Improving Post-Operative Pain and Recovery in Gynecologic Surgery
Phase: PHASE4
Conditions: Postoperative Pain, Opioid Use, Acetaminophen
Sponsor: Aultman Health Foundation

Improving Post-Operative Pain and 
Recovery in Gynecologic Surgery 
Protocol ID: 2019.08.20.MB 
ClinicalTrials.gov ID: NCT04175509 
12/12/2019 
 
 
 
Michaela Beynon, MD 
Sareena Singh, MD 
Ob/Gyn Department 
Aultman Health Foundation 
2600 6th St SW 
Canton, OH   44710 
 
 

 
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TABLE OF CONTENTS 
1.0  
INTRODUCTION ............................................................................................................................ 3 
1.1 
Abstract ................................................................................................................................ 3 
1.2 
Background/Rationale ......................................................................................................... 3 
2.0  
OBJECTIVES/STUDY AIMS ......................................................................................................... 4 
3.0  
SUBJECT SELECTION [ELIGIBILITY] ....................................................................................... 4 
 
3.1        Inclusion criteria .................................................................................................................. 4 
 
3.2        Exclusion criteria ................................................................................................................. 4 
4.0  
SUBJECT ENROLLMENT………………………………………………………………………..5 
 
4.1        Where Recruitment Will Occur ........................................................................................... 5 
 
4.2        Where/When Consent Will be Obtained ............................................................................. 5 
             4.3        Who Will Obtain Consent ................................................................................................... 5 
             4.4        Procedures for Screening ..................................................................................................... 5 
             4.5        Screening Failures ............................................................................................................... 5    
5.0  
STUDY DESIGN AND PROCEDURES ......................................................................................... 5 
5.1 
Identifying Subjects.............................................................................................................. 5 
5.2 
Obtain Informed Consent ..................................................................................................... 5 
5.3 
Pre-Operative Randomization .............................................................................................. 5 
5.4 
Pre-Operative Orders ............................................................................................................ 6 
5.5 
Medication Administration  .................................................................................................. 6 
5.6 
Post-Operative Orders .......................................................................................................... 6 
5.7 
In-Hospital Evaluation  ........................................................................................................ 6 
5.8 
Discharge Medication .......................................................................................................... 7 
5.9 
Data Collection..................................................................................................................... 7 
5.10 
Chart Review Procedures ..................................................................................................... 7 
5.11 
Adverse Reactions and Management.................................................................................... 8 
5.12 
Safety Management  ............................................................................................................. 8 
6.0  
STATISTICAL CONSIDERATIONS ............................................................................................. 9 
7.0  
REGULATORY REQUIREMENTS  .............................................................................................. 9 
8.0  
REFERENCES ............................................................................................................................... 10 
9.0 
APPENDICES ................................................................................................................................ 11 

 
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1.0 
INTRODUCTION 
The objective of this research project is to demonstrate that acetaminophen, whether administered 
rectally or intravenously, reduces post-operative pain, use of opioid medications, and thus 
improves the overall recovery process after minimally invasive gynecologic surgery. 
1.1 
Abstract 
This is a clinical investigation to determine the efficacy of rectal versus intravenous 
acetaminophen in patients undergoing a minimally invasive hysterectomy.  All women 
will receive acetaminophen either rectally or intravenously immediately postoperative, 
prior to extubation.  Patient's will be randomly assigned to either the rectal 
acetaminophen or the intravenous acetaminophen group.  Patient outcomes will be 
measured through a Numeric Rating Scale (NRS) from 0-10 for pain scores, and total 
opioid consumption measured in morphine milligram equivalent (MME) for the first 24 
hours following surgery, or upon discharge, whichever comes first. 
1.2 
Background/Rationale 
Patient's undergoing major gynecologic surgery require effective postoperative pain 
management in order to enhance recovery and ultimately allow patients to return to their 
preoperative functional state. Traditionally, acute postoperative pain control has been 
achieved largely with the use of opioid medications.  Excessive use of opioids can have 
adverse effects on the recovery process. Side effects include, but are not limited to 
dizziness, sedation, nausea/vomiting, respiratory depression, euphoria, constipation, and 
abuse (1). In addition, opioid monotherapy can delay post-operative ambulation, 
contribute to prolonged hospital stay and resumption of activities of daily living, and 
furthermore, have long-term sequelae for individuals as well as society at whole (1). 
Over the past decade, a multimodal approach to pain management has been explored in 
attempts to optimally treat acute postoperative pain (1-3).  This approach is one of the 
keys to improving the recovery process.  
Acetaminophen is a non-opioid analgesic with a well-established safety and tolerability 
profile that is commonly used in multimodal approach to treating surgical pain. It is 
available in oral, rectal and Intravenous (IV) formulation. IV acetaminophen in particular 
is increasingly used for pain control after surgery as it has demonstrated a significant 
analgesic benefit in a variety of surgery types by reduction in pain intensity while 
decreasing total opioid use (3,4). Many studies have evaluated the efficacy of 
acetaminophen based on route of administration. A systematic review demonstrated that 
there is no clear indication for intravenous acetaminophen for patients who can tolerate 
an oral dosage as there was no difference if efficacy outcomes (5). This is valuable 
information as the cost of IV acetaminophen is exponentially more than the oral form. 
Although the oral form of acetaminophen is as efficient as controlling pain when 
compared to IV, and is notably cheaper, it is not the best option for the nauseated patient 
or patients whom are restricted from oral intake following surgery. Rectal acetaminophen 
is therefore a feasible alternative option in such patients.  
Data on the use of rectal acetaminophen in adults for postoperative pain management is 
limited. Pettersson and colleagues (2005) compared oral, rectal and IV paracetamol in 
day surgery patients. Although they demonstrated significantly higher plasma 
paracetamol concentrations in patients who received oral and IV formations at multiple 

 
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time points, there was no difference in pain ratings. In another study, rectal paracetamol 
was shown to have a significant morphine-sparing effect after hysterectomy (7).  
At this time, there has been no study in the gynecologic literature to compare IV to rectal 
acetaminophen in terms of pain control and effect on overall opioid use in the acute post-
operative period.  
The rationale for this study is to determine the optimal way of managing post-operative 
pain in gynecologic surgery in attempt to improve the overall recovery process. More 
specifically, this study will determine if the route of administration of acetaminophen has 
an effect on post-operative pain and use of opioid medication following a minimally 
invasive hysterectomy. The results of this study may guide post-operative pain 
management after gynecologic surgery, and help limit the amount of opioid use, while 
potentially reducing pharmacological costs for patients and hospitals.  
 
2.0 
OBJECTIVES/STUDY AIMS 
2.1 
Primary Objective:  To demonstrate that rectal acetaminophen is not inferior to 
intravenous acetaminophen in decreasing subjective acute postoperative pain after a 
minimally-invasive hysterectomy.  
2.2 
Secondary Objective:  To demonstrate that rectal acetaminophen is not inferior to 
intravenous acetaminophen in decreasing opioid use during the hospital admission.  
3.0 
SUBJECT SELECTION [ELIGIBILITY] 
The study population will consist of all patients undergoing a minimally-invasive simple 
hysterectomy (total laparoscopic hysterectomy with or without robotic assist) for benign or 
malignant conditions.  
3.1 
Inclusion Criteria 
Patients eligible for inclusion in this study have to fulfill the following criteria: 
• 
Female patients age ≥ 18 years old  
• 
Willing to consent  
• 
Amendable to receive either rectal or intravenous acetaminophen 
• 
Planned hospital stay for at least 24 hours   
3.2 
Exclusion Criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 
• 
Patients unable to provide informed consent 
• 
Patients with a history of regular opioid use prior to surgery based on their current 
home medication list.  
• 
Patients who have required regular opioid intake for the 7 days preceding surgery   
• 
Patients with known hypersensitivity to acetaminophen 
• 
Patients with a baseline preoperative liver function enzymes (AST and ALT) that are 
greater than twice the upper limits   
• 
Unable to complete procedure as planned  

 
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4.0 
SUBJECT ENROLLMENT 
4.1 
Where will recruitment occur? 
Recruitment will occur prior to the day of surgery. Patient’s will be screened to ensure 
they are eligible for inclusion based on inclusion and exclusion criteria. The study will be 
discussed with patients who are eligible, and patients will be given a copy of the consent 
form to take home and review. This encounter will be documented in the patient’s 
medical record. 
4.2 
Where and when will consent be obtained? 
After the patient has had ample time to review the consent form and have all questions 
answered, the consent will be signed. This will be done in the office or in the Same Day 
Surgery Unit at Aultman Hospital prior to the start of the operation, and prior to 
admission of any sedating medications.   
4.3 
Who will obtain consent? 
Either Dr. Singh, or Dr. Beynon, or any other investigator involved in the study, will 
obtain consent.  
4.4 
What procedures will be used for screening? 
Dr. Singh’s office schedule will be reviewed to identify patients that are scheduled for a 
minimally-invasive simple hysterectomy. Patients will be evaluated during a pre-
operative visit to determine if they are eligible to participate in the study.   
4.5 
What happens with screen failures (including any data gathered during screening)? 
Any patient that does not receive protocol prescribed acetaminophen will not be included 
in the final analysis. 
5.0 
STUDY DESIGN/PROCEDURES 
5.1 
Potential Subject Identified 
Dr. Singh’s office schedule will be reviewed to identify patients that are scheduled for a 
minimally-invasive simple hysterectomy. When a potential patient is identified, Dr. 
Singh and Dr. Beynon will be notified and proceed with a more in-depth patient 
interview during a pre-operative visit.  
5.2 
Obtain Informed Consent 
Either Dr. Singh or Dr. Beynon, or any other investigator involved in the study, will 
obtain consent after the patient has reviewed the entire consent and all questions have 
been answered. Consent will be documented by having the patient sign the consent 
document and authorization for use of protected health information.  After consent has 
been obtained, the subject will be assigned to the rectal acetaminophen group or the 
intravenous acetaminophen group. The signed consent form will remain part of the 
patients’ medical record.  
5.3 
Pre-operative Randomization  
Patients will be randomly assigned to receive rectal acetaminophen or intravenous 
acetaminophen using a random number generator. Patients randomly assigned to group 1 
will be in the rectal acetaminophen study group. Patients randomly assigned to group 2 
will be in the intravenous acetaminophen study group. 
 

 
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5.4 
Pre-operative Orders 
Pre-operative orders will be standardized and include VTE prophylaxis with SCDs and 
preoperative antibiotics with a first generation cephalosporin or an appropriate 
alternative. 
 
5.5  
Medication administration  
Patients will receive either rectal or intravenous acetaminophen at the end of the surgery, 
just prior to extubation and awakening. Patients receiving the rectal acetaminophen will 
receive two 650mg suppositories rectally for a total dose of 1300mg, which has been 
used in prior pharmacokinetic studies (7). Patients receiving intravenous acetaminophen 
will receive one dose of 1000mg. The route of administration will be recorded in the 
patient’s medical record. Patients will be blind to their study group. Storage and 
dispensing of medication will be under the direction of the Aultman Pharmacy 
department pursuant to physician order.  
5.6 
Post-operative Orders 
All patients included in the study will receive the same post-operative order set. Patients 
will not have access to additional non-opioid medications, such as acetaminophen or 
ibuprofen products for pain control for the first 24 hours post-op, or until discharge 
whichever comes first. Patients will have oral Oxycodone available upon patient request. 
Intravenous Morphine or an appropriate alternative (i.e., Dilaudid) will be available for 
breakthrough pain. Patients will receive opioid medications based on their reported pain 
level using a standardized 0-10 pain scan.  
5.7 
In-Hospital Evaluation 
While in the hospital, all participants will be evaluated regularly by a registered nurse. 
Patients will be asked to report their pain level using a standardized pain scale from 0 (no 
pain) to 10 (worst pain) every 4 hours, which is standard protocol. Patients will receive 
medication if they request it and based on the pain level reported. For example, patients 
will receive Oxycodone 2.5mg PO for pain scale 1-3, Oxycodone 5mg PO for pain scale 
4-6, and Oxycodone 10mg PO for pain scale 7-10. Pain level and medication 
administration will be recorded in the Electronic Medical Record. If needed, the 
investigatory team can alter the frequency and amount of opioids available in order to 
control pain. If pain cannot be controlled with opioid medications, the investigatory team 
can administer other non-opioid anesthetics at their discretion. However, in cases where 
non-opioid anesthetics are administered to adequately control pain, data from these 
patients will not be included in final analyses.  

 
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5.8 
Discharge Medication  
 
Patients will be discharged with prescription medication(s) at the request of the attending  
 
Physician, which may include a combination of opioids and non-opioid medication.  
 
5.9 
Data Collection 
Baseline data to be obtained includes age, height, weight, BMI, indication for surgery 
(benign vs. malignant), and medical comorbidities. Comorbidities that will be documented 
include diabetes mellitus, hypertension, thyroid disease, pulmonary disease, 
anxiety/depression on medication, and obesity as defined as BMI ≥ 30. Procedure-related 
data includes estimated blood loss, operative time. Data collection regarding opioid 
medication administration will begin as soon as surgery is complete and after 
acetaminophen has been administered. Pain medications administered intraoperative by 
anesthesia will not be included in data collection and further analyses. Complications 
while in the hospital, adverse effects to acetaminophen, and the length of hospital stay will 
be recorded. Morphine milligram equivalents will be calculated from the electronic 
medical record. Data collection will conclude at 24 hours post-operatively or at discharge, 
whichever comes first.  
 
5.10 
Chart Review Procedures 
A list of patients (name, medical record number) by subject number separate from the 
data will be maintained only until the data has been verified.  Subject number will 
identify data only.  Once the data has been verified, the patients name and medical record 
number will be deleted. 
 
Data 
At Entry 
 Postoperatively 
     At Discharge 
Age 
X 
 
 
BMI 
X 
 
 
Indication for Surgery 
X 
 
 
Comorbidities 
X 
 
 
Route of Acetaminophen 
Administration 
X 
 
 
Estimated Blood Loss 
 
X 
 
Operative Time 
 
X 
 
Pathology 
 
X 
 
Complications While in Hospital 
 
 
                X 
Morphine Milligram Equivalents  
 
 
X 
Length of Hospital Stay 
 
 
X 
Adverse Effects to Acetaminophen 
 
 
X 
 
 
 
 

 
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After 24 hours post-operatively or at discharge, which ever comes first, a chart review will 
take place that will used to determine the patient-reported pain score and the total amount 
of opioids used in morphine milligram equivalents. Additional information will be 
obtained, including length of hospital stay, complications while in the hospital and 
reported adverse effects to acetaminophen. Chart review will conclude at the end of the 
study, which is 24 hours post-operatively or at discharge, whichever comes first.  
5.11 
Adverse Reactions and Management  
This section should include the following segments: 
5.11.1 Reporting Adverse or Unanticipated Events 
All serious adverse events and unanticipated problems will be collected until 24 
hours post-operatively or at discharge, whichever comes first.  The only non-
serious adverse event that will be collected are adverse reactions related to 
acetaminophen use, whether severe allergic reactions (hives, anaphylaxis, etc…) 
or significant side effects that requires withholding future use.  
5.11.2 Anticipated Reactions 
Allergic reactions, such as itching or rash, neither of which should cause 
significant distress and will be managed symptomatically. Rarely, acetaminophen 
may cause serious skin reactions such as acute generalized exanthematous 
pustulosis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis. In such 
cases, the use of acetaminophen will be discontinued immediately.  
5.11.3 Reaction Management 
Any patient with an allergic reaction to the included analgesics will be treated per 
standard management (Benadryl, Epinephrine, etc.)  Whether the patient remains 
on said analgesics, transitioned to different analgesics, or removed from the study 
will be determined by the severity of the reaction, patient input and investigator 
digression.  Any severe reactions may require consultation with Internal 
Medicine and other specialties throughout the hospital.  The Research Faculty 
Advisor will supervise all care. 
             5.12     Safety Management  
                          5.12.1 Data Safety Monitoring Plan 
The investigator will ask the HRRB/Compliance Office to assign a data safety 
monitor to review adherence to the protocol, occurrence of adverse events, and 
accuracy of the data.  The first review will be conducted after enrolling the first 
patient. The second review will occur after enrollment of the fifth patient. Upon 
study completion a final review will occur. Unscheduled random chart audits 
may also be performed to ensure data integrity. Any deficiencies found during 
these reviews will be addressed and reported to the PI, HRRB, and federal 
agencies as indicated. 
 
 
 

 
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6.0 
STATISTICAL CONSIDERATIONS  
For a medium effect size, alpha level (p value) 0.05 and power of 0.95, a total sample size of 36 
(18 per study group) is needed. A total of 40 participants (20 per study group) would be ideal to 
account for patients who drop out or are excluded from the study.  
The mean and median post-operative pain scores between groups across time will be compared. 
The value for the median morphine milligram equivalents of post-operative opioids will be 
compared between the two study groups.  
Differences between the study groups in baseline characteristics and outcome variables will be 
assessed with chi-square tests for normal variables, t tests for normally distributed continuous 
variables, or Mann-Whitney U tests for non-normal continuous variables.  
A statistician will assist in organizing data and conducting analyses.  
 
 
7.0        REGULATORY REQUIREMENTS 
7.1  
Informed Consent – It is the investigator’s responsibility to obtain written informed 
consent from the subject after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. This will take place before the procedure 
and after the patient has had ample time to review the consent.  The research subject 
must be given a copy of the signed informed consent document.  The original signed 
copy of the informed consent must be retained in the research records.   
7.2 
Patient Confidentiality – Documents will be kept in strict confidence by the 
investigator. Any use of personally identifiable data or private health information (PHI) will 
be used per the subject’s consent. 
 
 
 
 
 
 
 
 
 

 
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8.0        REFERENCES 
1. Cao X, et al. Effect of intraoperative or postoperative intravenous acetaminophen on 
postoperative pain scores and opioid requirements in abdominal and spinal surgery patients. 
Int J Clin Exp Med. 2018 April;11(4)4120-4125. 
 
2. Chou R et al. Management of postoperative pain: A clinical practice guideline from the 
American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, 
and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, 
Exclusive Committee, and Administrative Council. The Journal of Pain. 2016 Feb;17(2):131-
157 
 
3. Sconzo Jr FR, Ramamoorthy S. The role of multimodal analgesia in colorectal surgery: a 
review of clinical data and case-based presentations featuring Ofirmev (acetaminophen) 
injections. Diseases of the Colon & Rectum. 2015 Feb;58(2):1-15. 
 
4. Viscusi ER, Singla N, Gonzalez A, et al. IV acetaminophen improves pain management and 
reduced opioid requirements in surgical patients: a review of the clinical data and data-based 
presentations. Anesthesiology News. 2012. Pdfs.semanticscholar.org 
 
 
5. Jibril F, Sharaby S, Mohamed A, Wilby K.Intravenous versus oral acetaminophen for pain: 
systematic review of current evidence to support clinical decision-making. Can J Hosp 
Pharm. 2015 May-Jun; 68(3): 238-247.  
 
 
6. Petterson PH, Hein A, Owall A, Anderson RE, Jakobsson JG. Early bioavailability in day 
surgery: a comparison between orally, rectally, and intravenously administered paracetamol. 
J. of Ambulatory Surgery. 2005 Feb;12:27-30. 
 
7. Cobby TF, Crighton IM, Kyriakides K, Hobbs GJ. Rectal paracetamol has a significant 
morphine-sparing effect after hysterectomy. British Journal of Anaestheia. 1999 
Jan;83(2):253-256. 
 
8. Singla NK, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-
dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012 
Sep;12(7):523-32. 
 
9. Mahajan L, Mittal V, Gupta R, et al. Study to compare the effect of oral, rectal, and 
interveners infusion of paracetamol for postoperative analgesia in women undergoing 
cesarean section under spinal anesthesia. Anesth Essays Res. 2017 Jul-Sep;11(3):594-598. 
 
 
 
 
 

 
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9.0 
APPENDICES 
Consent Document