Krepski B. Peri-operative multimodal pain therapy for caesarean section: analgesia and fitness for discharge. Can J Anaesth. 1997 Aug;44(8):803-9.

Munishankar B, Fettes P, Moore C, McLeod GA. A double-blind randomised controlled trial of paracetamol, diclofenac or the combination for pain relief after caesarean section. Int J Obstet Anesth. 2008 Jan;17(1):9-14. Epub 2007 Nov 5.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hadley EE, Monsivais L, Pacheco L, Babazade R, Chiossi G, Ramirez Y, Ellis V, Simon M, Saade GR, Costantine M. Multimodal Pain Management for Cesarean Delivery: A Double-Blinded, Placebo-Controlled, Randomized Clinical Trial. Am J Perinatol. 2019 Sep;36(11):1097-1105. doi: 10.1055/s-0039-1681096. Epub 2019 Mar 1.

• Responsible Party: The University of Texas Medical Branch, Galveston
• ClinicalTrials.gov Identifier: NCT02922985
• Other Study ID Numbers: IRB 16-0121
• First Posted: October 4, 2016
• Results First Posted: July 24, 2018
• Last Update Posted: December 6, 2021
• Last Verified: October 2017

Keywords provided by The University of Texas Medical Branch, Galveston:

Cesarean delivery; Multimodal pain management

Additional relevant MeSH terms:

Acetaminophen; Ketorolac; Bupivacaine; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antipyretics