Conditions: Anesthesia Opioid Use Tonsillitis Sleep Disorder Surgery
Keywords: Tonsillectomy Opioid-Free Ketorolac Dexmedetomidine Acute postoperative pain relief Opioid Morphine Fentanyl
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: yes

Brief summary:
Prospective randomized controlled trial to determine if opioid-free anesthetic for tonsillectomy is non-inferior to standard opioid-containing anesthetic

Detailed description:
Objectives:

Primary: To determine if an opioid-free anesthetic provides equivalent acute postoperative pain relief in tonsillectomy.

Secondary: To determine if post-operative pain at home is not significantly different with an opioid-free regimen compared to an opioid containing regimen for tonsillectomy.

Study Design: Prospective, randomized, multi-center trial study

Study Interventions and Measures:

Subject will be randomized to 1:1 intra-operative opioid-free (OFG) vs traditional care anesthetic with opioids (TCG) group

The primary endpoint is the median pain score (calculated by a blinded validated observer in the recovery room at two time intervals) between the two cohorts.

Arms:
arm 1: Traditional anesthetic with opioids group will receive institutional standard clinical care for tonsillectomy, including a standardized opioid dose at the beginning of the case and again at the end if needed. Dexmedetomidine and Ketorolac will not be used intra-operatively in this cohort to prevent confounding. arm 2: Opioid-Free group will receive institutional standard clinical care for tonsillectomy, without opioids, but including Dexmedetomidine and Ketorolac.

Interventions: intervention 1: Ketorolac intervention 2: Dexmedetomidine intervention 3: Morphine intervention 4: Fentanyl
Intervention descriptions: intervention 1: Ketorolac (0.5mg/kg; maximum 15mg intravenously) will be given at end of procedure after evaluation for hemostasis. intervention 2: Dexmedetomidine (1ug/kg with maximum 50ug intravenously) will be given at beginning of procedure. intervention 3: Morphine (0.05-0.1 mg/kg intravenously) will be given intra-operatively per institutional standard clinical care. intervention 4: Fentanyl (0.5-2 ug/kg intravenously) will be given intra-operatively per institutional standard clinical care.

Protocol document:
ICF_005.pdf: 
CHOP IRB#: IRB 19-016618
Effective Date: 5/17/2023
Expiration Date: 11/16/2023
Page 1 of 11
Informed Consent and HIPAA Authorization Form
Study Title: 
Opioid-free versus traditional anesthetic with opioids for tonsillectomy 
Version Date:  
 December 18, 2020
Principal Investigator:
Tori Sutherland, MD MPH
Telephone: (267) 426-2961
Emergency Contact:          Hospital main number to page
Tori Sutherland, MD MPH
Telephone: (800) 879-2467
You, or your child, may be eligible to take part in a research study. This form gives you 
important information about the study. It describes the purpose of this research study, and 
the risks and possible benefits of participating. 
In the sections that follow, the word “we” means the study doctor and other research 
staff. If you are a parent or legal guardian who is giving permission for a child, please 
note that the word “you” refers to your child.
Study Overview
You are being asked to take part in this research study because you are scheduled for a 
tonsillectomy. Your surgeon has already talked to you about the risks of tonsillectomy 
that include bleeding, poor pain control, dehydration and readmission.
The purpose of this study is to find out if non-opioid medications (Ketorolac and 
Dexmedetomidine) could provide the same amount of pain control as compared to 
standard of care opioid medication during tonsillectomy.  Neither of these medications 
are FDA approved for tonsillectomy or approved for use in children. However, these 
medications are used in CHOP’s clinical pediatric anesthesia practice. 
If you agree to take part, your participation will last for up to thirty days after your 
surgery. As a participant in the research you will:

Be randomly assigned to one of two investigational groups, and you will not 
know to which you’ve been assigned:
o
Group 1: (Traditional care group – TCG) Receive regular pain care with 
opioid medications by IV during surgery, and other therapies including 
non-steroidal anti-inflammatory medications or acetaminophen by mouth 
in the hospital and at home  or 
o
Group 2 - Opioid-free group (OFG) Receive IV non-steroidal anti-
inflammatory medication – Ketorolac and Dexmedetomidine during 
surgery and other therapies including non-steroidal anti-inflammatory 
medications or acetaminophen by mouth in the hospital and at home 

Complete questionnaires 
Standard pain treatment for tonsillectomy often includes opioids. These are given with or 
without oral non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and/or 


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Effective Date: 5/17/2023
Expiration Date: 11/16/2023
Page 2 of 11
acetaminophen. We are asking you to participate in a study of a single dose of 
intravenous NSAID called Ketorolac. This will replace the dose of opioid after surgery. 
After this single dose, you will receive the usual treatment given to patients after 
tonsillectomy. In some studies, there has been a higher risk of bleeding with Ketorolac. 
This was seen especially in adults when given multiple doses and at higher doses than 
we will use in this study. Ketorolac is not approved by the FDA for use in children. 
Studies in children have shown some increased risk of bleeding but not after a single 
dose. There is also the risk of kidney damage when you take any NSAID. This can 
happen if you are not drinking and not making enough urine. If you choose not to 
participate in this study, your surgeon will give you a different NSAID (not Ketorolac) 
that is swallowed by mouth. This could be Ibuprofen (Advil, Motrin) or Celecoxib 
(Celebrex) and acetaminophen (Tylenol). You could also get an opioid medication like 
morphine, or oxycodone. If your pain is not well controlled after your initial treatments, 
you may also be given opioid pain medications. This would happen no matter which 
group you are in to treat your pain better. 
At CHOP, surgeons in the ENT department, but not all, instruct their patients to take the 
non-steroidal Celecoxib on the morning of surgery. There is no strong evidence that 
either taking or not taking this drug changes the course or outcome of your surgery. If 
you decide to participate in this study, surgeonwill instruct you to not take Celebrex the 
morning of surgery
Dexmedetomidine is part of a group of medications that provide pain control and can 
make you sleepy. The main risk is a decrease in heart rate; other risks include low or high 
blood pressure and a high heart rate. It is not FDA-approved for this indication.
If you are assigned the opioid-free group, you might benefit if the use of ketorolac results 
in taking less opioids (and therefore experiencing fewer opioid related side effects such 
as nausea, vomiting and itching, etc). If you are assigned to the traditional care group, 
you might benefit if standard care results in better pain relief and will avoid the possible 
side effects (e.g. bleeding, kidney issues, etc) that could result from administration of 
ketorolac. This research will help us better understand how to use opioid free medicines 
for tonsillectomies in children. 
If there is anything in this form you do not understand, please ask questions. Please take 
your time. You do not have to take part in this study if you do not want to. If you take 
part, you can leave the study at any time. If you do not choose to take part in this study, 
you can discuss treatment options with your doctor. Please see below for additional 
details about the study.
How many people will take part? 
About 550 children will take part in this study at CHOP. 
What is the current standard of treatment for this disease?
Currently, all children undergoing tonsillectomy receive at least one opioid medication 
(such as Morphine and Fentanyl), along with a possible combination of one to three of 
the following medications: Acetaminophen, Dexmedetomidine, and a non-steroidal anti-
inflammatory different from Ketorolac. Medication selection currently depends on your 
doctor’s preference. 


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What are the study procedures? 
Not taking Celecoxib: If you were prescribed Celecoxib/Celebrex to take on the 
morning of surgery and are participating in this research study, you should not take this 
drug prior to your surgery.
Randomization: You will be randomly assigned to either the Traditional care group with 
opioids or the opioid-free group starting with Dexmedetomidine and then Ketorolac. This 
means that the physician or anesthesiologist will not get to decide which group you will 
be assigned to. There is an equal chance of being in either group, just like flipping a coin. 
You will not know to which group you are assigned. Your initial therapy will be different 
depending on the group you are in but you will receive additional therapies, including 
acetaminophen (Tylenol), non-steroidal anti-inflammatories (ibuprofen – Advil) and 
possibly an opioid (oxycodone, morphine) to control your pain if needed. 
Study medication administration: The study groups differ based upon the medications 
that you will receive in the operating room.  

Group 1: The Traditional care group (TCG) receives morphine or fentanyl 
through the IV that is placed for surgery

Group 2: The opioid free group (OFG) receives Ketorolac and 
Dexmedetomidine (neither of which are FDA-approved but are commonly 
used at CHOP for other surgeries) through the IV.
All patients will receive intravenous Acetaminophen (Tylenol). You may also receive 
medication by mouth in the recovery room, if needed.
Study Monitoring and Assessment: You will be monitored and assessed at 15 and 30 
minutes after waking up from surgery to ask you about your  pain control and any side-
effects. You will receive standard of care pain medications after surgery, which could 
include intravenous opioids if your pain is considered to be severe. 
Questionnaires: You will be asked to answer a questionnaire before surgery on the day 
of surgery, and post-operative days 1 and 5 after surgery to ask how you are feeling and 
what other medications you have used. You will also receive a phone call from the 
hospital the morning after surgery to make sure that you are doing well, and it is 
important to pick up the phone so that we can check on you. You will also receive a brief 
questionnaire on Day 30 to make sure you did not need medical care outside of CHOP. 
The questionnaire can be completed on a paper form or over the phone and will take 
about 15 minutes, or text or email with a link to the online questionnaire which takes less 
than 5 minutes. 
Medical records review: We will review your medical records throughout the study to 
collect baseline medical information, detailed anesthesia information, surgical records, 
surgical recovery, and post-operative follow up information up to 30 days after surgery. 
Procedures that are not changed by this study:  Your surgery, your postoperative pain 
management, and all other postoperative care, are standard care and will not be changed 
by your being in this study.   You will receive oral medications and possibly intravenous 
opioid medications in the recovery room if your pain is severe.  Your surgeon will 
prescribe oral pain medications for use at home in the usual manner. 


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What will be done with my data during this study?
During the study, we will collect information from you (data). By agreeing to participate 
in this study, you agree to give this information to CHOP for research purposes.
What are the risks of this study?
Taking part in a research study involves inconveniences and risks. The main risks of 
taking part in this study are discussed below. 
Not taking Celecoxib: If you were prescribed Celecoxib/Celebrex to take on the morning 
of surgery and you do not take it, because of participating in this study, your post-
operative pain and pain control might not be the same. However, there is no strong 
evidence whether or not taking the drug will change the course or outcome of the surgery.
Risks Associated with Randomization: It is not known which treatment works best in 
managing pain. The treatment group you are assigned to may prove less effective or have 
more side effects than the other study group. 
Risks of Both Groups: Hemorrhage is not rare after tonsillectomy. At CHOP, 2-5% of 
all tonsillectomies develop bleeding after surgery with usual care. You will be monitored 
during the study for such events. Additionally, your hospital stay might last longer due to 
your participation in the study and/or you might need to be re-admitted. Up to 10% of 
patients are readmitted with side effects from narcotics (vomiting), pain-related 
complications (uncontrolled pain, dehydration) or bleeding. Both groups may receive 
opioid pain medications after surgery if they are needed to control your pain. 
Traditional Care Group - Risk of Opioid administration: Opioid medications are now 
given to all children at CHOP during their tonsillectomy surgery.  Risks include nausea, 
vomiting, itching, constipation, decreases in oxygen levels and slow breathing.  If you 
develop the last two, you might receive oxygen or a medication called Naloxone (Narcan) 
to treat these symptoms. 
OF Group - Risks of Ketorolac: While Ketorolac is given to children at CHOP in other 
departments, such as Urology and Orthopedic Surgery, and is given at some other 
children’s hospitals for tonsillectomy, it is not FDA approved for use in children. It is not 
routinely given for tonsillectomy at CHOP due to concerns about bleeding based on 
previous studies done mostly in adults. There is some risk of bleeding after tonsillectomy 
with all non-steroidal anti-inflammatory drugs (NSAIDs), and it may be somewhat higher 
with the only available IV formulation Ketorolac.  A large review suggests that Ketorolac 
use is not associated with an increased risk of bleeding in children under age 18 but did 
find a higher risk of bleeding in adults.  Ketorolac is well known to provide substantial 
relief of pain after surgery and this study is being conducted to find out if the pain relief 
from ketorolac is good enough and can be used safely to reduce pain and the need for 
opioid medications after surgery.  
After surgery all study participants will be given acetaminophen, possibly more NSAIDs 
by mouth (Ibuprofen –(Advil) or Celecoxib (Celebrex), and possibly an opioid 
medication like Oxycodone or Morphine if needed to control pain.  Uncommon side 
effects related to all NSAIDs including Ketorolac, Naproxen (Aleve), and Ibuprofen 
(Advil) include: headache, stomach pain, lightheadedness, fatigue and diarrhea. Although 
extremely rare, Ketorolac has a boxed warning for peptic ulcers, increased risk of 


CHOP IRB#: IRB 19-016618
Effective Date: 5/17/2023
Expiration Date: 11/16/2023
Page 5 of 11
bleeding, stomach bleeding, and holes in the stomach. The rare risks of taking NSAIDs 
include life-threatening, potentially fatal skin adverse events and hypersensitivity, 
including breathing distress caused by narrowing of the airways and anaphylaxis, which 
is a serious, potentially life-threating allergic reaction  that can occur in any patient.  
Patients with known sensitivity to NSAIDS  cannot join the study. There is an extremely 
rare risk of heart attack and stroke seen in adults taking NSAIDs; this is not expected in 
healthy children and is higher risk with patients who have known heart disease or risk 
factors or those who receive high doses. All NSAIDs, like Ketorolac, naproxen and 
ibuprofen, have these same risks. There is a specific boxed warning of the risk of 
increased bleeding in patients that have medical problems that are linked to higher 
bleeding risk, which is why these patients are also excluded from participating in the 
study. To be clear, if you are assigned to the OFG group, you will only receive one dose 
of Ketorolac during surgery. 
OF Group - Risks of Dexmedetomidine: Dexmedetomidine is part of a group of 
medications called Alpha-2 agonists. It provides pain control and can make you sleepy. 
The label states that rarely patients can have a lower breathing rate; however, at CHOP, 
Dexmedetomidine is often used for sedation and pain control because the risk of lower 
breathing rates is less than what is seen with opioids . The main risk is a decrease in heart 
rate; other risks include low or high blood pressure and a high heart rate. If you have 
heart disease or certain genetic syndromes that have higher risk of low heart rate, you will 
not be eligible to participate. Your heart rate will be closely monitored during and after 
surgery.  In the very rare event you developed a low heart rate, you would receive 
medication to treat it. 
OF Group - Risk of the combination of Ketorolac and Dexmedetomidine: There is no 
known increased risk of giving these two medications together. 
Risk of Acetaminophen: Acetaminophen, or Tylenol, is a medication commonly given 
to children. In children with liver problems, it can make them worse. You will not receive 
Acetaminophen if you have certain liver problems.
Risks of Medical Record Review, Questionnaires, and Monitoring and Assessment: 
As with any study involving collection of data, there is the possibility of breach of 
confidentiality of data. Every precaution will be taken to secure participants' personal 
information to ensure confidentiality.
At the time of participation, each participant will be assigned a study identification 
number. This number will be used on data collection forms and in the database instead of 
names and other private information so they cannot be identified without a key. A 
separate list will be maintained that will link each participant's name to the study 
identification number .
Are there any benefits to taking part in this study?
If you are assigned to OF group and do not need opioids after your surgery to control 
your pain, you may benefit directly with taking less opioids and fewer opioid related side 
effects such as nausea, vomiting and itching. If you are assigned to the traditional care 
group, you may benefit if standard care results in better pain relief and will be spared the 
possible side effects (e.g. bleeding, kidney issues, etc) that could result from 
administration of ketorolac. However, we cannot guarantee or promise that you will 


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Effective Date: 5/17/2023
Expiration Date: 11/16/2023
Page 6 of 11
receive any direct benefit by participating in this study.  The knowledge gained from this 
study may help doctors determine if an opioid-free anesthetic provides equal pain relief 
to a standard opioid-containing anesthetic for pain management associated with 
tonsillectomy.
Do you need to give your consent in order to participate? 
If you decide to participate in this study, you must sign this form. A copy will be given to 
you to keep as a record. 
What are your responsibilities?
Please consider the study time commitments and responsibilities as a research subject 
when making your decision about participating in this study.  
What happens if you decide not to take part in this study? 
Participation in this study is voluntary. You do not have to take part in order to receive 
care at CHOP. 
If you decide not to take part or if you change your mind later there will be no penalties 
or loss of any benefits to which you are otherwise entitled. 
Can you stop your participation in the study early?
You can stop being in the study at any time. You do not have to give a reason.
What choices do you have other than this study?
There are options for you other than this study including standard management for 
tonsillectomy.
What about privacy, authorization for use of Personal Health Information (PHI) 
and confidentiality? 
As part of this research, health information about you will be collected. This will include 
information from medical records and the surveys. Information related to your medical 
care at CHOP will go in your medical record. Medical records are available to CHOP 
staff. Staff will view your records only when required as part of their job. Staff are 
required to keep your information private. Information that could identify you will not be 
shared with anyone - unless you provide your written consent, or it is required or allowed 
by law. We will do our best to keep your personal information private and confidential. 
However, we cannot guarantee absolute confidentiality. Your personal information may 
be disclosed if required by law. 
The results of this study may be shown at meetings and published in journals to inform 
other doctors and health professionals. We will keep your identity private in any 
publication or presentation.
Several people and organizations may review or receive your identifiable information. 
They will need this information to conduct the research, to assure the quality of the data, 
or to analyze the data or samples. These groups include: 

Members of the research team and other authorized staff at CHOP; 


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
People from agencies and organizations that perform independent accreditation 
and/or oversight of research; such as the Department of Health and Human 
Services, Office for Human Research Protections;

The Food and Drug Administration.
By law, CHOP is required to protect your health information. The research staff will only 
allow access to your health information to the groups listed above.  By signing this 
document, you are authorizing CHOP to use and/or release your health information for 
this research. Some of the organizations listed above may not be required to protect your 
information under Federal privacy laws. If permitted by law, they may be allowed to 
share it with others without your permission.  
There is no set time for destroying the information that will be collected for this study. 
Your permission to use and share the information and data from this study will continue 
until the research study ends and will not expire. Researchers continue to analyze data for 
many years and it is not possible to know when they will be completely done. 
Can you change your mind about the use of personal information?
You may change your mind and withdraw your permission to use and disclose your 
child’s health information at any time. To take back your permission, it is preferred that 
you inform the investigator in writing. 
Dr. Tori Sutherland
The Children’s Hospital of Philadelphia
Department of Anesthesiology and Critical Care 
34th Street and Civic Center Blvd.
Philadelphia, PA 19104
In the letter, state that you changed your mind and do not want any more of your health 
information collected. The personal information that has been collected already will be 
used if necessary for the research. No new information will be collected. If you withdraw 
your permission to use your personal health information, you will be withdrawn from the 
study.
Financial Information 
Will there be any additional costs? 
The costs associated with drugs administered for your participation in this study will be 
billed to you or your insurance. Additionally, while you are in this study, the cost of your 
usual medical care – procedures, medications and doctor visits – will continue to be 
billed to you or your insurance. It is possible that you may receive one more or one less 
medication that you would normally receive, but we do not expect a difference in your 
bill. We can help you understand your financial responsibilities.


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
If your insurance does not pay for all the costs, you may be responsible for the 
remaining costs, including any co-payments and deductibles as required by 
your insurance.

If you do not have insurance, you will be responsible for the costs of taking 
part of this study.
CHOP has programs to help uninsured and underinsured families see if financial 
assistance is available. If you need financial assistance, you can talk with a financial 
coordinator.
Will you be paid for taking part in this study? 
You will not receive any payments for taking part in this study. 
Who is funding this research study?
The Division of Anesthesiology and Critical Care at The Children’s Hospital of 
Philadelphia is partially funding this research along with a Foerderer Fund of Excellence 
grant and a McCabe Grant. 
Please ask Dr. Tori Sutherland if you have any questions about how this study is funded. 
What if you have questions about the study?
If you have questions about this study or how your data are going to be used, call the 
study doctor, Dr. Tori Sutherland at 267-426-2961.  If the matter is urgent, you may have 
the hospital operator page Dr. Sutherland directly if there is no response at the number 
listed above. You may also talk to your own doctor if you have questions or concerns.
The Institutional Review Board (IRB) at The Children’s Hospital of Philadelphia has 
reviewed and approved this study. The IRB looks at research studies like these and makes 
sure research subjects’ rights and welfare are protected. If you have questions about your 
rights or if you have a complaint, you can call the IRB Office at 215-590-2830. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
What happens if you are injured during the study?
If you are hurt or get sick from something that was done as part of this study, doctors at 
the clinic or hospital can arrange for emergency medical care. The Hospital does not offer 
financial compensation or payment for injuries due to participation in this research. 
You and your insurance company will be billed for the costs of any care or injuries. 
If you think you have been injured from taking part in this study, call Dr. Sutherland at 
267-426-2961. She can go over things with you, let you know of resources that may be 
available and give you information on what you need to do.
In case of injury resulting from this study, you will not lose any legal rights by signing 
this form.


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What will be done with my data when this study is over? 
We will use and may share data for future research. They may be shared with 
researchers/institutions outside of CHOP. This could include for profit companies. We 
will not ask for your consent before using or sharing them. We will remove identifiers 
from your data, which means that nobody who works with them for future research will 
know who you are.  Therefore, you will not receive any results or financial benefit from 
future research done on your specimens or data.


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Consent to Take Part in this Research Study and Authorization to Use and 
Disclose Health Information for the Research
The research study and consent form have been explained to you by:
Person Obtaining Consent
Signature of Person Obtaining Consent
Date
By signing this form, you are indicating that you have had your questions answered, you 
agree to take part in this research study and you are legally authorized to consent to your 
child’s participation. You are also authorizing the use of your/your child’s health 
information as discussed above. If you don’t agree to the collection, use and sharing of 
health information, you cannot participate in this study. NOTE: A foster parent is not 
legally authorized to consent for a foster child’s participation.
Name of Subject
Signature of Subject (18 years or older)
Date
Name of Authorized Representative 
(if different than subject)
Relation to subject:
 Parent  
 Legal Guardian
Signature of Authorized Representative
Date


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Child Assent to Take Part in this Research Study
For children capable of providing assent:
I have explained this study and the procedures involved to __________________ in 
terms he/she could understand and that he/she freely assented to take part in this study.
Person Obtaining Assent
Signature of Person Obtaining Assent
Date
This study has been explained to me and I agree to take part.
Signature of Subject (optional)
Date
For children unable to assent: 
I certify that __________________ was not capable of understanding the procedures 
involved in the study sufficiently to assent to study participation. 
Person Responsible for Obtaining Assent
Signature of Person Responsible
Date

Prot_SAP_004.pdf: 
 
 
Title: 
OPIOID-FREE VERSUS TRADITIONAL ANESTHETIC WITH 
OPIOIDS FOR TONSILLECTOMY – Multi-Center 
Short Title 
Opioid-free Tonsillectomy 
Drug Name(s): 
Ketorolac and Dexmedetomidine 
Regulatory Sponsor: 
The Children’s Hospital of Philadelphia 
eIRB Number 
IRB 19-016618 
Protocol Date: 
May 15, 2020 
Amendment 1 Date: June 18, 2020 
Amendment 2 Date: September 29, 2020 
Amendment 3 Date: December 4, 2020 
 
Amendment 4 Date: May 25, 2021 
Tori Nicole Sutherland MD MPH 
The Children’s Hospital of Philadelphia 
34th Street and Civic Center Boulevard 
Philadelphia, PA, 19104 
Phone 443-631-5032 
email: sutherlant@email.chop.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OPIOID-FREE TONSILLETOMY SITE INVESTIGATORS SIGNATURE PAGE 
Protocol Title 
OPIOID-FREE VERSUS TRADITIONAL ANESTHETIC WITH 
OPIOIDS FOR TONSILLECTOMY – Multi-Center 
Version Date 
May 25, 2021 
Site Principal 
Investigator 
 
Institution 
 
 
 
 
 
 
I conﬁrm that I have read this protocol, I understand it, and I will conduct the study according to the protocol. I 
will also work consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
will adhere to the Ethical and Regulatory Considerations as stated. I conﬁrm that if I or any of my staff are 
members of the Institutional Review Board, we will abstain from voting on this protocol, its future renewals, 
and its future amendments.  
Send a copy of this page to the Study Principal Investigator.  
 
 
 
Site Principal Investigator Signature 
 
 
Date: 
 
 
 


ii 
 
 
Table of Contents 
ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................................................... 5 
ABSTRACT ...................................................................................................................................................................... 6 
PROTOCOL SYNOPSIS .................................................................................................................................................. 7 
TABLE 1: SCHEDULE OF STUDY PROCEDURES ..................................................................................................... 9 
TABLE 2: SCHEDULE OF MEDICATION TIMING ................................................................................................... 10 
FIGURE 1: STUDY DIAGRAM .................................................................................................................................... 11 
1 
BACKGROUND INFORMATION AND RATIONALE ...................................................................................... 12 
1.1 Introduction ............................................................................................................................................................ 12 
1.2 Description of Investigational Intervention ............................................................................................................ 12 
1.3 Relevant Literature and Data .................................................................................................................................. 13 
1.4 Compliance Statement ............................................................................................................................................ 13 
2 
STUDY OBJECTIVES........................................................................................................................................... 13 
2.1 Primary Objective ................................................................................................................................................... 13 
2.2 Secondary Objective ............................................................................................................................................... 13 
3 
INVESTIGATIONAL PLAN ................................................................................................................................. 14 
3.1 General Schema of Study Design ........................................................................................................................... 14 
3.1.1 Screening Phase ...................................................................................................................................................... 14 
3.1.2 Randomization ........................................................................................................................................................ 14 
3.1.3 Follow-up Phase ..................................................................................................................................................... 14 
3.1.3.1 
Chart Review ................................................................................................................................................. 14 
3.2 Allocation to Treatment Groups and Blinding ........................................................................................................ 14 
3.3 Study Duration, Enrollment and Number of Sites .................................................................................................. 15 
3.3.1 Duration of Study Participation .............................................................................................................................. 15 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected ........................................................................ 15 
3.4 Study Population ..................................................................................................................................................... 15 
3.4.1 Inclusion Criteria .................................................................................................................................................... 15 
3.4.2 Exclusion Criteria ................................................................................................................................................... 15 
4 
STUDY PROCEDURES ........................................................................................................................................ 16 
4.1 Screening Visit........................................................................................................................................................ 16 
4.2 Randomization ........................................................................................................................................................ 16 
4.3 Post-Op Recovery Assessment ............................................................................................................................... 16 
4.4 Follow up ................................................................................................................................................................ 16 
4.4.1 Questionnaires ........................................................................................................................................................ 16 
4.4.2 Chart Review .......................................................................................................................................................... 16 


iii 
 
 
4.5 Unscheduled Visits ................................................................................................................................................. 16 
4.6 Concomitant Medication......................................................................................................................................... 17 
5 
STUDY EVALUATIONS AND MEASUREMENTS ........................................................................................... 17 
5.1 Medical Record Review .......................................................................................................................................... 17 
5.2 Randomization ........................................................................................................................................................ 17 
5.3 Post-op Recovery Assessment ................................................................................................................................ 18 
5.3.1 Pain Assessment ..................................................................................................................................................... 18 
5.3.2 FLACC (Face, Legs, Activity, Cry, Consolability) assessment .............................................................................. 18 
5.3.3 Delirium assessment ............................................................................................................................................... 18 
5.4 Questionnaire .......................................................................................................................................................... 19 
5.5 Day 30 Chart Review .............................................................................................................................................. 20 
6 
STATISTICAL CONSIDERATIONS .................................................................................................................... 20 
6.1 Primary Endpoint .................................................................................................................................................... 20 
6.2 Secondary Endpoints .............................................................................................................................................. 20 
6.3 Statistical Methods .................................................................................................................................................. 20 
6.3.1 Baseline Data .......................................................................................................................................................... 20 
6.3.2 Efficacy Analysis .................................................................................................................................................... 21 
6.4 Sample Size and Power .......................................................................................................................................... 21 
7 
STUDY MEDICATION ......................................................................................................................................... 22 
7.1 Description ............................................................................................................................................................. 22 
7.1.1 Dosing..................................................................................................................................................................... 24 
7.1.2 Treatment Compliance and Adherence ................................................................................................................... 24 
8 
SAFETY MANAGEMENT ................................................................................................................................... 24 
8.1 Clinical Adverse Events.......................................................................................................................................... 24 
8.2 Adverse Event Reporting ........................................................................................................................................ 25 
9 
STUDY ADMINISTRATION................................................................................................................................ 26 
9.1 Treatment Assignment Methods ............................................................................................................................. 26 
9.1.1 Randomization ........................................................................................................................................................ 26 
9.1.2 Blinding .................................................................................................................................................................. 26 
9.1.3 Unblinding .............................................................................................................................................................. 27 
9.2 Data Collection and Management ........................................................................................................................... 27 
9.3 Confidentiality ........................................................................................................................................................ 27 
9.4 Regulatory and Ethical Considerations ................................................................................................................... 27 
9.4.1 Data and Safety Monitoring Plan ............................................................................................................................ 27 
9.4.2 Risk Assessment ..................................................................................................................................................... 27 
9.4.3 Potential Benefits of Trial Participation .................................................................................................................. 28 


iv 
 
 
9.4.4 Risk-Benefit Assessment ........................................................................................................................................ 29 
9.5 Recruitment Strategy .............................................................................................................................................. 29 
9.6 Informed Consent/Assent and HIPAA Authorization ............................................................................................. 29 
9.7 Payment to Subjects/Families ................................................................................................................................. 30 
10 
PUBLICATION...................................................................................................................................................... 30 
APPENDIX I: .................................................................................................................................................................. 31 
Appendix II: Case for IND Exemption, Ketorolac for Tonsillectomy ............................................................................ 33 
Table 1 
34 
Figure 1. 35 
Appendix III: Case for IND Exemption, Dexmedetomidine for Tonsillectomy ............................................................. 36 
Table 1: Literature review of Dexmedetomidine dose algorithms and adverse events in pediatric patients. ....... 37 
11 References ..................................................................................................................................... 38 
 
 
 
 
 
 
 
 
 


v 
 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
CHOP 
Children’s Hospital of Philadelphia 
AE 
Adverse event 
SAE 
Severe adverse event 
TCG 
Traditional care group (opioid regimen) 
OFG 
Opioid-free group (intervention regimen) 
POD 
NSAID 
Post-operative day 
Non-steroidal anti-inflammatory drug 


vi 
 
 
 
ABSTRACT 
Context: 
 
Over 2 million Americans have been diagnosed with an opioid use disorder (OUD), and in 2017, 47,600 
overdose deaths were attributable to opioids. 1,2 In 2016, 3.6% of adolescents (age 12-17) endorsed 
inappropriate opioid use; this number doubled among young adults aged 18-25.3 Single dental and 
perioperative opioid exposures are significantly associated with chronic opioid use among pediatric 
patients (4.8% exposed patients vs 0.1% non-exposed patients).4,5 Emerging literature suggests that limited 
opioid exposure significantly correlates with future risk of OUD, and that procedures associated with mild 
to moderate post-operative pain can be managed effectively without opioids.1,6 High-volume pediatric 
centers, including Seattle Children’s, report equivalent outcomes after tonsillectomy with both standard 
opioid-containing and opioid-free regimens (see Appendix III, data from Seattle Children’s opioid-free 
protocol).7 
Aim: 
• 
Primary Objective 
 
To determine if an opioid-free anesthetic provides equivalent acute postoperative pain relief in 
tonsillectomy. 
Study Design: 
• 
Prospective, randomized, multi-center trial  
• 
Setting/Participants: 
The setting including Children’s Hospital of Philadelphia and The University of Tennessee Health Science 
Center. 
 
The participants will include up to 350 subjects age 2-18 undergoing tonsillectomy. 
 
Study Interventions and Measures: 
The study will be a 1:1 block randomization per site by surgical type (classic versus intracapsular) 
to either standard anesthetic – traditional care group (TCG) or an opioid-free (OF) intra-operative 
anesthetic regimen.  Both groups are investigational. 
Main study outcome measures are as follows: 
● 
Baseline Questionnaire 
• 
Acute assessment: pain & delirium scores 
• 
POD 1 & 5 questionnaire: Bleeding, hydration, family satisfaction with patient recovery, pain 
medication use and (patient or parent) reported pain score 
• 
Chart review and brief questionnaire: POD 30 for readmission and medical reattendance, including 
calls to physician 


vii 
 
 
PROTOCOL SYNOPSIS 
Study Title 
OPIOID-FREE VERSUS TRADITIONAL ANESTHETIC WITH OPIOIDS 
FOR TONSILLECTOMY – Multi-Center study 
Funder 
CHOP (Foerderer and McCabe Fund grants) 
 
Study Rationale 
To date, an opioid-free anesthetic for tonsillectomy has not been rigorously studied in 
a randomized, controlled pediatric trial. If a randomized trial establishes that an 
opioid-free technique is equivalent, hundreds of thousands of annual pediatric opioid 
exposures, and subsequent risk of misuse, will be eliminated. This will also decrease 
post-operative opioid prescriptions, which have also been linked to widespread opioid 
misuse and abuse in communities. 
 
Study Objective(s) 
Primary 
To determine if an opioid-free anesthetic provides equivalent acute postoperative pain 
relief in tonsillectomy. 
 
Secondary 
To determine if post-operative pain at home is not significantly different with an 
opioid-free regimen compared to an opioid containing regimen for tonsillectomy. 
Test Article(s) 
Ketorolac, Dexmedetomidine 
Study Design  
Prospective, randomized, single-center trial study 
 
Subject Population 
 
Key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Males or females age 2 to 18 years. 
2. Girls after menarche must have a negative pregnancy test 
3. ASA ≤ 3 
4. Scheduled tonsillectomy or tonsillectomy combined with adenoidectomy 
and/or ear tube placement. 
5. Parental/guardian permission and if appropriate, child assent (patient 
consent if age 18). 
Exclusion Criteria 
1. Current (within the last 30 days) opioid use  
2. Patients that took pre-operative Celebrex on the day of service 
3. High risk for surgical site hemorrhage, including bleeding disorder 
diagnosis or poor intraoperative hemostasis 
4. Multiple scheduled surgeries at the same time other than 
adenoidectomy and/or ear tube placement 
5. History of drug abuse, chronic pain, bleeding disorder 
• 
Chronic Diseases such as Sickle Cell Disease for which 
treatment with opioids may be clinically indicated.  
6. Significant congenital disorders, medication allergies or 
comorbidities, specifically a pre-disposition to bradycardia or 
conduction abnormalities, cyanotic cardiac disease and use of 
medications that would increase risk of bleeding or bradycardia. 
• 
History of hepatic dysfunction, renal dysfunction, 
thrombocytopenia, or anemia (including pre-surgery 
laboratory abnormalities) 


viii 
 
 
• 
History of hypersensitivity to NSAIDs 
• 
Patients with asthma, including patients who have 
experienced aspirin- or NSAID-sensitive asthma or a 
history of exacerbation when aspirin or NSAIDs are 
administered (e.g. bronchospasm, urticaria, etc.) 
• 
Subjects receiving medications that could impact metabolism 
of either study drug should also be excluded 
• 
Trisomy 21 diagnosis 
6. Parents/guardians or subjects who, in the opinion of the 
Investigator, may be non-compliant with study schedules or 
procedures. 
7.Parents or subjects who do not speak English 
8. Patients on a Ketogenic diet 
 
*Eligibility will be confirmed on the day of surgery (e.g pregnancy testing results will 
not be available before then, current opioid use refers to timing of surgery). Only 
subjects who meet all of these criteria will complete study procedures. 
 
Number of Subjects  
550 subjects will be enrolled to produce 350 evaluable subjects. 
 
Study Duration  
Each subject’s participation will last up to 30 days, with chart review lasting up to 30 
days. 
The entire study is expected to last about three to four years. 
Study Phases 
 
Screening 
Study Treatment          
Follow-Up 
➢ Screening: identifying potential subjects and obtaining consent 
➢ Baseline questionnaire prior to surgery  
➢ Intervention: randomization 
➢ Follow-up: 
• 
Acute Assessment: pain and delirium scores 
• 
Home Assessment: POD1 phone call to ask about pain, bleeding and 
dehydration. POD 5 and POD 30 eSurvey via REDCap. Follow-up 
phone calls/referrals as necessary if responses warrant follow-up. (See 
Appendix I) 
• 
Chart review: up to 30 days post-op, in addition to brief questionnaire 
Efficacy Evaluations 
The primary endpoint is the median pain score (calculated by a blinded validated 
observer in the recovery room at two time intervals) between the two cohorts. 
 
Safety Evaluations  
Dexmedetomidine and Ketorolac are currently used frequently at participating 
institution clinical pediatric anesthesia practice. There is no reason to suspect an 
increase in risk from their use together in this study in excess of the known risks 
associated with each medication. Subjects will also be monitored during recovery, 
POD1 and POD 5 and POD 30. Subjects will also be contacted on day 1 by phone 
call to verify that they do not have bleeding and are drinking fluids and making urine. 
They will receive electronic questionnaires on POD5 and POD30. If the subject 
indicates on the electronic survey that “yes” they are having bleeding or “no” they are 
not eating or making urine, a local study investigator will call them. If subjects report 
that they have sought care outside of participating center for complications on the 
POD 30 electronic survey, a local study investigator will call them. Any study related 
AEs will be treated per institutional standard practice and all applicable referrals will 
be made. Data are attached from Seattle Children’s Hospital, an institution that uses 
ketorolac preferentially over opioids for all tonsillectomies.7 Colleagues at Albany 
Children’s and Emory routinely use ketorolac for tonsillectomy and are currently 


ix 
 
 
studying use to reduce opioid consumption (clinicaltrials.gov). 
 
Statistical and 
Analytic Plan 
 
Non-inferiority design to detect a difference that is equal to or less than the 
predefined largest clinically important difference between standard care and the 
intervention derived from quality improvement (QI) data. Using a value of the change 
in pain scores that is 15% of a single standard deviation as the non-inferiority margin 
(derived from internal QI data), the difference on a 0-10 pain scale is also smaller 
than any clinically relevant change. It will require 350 patients (175 patients per 
treatment group) to be 90% sure that the upper limit of a one-sided 95% confidence 
interval will be below 0.6 if the pain score is truly not worse for the intervention 
group. 
DATA AND 
SAFETY 
MONITORING 
PLAN 
 
Local PI will be responsible for oversight of the study safety and a Data Safety and 
Monitoring Board (DSMB), composed of three individuals with expertise in conduct 
of pediatric clinical trials, has been established. We expect no more than standard 
clinical risks associated with tonsillectomy, which include bleeding and dehydration. 
The interim analysis will occur after 50 patients, 15% of the target, have been 
enrolled. The DSMB board will meet at this point. In addition, The DSMB will have 
planned semi- annual meetings to review data and a meeting may be called by any 
investigator or CHOP clinician to review specific concerns. The DSMB will also 
receive monthly reports detailing bleeding rates in the two groups. The maximum 
bleeding rate requiring unscheduled clinic visits or visit to the ER, has been less than 
10% in any given month. If this is exceeded in a given month, this would also 
constitute a stopping criteria. The IRB will be immediately notified, and the study 
will be halted while the DSMB examines the data. If the DSMB determines that the 
rate increase was similar between groups and had no plausible correlation with 
Ketorolac or other study medications (i.e. a new surgical technique or operator), the 
study would be permitted to proceed. 
 
 


ix 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES 
 
Study Phase 
Screening 
Surgery Recovery 
(minutes) 
Follow-up 
Study Days 
0 
15±5 
30±10 
Day 
1+1 
Day 
5+3 
Day 
30±3 
Informed Consent/Assent 
X 
Review Inclusion/Exclusion Criteria 
X 
Demographics/Medical History 
X 
Prior/Concomitant Medications 
X 
Randomization 
X 
Pain Assessment 
X 
X 
X 
X 
X 
FLACC Assessment 
X 
X 
Delirium Assessment 
X 
X 
Questionnaire 
X 
X 
X 
X 
Chart Review 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 


x 
 
 
 
 
 
TABLE 2: SCHEDULE OF MEDICATION TIMING 
 
CASE START 
CASE END 
RECOVERY 
ROOM 
HOME 
TRADITIONAL 
CARE GROUP 
(TCG) 
Opioid/IV 
Acetaminophen 
Opioid (if 
needed) 
IV Opioid for 
severe pain; 
oxycodone as 
needed 
Acetaminophen 
+NSAID 
(Opioid if 
needed) 
OPIOID-FREE 
GROUP (OFG) 
Dexmedetomidine/IV 
Acetaminophen 
Ketorolac (if 
hemostasis 
verified) 
IV Opioid for 
severe pain; 
oxycodone if 
pain still not 
controlled 
Acetaminophen 
+NSAID 
(Opioid if 
needed) 


11 
 
 
 
FIGURE 1: STUDY 
DIAGRAM 
 
 
 
Subjects from whom written consent is obtained prior to the day of surgery that are no longer found 
to be eligible on the day of surgery will be withdrawn from the study 
 


12 
 
 
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Over 2 million Americans have been diagnosed with an opioid use disorder (OUD), and in 2017, 47,600 
overdose deaths were attributable to opioids. 1,2 In 2016, 3.6% of adolescents (age 12-17) endorsed 
inappropriate opioid use; this number doubled among young adults aged 18-25.3 Single dental and 
perioperative opioid exposures are significantly associated with the development of chronic opioid abuse 
by pediatric patients (4.8% of exposed patients vs 0.1% of non-exposed patients).4,5 Pediatric patients 
continue to receive perioperative opioids and are discharged with opioid prescriptions despite data that 
post-operative pain can be effectively managed without them in most cases.1,6,8,9 For example, opioids are 
routinely prescribed during and after tonsillectomy, the second most common pediatric surgery 
(>500,000/year), despite evidence that they are associated with adverse events and recent guidelines from 
the American Academy of Otolaryngology that nonsteroidal anti-inflammatory drugs (NSAIDs) should be 
used instead with acetaminophen.10-12 To date, an opioid-free anesthetic for tonsillectomy has not been 
rigorously studied in a randomized, controlled pediatric trial. If a randomized trial establishes that an 
opioid-free technique is equivalent, hundreds of thousands of annual pediatric opioid exposures, and 
subsequent risk of misuse, will be eliminated. This will also decrease post-operative opioid prescriptions, 
which are routine at participating centers, that have also been linked to widespread opioid misuse and 
abuse in communities. 
If the hypotheses are correct, study results would drastically alter the standard of care. Hundreds of 
thousands of children would avoid opioid exposures each year, and communities will be spared from 
availability of excess opioids. This will not only provide evidence to adapt newer anesthetic techniques but 
will hopefully highlight the value of clinical effectiveness trials in pediatric anesthesia. Several pediatric 
hospitals report equivalent outcomes with opioid free techniques for tonsillectomy, a procedure performed 
on over 500,000 children each year.7,11 However, there are no clinical effectiveness trials to support 
equivalent outcomes. 
1.2 
Description of Investigational Intervention 
The study will have two groups for intra-operative anesthetic regimen. Both groups are investigational. 
• 
Traditional Care Group (TCG): Traditional anesthetic with opioids group will receive participating 
center’s usual clinical care for tonsillectomy, including a standardized opioid dose at the 
beginning of the case and again at the end if needed. Some providers also administer 
Acetaminophen, Dexmedetomidine and/or Ketorolac in the operating room; however, all patients 
receive opioids as usual care. In addition to analgesia, opioids provide sedation; dexmedetomidine 
is intermittently used by some providers given its sedating qualities. Dexmedetomidine will not be 
used intra-operatively in this cohort to prevent confounding. 
• 
Opioid-Free Group (OFG): Opioid-Free group will receive the participating center’s usual 
clinical care for tonsillectomy, without opioids, but including Dexmedetomidine (beginning of 
case), and Ketorolac (end of case after evaluation for hemostasis). This combination is used 
exclusively by pediatric hospitals such as Seattle Children’s, given the sedating and analgesic 
qualities of Dexmedetomidine and the exclusive analgesic qualities of Ketorolac. 
All patients will receive standard of care post-operative pain management if pain control is inadequate. 
If pain continues to be poorly controlled per the criteria above (FLACC >4 and/or provider discretion), 
patients will receive standard weight-based liquid Oxycodone (0.05-0.1mg/kg) which is indicated for 
moderate pain (FLACC>4) at participating centers. The un-blinded PACU nurse will be encouraged to 
not administer oxycodone if a patient’s pain is clinically controlled with non-medical interventions 
such as a popsicle and re-direction, which is standard of care at participating centers. The home pain 


13 
 
 
control regimen will not be altered from each surgeon’s baseline protocol, which includes a NSAID 
(either Celecoxib or Ibuprofen), acetaminophen and a prescription for rescue opioids at the surgeon’s 
discretion. A third group prescribes opioids and Acetaminophen only (these providers have elected to 
not participate in the trial). 
1.3 
Relevant Literature and Data 
In the United States, opioid abuse is considered to have reached epidemic proportions. In 2016, 3.6% of 
adolescents (age 12-17) endorsed inappropriate opioid use; this number doubled among young adults aged 
18-25.3  A growing body of literature suggests that limited pediatric opioid exposure correlates strongly 
with future risk of OUD: even a single dental or perioperative opioid exposure has been significantly 
associated with chronic opioid use among pediatric patients (4.8% exposed patients vs 0.1% non-exposed 
patients).4,5 Adolescents in particular are at higher risk of addiction after exposure due to changes in the 
reward and habit centers of the brain.13-16 However, there is increasing evidence that procedures associated 
with mild to moderate post-operative pain can be managed effectively without opioids.1,6,8 Two sites 
(Albany Medical and Seattle Children’s) have reported equivalent outcomes with opioid-free anesthetic 
techniques for tonsillectomies using historical data for comparison in quality improvement initiatives at 
the latter institution without increased risk.7 Post-operative analgesia was not guided by protocol but was 
at provider discretion. Another benefit of the OF anesthetic was a significant decrease in post-operative 
nausea and vomiting (PONV). However, this technique has not been rigorously evaluated in a randomized 
trial. A well-conducted trial that demonstrated non-inferior outcomes would contribute to a decrease in 
unnecessary opioid exposure. 
To date, there are no pediatric clinical effectiveness trials that have addressed this question. We do 
know that opioid abuse is now the largest drug epidemic in American history and that pediatric 
perioperative exposure is significantly associated with future misuse. If this study determines that an 
opioid-free anesthetic is equally effective and satisfaction to patients and parents, this trial will alter the 
standard of care and associated risks for over a half million patients each year in the United States 
alone. 
1.4 
Compliance Statement 
This study will be conducted in full accordance all applicable participating center’s Research Policies and 
Procedures and all applicable Federal and state laws and regulations including 45 CFR 46 and the HIPAA 
Privacy Rule. All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent and assent, 
and will report unanticipated problems involving risks to subjects or others in accordance with 
participating center’s IRB Policies and Procedures and all federal requirements. Collection, recording, 
and reporting of data will be accurate and will ensure the privacy, health, and welfare of research 
subjects during and after the study. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to determine if an opioid-free anesthetic provides equivalent acute 
postoperative pain relief in tonsillectomy. 
2.2 
Secondary Objective 
The secondary objective is to determine if post-operative pain at home is not significantly different with 


14 
 
 
an opioid-free regimen compared to an opioid containing regimen for tonsillectomy. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
This study is a prospective, randomized, multi-centered controlled trial. 
3.1.1 
Screening Phase 
Potential subjects will be identified from patients scheduled for elective surgery per protocol inclusion and 
exclusion criteria. Parental/guardian permission (informed consent) and assent when indicated will be 
obtained prior to any study related procedures being performed. 
3.1.2 
Randomization 
Subject will be randomized to 1:1 intra-operative opioid-free (OFG) vs traditional care anesthetic with 
opioids (TCG) group per site. Randomization could occur prior to obtaining formal written consent, 
but will not occur until after the initial consent discussion has been completed and documented 
accordingly in REDCap. The treating anesthesiologist will be notified of consent status on the day of 
service and instructed to proceed with assigned treatment arm (emailed to them the day prior) if the 
patient/family has provided written consent.  If the family declines on the day of service or the participant 
is no longer found to be eligible on the day of service, the treating anesthesiologist will be notified 
immediately to proceed with standard of care anesthetic treatment. Confirmation of anesthesiologist’s 
acknowledgement of a) randomization b) consent status and c) screening confirmation on day of service 
will be documented in study EDC. 
3.1.3 
Follow-up Phase 
The follow-up phase will continue for up to 30 days after surgery. Per participating center’s standard 
clinical protocol, all patients discharged home after tonsillectomy will be contacted to assess general 
wellbeing and are specifically asked about hydration, bleeding and pain control.  If there are any concerns, 
the Otolaryngology clinic is immediately called to perform a same-day assessment and to escalate care, if 
indicated. Please see detailed information below with regard to a patient phone call from a study clinician 
(nurse or doctor) on POD1 and electronic surveys on POD 5 and POD 30. 
Questionnaire: Subjects will complete a baseline questionnaire after consent and prior to surgery. 
Subjects will be followed-up at POD 1,POD 5, and POD30. The questionnaire could be collected either 
over the phone or text link via REDCap to the parent’s phone at the parent/legal guardian’s preference. 
The online survey should take less than 5 minutes. The phone call should take less than 15 minutes. If 
families prefer to also complete the POD1 survey over the phone during the safety study follow-up call, 
this will be an option as well. After two attempts of calling family over the phone are unsuccessful, a text 
link will be sent to the family. 
3.1.3.1 
Chart Review 
Chart will be reviewed up to POD 30 and patients will be contacted electronically to collect any 
complications. If subject reports bleeding, not being able to drink or make urine, a study investigator will 
call them. 
3.2 
Allocation to Treatment Groups and Blinding 
The randomization sequence will be generated by statisticians by Data Coordinator Center (DCC). The 
randomization sequence will be maintained in study REDCap EDC by the study manager at DCC. Block 
randomization will be performed by surgical type (intracapsular versus classic) per site to ensure equal 
distribution. Randomization will occur with random block sizes of 2, 4 or 6 to ensure equal numbers of 


15 
 
 
OFG vs TCG subjects to avoid predictability of medication assignments. 
 
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 
Duration of Study Participation 
The study duration per subject will be up to 30 days post-surgery, with two follow-up questionnaires at 
Day 1, Day 5, and Day 30. All medical records will be reviewed up to Day 30 for medical re-
attendance. 
 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at The Children’s Hospital of Philadelphia (CHOP) and The University of 
Tennessee Health Science Center. It is expected that approximately 550 subjects will be enrolled to produce 
350 evaluable subjects. Any center enrollment should be capped at 80% of total study enrollment. 
3.4 
Study Population 
3.4.1 
Inclusion Criteria 
1. Males or females age 2 to 18 years. 
2. Girls after menarche must have a negative pregnancy test  
3. ASA ≤ 3 
4. Scheduled tonsillectomy or tonsillectomy combined with adenoidectomy and/or ear tube 
placement. 
5. Parental/guardian permission (informed consent) and if appropriate, child assent 
 
3.4.2 
Exclusion Criteria 
1. Current (within the last 30 days) opioid use  
2. Patients that took pre-operative Celebrex on the day of service  
3. High risk for surgical site hemorrhage, determined by bleeding disorder diagnosis or evidence or 
poor hemostasis 
4. Multiple scheduled surgeries at the same time other than adenoidectomy and/or ear tube placement 
5. History of drug abuse, chronic pain, bleeding disorder 
a. Chronic disease such as sickle cell disease for which treatment with opioids may be 
clinically indicated 
6. Significant congenital disorders, medication allergies or comorbidities, specifically a pre- 
disposition to bradycardia or conduction abnormalities, cyanotic cardiac disease and use of 
medications that would increase risk of bleeding or bradycardia. 
a. History of hepatic dysfunction, renal dysfunction, thrombocytopenia, or anemia (including 
pre-surgery laboratory abnormalities) 
b. History of hypersensitivity to NSAIDs 
c. Patients with asthma, including patients who have experienced aspirin- or NSAID- 
sensitive asthma or a history of exacerbation when aspirin or NSAIDs are administered 
(e.g. bronchospasm, urticaria, etc.) 
d. Subjects receiving medications that could impact metabolism of either study drug should 
also be excluded 
e. Trisomy 21 diagnosis 
7. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with 
study schedules or procedures. 


16 
 
 
8. Patients on a Ketogenic diet 
9. Parents or subjects who do not speak English 
 
Eligibility will be confirmed on the day of surgery (e.g pregnancy testing results will not be available before 
then, current opioid use refers to timing of surgery). Only subjects who meet all of these criteria will complete 
study procedures. Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with participating center’s IRB Policies and Procedures. 
 
4 
STUDY PROCEDURES 
4.1 
Screening Visit 
Below research activities will be conducted: 
• 
Informed Consent 
• 
Medical Record Review and data collection from standard of care 
• 
Baseline questionnaire collection 
 
4.2 
Randomization 
The study will be a 1:1 randomization to TCG or OFG Investigational Group anesthetic regimen per site 
level. A full summary of the intraoperative and postoperative medication doses and administration 
criteria are detailed in Section 7. This includes medications administered in the recovery room and 
medications that are prescribed to patients after discharge. 
 
4.3 
Post-Op Recovery Assessment 
These study activities will be conducted 15 and 30 minutes post-op at recovery room by the 
blinded observer. 
• 
Data collection as detailed in sections 5.1 and 6.3.2 
• 
FLACC (Face, Legs, Activity, Cry, Consolability) pain assessment 
• 
Delirium assessment 
 
4.4 
Follow up 
4.4.1 
Questionnaires 
Questionnaires will be obtained on POD 1,POD 5, and POD 30 (See Appendix I). Patients will 
be also be contacted on Day 30 to verify that they did not seek care outside of the participating 
center’s system for complications related to surgery, such as bleeding from surgical site. 
4.4.2 
Chart Review 
A manual Chart review will be conducted up to POD 30 to assess any AE/SAEs. All 
AE/SAEs will be reviewed by a blinded investigator and the DSMB, if indicated. 
4.5 
Unscheduled Visits 
The subject will be followed up daily (and more frequently, if indicated) for any study related and 
unanticipated adverse events until event resolution. Per participating center’s standard clinical care, the 
post-operative protocol for patients undergoing tonsillectomy includes a phone call to assess for bleeding, 
pain control and adequate hydration, along with general well-being. This information is documented in 
local eMR and any concerns are immediately conveyed to the Otolaryngology team for follow-up. 


17 
 
 
Because Ketorolac has a terminal duration of action of 30 hours, a research staff will call the patient on 
POD1 to verify they have no bleeding and are drinking and making urine. Additional follow-up 
information will be obtained via electronic questionnaire on POD5 and POD30, including a phone call if 
patient reports they sought care at an outside hospital. 
4.6 
Concomitant Medication 
All prior and concomitant pain medications used within 30 days prior to the screening visit and through 
the end of the study will be recorded. The dates of administration, dosage, and reason for use will be 
included. 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Medical Record Review 
The variables that will be abstracted from the medical chart: 
• 
PHI: Name, MRN, Date of birth and event dates, email, text and phone number, and 
pregnancy test if applicable 
• 
Demographics, including zip code 
• 
Medical history, including indication for the surgery (i.e. recurrent tonsillitis, sleep 
disordered breathing) 
• 
Vital Signs 
• 
Anesthesia records 
• 
Surgical records 
• 
Recovery records 
• 
Out-patient or ER records 
• 
Pharmacy records, including history of use of opioid pain medications 
 
5.2 
Randomization 
To ensure balance in treatment assignment, a block randomization approach will be applied by surgical 
type (intracapsular and classic). The block size will be varying (among 2, 4, 6) to avoid the predictability 
of assignment per site. 
Randomization will be conducted through the study REDCap program by an un-blinded researcher. 
Randomization could occur on the day before surgery, prior to obtaining written consent. Although 
randomization may occur prior to having the formally signed written consent form, it will not occur 
until after the initial consent discussion has been completed and documented in REDCap. The assigned 
anesthesiologist will be emailed immediately after randomizing with the patient’s assigned treatment 
arm. They are also cautioned that the patient has not provided written consent, yet, and they will receive 
another email and notified by study staff on the day of service with the consent status.  
If the patient/family signs the consent form on the date of service, the treating anesthesiologist will be 
instructed to proceed with assigned treatment arm (arm that was emailed to them the day prior).  If the family 
declines on the day of service or the participant is no longer found to be eligible on the day of service, the 
treating anesthesiologist will be notified immediately to proceed with standard of care anesthetic treatment. 
Confirmation of anesthesiologist’s acknowledgement of a) randomization b) consent status and c) screening 
confirmation on day of service will be documented in study EDC. 
To avoid protocol deviation or violation, randomization could only occur when all required study elements 
are met including re-confirmation of eligibility, surgical location and date, and research staff availability. 
The anesthesiologist will be notified of the anesthetic treatment group; he or she will verify that the patient 
is appropriate for the intervention arm by verifying that there is appropriate tonsillar bed hemostasis prior to 


18 
 
 
administering Ketorolac at the end of the case as noted in the protocol. Although not expected, any patients 
randomized to the OFG arm who receive intra-operative opioids will be followed per protocol and studied in 
a sub-group analysis. To avoid potential confounding, the surgeon will remain blinded to the patient’s 
intervention cohort assignment. 
5.3 
Post-op Recovery Assessment 
Pain, FLACC, and delirium assessments will be conducted by a blinded study staff or clinician at 
15±5 min and 30±10 min post-op after subject is awake from anesthesia. 
5.3.1 
Pain Assessment 
An age appropriate pain scale will be utilized for parent, and if appropriate, patient self-assessment of 
pain score at home. 
Modified Bieri pain scale will be utilized if the subject is less than 10 years old. 
 
 
 
Numeric Rating scale (NRS) 0-10 will be utilized if subject is 10 years or older. 
 
5.3.2 
FLACC (Face, Legs, Activity, Cry, Consolability) assessment 
Will be used to assess pain score in the recovery room by a blinded observer. 
 
Criteria 
Score 
0
Score 1 
Score 
2
Face 
No particular expression 
or smile 
Occasional grimace or frown, 
withdrawn, uninterested 
Frequent to constant quivering 
chin, clenched jaw 
Legs 
Normal position or 
relaxed 
Uneasy, restless, tense 
Kicking, or legs drawn up 
Activity 
Lying quietly, normal 
position, moves easily 
Squirming, shifting, back and forth, 
tense 
Arched, rigid or jerking 
Cry 
No cry (awake or asleep) 
Moans or whimpers; occasional 
complaint 
Crying steadily, screams or 
sobs, frequent complaints 
Consolability Content, relaxed 
Reassured by occasional touching, 
hugging or being talked to, 
Difficult to console or comfort 
 
5.3.3 
Delirium assessment 


19 
 
 
Delirium will be assessed with the Pediatric Anesthesia Emergence Delirium (PAED) 
scale.17 We will assess delirium as it is a common confounder for pain in children 
emerging from anesthesia. 
 
5.4 
Questionnaire 
Baseline, POD 1, POD 5 and POD 30 questionnaires will be collected. A RN or MD study team 
member will call the patient/family on POD1 to monitor for bleeding and dehydration. See below 
and Appendix I for additional information. This information will also be obtained on POD5 and 
POD30. Prior to discharge home, patients will be asked to record a daily maximum pain score to enter 
when they receive the corresponding survey. Patients will be also contacted on Day 30 to verify they did 
not seek care outside of the participating center for complications. The questionnaire will collect parent- 
and patient-reported pain scores, family satisfaction (Likert 7-point scale), and medication administration. 
The baseline questionnaire and a baseline pre-operative pain score, along with any recent medication use, 
will be assessed in the pre-operative area. 
All questionnaires could be collected either through text message or email with a link to the online survey 
from REDCap, or in-person, or phone call based on the parent/legal guardian’s preference. The online 
survey should take less than 5 minutes. The phone call should take less than 15 minutes. 
Renal insufficiency and bleeding are both rare, but extremely serious complications of NSAID 
administration. At participating center SOC, all patients who undergo tonsillectomy receive a phone call 
on POD1 to assess general well-being; they are specifically asked about bleeding, swallowing, hydration 
and pain control. If there are any concerns, there is a well-established communication network with the 
Otolaryngology clinic staff, who perform a same day assessment. In the event of a serious concern, such 
as bleeding or risk of airway compromise, there is a system in place to arrange emergency medical 
transport while the patient remains on the line. 
In addition to the phone call from clinical nursing staff, patients will also be contacted by research 
staff (research nurse or physician) on post-operative Day 1 who will ask: 
1. Has your child had any bright red blood in their mouth? 
2. Is your child drinking and making urine? 
If bleeding or dehydration is detected, the patient will be directed to the Emergency Department for 
assessment (or the local hospital if closer with coordination with the surgeon’s office) and the patient’s 
surgeon will be notified for follow-up. If dehydration is detected, the patient will be directed to have their 
Creatinine checked. If the family is willing, the remainder of the POD1 survey will be completed at this 
time. 
 
Electronic surveys that are sent on POD5 and POD30 will also ask: 


20 
 
 
1. Has your child had any bright red blood in their mouth? 
2. Is your child drinking and making urine? 
If subjects respond with “yes” to bleeding and/or “no” to drinking and making urine they will be called by 
a study RN or MD and be directed to the Emergency Department for assessment (or the local hospital if 
closer with coordination with the surgeon’s office) and the patient’s surgeon will be notified for follow-
up. If dehydration is detected, the patient will be directed to have their Creatinine checked. They will also 
be called by one of the study MD investigators if either complication is detected. The date of a bleeding 
(including time of event if it occurs on POD1) or dehydration event will be captured in RedCap by the 
research staff. 
5.5 
Day 30 Chart Review 
The chart will be reviewed up to 30 days after surgery to assess for medical re-attendance, including 
related phone calls or visits to a physician. 
6 
STATISTICAL CONSIDERATIONS 
Statistical analysis: Based upon the quality improvement data provided by a pediatric hospital (Seattle 
Children’s) with similar patient population demographics, we postulate that there will be no statistically 
significant difference between recovery room FLACC and pain scores in the two treatment groups. A non- 
inferiority design was specifically chosen because we are hypothesizing that there will not be a clinically 
important difference between an opioid-free anesthetic and the opioid-containing techniques (i.e. 
6.1 
Traditional anesthetic with opioids). 18,19Primary Endpoint 
The primary endpoint is median maximum pain score by investigational group in the recovery room, 
calculated by the blinded observer 15 and 30 minutes after awakening. We hypothesize that there will be 
no significant difference in two groups. 
6.2 
Secondary Endpoints 
Secondary endpoints include: 
• 
Frequency of nausea, vomiting, pruritis 
• 
Frequency of readmission and of seeking unplanned medical attention (phone calls, office visits, 
ED visits) 
• 
Frequency of non-artifactual SpO2<90% (>30 seconds) 
• 
Percentage of patients receiving rescue opioids 
• 
Family satisfaction with patient recovery based on seven-point Likert score 
• 
Bleeding prevalence 
 
6.3 
Statistical Methods 
6.3.1 
Baseline Data 
The following variables will be collected in eMR prior to surgery and after consent: age, date of 
surgery, surgeon years of experience (Resident, Fellow, <1 Year Attending, 1-5 Year Attending, 
6-10 Year Attending, 11-15 Year Attending, >15 Year Attending), height and weight, type of 
tonsillectomy (i.e. intracapsular), indication for tonsillectomy, co-morbidities including history of 
obstructive sleep apnea (OSA), zip code, and sleep study apnea-hypoxia index (AHI) and oxygen 
saturation nadir values, if available. The following information will be collected from the 
EPIC/EMR patient record after the study encounter: dose per kilogram (kg) of all pain 
medications administered in the operating room, dose of all intravenous rescue opioids 


21 
 
 
administered in the recovery room and dose of oxycodone, if administered. Vital signs, including 
instances of sustained SpO2 <90% and persistent oxygen administration once awake secondary 
to desaturations will be documented in both the recovery room and inpatient setting. 
 
6.3.2 
Efficacy Analysis 
The primary analysis will be based on an intention to treat approach and will include all subjects randomized 
at Visit 1. This will be followed by a secondary protocol analysis. Data will be analyzed in SAS software 
version 9.4 (SAS Institute Inc., Cary, NC). Demographic characteristics and medical conditions will be 
presented with standard statistics: mean and standard deviation (SD) or median and interquartile range 
(IQR), as appropriate, for continuous variable, and frequency and percentage for categorical variables. The 
balance in patients’ demographical and medical characteristics between treatment groups (i.e. opioid-free 
group and opioid-containing standard treatment group), as well as the relationship between patients’ 
demographical and medical characteristics with pain score, will be assessed using two-sample t-test or 
Wilcoxon Rank-sum test, as appropriate, for continuous variables, and Chi- square test or Fisher’s exact test, 
as appropriate, for categorical variables, with p<0.1 considered indicative of unbalance or association. 
Normality will be assessed using histogram, the value of skewness and kurtosis. The difference between 
treatment (opioid-free group minus opioid-containing standard treatment group) in pain score will be 
presented with mean and 95% confidence interval (CI), and the upper limit of 95% CI will be compared to 
the prespecified non-inferiority limit (d=0.6) to assess non-inferiority. Any deviations from protocol will be 
assessed in a sub-group analysis that will be dependent on the variable type, as described above, and the 
number of deviations. To account for unbalanced variables and confounders, including a possible difference 
between surgical type, a multivariable linear regression will also be done. Variables that are unbalanced 
between treatment groups, or related to pain score in bivariate analysis will be added as covariates in the 
model. The primary efficacy endpoint will be the difference in pain scores between TCG and OFG groups. 
Secondary endpoints will include the change in side effects associated with opioid use and family 
satisfaction. Patients may only be enrolled and randomized after being instructed to hold their pre-operative 
Celecoxib. These patients will not receive any pre-operative medication, which is the same practice as the 
proposed second site. The post-operative medication options in the original protocol incorporate the three 
most common practices at CHOP:  Ibuprofen and Acetaminophen (most common practice at second site), 
Celecoxib/Acetaminophen and Acetaminophen/Oxycodone. We will compare post-operative pain scores by 
surgery type, site and post-operative regimen and then only merge if no significant differences are noted for 
the final analysis. 
 
6.4 
Sample Size and Power 
Power calculations: We therefore have powered our study to detect a difference that is equal to or less 
than the predefined largest clinically important difference between standard care and the intervention 
derived from quality improvement (QI) data. The non-inferiority margin is determined based on both 
statistical consideration and clinical judgement.19 Using a value of the change in pain scores that is 15% of 
a single standard deviation as the non-inferiority margin (derived from QI data), 0.6 difference on a 0-10 
pain scale is also smaller than any clinically relevant change. Using the cited formula, we achieved our 
sample size.20 It will require 350 patients (175 patients per treatment group) to be 90% sure that the upper 
limit of a one-sided 95% confidence interval will be below 0.6 if the pain score is truly not worse for the 
intervention group.20 
 


22 
 
 
Figure. Overview of non-inferiority trial principles comparing the confidence interval (CI) of the mean difference to a predicted margin (used with 
permission, B. Zhang, CHOP); A,B,C: non-inferiority not demonstrated because the upper limit of CI exceeds the margin. D,E: Non-inferiority 
was demonstrated because the upper limit of CI did not exceed the margin 
 
7 
STUDY MEDICATION 
7.1 
Description 
Currently providers at participating center use a combination of Opioids, Acetaminophen, 
Dexmedetomidine and Ketorolac for analgesia during tonsillectomy and adenoidectomy. The universal 
standard includes opioids 
(intravenous Morphine or Fentanyl) first, followed by any combination, including all of the three other 
medications. It is important to note that while a few surgeons do currently permit use of Ketorolac for 
tonsillectomy, it is not the standard of care at participating center.  Patients randomized to the intra-
operative opioid- free investigational group will receive a standard inhalation induction (intravenous with 
Propofol at the provider’s discretion), 1ug/kg of Dexmedetomidine (maximum 50ug) over ten minutes and 
Propofol 1- 2mg/kg if indicated following intravenous line placement, intubation with appropriate oral 
RAE endotracheal tube, maintenance with sevoflurane at 2.5% until in suspension with a subsequent 
decrease to 1.7-2%, standard doses of ondansetron (0.1mg/kg, max 4mg), dexamethasone (0.5mg/kg, max 
10mg), 20 milliliters (ml/kg) of lactated ringers (LR) and ketorolac (0.5mg/kg; maximum 15mg21) at the 
end of the procedure, with extubation (awake or deep) at the provider’s discretion. All patients will receive 
intravenous Acetaminophen prior to the conclusion of the procedure (12.5mg/kg, max 1000mg, stratified 
by age in the participating center formulary). 
Patients randomized to the TCG investigational group will receive an identical anesthetic to the opioid-free 
group with two exceptions.  Dexmedetomidine and Ketorolac will not be administered intra-operatively. 
Patients will receive the institutional standard dosing for opioids in tonsillectomy (0.5-2ug/kg fentanyl OR 
0.05-0.1mg/kg morphine) 
If a patient has a pain score judged as severe (current PACU standard pain evaluation -FLACC>8) based 
upon a consensus panel composed of anesthesiologists and nursing providers, they will receive rescue 
intravenous Morphine or Fentanyl per a weight-based standardized algorithm that is contained within the 
participating center order set “Post-op Orders.” If pain continues to be poorly controlled per the criteria 
above, patients will receive standard weight-based liquid Oxycodone (0.05-0.1mg/kg).  The un-blinded 
PACU nurse will be encouraged to not administer oxycodone if a patient’s pain is clinically controlled 
with non-medical interventions such as a popsicle and re-direction, which is standard of care at 
participating centers.  
Regardless of investigational arm, if a child scores positive for emergence delirium using the attached 
PAED scale, the anesthesiologist may choose to treat this with 0.25-1ug/kg Dexmedetomidine, maximum 
50ug. Dosing will occur at the provider’s discretion and will be documented. 
Use of other NSAIDs: Administering post-op Ketorolac in PACU is prohibited for both groups.  
Recently, CHOP ENT departmental clinical practice has been changed regarding the use of pre-operative 
Celebrex. Surgeons at CHOP have begun to prescribe Celecoxib to be taken on the morning of (before) 
the scheduled surgery.  While the intent is to reduce postoperative pain, there is a paucity of evidence that 
this preoperative dose does so. In addition, this practice is followed by most but not all members of CHOP 
Otolaryngology Department and is not done widely outside of this participating center. Furthermore, 
many participating centers’ patients are unable to take Celecoxib because of age or insurance reasons. If 
patients are interested to in the study, they will be instructed to not take Celecoxib the morning of surgery 
by their surgeon.  There is no evidence to believe that this will have any impact on their intra-operative or 
immediate post-operative course. The participating center Otolaryngologists have all agreed to instruct 
their patients to not take Celecoxib the morning of surgery for the purposes of the study. As noted in the 
PACU and home sections, all other medications routinely used for pain will not be changed by the study. 


23 
 
 
At home, patients will be prescribed one of three well-established regimens that is determined by their 
surgeon: liquid Oxycodone and Acetaminophen (not currently prescribed by surgeons who have opted to 
participate), Acetaminophen and Ibuprofen with a rescue prescription for Oxycodone and Acetaminophen 
and Celecoxib with a rescue prescription for Oxycodone.  Because of the range of doses by weight and 
age, each patient is provided with a customized discharge medication list (prepared by their surgeon) prior 
to leaving the hospital. 
Morphine, Fentanyl, Oxycodone, Acetaminophen, Dexmedetomidine and Ketorolac are currently used 
frequently in participating center clinical pediatric anesthesia practice. The dose, route, and indication are 
standard of care for pediatric patients at participating center, although Ketorolac is not the standard of care 
for tonsillectomy at participating center. Dexmedetomidine and Ketorolac are FDA approved medications 
for adults only but are on the participating center formulary and are frequently used. Ketorolac has a Black 
Box warning associated with the following systemic risks: Gastrointestinal (peptic ulcers, gastrointestinal 
bleeding, and/or perforation of the stomach or intestines), Cardiovascular (serious thrombotic events, 
myocardial infarction and stroke), Renal (avoid with advanced renal impairment and in patients at risk for 
renal failure due to hypovolemia), Risk of Bleeding (contraindicated in patients with suspected or 
confirmed cerebrovascular bleeding due to inhibition of platelet function, patients with hemorrhagic 
diathesis, incomplete hemostasis and those at high risk of bleeding). Any patient identified with factors 
that place them at increased risk of bleeding are excluded from study participation. Ketorolac, and other 
non-specific NSAIDs have been associated with a small increased risk of bleeding after all surgical 
procedures. The sentinel Strom publication evaluated the risk of operative site bleeding among patients 
who had received 10, 272 parenteral Ketorolac doses compared to matched patients who received opioids 
and found that there was a slight non-significant elevation in adult patients (OR 1.02; 95% CI 0.95-1.10).22 
The POINT trial compared risks of serious adverse events, including increased surgical site bleeding, 
gastrointestinal bleeding, acute renal failure and allergic reactions, between 11,245 patients who were 
randomized to receive Ketorolac, Ketoprofen and Diclofenac.23  At the time, safety data were inconclusive 
with regard to Ketorolac compared to the other two non-steroidal anti-inflammatory agents. There were no 
significant differences for the key outcomes between all three groups (Forrest 2002; Br J Anaes). 
Historically, Ketorolac, as well as other NSAIDs, were associated with an increased risk of bleeding after 
tonsillectomy. 24 Patients will receive information in the consent that some studies have linked Ketorolac 
administration to a higher risk of bleeding, especially in adults and when multiple or high doses 
(>0.5mg/kg) are administered. The modern standard of care involves use of cautery, and the procedural 
risk of bleeding peaks 5-10 days after surgery when the eschar begins to dislodge in the oropharynx; 
Ketorolac’s terminal duration of action is 30 hours.25 A sentinel 2014 meta-analysis concluded that there 
was no increased risk of post-tonsillectomy hemorrhage in children who received Ketorolac for 
tonsillectomy, but the authors reported that the risk appeared to have a five-fold elevation among adults.25 
This meta-analysis specifically notes that the adult data are under-powered relative to the pediatric data to 
detect a difference in bleeding risk, but it must be emphasized that the association between Ketorolac use 
and bleeding was significant in adults.25 In a newer cohort study of adults undergoing tonsillectomy who 
received either a five-day course of oral Ketorolac versus a traditional opioid-containing regimen, there 
was no significant difference between postoperative hemorrhage between groups and there was no 
difference in severity of bleeding events.26 However, this study was not adequately powered to detect a 
significant difference. For adults, it is still unclear if the risk of bleeding after tonsillectomy is higher with 
Ketorolac given the small number of patients who undergo tonsillectomy as adults and the higher risk of 
bleeding.25,26Of note, Dexmedetomidine and Ketorolac are two medications are frequently used in 
combination (after excluding patients less than 44 weeks post- conceptual age and at risk for renal 
insufficency or increased bleeding risk) without increase in risk, specifically for urologic, orthopedic and 
otolaryngology procedures  (personal communication, Dr. 
Francis Kraemer, Chief, Acute and Chronic Pain Management, Department of Anesthesiology, 11 Oct 
2019). However, this is not the current standard of care at participating center for tonsillectomy. 
 
IND exemption form applications are attached. 


24 
 
 
1) Both Dexmedetomidine and Ketorolac are lawfully marketed in the United States. 
 
2) Their use in this study is not intended to be reported to FDA as a well-controlled study in support of a 
new indication and there is no intent to use the information that is collected to support any other significant 
change in the labeling of the drug or advertising of the drug, 
 
3) Their use does not involve a route of administration, dose, patient population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with their use. 
 
Dexmedetomidine and ketorolac will be supplied by participating center hospital pharmacy like all other 
anesthetic medications for the surgery. The drugs are included in participating center standard OR 
anesthesia cart. Investigational Pharmacy will not be involved in this study. 
 
7.1.1 
Dosing 
OFG investigational group: 
Dexmedetomidine is 1µg/kg with maximum 50 µg intravenously 
Ketorolac is up to 0.5mg/kg with maximum 15 mg intravenously. Although 30mg is recognized at the 
maximum dose at participating centers, there is evidence to support dose capping at 15mg given 
decreasing analgesic effect and the possibility of increased risk with higher doses.21 
 
All other medications are dosed in compliance with participating center standards as noted in Section 7.1. 
 
7.1.2 
Treatment Compliance and Adherence 
The anesthesiologist will be notified of the randomization assignment from a study member. As noted in 
exclusion criteria, any patient at high risk of hemorrhage secondary to a bleeding disorder diagnosis would 
be excluded from study participation. If a surgeon were to feel that the surgical bed was not hemostatic, 
they would notify the attending anesthesiologist prior to disclosure of the treatment arm and any patients 
randomized to the intervention arm would be crossed-over to the TCG and analyzed separately. This is not 
anticipated based upon data provided by our colleagues at Seattle Children’s Hospital for 965 
consecutively enrolled patients. Patients will be expected to respond to POD 1, 5 and 30 text queries. 
Study staff will follow-up within two days if these queries are not completed. Any loss to follow-up will 
be documented and released with the final data analysis. 
8 
SAFETY MANAGEMENT 
8.1 
Clinical Adverse Events 
 
Clinical adverse events (AEs) will be monitored throughout the study. AE/SAEs will be evaluated by a 
blinded study investigator. Our stopping criteria are as follows: if a maximum expected 10% risk of 
bleeding is exceeded in a given month, the trial will be halted, the IRB will be notified and the DSMB will 
conduct an audit to assess if the risk is higher in one group. The interim analysis will occur after 50 
patients, 15% of the target, have been enrolled. The DSMB board will meet at this point. In addition, the 
DSMB will have planned semi-annual meetings to review data and a meeting may be called by any 
investigator or participating center’s clinician to review specific concerns. The DSMB will also receive 
monthly reports detailing bleeding rates in the two groups. The IRB will be immediately notified, and the 
study will be halted while the DSMB examines the data if significant, unexpected deviations are detected. 
If the DSMB determines that the rate increase was similar between groups and had no plausible correlation 
with Ketorolac or other study medications (i.e. new surgical technique or operator with a higher rate of 
surgical complications), the study would be permitted to proceed. 
 
The following are anticipated SAEs for pediatric tonsillectomy at our institution. 


25 
 
 
The following are the known SAEs related to surgery that are anticipated based on current clinical 
experience, and the approximate rates that are expected. These SAEs will be recorded and their rates 
monitored carefully, but are reported differently to the IRB from the unanticipated SAEs. 
1. Postoperative hemorrhage (expected rate up to 10%) 
Hemorrhage is not rare after tonsillectomy, and is anticipated in both treatment groups. Rates are typically 
2-5%, but rates up to 10% have been observed in some months at participating center.  Hemorrhage is 
always considered a life-threatening SAE.  We further anticipate that rates of the two groups will be 
similar. 
Hemorrhage events, including hospitalization and surgical management, will be recorded, and their rates 
and outcomes monitored by the PI throughout the study. 
2. Postoperative readmission (expected rate up to 10%). 
From internal quality monitoring data over the last 2 years, rates of readmission of up to 10% have been 
observed. Historically these result from hemorrhage (described separately above), pain-related 
complications (uncontrolled pain, dehydration), and side effects from narcotics or anesthesia (e.g., nausea, 
vomiting). 
3. Prolonged initial admission (expected rate up to 30% of those kept overnight). 
Children who are admitted overnight after surgery often stay hospitalized a second night or longer. The 
most common reason is inadequate oral intake, which is most common in the younger children. Other 
reasons include inadequate pain control, the need for more time to wean off supplemental oxygen, or the 
need for an additional night of respiratory monitoring due to episodes of oxygen desaturation recorded the 
first night. 
 
Some admissions, however, are pre-planned and the standard of care for certain populations (i.e. 
age, disease severity, co-morbidities, or other considerations). These planned admissions are not 
considered as serious safety events. 
 
8.2 
Adverse Event Reporting 
If any unanticipated problems related to the research involving risks to subjects or others happen during 
the course of this study (including SAEs in access of expected SAEs and expected ranges) they will be 
reported to the IRB in accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to 
Subjects. AEs that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing review. 
Specifically, with regard to bleeding risk (although this plan also includes re-admission and prolonged 
initial admission), if bleeding in either cohort exceeds expected rates (10% during one month), the IRB 
will be notified as noted below and the DSMB will conduct a data audit. All FDA regulations and IRB 
policies will be followed. Study enrollment will be halted until input has been obtained from all Data and 
Safety monitoring team members listed below and the IRB office. 
As noted in Section 8.1, when the 50th patient is enrolled and/or if the bleeding rate exceeds 10% in one 
month, treatment groups will be blinded and bleeding events will be presented to the DSMB. If the DSMB 
agrees that the rate of the bleeding is not different from baseline established rates, the study will be 
permitted to proceed. The DSMB will have planned semi-annual meetings to review data and a meeting 
may be called by any investigator or CHOP clinician to review specific concerns. The study’s primary 
study coordinator will tally adverse events and will provide these to the DSMB each month. 
To provide an additional level of oversight, two well-qualified pediatric physician researchers will 


26 
 
 
participate in the evaluation of a severe adverse event, including bleeding in excess of established rates. 
These individuals are: 
• 
Dr. Todd Kilbaugh, an experienced translational researcher and intensivist at CHOP 
• 
Dr. Sydney Brown, a PhD-level Epidemiologist with significant experience in ethical study 
conduct and a practicing Anesthesiologist at CHOP 
• 
In the event of discordance, Dr. Ian Yuan, a clinical researcher who specializes in 
assessment of anesthetic depth in neonates, will step in to perform a third assessment. 
The Investigator will promptly notify the local IRB of all unanticipated, serious Adverse Events that are 
related to the research activity. Other unanticipated problems related to the research involving risk to 
subjects or others will also be reported promptly. Written reports will be filed using the eIRB system and 
in accordance with the timeline below. 
 
Type of 
Unanticipated 
Problem 
Initial Notification 
(Phone, Email, 
Fax) 
Written Report 
Death or Life Threatening 
SAEs (not listed in 
Section 8.1)* 
24 hours 
Within 2 calendar days 
*For the Anticipated SAEs listed in Section 8.1 above, the Investigator will report these events differently 
than other SAEs. If rates of Anticipated SAEs fall within the expected ranges listed in Section 8.1, they will 
be reported similarly to AEs, as a summary at the time of Continuing Review. However, if their rates exceed 
the expected ranges, they will be reported promptly to the IRB as per the above table (i.e., 24 hours for life 
threatening SAEs, 7 days for all other SAEs). Death will always be reported within 24 hours regardless of 
the circumstances. 
9 
STUDY ADMINISTRATION 
9.1 
Treatment Assignment Methods 
9.1.1 
Randomization 
The randomization schedule will be generated by a statistician at DCC and randomized by using the 
REDCap randomization feature. The subject is required to be registered in REDCap prior to 
randomization. To avoid protocol deviation, only eligible subjects are able to be randomized in 
REDCap by a designated unblind study staff. 
9.1.2 
Blinding 
The study has blinded and unblinded staff. 
The unblinded members are the treating anesthesiologist for the case, staff who randomize,  and collect 
and enter medications into REDCap. The otolaryngologist will remain blinded. All staff and parents could 
All other SAEs 
(not listed in Section 8.1)* 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days 
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important AEs 
may be reported at time of 
continuing review 


27 
 
 
be un- blinded once the 30 day chart review and AE/SAE evaluations are completed. Group randomization 
assignment in REDCap will be only visible to limited unblinded staff including the study manager and data 
entry staff. 
Blinded members include the subject and their family members, the surgeon, staff who will perform post- 
op assessment, and at least one physician investigator who will perform any AE/SAE assessments. 
Statistician and DSMB should also be kept as blinded. 
9.1.3 
Unblinding 
Subject intra-op medication will be unblinded and documented in eMR. If the “blinded” assessor is 
unblinded at the time of assessment, then unblinded date and reason will be documented in REDCap. 
Another blinded staff may be assigned for the remaining assessments. 
9.2 
Data Collection and Management 
Minimal identifiable information might be printed and recorded on paper for study eligibility 
clarification, study data collection, and data validation. Paper records which contain direct PHI will be 
stored in either locked file cabinets or in a secured locked research staff or investigator’s office with 
access only to authorized personnel. Study data will be stored on a participating center password 
protected research drive with access limited to research personnel. REDCap will be utilized to capture 
study data. 
 
When the study is completed, all study paper records may be scanned to store along with other electronic 
study records for retention. All study materials including PHI will be retained for 6 years post-study 
completion per institutional data retention policy. Paper consent forms will be scanned and uploaded into 
study REDCap for retention. 
 
Master List sharing will be limited among the research team. Limited dataset with dates will be shared 
with the statistician for data analysis. 
9.3 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance with institutional 
policies and HIPAA on subject privacy. No identifiable data will be used for future study without first 
obtaining IRB approval. The investigator will obtain a data use agreement between the provider (the PI) of 
the data and any recipient researchers (including others at DCC) before sharing a limited dataset. 
Safeguards to maintain subject confidentiality are described under Data Collection and Management. 
 
9.4 
Regulatory and Ethical Considerations 
9.4.1 
Data and Safety Monitoring Plan 
This is a greater than minimal risk study, and there are stringent exclusion criteria given the risks 
associated with the study medications (specifically bradycardia and higher bleeding risk) in small sub-sets 
of the surgical population.  The data monitoring plan is outlined in Section 8.2, and we have consulted 
with two external experts in pain research and ethical research conduct. During the study period, the 
DSMB and PI will monitor study progress, ensure subject safety, and the accuracy and security of the data 
at participating certers, and will report any adverse events in accordance with the FDA regulations and 
IRB policies. 
9.4.2 
Risk Assessment 
Dexmedetomidine and Ketorolac are currently used frequently in participating center clinical pediatric 
anesthesia practice (see Appendix II and III), although Ketorolac is not the standard of care for 
tonsillectomy at participating center. There is no reason to suspect an increase in risk from their use in this 


28 
 
 
study after children with risk of complications have been excluded from participation, although there is 
evidence that adults are at higher risk of bleeding with Ketorolac administration.27,28  Many 
otolaryngologists, along with the entire anesthesia department, have agreed to have their patients 
randomized. There is the possibility that OFG subjects’ pain will not be adequately controlled without 
opioids. If the pain is not controlled in the OFG group they will receive opioids in the same manner as the 
TCG group where severe pain is managed with additional opioids. 
Risks of Ketorolac: While Ketorolac is routinely given to children at participating centersfor certain 
procedures, it is not FDA approved for use in children. Its use is increasing for tonsillectomy, but it 
is not the standard of care at participating center and is only used by a sub-set of Otolaryngologists 
(nine have agreed to have their patients randomized to receive Ketorolac). Some surgeons avoid 
Ketorolac entirely. As noted in more detail below, historic data found that there was an increased 
risk of bleeding after tonsillectomy with Ketorolac administration and may be related to excessively 
high doses that were administered. The FDA label also warns that Ketorolac can cause peptic ulcers, 
stomach bleeding and holes in the stomach, which is why it is never used more than five days in a 
row.  All non-steroidal anti-inflammatory drugs (NSAIDs), like Ketorolac and Ibuprofen, have a 
similar risk profile, although these risks may be higher with the IV formulation. There is a black box 
risk associated with increased bleeding. All children with bleeding disorders or certain kidney 
problems are excluded from participation. 
 
Ketorolac, and other non-specific NSAIDs have been associated with a small increased risk of bleeding 
after all surgical procedures. The sentinel Strom publication evaluated the risk of operative site bleeding 
among patients who had received 10, 272 parenteral Ketorolac doses compared to matched patients who 
received opioids and found that there was a slight non-significant elevation in adult patients (OR 1.02; 95% 
CI 0.95-1.10).22 The POINT trial compared risks of serious adverse events, including increased surgical site 
bleeding, gastrointestinal bleeding, acute renal failure and allergic reactions, between 11,245 patients who 
were randomized to receive Ketorolac, Ketoprofen and Diclofenac.23 At the time, safety data were 
inconclusive with regard to Ketorolac compared to the other two non-steroidal anti-inflammatory agents. 
There were no significant differences for the key outcomes between all three groups.23 Historically, 
Ketorolac, as well as other NSAIDs, were associated with an increased risk of bleeding after tonsillectomy. 
24 With current surgical technique, the procedural risk of bleeding peaks 5-10 days after surgery when the 
eschar begins to dislodge in the oropharynx.25 A sentinel 2014 meta-analysis concluded that there was no 
increased risk of post-tonsillectomy hemorrhage in children who received Ketorolac for tonsillectomy, but 
the authors reported that the risk appeared to have a five-fold elevation among adults.25 This meta-analysis 
specifically notes that the adult data are under-powered relative to the pediatric data to detect a difference 
in bleeding risk, but it must be emphasized that the association between Ketorolac use and bleeding was 
statistically significant in adults.25 In a newer cohort study of adults undergoing tonsillectomy who received 
either a  five-day course of oral Ketorolac versus a traditional opioid-containing regimen, there was no 
significant difference between postoperative hemorrhage between groups and there was no difference in 
severity of bleeding events.26  It is currently unclear if adults are at higher risk of hemorrhage after 
tonsillectomy with Ketorolac administration.25,26 
 
Risks of Dexmedetomidine: Dexmedetomidine is part of a group of medications called Alpha-2 agonists that 
provides pain control and causes sedation but has negligible impact on respiratory drive. The primary risk is a 
decrease in heart rate, which is why children with unrepaired congenital cardiac disease or syndromes with 
predisposition to bradycardia are excluded from participation. If severe bradycardia developed, it would be 
medically treated with either Atropine or Glycopyrrolate. 
Risk of the combination of Ketorolac and Dexmedetomidine: There is no increased risk of giving these two 
medications together. 
 
9.4.3 
Potential Benefits of Trial Participation 
Subjects who are randomized to the OF Group will likely avoid a potentially high-risk opioid exposure. In 


29 
 
 
addition, it is likely that the incidence of nausea and vomiting will be significantly reduced. The Opioid- 
Free technique could reduce hundreds of thousands of annual pediatric opioid exposures, and subsequent 
risk of misuse among pediatric patients. 
9.4.4 
Risk-Benefit Assessment 
There are potential benefits to the greater population of children in that we will have knowledge with 
regard to outcomes and satisfaction for the opioid-free technique for tonsillectomy. 
9.5 
Recruitment Strategy 
The PI will provide an in-service to all recruiting locations at participating centers. Potential subjects will 
be identified from the scheduled surgical list. The study introduction will be initiated by any study 
investigator. 
The risks and benefits will be discussed at the consent conference. The study research flyer could be 
given to each potential subject/family either at the pre-op clinic visit (in-person) or via email/text with 
link to the informed consent form .The family could view consent form via the link or scan QR code on 
the flyer. After study information has been provided, a member of the study staff screens interested 
patients and reviews inclusion and exclusion criteria as described in the Screening Visit section. 
 
9.6 
Informed Consent/Assent and HIPAA Authorization 
 
A combined consent-authorization document will be used. Only one signature from parent or legal guardian 
will be required for this study. 
 
For the subjects who were unable to perform the Informed Consent process at the clinic visit prior to the day 
of surgery or require additional time to review the study documents and consent form, the following will 
occur. A Study Team member will telephone, email, or send text via REDCap, which includes a link to 
referral form, to the potential subject any time after ENT pre-clinic visit but before the scheduled surgery day 
depending on the family’s availability, explain the study to them, and perform screening assessments as 
described above. The text message or email which contains the link to download the study consent will only 
be sent to permissible  subjects/families after the study has been briefly been introduced and subjects/families 
have expressed interest in learning more.  
 
 The actual Informed Consent/Assent process will occur as follows. A study physician will be immediately 
available by telephone to answer any questions about the study procedures or risks. The formal consent 
discussion (including discussion of risks like bleeding) will not occur on the day of surgery. The consent 
discussion will occur in advance (and will be documented in the study REDCap), but it is acceptable for the 
signed form to be returned on the day of surgery or to be signed on the day of surgery. 
 
The consent interview could also be conducted by telephone when the parent can read the consent form during 
the discussion (and when the child is available for assent, if applicable). The consent form will be signed 
either before or on the day of surgery. The parent will have the opportunity to ask questions and receive 
answers prior to signing the form. A study physician will either be immediately available during the call to 
answer any questions about the study procedures or risks, or the parent will be given a description of how and 
when they will receive answers to their questions (usually by a telephone call later from the physician) prior to 
the date of surgery. Family will be informed during the consent process that they might not be able to 
participate even if consented due to unexpected circumstances such as rescheduling, limited researcher 
availability, and eligibility.  Consent will be conducted in a private area. 
 
Regardless of method of obtaining consent, subjects will be instructed to not sign the document until all 
questions they have for a physician are answered.  Subjects are counseled that they may freely choose not to 
participate in the study, but if so, they will not receive an opioid-free anesthetic. They will be informed that 
this will not otherwise affect their other medical care or treatment. In particular, it will be emphasized that 


30 
 
 
their pain control would follow standard of care outside the study, and that they will still obtain the 
recommended surgery in the usual fashion. Families will also be counseled that they will be responsible for 
costs of care not covered by their insurance and that participating center does have additional resources if they 
are uninsured or underinsured. Families are given as much time as they need to make their decision and ask 
questions of the staff and physician, who will ensure that subjects comprehend the nature of the study, the 
study procedures and the risks and benefits of participation before providing consent. 
9.7 
Payment to Subjects/Families 
There will be no payment to subjects/families. 
10 PUBLICATION 
After collection, review, and analysis of data, the results of this study will be submitted for publication in a 
peer-reviewed scientific journal. 
 
The study is funded by participating center local grant. 


31 
 
 
 
APPENDIX I: 
 
Baseline Questionnaire 
 
1. Have any other children living in your household had a tonsillectomy and/or adenoidectomy? (Yes)/(No) 
2. Has anyone in (Child’s Name) taken opioids in the past 30 days? (Yes)/(No) 
3. Does (Child’s Name) have pain today? (Yes)/(No) 
4. Has your child said they have pain anywhere in their body in the last 30 days? 
5. If yes, how would you rate it on a scale of 1-10 (1 meaning very mild pain, 10 meaning the worst pain of their 
life) 
6. Has your child been given opioid medications (i.e. oxycodone, morphine, etc.) for pain control within 30 days? 
 
Questionnaire for POD1 and POD5, POD30 
 
*The same questionnaire will be asked (either by electronic questionnaire or via phone, if indicated as the family's 
preference) on POD5 and POD30. 
1. Are you satisfied with your child’s recovery? 
• 
1-7 Likert scale 
• 
 
2. Are you satisfied with your child’s pain control at home? 
• 
1-7 Likert scale 
• 
 
3. Did your child experience severe nausea or vomit after leaving the recovery room (POD1 
questionnaire only) 
 
4. How would you rate your child’s pain today (have your child provide assessment if age 
appropriate) on the provided pain scales (Modified Bieri <10 years, NRS >10years) 
 
• 
For POD5 survey only; please fill in the average pain score for POD2, POD3, POD4 and 
POD5 (today) 
 
5. Have you given your child any Acetaminophen (Tylenol)? 
• 
If yes: Fill in number of total doses [by day] 
6. Have you given your child any Celecoxib (Celebrex) or Ibuprofen (Motrin)? 
• 
If yes: Fill in number of total doses [by day] 
7. Did you receive a prescription for oxycodone? 
• 
If yes, did you fill this prescription? 
• 
If you filled this prescription, how many tablets has your child used? 
8. Will be completed by phone for POD1: Has your child had any bright red blood in their mouth? 
(yes/no) 
• 
If yes, please insert date/time of event 
• 
Were you/your child evaluated in an outside ER or hospital. If so, was admission and/or 
reoperation required? 
9. Will be completed by phone for POD1: Has your child not met any of the hydration guidelines that 
were provided prior to discharge? (yes/no) 


32 
 
 
Phone Script for questions 8 and 9: 
Provider: My name is XXX and I am a research (physician or nurse) with the Opioid-free tonsillectomy study. I am 
calling to see how your child has been doing since they went home yesterday. [Will ask questions 8 and 9]. If both 
answers are no, the provider will state, “if you would like, I can complete the rest of survey questions [1-7] with you 
on the phone right now”. At the end, the provider will state, “Thank you for your time” 
1. Will be completed by phone for POD1: Has your child had any bright red blood in their mouth? 
(yes/no) 
2. Will be completed by phone for POD1: Has your child been drinking and making urine? (yes/no) 
 
If subjects respond with “yes” to bleeding and/or “no” to drinking and making urine they will be called by a study 
MD (if RN is making the POD1 call) and be directed to the participating center’s Emergency Department for 
assessment (or the local hospital if closer with coordination with the surgeon’s office) and the patient’s 
participating center surgeon will be notified for follow-up. If dehydration is detected, the patient will be directed to 
have their Creatinine checked. The date of a bleeding (including time of event if it occurs on POD1) or dehydration 
event will be captured in RedCap by the research staff. 
 
***Please note that you will receive a call from the study team and/or the Otolaryngology clinic if you answer 
Yes to either Question 8 or 9 on POD5 or POD30**** 
3. Day 30 only: Did you see a doctor or nurse outside of participating center for: 
• 
Bleeding, poor pain control, severe nausea, constipation, dehydration and/or inability to take 
in adequate nutrition 
A study doctor will contact you to learn more about your child’s experience. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


33 
 
 
Appendix II: Case for IND Exemption, Ketorolac for Tonsillectomy 
Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily depends on the intent of 
the investigation and the degree of risk associated with the use of the drug in the investigation. A clinical 
investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an exemption in § 
312.2(b) are met: 
• The drug product is lawfully marketed in the United States. 
 
Ketorolac is lawfully marketed in the US. 
• 
The investigation is not intended to be reported to FDA as a well-controlled study in support of a new 
indication and there is no intent to use it to support any other significant change in the labeling of 
Ketorolac. 
 
The study is not intended to support a new indication or change in labeling of Ketorolac. 
• 
In the case of a prescription drug, the investigation is not intended to support a significant change in the 
advertising for Ketorolac. 
 
The study does not intend to support a change in advertising of Ketorolac. 
• 
The investigation does not involve a route of administration, dose, patient population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug 
product (21 CFR 312.2(b)(1)(iii)). 
 
The route of administration matches the product label (intravenous). 
For the population to be studied, children aged 2-18 undergoing tonsillectomy, the investigators do not consider this 
population to be at added risk for the indication, pain control, for which this medication has been approved by the 
participating center formulary (30mg dose equivalent to 12mg morphine). The Ketorolac dose planned for the study is 
equivalent to the approved dose (0.5mg/kg, maximum 30mg; of note, the study maximum is set more conservatively at 
15mg). Many patients undergoing tonsillectomy have a sleep- disordered breathing diagnosis that is worsened by 
administration of opioid pain medications, for which Ketorolac provides equivalent analgesia (i.e. a 10kg child would 
routinely receive 0.1mg/kg, or 1mg morphine intra-operatively, and the participating center formulary analgesic 
equivalent dose for Ketorolac would be 2.5mg, well below the acceptable 0.5mg/kg dose of 5mg). A prospective 
randomized controlled trial found that children with sleep-disordered breathing who were exposed to opioids 
perioperatively had an average increase of 11.17 (+/-15.02) desaturation events per hour.6 Per the participating center 
formulary, children with renal dysfunction or a bleeding disorder would be ineligible to receive Ketorolac. 
 
Historically, there was concern that non-steroidal anti-inflammatory drugs (NSAIDs) were related to an increased 
bleeding risk among children undergoing tonsillectomy. Several contradictory studies were underpowered to detect 
bleeding risk; the concern for bleeding risk exists 7-10 days after surgery.29,30 Ketorolac’s half-life is 5-6 hours and any 
change in platelet function returns to baseline 24-30 hours after a single dose, well before the period associated with 
higher bleeding risk.31,32 A large meta-analysis demonstrated that there is no increased risk of post-tonsillectomy 
bleeding in children under 18 years, however, the same study identified a 5-fold increased bleeding risk among adults 
and this was statistically significant.25,26 Of note, oral NSAIDS, along with acetaminophen, are now the standard of care 
for post- operative analgesia for tonsillectomy, and a large internal retrospective review noted no increased risk of post-
tonsillectomy bleeding with NSAID administration post-operatively.33,34 
 
Although there are little published data, Ketorolac is routinely used at similar sites such as DuPont Hospital for 
Children, Emory, Albany Children’s and Seattle Children’s without evidence of increased bleeding risk among 
children undergoing tonsillectomy. Seattle Children’s has transitioned to the same opioid-free protocol listed in the 
study application. Data output obtained via a quality improvement initiative at Seattle Children’s are notable for no 
increased bleeding risk (return to OR rate is 0.8 among 612 patients undergoing the opioid-free protocol with Ketorolac 
and 1.17% among 1,724 children receiving a standard opioid-containing protocol), no significance in maximum post-
operative pain score and a decrease in post-operative nausea and vomiting (see Figure 1; personal communication, Dr. 


34 
 
 
Daniel Low, June 28 2019). Seattle Children’s continues to provide monthly data updates to the investigators and has 
already treated 965 pediatric patients (up to age 19), more than the number proposed in this Year 1 protocol. Emory 
and Albany have published trial protocols on clinicaltrials.gov with the intent of demonstrating decrease in post-
operative opioid requirements by using Ketorolac for tonsillectomy in children (NCT03453541 and NCT03467750). 
 
Therefore, the investigative team believes that the use of Ketorolac in the study is IND exempt, and that there is no 
increased risk or decreased acceptability of the risk, of administering 0.5mg/kg of Ketorolac to children age 2-18 
undergoing tonsillectomy. 
 
Table 1: Literature review of Ketorolac dose algorithms and adverse events in pediatric 
patients undergoing tonsillectomy. 
 
Author 
N 
Age 
Dose 
Adverse Events 
Chan 201425 
Meta-analysis of 
10 studies 
reporting ketorolac 
administration and 
bleeding risk 
Under 18 
Variable 
Relative risk of any bleeding under 
age 18: 1.39; 95% CI: 0.84–2.30; 
p=0.20; conclusion that there is no 
increased risk of bleeding under 
age 18 with ketorolac 
administration (either intra- or 
post-operatively) for tonsillectomy 
Low 2019 (QI 
data, see Figure 
1) 
612 children 
Age 2-19 
0.5mg/kg, maximum 
30mg 
Return to OR for bleeding among 
0.79% of children receiving 
Ketorolac; 1.17% among children 
receiving morphine/acetaminophen 


35 
 
 
 
 
Figure 1. Summary of quality improvement data, Seattle Children’s (through 6/28/2019) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
 
The study will be conducted after IRB approval, with an IRB-approved consent. 
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). 
 
The study is not intended to promote or commercialize the drug product. 


36 
 
 
Appendix III: Case for IND Exemption, Dexmedetomidine for Tonsillectomy 
Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily depends on the 
intent of the investigation and the degree of risk associated with the use of the drug in the investigation. A 
clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an 
exemption in § 312.2(b) are met: 
• The drug product is lawfully marketed in the United States. 
 
Dexmedetomidine is lawfully marketed in the US. 
• The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of Dexmedetomidine. 
 
The study is not intended to support a new indication or change in labeling of Dexmedetomidine. 
• In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for Dexmedetomidine. 
 
The study does not intend to support a change in advertising of Dexmedetomidine. 
• The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
 
The route of administration matches the product label (intravenous). 
For the population to be studied, children aged 2-18 undergoing tonsillectomy, the investigators do not 
consider this population to be at added risk for the indication, procedural sedation and anesthesia, for 
which this medication has been approved by the participating center formulary.  The Dexmedetomidine 
dose planned for the study will not exceed the approved dose. Dexmedetomidine has been approved at 
participating center for infants and children up to doses of 2ug/kg for procedures; our study proposes 
1ug/kg (maximum 50ug). Many patients undergoing tonsillectomy have a sleep-disordered breathing 
diagnosis that is worsened by administration of opioid pain medications. A prospective randomized 
controlled trial found that children with sleep-disordered breathing who were exposed to opioids 
perioperatively had an average increase of 
11.17 (+/-15.02) desaturation events per hour.6 A randomized controlled trial demonstrated that 1ug/kg of 
Dexmedetomidine is equivalent to 0.1mg/kg morphine for post-operative analgesia for tonsillectomy 
without the respiratory depression and nausea risk associated with opioids.28 There are extensive data with 
regard to the safety of Dexmedetomidine use in the pediatric population for sedation; additional benefits 
include protection against end-organ ischemia.35,36 Dexmedetomidine has been studied in children 
undergoing tonsillectomy and was found to significantly reduce the risk of emergence delirium without 
causing an increase in extubation time or hemodynamic changes. 27,37 Therefore, the investigative team 
believes that the use of dexmedetomidine in the current study is IND exempt, and that there is no 
increased risk or decreased acceptability of the risk, of administering 1ug/kg of Dexmedetomidine to 
children age 2-18 undergoing tonsillectomy. 


37 
 
 
 
Table 1: Literature review of Dexmedetomidine dose algorithms and adverse 
events in pediatric patients. 
 
Author 
N 
Age 
Dose 
Adverse Events 
Olutoye28 
109 
Mean age 6.4 
years (3-12 
years) 
Drug was administered by 
infusion over ten minutes at 
0.5ug/kg and 1ug/kg 
Assessed; None related to drug use 
Gupta35 
94 (52 
receiving 
drug) 
Mean age 
10.5 months 
(infant-18 
years; 5.0 
months in 
control 
group) 
Drug administered as infusion 
>96hrs at 0.3-1.0ug/kg/hr. 
One patient experienced junctional 
heart rate at 130 beats/min requiring 
pacing (critically ill children with 
cardiac disease; unclear if drug 
related). Group receiving drug had 
decreased inotrope, opioids and 
benzodiazepine requirements 
Patel27 
122 (61 
receiving 
drug) 
Mean age 4.0 
years (2-10 
years) 
Drug was administered as 
2ug/kg bolus over 10 minutes, 
followed by 0.7ug/kg/hr 
infusion 
Assessed; None related to drug use. 
Decreased post-operative opioid 
doses, desaturation events and 
emergence delirium. 
Tsiotou37 
60 (31 
receiving 
drug) 
Mean age 6.2 
years (3-14 
years) 
Drug was administered as a 
1ug/kg bolus over 10 minutes 
Assessed; None related to drug use. 
Three-fold decrease in emergence 
delirium risk 
 
• The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) 
and with the requirements for informed consent (21 CFR part 50). 
The study will be conducted after IRB approval, with an IRB-approved consent. 
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not 
intended to promote or commercialize the drug product). 
The study is not intended to promote or commercialize the drug product.  
 
 
 
 
 
 


38 
 
 
References 
1. Volkow ND, Jones EB, Einstein EB, Wargo EM. Prevention and Treatment 
of Opioid Misuse and Addiction: A Review. JAMA Psychiatry. 2018. 
2. Scholl L., Seth P., Kariisa M., Wilson N., Baldwin G. Drug and Opioid-Involved 
Overdose Deaths - United States, 2013-2017. Centers for Disease Control (CDC). 
Accessed on 16 Jan 2019 at url: 
https://www.cdc.gov/mmwr/volumes/67/wr/mm675152e1.htm. 
3. Substance Abuse and Mental Health Services Administration. (2017). Key substance use 
and mental health indicators in the United States: Results from the 2016 National Survey on 
Drug Use and Health (HHS Publication No. SMA 17-5044). Rockville, MD: Center for 
Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services 
Administration. Accessed on 16 Jan 2019 at url: https://www.samhsa.gov/data/. 
4. Harbaugh CM, Lee JS, Hu HM, et al. Persistent Opioid Use Among Pediatric Patients 
After Surgery. Pediatrics. 2018;141(1). 
5. Harbaugh CM, Nalliah RP, Hu HM, Englesbe MJ, Waljee JF, Brummett CM. Persistent 
Opioid Use After Wisdom Tooth Extraction. JAMA. 2018;320(5):504-506. 
6. Kelly LE, Sommer DD, Ramakrishna J, et al. Morphine or Ibuprofen for post- 
tonsillectomy analgesia: a randomized trial. Pediatrics. 2015;135(2):307-313. 
7. Franz AM, Dahl JP, Huang H, et al. The development of an opioid sparing anesthesia 
protocol for pediatric ambulatory tonsillectomy and adenotonsillectomy surgery-A quality 
improvement project. Paediatr Anaesth. 2019. 
8. Frauenknecht J, Kirkham KR, Jacot-Guillarmod A, Albrecht E. Analgesic impact of intra- 
operative opioids vs. opioid-free anaesthesia: a systematic review and meta-analysis. 
Anaesthesia. 2019;74(5):651-662. 
9. Elkassabany NM, Mariano ER. Opioid-free anaesthesia - what would Inigo Montoya say? 
a. Anaesthesia. 2019;74(5):560-563. 
10. Mitchell RB, Archer SM, Ishman SL, et al. Clinical Practice Guideline: Tonsillectomy in 
Children (Update). Otolaryngol Head Neck Surg. 2019;160(1_suppl):S1-S42. 
11. Baugh RF, Archer SM, Mitchell RB, et al. Clinical practice guideline: tonsillectomy in 
children. Otolaryngol Head Neck Surg. 2011;144(1 Suppl):S1-30. 
12. Cote CJ, Posner KL, Domino KB. Death or neurologic injury after tonsillectomy in 
children with a focus on obstructive sleep apnea: houston, we have a problem! Anesth 
Analg. 2014;118(6):1276-1283. 
13. McCabe SE, Schulenberg JE, O'Malley PM, Patrick ME, Kloska DD. Non-medical use of 
prescription opioids during the transition to adulthood: a multi-cohort national longitudinal 
study. Addiction. 2014;109(1):102-110. 
14. McCabe SE, West BT, Boyd CJ. Medical use, medical misuse, and nonmedical use of 
prescription opioids: results from a longitudinal study. Pain. 2013;154(5):708-713. 
15. McCabe SE, West BT, Boyd CJ. Leftover prescription opioids and nonmedical use among 
high school seniors: a multi-cohort national study. J Adolesc Health. 2013;52(4):480-485. 
16. Winters KC, Arria A. Adolescent Brain Development and Drugs. Prev Res. 
a. 2011;18(2):21-24. 
17. Mason KP. Paediatric emergence delirium: a comprehensive review and interpretation of 
the literature. Br J Anaesth. 2017;118(3):335-343. 
18. Julious SA. Sample sizes for clinical trials with normal data. Stat Med. 2004;23(12):1921- 
1986. 
19. Althunian TA, de Boer A, Klungel OH, Insani WN, Groenwold RH. Methods of defining 
the non-inferiority margin in randomized, double-blind controlled trials: a systematic 


39 
 
 
review. Trials. 2017;18(1):107  
20. Sealed Envelope Ltd. 2012. Power calculator for continuous outcome non-inferiority trial. 
[Online] Available from: https://www.sealedenvelope.com/power/continuous-noninferior/ 
[Accessed Apr 25 2019]. 
21. Buck, ML. Use of Intravenous Ketorolac for Postoperative Analgesia in Infants: Pediatric 
Pharmacotherapy, A Monthly Newsletter. . 2011; https://med.virginia.edu/pediatrics/wp- 
content/uploads/sites/237/2015/12/201108.pdf. Accessed January 6, 2020. 
22. Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and 
operative site bleeding. A postmarketing surveillance study. JAMA. 1996;275(5):376- 382. 
23. Forrest JB, Camu F, Greer IA, et al. Ketorolac, diclofenac, and ketoprofen are equally safe 
for pain relief after major surgery. Br J Anaesth. 2002;88(2):227-233. 
24. Mowatt G, Cook JA, Fraser C, McKerrow WS, Burr JM. Systematic review of the safety of 
electrosurgery for tonsillectomy. Clin Otolaryngol. 2006;31(2):95-102. 
25. Chan DK, Parikh SR. Perioperative ketorolac increases post-tonsillectomy hemorrhage in 
adults but not children. Laryngoscope. 2014;124(8):1789-1793. 
26. McClain K, Williams AM, Yaremchuk K. Ketorolac usage in tonsillectomy and 
uvulopalatopharyngoplasty patients. Laryngoscope. 2019. 
27. Patel A, Davidson M, Tran MC, et al. Dexmedetomidine infusion for analgesia and 
prevention of emergence agitation in children with obstructive sleep apnea syndrome 
undergoing tonsillectomy and adenoidectomy. Anesth Analg. 2010;111(4):1004-1010. 
28. Olutoye OA, Glover CD, Diefenderfer JW, et al. The effect of intraoperative 
dexmedetomidine on postoperative analgesia and sedation in pediatric patients undergoing 
tonsillectomy and adenoidectomy. Anesth Analg. 2010;111(2):490-495. 
29. Lee MS, Montague ML, Hussain SS. Post-tonsillectomy hemorrhage: cold versus hot 
dissection. Otolaryngol Head Neck Surg. 2004;131(6):833-836. 
30. Diercks GR, Comins J, Bennett K, et al. Comparison of Ibuprofen vs Acetaminophen and 
Severe Bleeding Risk After Pediatric Tonsillectomy: A Noninferiority Randomized 
Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2019. 
31. Mroszczak EJ, Jung D, Yee J, Bynum L, Sevelius H, Massey I. Ketorolac tromethamine 
pharmacokinetics and metabolism after intravenous, intramuscular, and oral 
administration in humans and animals. Pharmacotherapy. 1990;10(6 ( Pt 2)):33S-39S. 
32. Macario A, Lipman AG. Ketorolac in the era of cyclo-oxygenase-2 selective nonsteroidal 
anti-inflammatory drugs: a systematic review of efficacy, side effects, and regulatory 
issues. Pain Med. 2001;2(4):336-351. 
33. Mitchell RB, Archer SM, Ishman SL, et al. Clinical Practice Guideline: Tonsillectomy in 
Children (Update)-Executive Summary. Otolaryngol Head Neck Surg. 2019;160(2):187- 
205. 
34. Mudd PA, Thottathil P, Giordano T, et al. Association Between Ibuprofen Use and 
Severity of Surgically Managed Posttonsillectomy Hemorrhage. JAMA Otolaryngol Head 
Neck Surg. 2017;143(7):712-717. 
35. Gupta P, Whiteside W, Sabati A, et al. Safety and efficacy of prolonged dexmedetomidine 
use in critically ill children with heart disease*. Pediatr Crit Care Med. 2012;13(6):660- 
666. 
36. Mahmoud M, Mason KP. Dexmedetomidine: review, update, and future considerations of 
paediatric perioperative and periprocedural applications and limitations. Br J Anaesth. 
2015;115(2):171-182. 
37. Tsiotou AG, Malisiova A, Kouptsova E, Mavri M, Anagnostopoulou M, Kalliardou E. 
Dexmedetomidine for the reduction of emergence delirium in children undergoing 
tonsillectomy with propofol anesthesia: A double-blind, randomized study. Paediatr Anaesth. 


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2018; 28(7):632-638.