Clinical trial NCT04175509
Conditions: Postoperative Pain Opioid Use Acetaminophen
Keywords: Postoperative Pain Minimally-invasive Hysterectomy Opioid Use Acetaminophen Hysterectomy
Sponsor: Aultman Health Foundation
Start date: 2019-12-23; Completion date: 2021-06-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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. 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.

Over the past decade, a multimodal approach to pain management has been explored in attempts to optimally treat acute postoperative pain. 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. 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. 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 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.

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.

Arms: arm 1: Patients will receive two 650mg suppositories rectally of acetaminophen for a total dose of 1300mg at the end of surgery. arm 2: Patients will receive one dose of 1000mg of acetaminophen, administered intravenously, at the end of surgery.
Interventions: intervention 1: Rectal acetaminophen intervention 2: Intravenous acetaminophen
Intervention descriptions: intervention 1: Rectal 1300mg intervention 2: Intravenous 1000mg

Protocol documents:
ICF_001.pdf: 
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CONSENT TO PARTICIPATE IN RESEARCH 
AND 
AUTHORIZATION FOR RELEASE OF 
PROTECTED HEALTH INFORMATION 
Improving Post-Operative Pain and 
Recovery in Gynecologic Surgery 
Michaela Beynon, MD and Sareena Singh, MD 
Protocol ID: 2019.08.20.MB 
ClinicalTrials.gov ID: NCT04175509 
INTRODUCTION  
You are being asked to take part in a research study.  The following information is being 
given to you to explain the purpose of the study, what you will be asked to do as a 
participant, and the potential risk and benefits.  It will also explain that you do not have to 
participate in this study to receive medical care.  You are encouraged to ask questions 
before deciding whether you wish to participate, or at any time during the course of the 
study.  You will be told of any new findings that may influence your decision to continue 
to participate. 
We understand that information about you and your health is personal.  We are 
committed to protecting the privacy of that information.  Because of this commitment, we 
must obtain your authorization before we may use or disclose your protected health 
information for the purposes of this clinical trial.  This form provides that authorization 
and helps us make sure that you are properly informed of how this information will be 
used or disclosed.  Please read this information carefully before signing this form. 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to demonstrate that rectal acetaminophen is not inferior to 
intravenous acetaminophen in managing pain following major gynecologic surgery.  
HOW DOES THIS STUDY DIFFER FROM THE WAY POST-OPERATIVE 
PAIN IS NORMALLY MANAGED? 
Opioids, such as Oxycodone and Morphine are frequently used to manage post-operative 
pain. More recently, health care providers have been utilizing non-opioid medications, 


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such as acetaminophen, to help with post-operative pain. This study allows patients to 
receive opioid pain medication in a similar fashion as patients not enrolled in the study. 
However, patients enrolled in the study will not have access to additional non-opioid 
medications, such acetaminophen or ibuprofen during their first 24 hours post-op of your 
hospital stay . All other aspects of your care will be the same as patients not enrolled in 
the study. All the medications used in this study are already FDA approved and 
commonly used for post-operative pain.    
WHO CAN TAKE PART IN THIS STUDY? 
You are being asked to take part in this study because you have been scheduled for a 
hysterectomy via a minimally invasive approach.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
Approximately 40 patients will take part in this study.  
WHAT IS INVOLVED IN THE STUDY? 
 
BEFORE YOU BEGIN THE STUDY… 
The study purpose and procedures will be explained to you by one of the research team 
members.  If you decide to participate, you will be required to read this consent in its 
entirety and sign where indicated.  Your past and present medical history will be 
reviewed for eligibility to participate in this study. A chemistry panel to evaluate liver 
enzymes will be included in your pre-operative laboratory studies. 
 
DURING THE STUDY… 
If you are eligible, you will then be “randomized”.  
Randomization is a standard procedure used in clinical trials where subjects are assigned 
by chance to one study group or another. It is used to make sure that the results of the 
study are not influenced by the selection of subjects/patients in one group as compared to 
the other. This is important to make certain that study results are accurately interpreted 
and therefore beneficial to future patients. In this study, you have a 50% chance of being 
assigned to one group or another. 
Group 1:  Rectal acetaminophen  
 
Patients randomized to this group will undergo surgery at Aultman Hospital as 
scheduled by their physician. Patients randomized to this study group will receive 
rectal acetaminophen at the end of surgery prior to waking up from anesthesia. 
Patients will be prescribed oral Oxycodone as needed to manage post-operative 
pain.   Oxycodone is one of the active ingredients in brand name medications such 
as Percocet. Intravenous morphine (or alternate opioid) will also be available as 


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needed for pain that is not controlled with oral Oxycodone. You will not be able 
to receive additional non-opioid medications, such acetaminophen or ibuprofen  
during the first 24 hours post-op of your hospital stay.  
Group 2: Intravenous acetaminophen  
Patients randomized to this group will undergo surgery at Aultman Hospital as 
scheduled by their physician. Patients randomized to this study group will receive 
intravenous acetaminophen at the end of surgery prior to waking up from 
anesthesia. Patients will be prescribed oral Oxycodone as needed to manage post-
operative pain. Oxycodone is one of the active ingredients in brand name 
medications such as Percocet. Intravenous morphine (or alternate opioid) will also 
be available as needed for pain that is not controlled with oral Oxycodone. You 
will not be able to receive additional non-opioid medications, such acetaminophen 
or ibuprofen during the first 24 hours post-op of your hospital stay.  
HOW LONG WILL I BE IN THE STUDY? 
Your participation in the study will begin when you sign this informed consent form and 
will end in 24 hours post-operatively or at discharge, whichever comes first.  
CAN I STOP BEING IN THE STUDY? 
Yes.  You can decide to stop at any time.  Tell the doctor if you are thinking about 
stopping or decide to stop.  
WHAT ARE THE RISKS OF THE STUDY? 
You may have complications while in the study. Everyone taking part in the study will be 
watched carefully for any complications and may be removed from the study if 
necessary. You should talk to your doctor about any complications that you have while 
taking part in the study.  
 
Although all of these medications are commonly used for post-operative pain 
management, the following adverse effects are commonly seen:  
Acetaminophen:  rash and itching 
Oxycodone: drowsiness, dizziness, itching, constipation, nausea, vomiting 
Morphine: low heart rate, low blood pressure, drowsiness, dizziness, fever, confusion, 
itching, dry mouth, constipation, nausea, vomiting, urinary retention, pain at injection 
site, weakness, decreased respiratory rate and oxygen saturation  
 
There is a possibility that other complications may occur. You will be monitored for the 
occurrence of complications and should report any unusual events to the study staff.  


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The study group to which you are assigned may prove to be less effective or have more 
side effects than the other study group. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
Taking part in this study may or may not improve your post-operative outcome.  While 
doctors know that the use of non-opioid pain medication, such as acetaminophen, reduce 
the use and need for opioid medications, it is unknown whether rectal or intravenous 
acetaminophen are equally effective in managing pain following gynecologic surgery. 
We do know that the information from this study will help doctors learn more about 
helping to manage post-operative pain and improve overall recovery.  This information 
could help future patients.  
WHAT OTHER OPTIONS ARE THERE? 
You may choose not to participate and continue to receive standard care.  
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study will not lead to any foreseeable added cost to you.  
You will receive no payment for taking part in this study. 
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY? 
In the case of life-threatening emergencies, call 911 first.  If you experience adverse 
events that are not life-threatening, contact Michaela Beynon, MD at 330-363-6242 or 
Sareena Singh, MD, at 330-904-1280 immediately. 
 
Immediate and necessary care for research related adverse events will be provided at 
Aultman hospital if you are injured because of participation in this research project.  Any 
cost associated providing this care not paid for by her insurance will be your 
responsibility.  Aultman Hospital has not made arrangements to provide compensation 
for any injury you may suffer as a direct consequence of the non-negligent performance 
of the procedure as described above.  However, by signing this form, you do not give up 
your right to seek payment for harm you receive while participating in the study. 
 
Dr. Beynon and Dr. Singh, or any other physicians involved with the study will answer 
any questions you have about this study.  These individuals are available to answer 
questions before, during, and after the study.  They can be contacted at the Aultman 


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Medical Group-Gynecologic Oncology, 2600 Tuscarawas St SW, Suite 420 Canton, OH 
44708, 330-994-1280. 
 
. If you have any questions about your rights as a research subject, contact the Aultman 
Health Foundation Human Research Review Board in the Office of Research, 2600 6th 
St. SW, Canton, OH 44710 (330-363-6793) or e-mail HRRB@aultman.com.  You may 
also contact them if you feel pressured to enroll or continue with participation in the 
study. 
 
Description of this clinical trial will be available on http://clinicaltrials.gov, as required 
by US law.  This website will not include any information that can identify you.  At most, 
the website will include a summary of the study and the results.  You can search this 
website at any time. 
WHAT ARE MY RIGHTS IN THIS STUDY?  
Your participation in this project is voluntary. If you agree to be in the study, you are free 
to change your mind at any time. Refusal to participate, or a decision to discontinue 
participation will involve no penalty or loss of benefits to which you are otherwise 
entitled. You may withdraw from this study whenever you want, and you still have access 
to healthcare at Aultman Health Foundation.  
The quality of care you receive will be the same regardless of whether you participate or 
not. If you decide to withdraw, we ask that you contact Dr. Beynon in writing at the 
above address to ensure your well-being.  


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AUTHORIZATION FOR RELEASE OF 
PROTECTED HEALTH INFORMATION 
HOW WILL MY CONFIDENTIALITY BE PROTECTED? 
WHAT WILL THE INVESTIGATORS TO DO MAKE SURE THAT THE 
INFORMATION COLLECTED WILL REMAIN SECURE? 
Your privacy is very important to us and the researchers will make every effort to protect 
it.   
You have rights regarding the privacy of your medical information collected prior to and 
in the course of this research study.  These rights are protected by a federal law that 
requires the Aultman Health Foundation and its affiliated hospitals and clinics, 
researchers, health care providers and physicians to protect the privacy of information 
that identifies you and relates to your past, present, and future physical and mental health 
and conditions (“protected health information”).  If you decide to participate in the 
research described in this consent form, your protected health information will be used 
and shared with others as explained below. 
WHAT PROTECTED HEALTH INFORMATION ABOUT ME WILL BE USED 
OR SHARED WITH OTHERS DURING THIS RESEARCH? 
To do this research study, we need your permission to collect and use some of your 
health information, or you cannot be in the study.  This information may come from 
questions we ask, forms we ask you to fill out, or your medical record, as described 
below.  We will only collect and use information needed for the study.   
The health information to be collected and used for this study is: 
• Existing medical records; 
• New health information created from study related tests, procedures, visits, and/or 
questionnaires; 
• Demographic information [name, address, telephone number] or numbers or 
codes that will identify you, such as your social security number and medical 
record number;  
• The history and diagnosis of your disease; 
• Specific information about the treatments you received, including previous 
treatment(s) you may have had; 
• Information about other medical conditions that may affect your treatment; 


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• The results of physical exams [blood pressure reading, heart rate, breathing rate, 
and temperature], laboratory blood test results, CT scans, MRIs, x-rays, pathology 
results, other diagnostic and medical procedures, as well as your medical history; 
• Information on side effects you may experience and how these were treated; 
• Long term information about your general health status and the status of your 
disease; 
• Data that may be related to tissue and/or blood samples that may be collected 
from you; 
• Family medical history; 
• Allergies; 
• Information about current and past medications or treatments. 
For this study, we will collect and use your entire medical history. 
WHY WILL PROTECTED HEALTH INFORMATION [PHI] ABOUT ME BE USED 
OR SHARED WITH OTHERS? 
The main reasons include: 
• To conduct and oversee the research described in the section, “WHAT IS 
INVOLVED IN THE STUDY?” and for all purposes necessary to conduct and 
ensure the integrity of the study. 
• To ensure the research meets legal, institutional, and accreditation requirements; 
and 
• To conduct public health activities (including reporting of adverse events or 
situations where you or others may be at risk of harm). 
Other reasons may include for treatment, payment or health care operations.  For 
example, some medical information produced by this study may become part of your 
hospital medical record because the information may be necessary for your medical care. 
WHO WILL USE OR SHARE PROTECTED HEALTH INFORMATION ABOUT 
ME AT THE AULTMAN HEALTH FOUNDATION? 
We will make every reasonable effort to protect the information and keep it confidential.  
The only Aultman Hospital employees allowed to handle your health information are 
those on the study team, and the Aultman Human Research Review Boards and Aultman 
officials who review the research plan and check the research activities to make sure the 
hospital’s rules are followed. 
 
 


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Dr. Beynon and her study team will use and share your protected health information with: 
• The Aultman Health Foundation Human Research Review Board, the committee 
that oversees research at this Institution; 
• We may record your research information, including results of tests and 
procedures done for research, in your Aultman Hospital medical record.  As a 
result, this research information may be seen by authorized members of the 
Aultman Hospital workforce who need to access your medical record in the 
performance of their duties (for example, to provide treatment, to ensure integrity 
of the research, accounting or billing matters, etc.) 
WILL MY PROTECTED HEALTH INFORMATION BE SHARED WITH 
PEOPLE OUTSIDE THE AULTMAN HEALTH FOUNDATION? 
We may share your information with people who do not work at Aultman Hospital 
because they planned, pay for, or work with us on this study. The Federal Privacy 
Rule may no longer protect your health information once it leaves Aultman 
Hospital. For this study, we plan to share information with those doctors, 
researchers or government representatives working with us on this study at the 
institutions or companies listed here:  
• Your insurance company  
WHAT ARE THE RISKS OF SHARING THIS HEALTH INFORMATION? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study.  While the study team makes every effort to 
keep the information confidential, an unauthorized person might see it.  Depending on the 
kind of information being collected, it might be used in a way that could embarrass you 
or affect your ability to get insurance.  If you have questions, you can talk to the study 
doctor about whether this could apply to you. 
HOW LONG WILL PROTECTED HEALTH INFORMATION ABOUT ME BE 
USED OR SHARED WITH OTHERS? 
There is no scheduled date at which time your protected health information that is being 
used or shared for this research will be destroyed. Research is an ongoing process.  
MAY I HAVE ACCESS TO MY MEDICAL INFORMATION THAT RESULTS 
FROM MY PARTICIPATION IN THIS RESEARCH STUDY? 
In accordance with the Aultman Health Foundation Notices of Privacy Practices 
document that you have been provided, you are permitted access to information 
(including information resulting from your participation in this research study) contained 
within your medical records filed with your health care provider.  


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During your participation in this study, you will have access to your medical record and 
any study information that is part of that record. 
STATEMENT OF PRIVACY RIGHTS 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to Michaela Beynon, MD at Department of 
Obstetrics and Gynecology, Aultman Hospital, 2600 6th St SW Canton, Ohio 44710.  
The letter must say that you have changed your mind and do not want the researcher to 
collect and share your health information.  At that time, we may decide that you cannot 
continue to be part of the study.  We may still use the information we have already 
collected. 
You have the right to limit the use and sharing of your PHI, and you have the right to see 
your medical records and know who else is seeing them. 
You do not have to give this permission for use of your PHI.  If you decide not to provide 
permission, you will not be able to participate in this research study.   
PUBLICATION OF RESULTS OR USE FOR TEACHING PURPOSES 
The information from this study may be published in scientific journals or presented at 
scientific meetings but your identity will be kept strictly confidential.  Your name or 
other identifiers will not be used in any publication or teaching materials without your 
specific permission. 


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CONSENT TO PARTICIPATION IN 
By signing my name below, I confirm the following 
• I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
• The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
• I agree to let the study team use and share the health information and other 
information gathered for this study. 
• I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
IMPORTANT:  You will be given a copy of this signed document for your records.  A second 
copy will be kept together with the Investigator’s research records on this study.  A third copy 
will be placed in your Aultman Hospital medical record. 
Please keep it where you can find it easily.  It will help you remember what we discussed today. 
Research Participant’s Name [PRINT]: 
 
Research Participant’s Signature: 
Date/Time 
INVESTIGATORS CONFIRMING STATEMENT 
I have given this research subject information on the study, which in my opinion is accurate and 
sufficient for the subject to understand fully the nature, risks and benefits of the study, and the 
rights of a research subject.  There has been no coercion or undue influence.   
INVESTIGATOR/INDIVIDUAL OBTAINING CONSENT 
Date 
I have explained the purpose of the research, the study procedures, identifying those that are 
investigational, the possible risks and discomforts and potential benefits.  I have answered any questions 
regarding the research study to the best of my ability. 
 

Prot_SAP_002.pdf: 
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. 
 


 
6
 
  
 
 
 
 
 
 
 
 
 
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.  


 
7
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 
 
 
 
 


 
8
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. 
 
 
 


 
9
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. 
 
 
 
 
 
 
 
 
 


 
10
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