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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo Control Group | Placebo Comparator | 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. |
|
| Multimodal Pain Regimen Group | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intravenous acetominophen | Drug | One dose if 1 gram intravenous to be given pre-surgery |
|
| Measure | Description | Time Frame |
|---|---|---|
| Total Opioid Intake in Morphine Milligram Equivalents in the First 48 Hours After Cesarean Delivery (CD) | Every opioid intake by the patient in the first 48 hours after CD will be recorded and quantified in morphine milligram equivalents | 48 hours post cesarean delivery |
| Measure | Description | Time Frame |
|---|---|---|
| Time to First Administration of Opioid Pain Medication Post Operatively | Time, in hours, to first administration of opioid pain medication post operatively | 48 hours post cesarean delivery |
| Pain Score at 6-12 Hours Post Operatively |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Emily E Hadley, MD | University of Texas | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Texas Medical Branch | Galveston | Texas | 77555 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26824844 | Background | 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. | |
| 25461352 | Background | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Control Group | Patients will receive a placebo dose of all three study medications 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. |
| FG001 | Multimodal Pain Regimen Group | Patients will receive the actual study medication for all three study medications. Intravenous acetominophen: One dose if 1 gram intravenous to be given pre-surgery Ketorolac, intramuscular: One dose of 60 mg Intramuscular to be given at time of skin closure Bupivacaine, subcutaneous: Inject 20 mL of 0.25% bupivacaine at the site of anticipated skin incision. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo Control Group | Patients will receive a placebo dose of all three study medications 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. |
| BG001 | Multimodal Pain Regimen Group |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Opioid Intake in Morphine Milligram Equivalents in the First 48 Hours After Cesarean Delivery (CD) | Every opioid intake by the patient in the first 48 hours after CD will be recorded and quantified in morphine milligram equivalents | Posted | Median | Inter-Quartile Range | morphine milligram equivalents | 48 hours post cesarean delivery |
|
9 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo Control Group | Patients will receive a placebo dose of all three study medications 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| October 2016-May 2017 | Pregnancy, puerperium and perinatal conditions | Systematic Assessment | Postpartum hemorrhage |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| October 2016-May 2017 | Skin and subcutaneous tissue disorders | Systematic Assessment | Severe skin itching |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Emily Hadley | University of Texas Medical Branch | 4022028626 | ehadley15@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 22, 2016 | Jun 27, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010146 | Pain |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| D020910 | Ketorolac |
| D007273 | Injections, Intramuscular |
| D020911 | Ketorolac Tromethamine |
| D002045 | Bupivacaine |
| D007279 | Injections, Subcutaneous |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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| Ketorolac, intramuscular | Drug | One dose of 60 mg Intramuscular to be given at time of skin closure |
|
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| Bupivacaine, subcutaneous | Drug | Inject 20 mL of 0.25% bupivacaine at the site of anticipated skin incision. |
|
| Normal saline | Drug | 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. |
|
Pain score at 6-12 hours post-operatively, expressed on a pain scale from 0-10 with the higher score meaning worse pain (outcome).
| 6-12 hours post-operatively |
| Number of Opioid Pain Tablets Remaining on Post-operative Day #7 From the Discharge Prescription. | Number of opioid pain tablets remaining on post-operative day #7 from hospital discharge as reported by patients | 7 days post delivery |
| Hospital Length of Stay | Time to discharge from hospital, measured in hours | From time of hospital admission to time of discharge home up to 168 hours. |
| Pain Score at 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). | 24 hours post-operatively |
| Pain Score at 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). | 48 hours post-operatively |
| Apgar Score at 5 Minutes | 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. | 5 minutes after birth |
| NICU Admission | Rate of admission to the neonatal intensive care unit | after birth and before hospital discharge |
| Need for Respiratory Support | neonate receipt of oxygen by nasal cannula or mechanical ventilation | after birth and before hospital discharge |
| 9260006 | Background | 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. doi: 10.1007/BF03013154. |
| 17981455 | Background | 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. doi: 10.1016/j.ijoa.2007.06.006. Epub 2007 Nov 5. |
| 30822800 | Derived | 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. |
Patients will receive the actual study medication for all three study medications. Intravenous acetominophen: One dose if 1 gram intravenous to be given pre-surgery Ketorolac, intramuscular: One dose of 60 mg Intramuscular to be given at time of skin closure Bupivacaine, subcutaneous: Inject 20 mL of 0.25% bupivacaine at the site of anticipated skin incision. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| worst pain in the last 24 hours prior to cesarean delivery | patients report of the score of worst pain in the last 24 hours prior to cesarean delivery, expressed on a scale from 0-10. A higher score means worse pain (worse outcome). | Median | Inter-Quartile Range | score on a scale |
|
|
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| Secondary | Time to First Administration of Opioid Pain Medication Post Operatively | Time, in hours, to first administration of opioid pain medication post operatively | Posted | Median | Inter-Quartile Range | hours | 48 hours post cesarean delivery |
|
|
|
| Secondary | Pain Score at 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). | Posted | Median | Inter-Quartile Range | score on a scale | 6-12 hours post-operatively |
|
|
|
| Secondary | Number of Opioid Pain Tablets Remaining on Post-operative Day #7 From the Discharge Prescription. | Number of opioid pain tablets remaining on post-operative day #7 from hospital discharge as reported by patients | We could not get the outcome on two patients from placebo control group and three patients from multimodal pain regimen group due to patients not responding to calls. These 5 five subjects were considered lost to follow up for this outcome. | Posted | Median | Inter-Quartile Range | Tablets | 7 days post delivery |
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| Secondary | Hospital Length of Stay | Time to discharge from hospital, measured in hours | Posted | Median | Inter-Quartile Range | hours | From time of hospital admission to time of discharge home up to 168 hours. |
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| Secondary | Pain Score at 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). | Posted | Median | Inter-Quartile Range | score on a scale | 24 hours post-operatively |
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| Secondary | Pain Score at 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). | Posted | Median | Inter-Quartile Range | score on a scale | 48 hours post-operatively |
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| Secondary | Apgar Score at 5 Minutes | 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. | Posted | Median | Inter-Quartile Range | score on a scale | 5 minutes after birth |
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| Secondary | NICU Admission | Rate of admission to the neonatal intensive care unit | Posted | Count of Participants | Participants | after birth and before hospital discharge |
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| Secondary | Need for Respiratory Support | neonate receipt of oxygen by nasal cannula or mechanical ventilation | Posted | Count of Participants | Participants | after birth and before hospital discharge |
|
|
|
| 0 |
| 60 |
| 2 |
| 60 |
| 1 |
| 60 |
| EG001 | Multimodal Pain Regimen Group | Patients will receive the actual study medication for all three study medications. Intravenous acetominophen: One dose if 1 gram intravenous to be given pre-surgery Ketorolac, intramuscular: One dose of 60 mg Intramuscular to be given at time of skin closure Bupivacaine, subcutaneous: Inject 20 mL of 0.25% bupivacaine at the site of anticipated skin incision. | 0 | 60 | 1 | 60 | 2 | 60 |
|
| October 2016-May 2018 | Pregnancy, puerperium and perinatal conditions | Systematic Assessment | Fascial dehiscence |
|
|
| October 2016-May 2018 | Renal and urinary disorders | Systematic Assessment | Urinary retention |
|
| October 2016-May 2017 | Cardiac disorders | Systematic Assessment | Chest pain |
|
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| Aniline Compounds |
| D000588 | Amines |
| D007213 | Indomethacin |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D007267 | Injections |
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |