Clinical trial NCT04805073
Conditions: Pruritus Pregnancy Related
Keywords: cesarean section
Sponsor: University of Florida
Start date: 2021-08-09; Completion date: 2024-05-30
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Neuraxial narcotics are commonly used in obstetric patients for cesarean delivery to help with pain control over the first 24 hours after the surgery. The aim is to evaluate effectiveness of promethazine (IMP) treatment of intrathecal morphine induced pruritus (ITIMIP). A treatment for ITMIP, other than naloxone, will allow for increased use of intrathecal narcotics and decrease the use of systemic opioids in the initial post-operative period.

Detailed description:

Arms: arm 1: The treatment will consist of a blinded syringe of 1cc clear liquid 25mg/ml Promethazine arm 2: The treatment will consist of a blinded syringe of 1cc 0.9% Sodium Chloride
Interventions: intervention 1: Promethazine intervention 2: Placebo
Intervention descriptions: intervention 1: 1cc 25mg/ml Promethazine (study medication) intervention 2: 1cc 0.9% Sodium Chloride (placebo)

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
Protocol 
1. Title: 
Assessing Efficacy of Intramuscular Promethazine for the Treatment of Intrathecal Morphine Induced Pruritus   
 
Version   2.0 
 
Date April 22, 20225 
 
2. Investigators 
Principal Investigator:  
Adam Wendling, MD  
 
Co-Investigators:   
 Brandon Lopez, MD 
 
 
 
Tammy Euliano, MD 
 
 
 
Matthew Andoniadis, MD 
 
 
 
Andrea Macias Mendoza, MD 
 
 
 
Barys Ihnatsenka, MD 
 
 
 
Cynthia Garvan, PhD, MA 
 
 
 
 
 
Study Coordinators:  
   Brandi Lattinville 
 
 
 
 
 
3. Abstract: 
This study aims to analyze a novel approach for prophylaxis against pruritis caused by neuraxial 
narcotics. Neuraxial narcotics are commonly used in obstetric patients for cesarean delivery to help 
with pain control over the first 24 hours after the surgery. Slappendel demonstrated intramuscular 
promethazine (IMP) was an effective treatment for intrathecal morphine induced pruritis (ITMIP).1 No 
other studies evaluated IMP for treatment of ITMIP. The primary aim of this study will be to evaluate 
effectiveness of IMP prophylaxis of ITIMIP. Finding a prophylaxis for ITMIP other than naloxone, will 
allow for increased use of intrathecal narcotics and potentially decrease the use of systemic opioids in 
the initial post-operative period. 
 
This study will use in-patients undergoing cesarean delivery at UF Health Shands Hospital in Gainesville, 
Florida.  
 
4. Background and Significance:  
Intrathecal morphine given during cesarean deliveries is one of the many ways providers currently help 
post-partum women with pain control. One major downside of intrathecal morphine is pruritus that 
occurs over the next 24-48 hours. During this time the mother should be enjoying time with her new 
infant, but instead is having to deal with the itching from the pain reliever we have given her. The 


 
 
cause for the pruritus is not well known, but what is known is that anti-histamines such as 
diphenhydramine do not work. One class of medications known to help decrease ITMIP include mu 
opioid antagonists such as naloxone but some suggest there may be decreased analgesia when mu 
opioid antagonists are utilized. Further, due to the short half-life of naloxone, infusions of the 
medication must be used to adequately prevent recrudescence of symptoms in the setting of ITMIP. 
The related medication, nalbuphine, a partial opioid agonist has been found to be effective at treating 
ITMIP at the expense of increasing sedation and possibly nausea.2-5 Nausea and vomiting is a frequent 
complication during cesarean delivery.  
After reviewing the literature, three investigations have evaluated promethazine for 
prophylactic or treatment of neuraxial morphine induced pruritus. First, Eldor and colleagues found 
intramuscular promethazine was effective at reducing the incidence and severity of pruritis induced by 
epidural morphine.6 Eldor conducted a randomized study among participants who had cesarean 
deliveries with epidural morphine. Those who received prophylactic IMP reported no pruritus while 
35% of the control group experienced pruritus necessitating rescue treatment. Slappendel 
demonstrated that IMP was very effective at treating ITMIP.1 Slappendel gave IMP to treat pruritus 
after varying doses of intrathecal morphine in orthopedic patients. Only one patient out of 143 
subjects required escalation of therapy beyond IMP to treat ITMIP.1 The article has not been confirmed 
nor refuted. This study was not blinded to the physician or the patient as this was their sole initial 
treatment for pruritus.  Horta examined the potential of one of four different drugs to prevent ITMIP in 
patients undergoing cesarean delivery.7 In this randomized study, 300 women undergoing elective 
cesarean delivery were randomized to one of five groups (intravenous alizapride 100mg, propofol 20, 
droperidol 1.25mg, promethazine 50mg or saline control). Horta failed to find a prophylactic effect of 
intravenous promethazine to prevent ITMIP. We would like to study IMP in post-partum patients that 
have just undergone a cesarean delivery in a blinded study to see if this is an effective prophylaxis for 
pruritus. This would benefit the mother to not itch while also allowing the morphine to continue with 
pain relief. 
In 2018, Vice O’Con et. al8 reviewed medications that were effective for treatment of post 
opioid pruritus and IM promethazine was not cited. They cited IV promethazine did not provide relief 
in this paper but could not find evidence for IM. Since very few medications actually work for this side 
effect, we would like to study IM promethazine in hopes to give another prophylaxis/treatment option 
that would not reverse the intrathecal narcotic. This paper cited that anti-dopaminergic medications 
did help decrease the pruritus but increased sedation in the forms given.  Promethazine has a small 
amount of anti-dopaminergic activity and should decrease pruritus if it is truly a dopamine receptor 
mediated process. 
 
5. Specific Aims: (research question/objectives)  
Hypothesis: Prophylactic intramuscular promethazine does not decrease pruritus in post-partum 
females that received 100mcg intrathecal morphine. 
 
 
Alternate Hypothesis: Prophylactic intramuscular promethazine does decrease pruritus in post-partum 
females that received 100mcg intrathecal morphine. 
 


 
 
Pruritus will be quantified by the ItchyQuant Scale, developed and validated by CG Haydek as seen 
below.9  
 
Secondary Analysis 
-Promethazine does not increase sedation compared to placebo (RASS scale) 
-Promethazine does not increase pain compared to placebo (DVPRS scale) 
-Promethazine decreases nausea and vomiting (rated as none, mild, moderate, severe) 
 
6. Research Plan: 
 
Inclusion criteria: 
1. Pregnant adult female patients of at least 18 years of age consenting to a cesarean birth; 
2. Willing to consent to study. 
 
Exclusion criteria: 
1. Male patients; 
2. Incarceration; 
3. Inability to communicate with the investigators; 
4. Allergies to any medications used in the study; 
5. Possessing any contraindication to spinal anesthesia (lack of consent, elevated intracranial 
pressure, preexisting neurological disease, thrombocytopenia/coagulopathy, hypovolemia, 
infection at the site of the procedure); 
6. Patients with an already prolonged QTc (>500 ms) 
7. Any reason an investigator believes study participation would not be in the best interest of the 
potential subject. 
 
DESIGN 
STUDY PROCEDURES  
Recruitment  


 
 
Pregnant female patients already scheduled for a cesarean section operative procedure, as described 
in this protocol, will qualify for this study. The surgical schedule will be reviewed by the PI, Dr. 
Wendling, or one of the Co-I's, Drs., Lopez, Euliano, Andoniadis, or Mendoza as a part of their clinical 
duties. The PI and Co-I’s are all Department of Anesthesiology staff and routinely work in the obstetrics 
unit, therefore, they all have a direct clinical relationship with the potential patients in this study. At 
least one of the PI or Co-I’s will be working the obstetrics unit at the time of recruitment. Investigators 
(directly involved in clinical care) will review the surgical schedule and medical records of potential 
patients (as part of their routine clinical duties) greater than 1 day prior to surgery to more carefully 
evaluate the inclusion/exclusion for potential contraindications that could preclude or affect the 
patient's safety in the study. The extra step of oversight will help ensure potential patient safety prior 
to the surgeon approaching a patient to discuss the study.  
 
Greater than 1 day prior to their scheduled surgery, all potential study participants identified as above 
will be contacted by phone and/or email if available by the PI or Co-I’s. At this time, the PI or Co-I’s will 
ask the patient if they are comfortable with a study coordinator contacting them and discussing a 
research study for which they qualify (phone script will be read). If the potential subject is interested, 
they will be provided the ICF. On the morning of surgery, additional questions and concerns will be 
addressed by one of the investigators (anesthesiologists) participating in the study and ICF will be 
completed. After obtaining written informed consent, women will be randomized into one of two 
groups: control or promethazine group. Method of randomization will be discussed below. 
 
The hard copy consents will be stored in the study binder.  
 
Patient typical day 
The patient will come to the obstetric (OB) pre-operative holding area where we will obtain her 
medical history, perform a physical exam and consent her for the cesarean delivery. The patient will 
have already spoken with a study coordinator and/or PI/Co-I more than one day prior to arrival 
regarding potential participation in the study. The patient will be approached by one of the study team 
members (anesthesiologists). We will review the consent form, explaining that itching is a common 
side effect of the intrathecal morphine and we are trialing a medication that would prevent the itching.  
If the patient agrees to participate, we will obtain signed consent, contact the study coordinator to be 
prepared for questionnaires post-procedure and then obtain a blinded syringe from pharmacy for the 
treatment. Dr. Garvan will randomize the patient for the study to determine which medication the 
mother will receive using a stratified randomization design generated with MAPLE software. 
 
The patient will then go back to the operating room when it is her operative time, and we will 
perform the spinal with bupivacaine, morphine and fentanyl, which is standard at our institution (see 
standard of care medications below).  Once the spinal is confirmed to be adequate, the surgical team 
will be called in to perform the procedure. Once the baby is delivered and the procedure is completed, 
we will inject the blinded syringe of medication into the patient’s left thigh since she will still be numb 
from the spinal.  When the patient arrives to the PACU, we will assess the 4 variables 1 hour after 
medication is given in PACU and then between 4-5 hours post-op and at 24 hours post-op (+/- 2 hours). 
All evaluations will be done in person or by phone call from study coordinator. 
If patients are still reporting pruritis that is not controlled, the rescue treatment will be 
butorphanol 1mg IV q3h, as this is the current regimen at our institution. 
 
 


 
 
 
 
Treatment/Therapy 
The treatment will consist of a blinded syringe of 1cc clear liquid (blinded to patient and physician – 
only pharmacist will know what it contains). This injection will be given in the left thigh after the 
cesarean delivery is completed. 
 
Contents of syringe: (either) 
- 
1cc 0.9% Sodium Chloride (placebo) 
- 
1cc 25mg/ml Promethazine (study medication) 
 
Extra studies/procedures required 
It is standard of care for all patients for this surgery to have intraoperative 5 lead EKG monitoring. All 
study patients will have QTc evaluated on the anesthesia monitor. As part of the study, rhythm strips 
will be printed out and saved in study binder. Any patients with an already prolonged QTc (>500 ms) 
will be excluded from the study. 
 
Recording data responsibilities 
1. Anesthesia attending on OB for the day will consent patient if they agree to the study. 
2. Dr. Garvan’s team will perform randomization. 
3. Study coordinator will be contacted once patient is enrolled. 
4. Time 0 will be recorded by resident/attending in the room at the time the medication is given. 
5. Study coordinator will contact patient in person or by phone at 1 hour, 4-5 hours , and 24 (+/- 2 
hours) hours to assess given variables. 
 
Drugs that will be given as STANDARD OF CARE during the study will be: 
1: Bupivacaine 0.75% 1.4-2.0 lT (Spinal anesthetic) 
2: Fentanyl 20 mcg IT (Spinal anesthetic) 
3: Preservative Free Morphine 100 mcg IT (Spinal anesthetic) 
4: Butorphanol 1mg IV every 3 hours (rescue treatment) 
5: Nalbuphine 2.5mg IV every 6 hours as needed for itching 
6: Ondansetron 4mg IV every 6 hours as needed for nausea 
7: Ketorolac 30mg IV once 
8: Acetaminophen 975mg by mouth every 6 hours (scheduled) 
9: Phenylephrine 100-200mcg as needed every 2 min and phenylephrine infusion 0.1 mcg/kg/min IV 
titrated to maintain maternal BP within 20% of baseline. 
10: Ephedrine 5-10mg IV as needed every 2 min to maintain maternal BP within 20% of baseline, 
secondary agent to phenylephrine bolus and infusion and/or if maternal HR falls below 70 bpm. 
11: Cefazolin 2g IV once before incision 
12: Azithromycin 500mg IV once before incision 
13: Clonidine 15-30mcg IT (Spinal anesthetic) 
 
If penicillin allergic (given as STANDARD OF CARE):  
1: Clindamycin 900mg IV once before incision 
2: Gentamicin 1.5mg/kg IV once before incision 
 
Drugs that will be given as part of the study: 


 
 
1: Intramuscular Promethazine 25mg (25mg/mL) 
2: Intramuscular 0.9% Sodium Chloride (placebo, also 1mL) 
 
Table of Study Events 
 
 
Activity 
Time Point 
Time Point 
Time Point 
Time Point 
Injection of blinded medication 
0 
 
 
 
First Evaluation of variables (Phone call from coordinator) 
 
1 h 
 
 
Second Evaluation of variables (Phone call from coordinator) 
 
 
4-5 h  
 
Final Evaluation of variables (Phone call from coordinator) 
 
 
 
24 h 
 
STATISTICAL METHODS, DATA ANALYSIS, AND INTERPRETATION: 
Our plan is to recruit 50 patients for each arm of the study.  With 50 patients on placebo and 50 
patients on Phenergan, there will be a greater than 80% chance of detecting a significant difference of 
20% or more at a two-sided 0.05 significance level. This assumes that severe itching occurs is in 50% of 
patients and Phenergan reduces this proportion to 20%. 
 
We will use Fisher’s exact test to compare groups on severity of itching. We will also use Wilcoxon’s 
rank sum test to compare groups on degree of itching as measured by the ITCHYQUANT. Dr. Garvan, 
the study biostatistician, will perform all statistical analyses. 
 
DATA STORAGE AND DE-IDENTIFICATION PLANS:  
The original, hard-copy signed informed consent forms and rhythm strips will be stored within the 
locked Anesthesiology research office and will remain with the Principal Investigator for at least 7 
years.  Data will be entered into an Excel spreadsheet kept on a password-protected and encrypted 
computer and retained by the Principal Investigator for at least 7 years. 
 
Patients will be de-identified. No names, MRN’s, or other identifying information will be stored in the 
spreadsheet.  Pain, itching, sedation and nausea/vomiting will be collected at three intervals by a study 
coordinator and added to the de-identified spreadsheet. Age group, medical conditions such as 
diabetes and pre-eclampsia as well as BMI groups, will be used to determine confounders in the data. 
None of this collected information will be used to identify the patients. 
 
7. Potential Risks:  
Subjects will be given clear verbal and written instructions to contact Dr. Wendling in the Department 
of Anesthesiology with questions or concerns regarding their study participation. If a patient 
experiences an injury that is directly caused by this study, they will receive professional medical care at 
the University of Florida. No other compensation is offered. Any adverse events will be reported to the 


 
 
IRB using the standard adverse events reporting website and on continuing reviews (depending upon 
severity, as defined by the IRB). 
1. Sedation (study variable). Promethazine can cause sedation which will be studied. 
2. Concern for QT prolongation on the ECG causing cardiac arrhythmias. QTc evaluated on patient 
monitor, rhythm strip to be printed off and saved in research binder with QTc labeled clearly. 
3. Respiratory depression 
4. Painful injection site once spinal wears off. Patients will be given the injection while spinal 
anesthesia is still working to prevent pain during injection. 
5. Tissue damage at site of injection 
6. There is the risk of loss of confidentiality.  The following procedures will be done to maintain 
confidentiality:  written, paper forms will be kept in the locked Anesthesia Research Office.  
Computerized and de-identified records containing personal health information will be stored on 
password-protected and encrypted computers. 
 
Routine medications that are provided to patients participating in the study may be provided to you. 
These are part of normal clinical care. The participant will be responsible for any deductible, co-
insurance, or co-payments. Some insurance companies may not cover costs associated with research 
studies or research-related injuries. If the participant is injured as a direct result of participation in the 
study, only professional services received from any University of Florida Health Science Center 
healthcare provider (physicians, physician assistants, nurse practitioners, dentists or psychologists) will 
be provided without charge. Any other expenses, including Shands hospital expenses, will be billed to 
the subject’s insurance provider or the subject themselves.  
Safety Endpoint 
During the study, we will log our adverse events. If the incidence for adverse events is greater than 
expected we will review the study design as a team to decide if we should proceed with the study or 
stop the study. If we have an increase incidence of serious injection site reactions, we will review 
whether the medication or placebo is causing the injection site reaction. If any major adverse reactions 
occur we will have a meeting with the investigators to address if this was an unanticipated or 
potentially expected event given the expected incidences. 
8. Potential Benefits: 
The potential benefit of this study would be to find a prophylactic treatment for intrathecal opioid 
pruritus.  The patients would undergo minimal risk with an IM injection in attempts to decrease one of 
the major side effects of intrathecal opioids.  The study will benefit future women undergoing cesarean 
section as we could give intrathecal morphine for post-op pain control with less side effects. 
 
If the hypothesis were rejected, we could also perform future studies to see if the dose of 
morphine in the spinal could be changed for increase pain control.  This study could be also used 
outside the obstetrics realm and adopted for many different patients receiving intrathecal opioids to 
decrease post-op pruritus. 
 
9.  Conflict of Interest: 
There are no known conflicts of interest for the staff that will be working on this research proposal. 


 
 
 
 
10. References: 
1. Slappendel, R., et al. “Itching after Intrathecal Morphine. Incidence and Treatment.” European 
Journal of Anaesthesiology, vol. 17, no. 10, 2000, pp. 616–621., doi:10.1097/00003643-200010000-
00004. 
2. Penning JP, Samson B, Baxter AD. Reversal of epidural morphine-induced respiratory depression 
and pruritus with nalbuphine. Can J Anaesth. 1988;35:599-604.  
3. Morgan PJ, Mehta S, Kapala DM. Nalbuphine pretreatment in cesarean section patients receiving 
epidural morphine. Reg Anesth. 1991;16:84-8.  
4. Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is better than naloxone for 
treatment of side effects after epidural morphine. Anesth Analg. 1992;75:747-52. 
5. Alhashemi JA, Crosby ET, Grodecki W, Duffy PJ, Hull KA, Gallant C. Treatment of intrathecal 
morphine-induced pruritus following caesarean section. Can J Anaesth. 1997;44(10):1060-5. doi: 
10.1007/BF03019227. 
6. Eldor J, Fishelev V, Levine S, Guedj P, Dudakova I. Prevention of epidural morphine pruritus by 
intramuscular promethazine in parturients. Reg Anesth. 1994;19(6):433-4. PMID: 7848959.  
7. Horta ML, Morejon LC, da Cruz AW, Dos Santos GR, Welling LC, Terhosrst L, Costa RC, Alam RU. 
Study of the prophylactic effect of droperidol, alizapride, propofol and promethazine on spinal 
morphine-induced pruritus. Br J Anaesth. 2006;96(6):796-800. doi: 10.1093/bja/ael072. 
8. Vice-O'Con K, Austin PN, Pugh MA. Pharmacologic Methods for Preventing Pruritus in Patients 
Receiving Intrathecal Opioids for Cesarean Delivery. AANA J. 2018;86(1):59-66. 
9. Haydek CG, Love E, Mollanazar NK, Rodriguez RV, Lee H, Yosipovitch G, Tharp MD, Hanifin JM, Chen 
KH, Chen SC. Validation and banding of the ItchyQuant: a self-report itch severity scale. J of 
Investigative Dermatology. 2017;137:57-61.