Clinical trial NCT04015908
Conditions: Opioid Use
Sponsor: University of Utah
Start date: 2019-08-01; Completion date: 2023-01-31
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to determine whether the combination of three non-opioid analgesics (multimodal analgesia) can significantly reduce or eliminate the need for opioids after ambulatory surgery.

A secondary objective would be to present credible data for insurance providers about the opioid sparing effect of these medications. This data may encourage insurance providers to support payment for short term use of certain analgesics that currently require prior authorization.

Detailed description:
Prescription opioids are associated with addiction and accidental overdose, yet they continue to be the most commonly prescribed analgesics after ambulatory surgery.

Multimodal analgesia is a promising alternative to opioids. It is based on the theory that a combination of more than one analgesic (with non-opioid mechanisms of action) can provide pain relief equal to or exceeding that of traditional opioids.

Multimodal analgesia is not associated with opioid related side effects such as respiratory depression, nausea, constipation, and itching.

Implementation of multi-modal analgesia in an ambulatory setting is challenging for a number of reasons.

First, patient compliance with multiple medications and complex dosing schedules is poor.

Second, misinformation still exists about the dosing of acetaminophen and NSAIDS (non-steroidal anti-inflammatory drugs). For example, many patients and health care providers believe that acetaminophen and NSAIDS cannot be taken concurrently. As a result, the additive analgesic effect of combining these drugs is not achieved.

Finally, some medications used for multimodal analgesia can be difficult to procure in the ambulatory setting. For example, pregabalin (trade name Lyrica) has been used successfully to treat acute pain and reduce opioid requirements after surgery. However, its mechanism of action is similar to that of gabapentin (an older and less expensive drug) and insurers are reluctant to approve its use over the expensive alternative.

Although gabapentin is a useful analgesic for chronic pain, its delayed onset of activity and unpredictable blood levels after oral administration make it impractical to use in the setting of acute pain. In fact, optimal dosing of gabapentin may require several days or weeks to establish.By contrast, pregabalin has a rapid onset of action with consistent and predictable plasma levels after oral administration.

For this trial, patients in the control group would receive traditional postoperative pain medication consisting of a combination of oxycodone and acetaminophen (trade name Percocet) as needed at 4-6 hour intervals.

Patients in the study group would receive the following:

* Three non-opioid pain medications (acetaminophen,celecoxib, and pregabalin) would be taken concurrently at six hour intervals for a period of 7 days.
* These three non-opioid medications (acetaminophen, celecoxib, and pregabalin ) would be provided in a "blister pack". All scheduled pain medication for a given 6 hour interval would be contained in a single compartment to simplify compliance for the patient. Study patients would also have access to oxycodone as a "rescue medication".

The principles of postoperative pain management addressed in this protocol are supported by existing literature.

1. Patient compliance with complex medication dosing protocols may be improved using calender and time based "blister packs".
2. Pain control using combined acetaminophen and NSAID is superior to that either drug in isolation
3. Pregabalin can reduce opioid requirements and opioid related nausea when treating acute pain.

The primary objective of this trial is to determine whether the combination of three non-opioid analgesics (multimodal analgesia) can significantly reduce or eliminate the need for opioids after ambulatory surgery.

A secondary objective would be to present credible data for insurance providers about the opioid sparing effect of these medications. This data may encourage insurance providers to support payment for short term use of certain analgesics that currently require prior authorization.

Arms: arm 1: 3 Different Non-opioid pain medication taken every 6 hours

Celecoxib 100mg

Acetaminophen 325mg

Pregabalin 50 mg

Plus, for breakthrough pain

oxycodone 5-10 mg will be taken every 4 hours as needed for pain. arm 2: 7 day supply of Percocet (oxycodone 5mg/acetaminophen 325 mg) to be taken 1-2 by mouth every 4 hours as needed for pain.
Interventions: intervention 1: Celecoxib intervention 2: Acetaminophen intervention 3: Pregabalin intervention 4: Oxycodone intervention 5: Percocet
Intervention descriptions: intervention 1: Celecoxib 100mg intervention 2: Acetaminophen 325mg intervention 3: Pregabalin 50 mg intervention 4: oxycodone 5-10 mg intervention 5: Percocet (oxycodone 5mg/acetaminophen 325 mg)

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 1 of 10 
 
IRB Approval 8/6/2020 
 
 
A Multimodal Analgesia Protocol Adapted for Ambulatory 
Surgery 
 
Protocol Summary 
 
 
 
IRB Approval 
Date of 
Current 
Version: 
8/6/2020 
University of 
Utah IRB #: 
IRB_00121505 
Sponsor:  
NCT#: NCT04015908 
Principal 
Investigator: 
Jeffrey Swenson 
Internal Staff 
and  Sub-
Investigators: 
Site Name 
Staff Names 
University of Utah Jeffrey Swenson 
 
 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 2 of 10 
 
IRB Approval 8/6/2020 
 
Background and Introduction 
 
Opioids are associated with addiction and accidental overdose, yet they continue to be the 
most commonly prescribed analgesics after ambulatory surgery. In 2017, there were 
456 deaths from opioid overdose in Utah. Prescription opioids accounted for 70% of those 
deaths (wonder.cdc.gov). 
Multimodal analgesia is a promising alternative to opioids. It is based on the theory 
that combining more than one non-opioid analgesic can provide pain relief equal to or 
exceeding that of opioids alone. 
The three drug classes that have demonstrated analgesic effects capable of reducing opioid 
requirements are GABA agents (pregabalin, gabapentin), NSAIDS (ibuprofen,celecoxib), and 
acetaminophen. Although many studies have been performed using these drugs in isolation, 
surprisingly little information exists about their combined effect on opioid requirements.  
The combination of three non-opioid analgesics may provide effective analgesia while 
reducing or eliminating opioid related side effects such as respiratory depression, nausea, 
constipation, and itching.  
Implementation of multi-modal analgesia in an ambulatory setting is challenging for a number 
of reasons. 
First, patient compliance with multiple medications and complex dosing schedules is poor. 
Second, widespread misinformation exists about concurrent dosing of acetaminophen 
and NSAIDS (non-steroidal anti-imflammatory drugs). For example, many patients and health 
care providers believe that acetaminophen and NSAIDS cannot be taken simultaneously. As a 
result, the additive analgesic effect of combining these drugs is not achieved.  
Finally, some medications used for multimodal analgesia cannot be procured in the ambulatory 
setting. For example, pregabalin (trade name Lryica) has been used successfully to treat acute 
pain and reduce opioid requirements after surgery. However, because its mechanism of action 
is similar to that of gabapentin (an older and less expensive drug), insurers are reluctant to 
approve its use over the expensive alternative. 
Although gabapentin is a useful analgesic for chronic pain, its delayed onset of activity and 
unpredictable blood levels after oral administration make it impractical to use in the setting of 
acute pain. In fact, optimal dosing of gabapentin may require several days or weeks to 
establish.By contrast, pregabalin has a rapid onset of action with consistent and predictable 
plasma levels after oral administration.        
For this trial, patients in the control group would receive traditional postoperative pain 
medication consisting of a combination of oxycodone and acetaminophen (trade name 
Percocet) as needed at 4-6 hour intervals. 
Patients in the study group would receive the following: 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 3 of 10 
 
IRB Approval 8/6/2020 
 
- Three non-opioid pain medications (acetaminophen,celecoxib, and pregabalin) would be 
taken concurrently at six hour intervals for a period of 7 days. 
-These three non-opioid medications (acetaminophen, celecoxib, and pregabalin ) would be 
provided in a "blister pack". All scheduled pain medication for a given 6 hour interval would 
be contained in a single compartment to simplify compliance for the patient. Study patients 
would also have access to oxycodone as a  "rescue medication". 
The principles of postoperative pain management addressed in this protocol are supported 
by existing literature.  
1. Patient compliance with complex medication dosing protocols may be improved using 
calander and time based "blister packs".[1] 
2. Pain control using combined acetaminophen and NSAID is superior to that either drug in 
isolation.[2] 
3. Pregabalin can reduce opioid requirements and opioid related nausea when treating acute 
pain.[3]   
  
 
 
 
Purpose and Objectives 
 
The primary objective of this trial is to determine whether the combination of three non-opioid 
analgesics (multimodal analgesia) can significantly reduce or eliminate the need for opioids 
after ambulatory surgery. 
A secondary objective would be to present credible data for insurance providers about the 
opioid sparing effect of these medications. This data may encourage insurance providers to 
support payment for short term use of certain analgesics that currently require prior 
authorization.  
  
  
 
 
 
Study Population 
 
Age of Participants: 18-65 
 
Sample Size: 
At Utah: 
300  
All Centers: 
300 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 4 of 10 
 
IRB Approval 8/6/2020 
 
 
Inclusion Criteria: 
All patients between the ages of 18 and 65 having one of three elective procedures as an 
outpatient. These procedures are associated with moderate to severe postoperative pain. 
 1. anterior cruciate ligament reconstruction (knee) 
 2. ankle ligament reconstruction (foot/ankle) 
 3. ligament reconstruction with tendon interposition (hand) 
  
Patients should have operative risk category of ASA 1 or 2 (American Society of 
Anesthesiolgists). 
Patients weighing between 70-100kg will be included to allow standardization of medication 
dosing   
 
 
Exclusion Criteria: 
Exclusion criteria include: 
 Allergy to Study Medications 
 Previous History of chronic opioid or any central nervous system depressant use 
 Patient Refusal to Participate 
 Known of Suspected History of Sleep Apnea 
 Known History of Chronic Pain Syndrome 
 Weight less than 70kg or greater than 100kg due to standardization of medication doses. 
 Revision Surgery  
 Inability to take study medications due to medication incompatibility or co-existing disease 
 Patients refusing or unable to receive US guided nerve block for postoperative pain 
 Patients unable to read and comprehend written consent document  
Pregnant or lactating women  
  
 
 
 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 5 of 10 
 
IRB Approval 8/6/2020 
 
Design  
 
Prospective Biomedical Intervention or Experiment 
Randomized Trial 
 
 
 
 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
In the orthopedic clinic, patients being scheduled for the following surgeries will be 
considered: 
Ligament Resection with Tendon Interposition (hand) 
Ankle Ligament Recontruction (foot/ankle) 
Anterior Cruciate Ligament Reconstruction (knee) 
  
Patients without exclusion criteria will be introduced to the pending study protocol. 
Specifically, they will be told that the study involves postoperative pain management and 
alternatives to opioid analgesics. Those patients who express a willingness to participate will 
be given a copy of the written consent form to review before the scheduled date of surgery.  
On the day of surgery, patients who agree to participate will have any further questions 
answered and may choose to enroll in the study. 
  
 
 
Informed Consent: 
Description of location(s) where consent will be obtained:  
University of Utah Orthopedic Center 
 
Description of the consent process(es), including the timing of consent:  
Patients will be introduced to the study concept during the orthopedic clinic visit. Those 
patients who meet study criteria will be given a copy of the study consent to review for at least 
one week before actually signing the consent on the day of surgery. 
 
Procedures: 
After written informed consent, patients will be randomized to receive either multi-modal or 
conventional postoperative pain medication. Each of the three surgical procedures will have a 
separate randomization sequence. These three randomization sequences will be generated 
using Research Randomizer (Lancaster, Pennsylvania). 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 6 of 10 
 
IRB Approval 8/6/2020 
 
Surgery, anesthesia, and intra-operative care will be standardized for all patients. Likewise, 
all patients will receive an US guided peripheral nerve block for pain control after surgery. 
All patients in the study will have continuous cell phone access to the senior investigator for 
questions or concerns about the protocol or for reporting inadequate pain control. 
Multimodal Treatment Group 
3 Different Non-opioid pain medication taken every 6 hours   
Celecoxib 100mg 
Acetaminophen 325mg 
Pregabalin 50 mg 
Plus, for breakthrough pain, oxycodone 5-10 mg  will be taken every 4 hours as needed.  
Prior to discharge from the PACU, patients in the multi-modal treatment protocol will receive 
a "blister pack" containing a 7 day supply of multi-modal pain medication. This pill pack will 
be prepared by the University of Utah Pharmacy. 
The pack will consist of 7 rows of pre-filled drug compartments. Each row will have 4 
compartments corresponding to the 6 hour dosing intervals for each day. 
Each compartment will contain pregabalin 50 mg, celecoxib 100 mg, and acetaminophen 325 
mg.   
In addition, patients in the multimodal group will be given a 7 day supply of oxycodone to be 
taken as needed for "breakthrough" pain. The dosing for oxycodone will be 5-10 mg by mouth 
every 4 hours as needed for pain.  
Control Group 
Patients in the control group will be given a 7 day supply of oxycodone 5-10 
mg/acetaminophen 325 mg (a combination drug commonly known as Percocet) to be taken by 
mouth every 4 hours as needed for pain.  
Patient Assessment 
All patients will be asked to rate their average pain on an 11 point scale (0-10) at awakening 
each morning and evening before bed. At the same intervals, patients will be asked to 
rate nausea and itching on an 11 point scale (0-10). These notations will be made by each 
patient in a written log provided for the patient. 
During the postoperative period, patients may transition to plain acetaminophen or stop all 
pain medication at their discretion. 
Patient Follow-up 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 7 of 10 
 
IRB Approval 8/6/2020 
 
All patients will be evaluated in the orthopedic surgery clinic one week following surgery. At 
that time, the blister pack will be collected and unused medication returned.  
All PHI will be kept separate from study data. PHI will be stored on an excel file containing a 
study ID. The study ID will be used in the data files. All study files will be stored on encrypted 
computers in locked offices on the SOM campus.  
 
 
Procedures performed for research purposes only:  
All patients are given a pregnancy test prior to survey. This information will be used to 
determine if the patient should be included in the study. This is a standard of care procedu
After written informed consent, patients will be randomized to receive either multi-modal 
conventional postoperative pain medication. Each of the three surgical procedures will hav
separate randomization sequence. These three randomization sequences will be generated 
using Research Randomizer (Lancaster, Pennsylvania). 
All patients in the study will have continuous cell phone access to the senior investigator f
questions or concerns about the protocol or for reporting inadequate pain control. 
Multimodal Treatment Group 
3 Different Non-opioid pain medication taken every 6 hours   
Celecoxib 100mg 
Acetaminophen 325mg 
Pregabalin 50 mg 
Plus, for breakthrough pain, oxycodone 5-10 mg  will be taken every 4 hours as needed.  
Prior to discharge from the PACU, patients in the multi-modal treatment protocol will rece
a "blister pack" containing a 7 day supply of multi-modal pain medication. This pill pack w
be prepared by the University of Utah Pharmacy. 
The pack will consist of 7 rows of pre-filled drug compartments. Each row will have 4 
compartments corresponding to the 6 hour dosing intervals for each day. 
Each compartment will contain pregabalin 50 mg, celecoxib 100 mg, and acetaminophen 3
mg.   
In addition, patients in the multimodal group will be given a 7 day supply of oxycodone to
taken as needed for "breakthrough" pain. The dosing for oxycodone will be 5-10 mg by m
every 4 hours as needed for pain.  
Control Group 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 8 of 10 
 
IRB Approval 8/6/2020 
 
Patients in the control group will be given a 7 day supply of oxycodone 5-10 
mg/acetaminophen 325 mg (a combination drug commonly known as Percocet) to be taken by 
mouth every 4 hours as needed for pain.  
Patient Assessment 
All patients will be asked to rate their average pain on an 11 point scale (0-10) at awakening 
each morning and evening before bed. At the same intervals, patients will be asked to 
rate nausea and itching on an 11 point scale (0-10). These notations will be made by each 
patient in a written log provided for the patient. 
During the postoperative period, patients may transition to plain acetaminophen or stop all 
pain medication at their discretion. 
Patient Follow-up 
All patients will be evaluated in the orthopedic surgery clinic one week following surgery. At 
that time, the blister pack will be collected and unused medication returned.  
All PHI will be kept separate from study data. PHI will be stored on an excel file containing a 
study ID. The study ID will be used in the data files. All study files will be stored on encrypted 
computers in locked offices on the SOM campus.  
 
 
 
Statistical Methods, Data Analysis and Interpretation 
 
Sample Size 
ClinCalc.com was used to calculate sample size   
Primary outcome measure - Anticipated reduction in 24 hr opioid(oxycodone) consumption 
Anticipated 24 hr opioid (oxycodone) use for control group is 30 mg (S.D. 10mg). 
The anticipated reduction in opioid use is 20%. 
Alpha value was 0.05, Power =80%. 
Based on these parameters, sample size needed to detect this difference would be 44 in each 
group.  
We plan to include 50 patients in each group to allow for attrition that may occur 
The request to enroll 300 patients is based on the intent to study 3 separate surgical 
procedures. 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 9 of 10 
 
IRB Approval 8/6/2020 
 
This would allow 100 patients for each procedure (50 patients for study group/ 50 patients 
for control group)  
  
Statistical Analysis 
The multimodal and control groups will be compared with respect to opioid use, pain scores 
and the incidence of opioid related side effects. 
The primary outcome measure will be the amount and duration of opioid use in the multimodal 
and control groups. 
Secondary outcome measures will include average pain scores, nausea, itching (scale 0-10). 
These scores will be recorded twice daily at awakening and retiring. 
  
Data Analysis 
Demographic Data will be compared using an unpaired "t" test  
Single Measures of opioid consumption will be compared using an unpaired "t" test 
Repeated measures of secondary outcomes such as pain, nausea, itching willbe compared 
using a repeated measures analysis of variance  (ANOVA)  
For all comparisons, a "p-value" of  <0.05 will be considered significant 
  
 
 
 


 
Protocol Summary (ERICA) 
 
IRB_00121505 
Page 10 of 10 
 
IRB Approval 8/6/2020 
 
Statistical Analysis Plan 
 
The sample size was based on an anticipated reduction in opioid consumption of 20% in the intervention group. With a chosen 
alpha of .05 and setting power of 80%, the sample size per group was 44 patients (http://ClinCalc.com). To account for possible 
attrition of patients, the planned study size was 100 patients with a 1:1 balance of intervention and control groups. Demographic 
and anesthetic agent variables were displayed as mean (±SD) or count (%). Covariate balance between the intervention and 
control groups after randomization and before intervention was done by standardized mean difference (SMD). The primary 
outcome measure was pain reported twice daily for 6 days. The planned secondary outcomes were nausea and itching, also 
reported twice daily for 6 days. A post hoc secondary outcome was daily oxycodone use (number of tablets) for 6 days. The 11-
point verbal scale scores and the count of oxycodone tablets were analyzed as ordinal variables. Cumulative patient scores for 
pain, nausea, itching, and tablet use for the 6 days were compared between groups by Wilcoxon rank-sum test with estimation of 
the median of the difference between intervention and control samples. The 6 days of measurements represent longitudinal data. 
To avoid assumptions about the probability distribution of the ordinal outcomes, robust rank-base analysis of variance methods 
was used to compare intervention and control samples with interaction by postoperative day.20 Also, pairwise comparison for 
each 12-hour or 24-hour period was estimated by Wilcoxon nonparametric tests, with a false discovery rate adjustment of the P 
values using the Benjamini-Yekutieli procedure. Tolerance intervals are estimated from a sample and provide limits that at least a 
certain proportion of a population falls within a given confidence interval.29 In addition to comparing the cumulative opioid 
requirements for patients in the control and intervention groups, analysis was performed to determine the upper tolerance limit to 
provide sufficient oxycodone tablets without requiring a refill (the opioid requirements) in 90% or 95% of control and 
intervention patients, respectively. All analyses were performed using the R software language (Version 4.1.0) and the R 
packages nparLD (Version 2.1) and tolerance (Version 2.0.0). No data were imputed for the control patient who was lost to 
follow-up. The null hypothesis was rejected for P < .05; 95% CIs were obtained. Some statistics were rounded.