Randomized Clinical Trial of Non-Opioid Pain Medications After Adenotonsillectomy
Phase: PHASE1
Conditions: Adenotonsillectomy, Post-operative Analgesia, Opioid Use
Sponsor: David Chi, MD

Page 1 of 11 
 
Study Protocol  
 
 
 
 
 
 
Official Title: Randomized Clinical Trial of Non-Opioid Pain 
Medications After Adenotonsillectomy 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT03618823 
 
 
 
Protocol Date: 03/19/2020 
 
 
 
 

Page 2 of 11 
 
Scientific Background 
 
In the present climate, there is a significant lack of consensus regarding the optimal management 
of pain for pediatric patients post-operatively (1). To further complicate matters, the growing 
opioid epidemic sweeping the United States makes the prescription of opioid pain medications 
for post-operative pain control after certain procedures subject to scrutiny. Indeed, just in 2015, 
opioid related drug overdoses were responsible for 33,091 deaths in the United States – of those 
deaths, nearly half involved prescription opioids (2,3). It has been identified that patients often 
use less opioids than prescribed, thus leaving an excess of opioids to be potentially abused by 
others or the patients themselves (4). In fact, in pediatric populations, one study showed that 58% 
of the opioid doses dispensed upon discharge were unused – only 4% of patients disposed of the 
remaining dose properly (5). However, it is important to note that under-treatment of post-
operative pain has been shown to be an independent and significant predictor of complication in 
various surgical procedures (6,7). Patients who have found their pain to be unacceptable were 
65% more likely to experience a complication within 30 days post-operatively when controlled 
for other factors and comorbidities (7). 
 
A double blinded study done by Bean-Lijewski, et al. showed that rofecoxib, a non-steroidal 
anti-inflammatory (non-opioid), was more effective than opioids in the first 72 hours after 
tonsillectomy in pediatric children. Though rofecoxib has since been withdrawn from the market, 
it illustrates that perhaps pain in children post-operatively can be managed without the use of 
opioids - at least in the short term (8). In fact, Kaiser Permanente Northwest in 2016 instituted a 
new policy restricting the use of opioids in patients younger than 7, requiring physician override 
in the electronic medical record in order to prescribe narcotics. As a result, opioid prescription 
post-tonsillectomy decreased by 66% in their system, with no change in ED utilization (9). A 
smaller study published by Kelly, et al. investigated the use of morphine (opioid) and 
acetaminophen versus ibuprofen and acetaminophen (non-opioids) for post-operative pain 
control after tonsillectomy. The trial demonstrated that pain control (measured only on day 1 and 
5) was adequate on either regimen, but the use of morphine was associated with complications 
and was deemed unsafe in certain children (10). 
 
With a previous retrospective review performed here at UPMC, it was found that after November 
2016, the average amount of oxycodone prescribed for children post-tonsillectomy was 0.05 
mg/kg for an average of 6.7 days. Typically, this dosage would be taken every 4-6 hours or as 
needed (11). This falls well into the Epocrates recommended 0.05-0.15 mg/kg dosing every 4-6 
hours (not to exceed 5 doses in 24 hours) (12). While the average dosage for acetaminophen and 
ibuprofen was not previously reported, according to Medscape, acetaminophen can be safely 
given at a dosage of 10-15 mg/kg every 4-6 hours with no more than five doses in 24 hours (13). 
Ibuprofen can be safely given at 4-10 mg/kg every 6-8 hours. Maximum single dose is 400 
mg/dose, and maximum daily dose is 40 mg/kg/day up to 1200 mg/day (14). 
 
While prescription opioids are one of the most effective options for control of post-operative 
pain, the growing opioid crisis in the United States makes it prudent to study the effectiveness of 
other non-opioid pain regiments. Our purpose is to determine if non-opioid pain control is a safe 
and effective option in the treatment of post-operative pain following adenotonsillectomy in 
various pediatric age groups. 

Page 3 of 11 
 
 
1. Van Cleve WC, Grigg EB. Variability in opioid prescribing for children undergoing 
ambulatory surgery in the United States. J Clin Anesth 2017;41:16-20 
2. Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths 
- United States, 2010-2015. MMWR Morb Mortal Wkly Rep 2016;65(5051):1445-1452. 
3. Schuchat A, Houry D, Guy GP. New data on opioid use and prescribing in the united states. 
JAMA 2017;318(5):425-426. 
4. Feinberg AE, Chesney TR, Srikandarajah S, Acuna SA, McLeod RS, Best Practice in Surgery 
Group. Opioid use after discharge in postoperative patients: A systematic review. Ann Surg 
2017. 
5. Monitto CL, Hsu A, Gao S, et al. Opioid prescribing for the treatment of acute pain in children 
on hospital discharge. Anesth Analg 2017;125(6):2113-2122. 
6. Holte K, Kehlet H. Effect of postoperative epidural analgesia on surgical outcome. Minerva 
Anestesiol 2002;68(4):157-161. 
7. Van Boekel RLM, Warlé MC, Nielen RGC, et al. Relationship Between Postoperative Pain 
and Overall 30-Day Complications in a Broad Surgical Population: An Observational Study. 
Ann Surg 2017. 
8. Bean-Lijewski JD, Kruitbosch SH, Hutchinson L, Browne B. Post-tonsillectomy pain 
management in children: can we do better? Otolaryngol Head Neck Surg. 2007 Oct;137(4):545–
551. 
9. Luk LJ et al. Implementation of a pediatric posttonsillectomy pain protocol in a large group 
practice. Otolaryngol Head Neck Surg 2016. Apr;154(4):720-2 
10. Kelly LE, Sommer DD, Ramakrishna J, Hoffbauer S, Arbab-Tafti S, Reid D, et al. Morphine 
or Ibuprofen for post-tonsillectomy analgesia: a randomized trial. Pediatrics. 2015 
Feb;135(2):307–313. 
11. Whelan RL, Mccoy J, Mirson L, Chi D. Opioid prescribing patterns and post-tonsillectomy 
outcomes following implementation of opioid consent forms. Accepted at American Society of 
Pediatric Otolaryngology Conference Presentation. April 2018. 
12. Epocrates Online. Oxycodone Pediatric Dosing. 
https://online.epocrates.com/drugs/5902/oxycodone/Peds-Dosing. Accessed February 4, 2018. 
13. Farinde, A. Medscape. Pediatric Acetaminophen Dosing. Medscape. 
https://emedicine.medscape.com/article/2172407-overview. Updated September 15, 2015. 
Accessed February 4, 2018. 
14. Farinde, A. Medscape. Pediatric Ibuprofen Oral Dosing. Medscape. 
https://emedicine.medscape.com/article/2172401-overview. Updated September 15, 2015. 
Accessed February 4, 2018. 
 
 
 
 
 
 
 
 

Page 4 of 11 
 
Study Objectives 
 
Aim: To determine if non-opioid pain control is a safe and effective option in the treatment of 
post-operative pain following adenotonsillectomy in various pediatric age groups. 
 
Hypothesis 1: Post-operative pain will not be higher in patients assigned to the non-opioid only 
group (experimental) as compared to the group receiving both opioid and non-opioid pain 
medications (control). 
 
Hypothesis 2: There will not be an increased rate of post-operative complications in the non-
opioid only group as compared to the group receiving both opioid and non-opioid pain 
medications. 
 
 
Study Design & Methods 
 
Design: Experimental, open-label randomized control trial. 
 
Methods: 
 
1. The otolaryngology nurses will screen patients at the pre-operative appointment based on past 
medical history that is either in the electronic medical record or elicited from the patient during 
the appointment to determine if they qualify for the study. They will then inform the 
otolaryngologists to review the consent form with the family. 
Between the pre-operative appointment and day of surgery, one of the members of the research 
team will once again check the patient's eligibility to enroll in this trial using the electronic 
medical record system. 
 
2. A list of possible qualifying T&A surgery patients will be provided to the research team by the 
surgery administration. Patients will be screened using the electronic medical record system for 
inclusion criteria. The family can then be consented the day of surgery. This screening method 
will be used with telemedicine visits, especially during the COVID-19 restrictions. 
 
The otolaryngology nurses will be responsible for the initial screening of patients at the pre-
operative appointment during the standard pre-operative education for adenotonsillectomy 
surgery. The nurses will then consult the physicians for who qualifies for the study. The 
physicians will confirm that the patients meet inclusion criteria for the study, and they will be 
responsible for attaining consent from the caregiver. Additionally, they will be responsible for 
attaining a completed assent form for children, acknowledging their willingness to participate. 
Girls of reproductive age (13-17) will be counseled on the importance of using contraception if 
sexually active since pain medication may affect a developing fetus. This will take place in the 
private medical office exam room. The patient and caregiver will be informed that they will 
receive a payment of $25.00 for participation in the trial, provided they complete the trial. 
Families can also be consented the day of surgery. Patients will be screened by the research team 

Page 5 of 11 
 
using electronic medical records. This will provide all families the opportunity to participate. 
Oftentimes, a parent is not available at the pre-operative appointment to sign consent or families 
need time to think about participation. During the COVID-19 restrictions and for future 
telemedicine visits, the study will be brought up during the pre-operative visit but will be signed 
the day of surgery. This will help families to discuss the study in more detail after the 
appointment, as there is no down time in telemedicine appointments. During the restrictions, 
only one parent is able to attend an appointment as well. 
 
Between the time of the pre-operative appointment and the day of surgery, all listed investigators 
will be involved in the use of the electronic medical record to confirm that patients meet 
inclusion criteria, and to exclude any patients who meet the exclusion criteria. Upon completion 
of screening, patients will be randomized using a block randomization algorithm in order to have 
an equal distribution of opioid and non-opioid regimens among three age groups - young 
children (ages 3-7), preadolescents (ages 8-12), and teenagers (ages 13-17). Patients or parents 
will maintain the right to request and receive oxycodone at any point during the trial provided 
there are no contraindications to their usage. 
 
At the day of surgery, the parents will receive the patient pain diary. A separate sheet with the 
Wong-Baker FACES Pain Rating Scale instructions will be included in the patient folder. Along 
with the standard post-operative information provided for adenotonsillectomy (which includes 
items such as emergency contact information, contact information for medical questions, and 
expected post-operative progress), they will also receive a prescription for the pain medications 
they have been assigned, along with instructions on the dose, frequency, and duration of use. 
 
For the opioid group, oxycodone will be prescribed at a dose range of 0.025 mg/kg to 0.10 mg/kg 
every four hours or as needed. The total supply will be limited to seven days. This dose range is 
the standard of care already provided at CHP and will not reflect a change in standard dose 
prescribed after adenotonsillectomy surgery. This range is necessary for adequate pain 
management in all age groups. Ibuprofen will be prescribed at 10 mg/kg every 6 hours or as 
needed, and acetaminophen will be given at 15 mg/kg every 4 hours or as needed. For the non-
opioid groups, ibuprofen will be prescribed at 10 mg/kg every 6 hours or as needed, and 
acetaminophen will be given at 15 mg/kg every 4 hours or as needed. All medications will be 
prescribed in liquid suspension form for ease of use in pediatric populations. Subjects or parents 
will purchase medications and dosage will be given to subjects in easy-to-understand language 
on a parent instruction sheet (ig. x mL every 4 hours or as needed, with maximum allowable 
amount of y mL in a day). 
A parent instruction sheet for each group was developed with the following information: 
Non-opioid group – 
 
Parents will be advised: 
-to give their child acetaminophen every 4 hours and ibuprofen every 6 hours around the clock 
for the first 3 days post-surgery. 
-after the first 3 days, give subject both medications on an as needed basis, depending on the 
ability of the subject to take liquids by mouth (>32 oz/day) and/or if the child complains or 
behaves like they are in pain. 
-Parents may request opioids from the physician at any point during the trial. (For example, if 

Page 6 of 11 
 
pain level is unmanaged). The decision whether or not to prescribe opioids will be up to your 
child’s physician. 
Read the directions on the bottle to know how often you are to give this 
medication. Your nurse will go over this with you before you leave. 
Pain peaks at days 5-10. You may want to continue scheduled Tylenol and 
Motrin during your child’s most painful times. 
 
Opioid group - 
 
Parents will be advised: 
-to give their child acetaminophen every 4 hours and ibuprofen every 6 hours around the clock 
for the first 3 days post-surgery. 
-after the first 3 days, give subject both medications on an as needed basis, depending on the 
ability of the patient to take liquids by mouth (>32 oz/day) and/or if the child complains or 
behaves like they are in pain. 
-that if acetaminophen and ibuprofen are both given and the child is still demonstrating the 
inability to drink and/or complain or behave like they are in pain, oxycodone is advised. The 
Oxycodone prescription is for 7 days and is prescribed based on weight. 
The Opioid group is not required to take any amount of the oxycodone during the trial. 
Read the directions on the bottle to know how often you are to give this 
medication. Your nurse will go over this with you before you leave. 
Pain peaks at days 5-10. You may want to continue scheduled Tylenol and 
Motrin during your child’s most painful times. 
 
This diary is a questionnaire which caregivers will use to assess variables of interest such as 
amount/frequency of medications taken, pain level, socioeconomic factors, side effects, and 
satisfaction with pain relief. The diary will be completed by post-operative day 14. 
Families can return the pain diary in multiple ways: 
-A post-operative appointment at CHP Main can be scheduled and the patient and caregiver will 
return the diary in person in order to receive the compensation for participating in this trial. 
These families can also email or mail the diary. During COVID-19 restrictions, families will be 
encouraged to return the Pain Diary via mail or email. As a last resort, families may bring the 
Pain Diary to their in-person appointment, however a post-op appointment for T&A may be rare 
during the restrictions due to the level of urgency of a patient without complications. 
 
-For families that have a post-operative appointment at locations other than the main hospital or 
do not want a post-operative appointment, they can return the pain diary by scanning the diary or 
taking pictures of the diary on their phone and emailing an electronic copy to the research team. 
They can also mail the diary using the post-marked envelope provided. The $25 compensation 
will then be mailed to the family when the electronic or physical copy is received. The research 
team will call participants anywhere from 2 to 6 weeks after surgery for a reminder to return the 
study diary. At this time, participants may request another post-marked envelope sent to their 
home address instead of scanning the diary electronically. The research team will call the 
families after the surgery to see if they have any additional questions about filling out the pain 
diary. This will occur anywhere from the day after surgery to a week later. 
 

Page 7 of 11 
 
Finally, further research activities will include viewing medical charts of the included subjects, 
harvesting the data from these medical records, placing these data on a datasheet, and then 
placing the data in a database for statistical analysis. All listed investigators will work together to 
obtain the data. Prior to harvesting the data, we will assign subject numbers for all participants so 
that subjects' names do not need to be recorded on our datasheets or in our database. Data 
collection and analysis is estimated to be completed in 1-2 years by the listed investigators. 
 
A post-operative appointment can be scheduled at CHP Main and the family can return the diary 
to receive compensation for participation in person. If the family does not schedule a post-
operative appointment at the main hospital, has forgotten the diary at the appointment or for 
convenience, the pain diary must be emailed to the research team by scanning the diary or taking 
pictures on their phone. If the family did not make a post-operative appointment at the main 
hospital by 2 weeks post-surgery, the research team will call the caregiver 2-6 weeks after 
surgery to remind them to email an electronic copy of the pain diary. 
 
Eligibility Criteria  
 
Inclusion:  
Patients age 3 - 17 undergoing adenotonsillectomy meet inclusion criteria 
 
Exclusion: 
Patients with Down syndrome 
Patients with a history of coagulopathy 
Patients with craniofacial abnormalities 
Caregivers who cannot speak, read, or write in English proficiently 
Patients who take opioids during the enrollment period 
Patients who take chronic opioids 
Patients who are pregnant 
Patients with allergy to or contraindication for taking any of the study medications 
Patients who have the inability to communicate 
Patients who have the inability to localize pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 8 of 11 
 
Statistical Analysis Plan  
 
 
 
 
 
 
Official Title: Randomized Clinical Trial of Non-Opioid Pain 
Medications After Adenotonsillectomy 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT03618823 
 
 
 
Protocol Date: 11/19/2018 
 
 
 
 

Page 9 of 11 
 
Study Objectives 
 
Aim: To determine if non-opioid pain control is a safe and effective option in the treatment of 
post-operative pain following adenotonsillectomy in various pediatric age groups. 
 
Study Outcomes 
 
Primary Outcome 
• Average pain burden 14 days post-operatively. This will be self-reported and measured 
on the Wong-Baker FACES Pain Rating Scale (0 to 10) before and after taking pain 
medication via the study take-home pain diary. 
 
Secondary Outcomes 
• Emergency department or urgent care visits 14 days post-operatively from the pain diary 
and from the patients’ medical record. 
• Side effects of medications within 14 days post-operatively, including nausea, vomiting, 
constipation, stomach ache, difficulty breathing. This is reported by the child’s caregiver 
after all medication administration is completed. The question is check all that apply and 
assessed via study take-home pain diary. 
 
Other Outcomes 
• Number of hospital readmissions within 14 days post-operatively 
- 
Measured via medical record  
 
• Average dose of each analgesic used 14 days post-operatively  
- 
Measured via the study take-home pain diary. 
 
 
• Duration of each analgesic used 14 days post-operatively 
- 
Measured via the study take-home pain diary. 
 
• Mean of total quantity of pain medications taken 14 days post-operatively 
- 
Measured via the study take-home pain diary. 
 
• Overall pain satisfaction over 14 days post-operatively  
- 
Measured via the study take-home pain diary. 
 
• Post-operative nursing phone calls within 14 days post-operatively  
- 
Measured via medical record  
 
• Night-time awakenings within 14 days post-operatively 
- 
Measured via the study take-home pain diary. 
 
• Non-opioid group switching to opioid group within 14 days post-operatively  
- 
Measured via the study take-home pain diary. 

Page 10 of 11 
 
 
• Need for follow-up appointment within two months post-operatively 
- 
Measured via the study take-home pain diary. 
 
• Socioeconomic variables at the time of caregivers’ filling out the pain diary 
- 
Measured via the study take-home pain diary. 
• Household income – Check the box that matches income categories  
• Education level – Check the box that matches the highest education level achieved by 
anyone in the household  
 
 
Sample Size Calculation 
 
Power analysis was conducted with an alpha of 0.05, power (1-beta) of 0.8 and a desired effect 
size of 0.30 with a 1:1 allocation ratio. A one tail Wilcox-Mann-Whitney test was used through 
G*Power on the opioid and non-opioid pain regimens arms to determine a sufficient sample size 
to power the study based on a previous study performed at UPMC Children’s Hospital of 
Pittsburgh. A size of n = 145 in each group, for a total of n = 290, was calculated to be sufficient 
to power the study. We decided to use 300 total in case of data censorship or an imbalance of 
patient allocation to one of the two groups. Given that 300 children will be necessary for the 
study, 300 parents will be necessary to complete the questionnaire for their child. We are 
screening up to 1000 total patients for the study. This will include patients not meeting inclusion 
criteria and families not interested in participating. 
 
[1] 
Whelan RL, McCoy J, Mirson L, Chi DH. Opioid prescription and postoperative 
outcomes in pediatric patients. Laryngoscope 2019;129:1477–81. 
https://doi.org/10.1002/lary.27614. 
 
Analyses 
 
SPSS version 24 will be used for all statistical analysis.  
All outcomes will be analyzed between opioid and non-opioid groups.  
P value < .05 will be used for statistical significance.  
 
Primary Outcome 
The primary outcome measure ‘average pain burden 14 days post-operatively’ will be analyzed 
with a two-way mixed-model analysis of variance (ANOVA) between opioid versus non-opioid 
groups from before medication to after. Total duration of medication use will be controlled for. 
Means, standard errors, and 95% confidence intervals (CI) will be reported. 
 
Secondary Outcome 
The secondary outcome measure ‘emergency department or urgent care visits 14 days post-
operatively’ and ‘side effects of medications within 14 days post-operatively’ will be analyzed 
with Fisher’s Exact test and logistic regression for dichotomous outcomes and Mann-Whitney U 
test for continuous outcomes. Odds ratios (OR) and 95% CI will be reported. 

Page 11 of 11 
 
 
Other Outcomes 
Along with descriptive statistics, likelihood ratio, Mann-Whitney U test and Wilcoxon signed-
ranks test will be used for additional analysis.  
 
Cross-Over 
A sub-group analysis will be performed without those patients who had drug cross-over. 
 
Analysis Inclusion  
Only those who return the pain diary will be included in the final analysis.  
 
Missing Data 
Data imputation will not be used for missing data.  
 
Harms 
 
Serious Adverse Events and adverse events will be collected up until the post-operative 
appointment with a maximum of 9 weeks post-operatively.