Clinical trial NCT05820685
Conditions: Trauma Injury
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2023-07-27; Completion date: 2024-04-29
Enrollment: 484 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to identify the effect dronabinol has on opioid exposure when used as an adjunct to the current standard multi-modal pain regimen (MMPR)

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Standard of Care (acetaminophen +naproxen +gabapentin + as needed oxycodone or Tramadol) intervention 2: Dronabinol
Intervention descriptions: intervention 1: Participants will receive acetaminophen 1000 mg every six hours, naproxen 500 mg every 12 hours, and gabapentin 300 mg every eight hours. Participants will also receive Oxycodone 5 mg or Tramadol 50 mg every six hours as needed for breakthrough pain. Providers will have the ability to adjust this pain regimen based on clinical judgement. intervention 2: Participants will receive Dronabinol 10 mg every 12 hours scheduled. Providers will have the ability to adjust this pain regimen based on clinical judgement.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT1E: 04/24/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dronabinol on the Pain Experience (DOPE): a pragmatic randomized- controlled trial 
 
NCT05820685 
 
Version Date: 04/24/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT2E: 04/24/2023 
 
Protocol Title: Dronabinol on the Pain Experience (DOPE): a pragmatic randomized- 
controlled trial 
 
Principal Investigator: James Klugh, MD 
Resident, Department of General Surgery 
 
Co-Investigators:  John A. Harvin, MD, MS, FACS 
Associate Professor of Surgery 
Faculty, Center for Translational Injury Research (CeTIR) 
 
Krislynn Mueck, MD 
Assistant Professor of Surgery 
 
Population:  Adult trauma patients admitted to the Surgical Ward (Floor), Surgical 
Intermediate Unit (SIMU), and Shock Trauma Intensive Care Unit (STICU) at 
Memorial Hermann Hospital-Texas Medical Center (MHH-TMC). 
 
Number of Sites: 
Single center, MHH-TMC 
 
Study Duration: 
5 to 6 months 
 
Subject Duration: 
Time while hospitalized 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT3E: 04/24/2023 
 
Table of Contents 
General Information 
3 
Background Information 
3 
Objectives 
4 
Study Design 
4 
Study Population 
6 
Study Procedures 
6 
Statistics 
7 
Ethics 
8 
Data Handling and Record Keeping 
8 
Quality Control and Assurance 
8 
Publication Plan 
8 
References 
9 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT4E: 04/24/2023 
 
 
General Information: 
The optimal strategy for providing safe and effective pain management after acute traumatic 
injury is unknown. A recent randomized control trial (MAST) performed at MHH-TMC 
demonstrated the effectiveness of multi-modal pain regimen (MMPR) in reducing opioid 
exposure while maintaining pain control.[1] Adjunct analgesic medications are commonly added 
to MMPRs to diversify the pain management with additional drug classes. One such medication 
is dronabinol, a synthetic delta-9-tetrahydrocannabinol (delta-9-THC) medication. The proposed 
project is a randomized comparative effectiveness trial of current pain management strategies in 
acutely injured trauma patients. A parallel group, randomized trial of our current institutional 
MMPR with the addition of dronabinol compared to our current institutional MMPR will be 
performed and analyzed using Bayesian statistics. 
 
 
Background Information: 
 
 
 
The opioid epidemic is an ongoing public health crisis that has only intensified during the 
COVID-19 pandemic.[2-4] Trauma patients are a known group at risk for opioid use 
disorder.[5,6] Due to the nature of multisystem injuries, need for multiple painful procedures, 
and lengthy hospitalization, injured patients’ acute pain control needs differ from those in other 
surgical specialties.[7] In an effort to reduce opioid exposure while still providing optimal pain 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT5E: 04/24/2023 
 
control, surgeons are increasingly prescribing MMPRs.[8-12] Our current institutional MMPR is 
derived from the Multi-Modal Analgesic Strategy for Trauma (MAST) trial and was 
demonstrated to reduce opioid exposure as measured by morphine milligram equivalents (MME) 
while maintaining pain control.[1] However, this MMPR is just a starting point and many 
adjunct medications are added to improve pain control. One such adjunct is dronabinol, a 
synthetic delta-9-tetrahydrocannabinol (delta-9-THC) medication that has FDA approval for 
anorexia in patients with AIDS and chemotherapy-induced nausea and vomiting. Currently 
dronabinol is used off-label for its analgesic properties but the data supporting its use for acute 
pain after traumatic injury is limited.[13] 
 
Objectives: 
To perform a randomized comparative effectiveness trial to identify the effect dronabinol has on 
opioid exposure when used as an adjunct to the current standard MMPR. 
 
 
Study Design: 
 
This will be a pragmatic, single-blind, randomized comparative effectiveness trial conducted at 
the Red Duke Trauma Institute at MHH-TMC. 
 
Study Arms: Treatment Strategies 
 
Treatment Strategy #1 
Treatment Strategy #2 
Central Prostaglandin 
Inhibitor 
Acetaminophen 
Acetaminophen 
NSAID COX Inhibitor 
Naproxen 
Naproxen 
Gabapentinoid 
Gabapentin 
Gabapentin 
Local Anesthetics 
Lidocaine Patch 
Lidocaine Patch 
Cannabinoid 
None 
Dronabinol 10 mg Q12h 
PRN Medication 
Tramadol 
Other opioids 
Regional Anesthesia 
Tramadol 
Other opioids 
Regional Anesthesia 
 
Each patient once randomized will be started on the corresponding treatment strategy. Dosing of 
other medications will be started based on current standard at our institution unless the patient 
requires dosing adjustment due to medical comorbidities. Continuing pain management and 
alteration of the MMPR will be at the discretion of the provider. 
 
A normal dosing strategy will consist of acetaminophen 1000 mg every six hours, naproxen 500 
mg every 12 hours, gabapentin 300 mg every eight hours, and Tramadol 50 mg every six hours 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT6E: 04/24/2023 
 
as needed for breakthrough pain. Dronabinol 10 mg every 12 hours will be started for the 
intervention arm. Providers will have the ability to adjust this pain regimen based on clinical 
judgement. Patients who are NPO for surgery will still be able to take medications with sips of 
water. Patients who are intubated or are unable to take oral medications will have enteral access 
placed via small bore nasogastric tube or feeding tube as the discretion of the provider per 
routine clinical practice. Patients who are strict NPO will not have oral medications until deemed 
appropriate by the provider. 
 
At discharge patients will be provided a script with the medications they were requiring for pain 
control prior to discharge at the discretion of the provider. Dronabinol is not commonly given as 
a prescription at discharge as part of routine clinical practice and will not be prescribed at 
discharge in this trial. 
 
 
Setting 
This study will be conducted at the Red Duke Trauma Institute at Memorial Hermann Hospital- 
Texas Medical Center (MHH-TMC). It is one of two Level 1 trauma centers in the Houston 
metropolitan area, an area in which over 6 million people reside with approximately 2,000 
admissions to the adult Trauma Service per year. 
 
Time Period 
IRB submission for the study will occur in January 2023. Using an alpha of 0.05 and a power of 
80% to detect a 15% reduction from previously reported MME/d of 34 +/- 23 from the MAST 
trial to 29 MME/d (equal to 1 x 50 mg Tramadol) a total of 664 patients would need to be 
enrolled or 332 per arm. Based on admittance patterns this would take approximately 5-6 
months. 
 
Outcomes 
The primary outcome of the study will be the reduction in opioid exposure measured by MMEs 
per day, calculated by taking the total of MMEs from all opioids received and dividing by length 
of stay. MMEs will be measured based on a standard conversion factor listed in the table below: 
 
Opioid 
Conversion 
Factor 
Oral Opioids 
Codeine (mg) 
0.15 
Tramadol (mg) 
0.1 
Hydrocodone (mg) 
1 
Oxycodone (mg) 
1.5 
Methadone 
1-20 mg/day 
4 
21-40 mg/day 
8 
41-60 mg/day 
10 
≥61-80mg/day 
12 
Morphine (mg) 
1 
Hydromorphone (mg) 
4 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT7E: 04/24/2023 
 
Transdermal Opioids 
Fentanyl (mcg/hr) 
2.4 
Intravenous Opioids 
Morphine (mg) 
3 
Hydromorphone (mg) 
15 
Fentanyl (mcg) 
0.2 
 
Secondary Outcomes include the following: 
● Total MMEs over hospital stay 
● Pain Scores calculated by the defense and veterans pain rating scale. Pain scores will be 
recorded by nursing at timepoints per unit protocol as part of routine practice. An average 
will be calculated for the entire hospital stay as well for the first 72 hours. Pain scores are 
already routinely recorded in the electronic medical record (EMR). 
● Discharge from the hospital with or without a prescription for an opioid medication 
● Incidence of opioid-related complications, such as ileus, aspiration, unplanned intubation, 
unplanned admission to an intensive care unit, and use of an opioid-reversal agent. These 
are tracked by the institution trauma registry and will be obtained once available from the 
registry. 
● Lengths of stay 
○ Hospital length of stay 
○ ICU length of stay 
○ Ventilator length of stay 
○ Hospital free days 
○ ICU free days 
○ Ventilator free days 
 
 
Study Population: 
 
Screening 
All adult patients (≥16 years) admitted to the trauma service will be screened for eligibility in the 
study. Clinical research staff are available on a 24/7 basis to conduct screening and collect data 
on those patients meeting inclusion criteria. Research staff will inform the physicians of 
randomization allocation to each treatment arm. Drug regimen dosing will be available for 
providers placing orders and there is an order set in place for the current MMPR. All patient care 
aspects other than the randomization to treatment strategy will follow the MHH-TMC policies 
and guidelines. 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
1. Adult trauma (≥16 years) patients admitted to the floor, SIMU, STICU at MHH-TMC 
Exclusion Criteria: 
1. Pediatric patient (<16 years) 
2. Age > 80 years old 
3. 
4. Pregnant 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT8E: 04/24/2023 
 
5. Prisoner 
6. Patients placed in observation unit 
7. Non-acute trauma 
8. Admitted with primary burn injury 
9. Expired prior to admission 
10. Moribund 
11. Discharge from emergency department 
12. Left against medical advice 
 
Patients will not be excluded if they have a contraindication to a specific drug class to keep with 
the pragmatic design. 
 
If a patient meets inclusion criteria without any exclusion criteria, they will be randomized in the 
Emergency Department so that medications can be ordered and administered as quickly as 
possible. 
 
Study Procedure: 
 
Randomization 
Allocation will occur through a random number generator via the Redcap system. Research 
assistants will inform the resident writing admission orders in the Emergency Department of 
group assignment. Randomization will be stratified by unit of admission (ICU, IMU, or floor). 
 
Data Collection 
Data collection will occur by one of two methods: manual entry or automatic capture of data. 
Data will either be obtained from the National Trauma Database registry, or automatically 
captured from the electronic medical record. 
 
Follow up 
No study-specific follow-up will be required. 
 
Statistics: 
Sample Size 
 
Using an alpha of 0.05 and a power of 80% to detect a 15% reduction from previously reported 
MME/d of 34 +/- 23 from the MAST trial to 29 MME/d (equal to 1 x 50 mg Tramadol) a total of 
664 patients would need to be enrolled or 332 per arm. Based on admittance patterns this would 
take approximately 5-6 months with 75% enrollment of admissions achieved in previous trials. 
 
Data Analysis Plan 
 
A Bayesian statistical model will be the primary model used due to its ability to incorporate 
previously observed data to form a posterior distribution which then captures the current state of 
the evidence for the probability that an effect of some magnitude exists. Using the data gathered 
from the MAST trial a Bayesian approach will better evaluate the evidence from this trial that 
there is some probability that an effect of some magnitude exists. Broadly, the data analytic 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT9E: 04/24/2023 
 
strategy will use generalized linear multilevel modeling with level-two random effects to account 
for clustering of participants within site and, where applicable, observations within participants. 
Modeling will use R v. 4.2.[14] Initial analyses examining group differences for baseline 
variables will use cross-tabulation, ANOVA’s, and examination of correlations between baseline 
variables and specified outcomes. For the purposes of evaluating the comparability of groups, a 
posterior probability of > 95% will constitute evidence for statistically reliable differences. 
Baseline or demographic variables on which group differences are detected and which are 
correlated with outcomes meet the definition of confounders and will result in two sets of 
analyses: one in which the relevant variable is included as a covariate and one in which it is 
not.[15,16] This will permit determination of the degree to which any group differences might 
confound conclusions regarding treatment. All analyses will be conducted on an intention-to- 
treat basis. Bayesian approaches will implement joint modeling of observed outcomes and the 
missing data which is robust to ignorable missingness (i.e., MCAR and MAR).[17] Sensitivity 
analyses will evaluate robustness of analytic conclusions to missing data. Non-ignorable missing 
data patterns will be addressed through pattern-mixture modeling methods.[18] Convergence of 
Bayesian analyses on the posterior distributions via Monte-Carlo Markov chain (MCMC) will be 
assessed via graphical (Gelman-Rubin Plots) and quantitative (Gelman-Rubin Diagnostics and 
Effective Sample Size) evidence. Evaluation of posterior distributions will permit statements 
regarding the probability that effects of varying magnitudes exist, given the data. Priors will be 
drawn from the effect size seen in the MAST trial.[1] 
 
 
Ethics: 
Due to the acute clinical status of the trauma patient population (intubation, intoxication, severe 
pain), it is often not feasible to obtain informed consent from a patient or legally authorized 
representative prior to administering of pain medications. Therefore, delayed consent will be 
used and patients will be randomized and enrolled prior to consent. Post-enrollment, a member 
of the trauma research team will make attempts to contact either the patient or the legally 
authorized representative to obtain consent for this study. Competency will be assessed by 
providers and the trained research assistants who will be obtaining consent. Assent will be 
sought to the extent possible if the subject is unable to give informed consent. Once appropriate 
to approach the patient for consent, a study team member will explain the study, its implications 
for the patient, and give the patient written study information. If the subject consents to 
participation, they will sign the consent document. If the subject refuses, data collection will stop 
at time of refusal. If after 5 days the patient remains unable to self-consent and no legally 
authorized representative is available, the consent will be waived and data included. 
Additionally, if the subject does not survive following the traumatic injury or is discharged from 
the hospital before the study team is able to obtain consent, their information will be included in 
the data analysis. 
 
Data Handling and Record Keeping: 
 
If data is to be extracted by hand, it will be entered into a standardized case report form and 
entered into a RedCap™ database. Each subject will be assigned a study-specific number. Data 


IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DAT10E: 
 
will be collected until hospital discharge. Remaining data will be drawn from the Trauma 
registry database. All hard copy source documentation will be kept in a secured, locked cabinet 
in the research coordinator’s office. All study documents will be maintained in a secure location 
for two years following study completion. 
 
Quality Control and Assurance: 
 
Each item on the web forms will have validity checks performed to ensure that the data entered 
are accurate and that items are not skipped during entry by mistake. Bi-weekly audits of data will 
be performed by both clinical investigators and research assistants. 
 
Publication Plan: 
 
Plan to publish (1) protocol detailing the proposed project and (2) clinical results of the 
randomized control trial. 
 
References: 
 
1. Harvin JA, Albarado R, Truong VTT, Green C, Tyson JE, Pedroza C, Wade CE, Kao LS; 
MAST Study Group. Multi-Modal Analgesic Strategy for Trauma: A Pragmatic 
Randomized Clinical Trial. J Am Coll Surg 2021 -03;232(3):241-251.e3. 
2. Nair L, Duggan RP, Moliver CL. The Opioid Epidemic in the Age of the COVID-19 
Pandemic. Aesthet Surg J 2021 -10-15. 
3. Haley DF, Saitz R. The Opioid Epidemic During the COVID-19 Pandemic. JAMA 2020 
-10-27;324(16):1615-1617. 
4. Alexander GC, Stoller KB, Haffajee RL, Saloner B. An Epidemic in the Midst of a 
Pandemic: Opioid Use Disorder and COVID-19. Ann Intern Med 2020 -07-07;173(1):57- 
58. 
5. Yoon JH, Suchting R, Kessler D, Soder HE, Kapoor S, Stotts AL, Heads AM, Harvin JA, 
Green CE, Lane SD, et al. Utility of a brief assessment of opioid demand among post- 
discharge trauma care patients. Exp Clin Psychopharmacol 2020 -07-16. 
6. Yorkgitis BK, Brat GA. Postoperative opioid prescribing: Getting it RIGHTT. The 
American Journal of Surgery 2018 April 1,;215(4):707-711. 
7. Harvin JA, Truong VTT, Green CE, Allen L, Murry J, Radosevich JJ, Bogert JN, 
Murphy PB, Padilla-Jones BB, Zarzaur BL, et al. Opioid exposure after injury in United 
States trauma centers: A prospective, multicenter observational study. J Trauma Acute 
Care Surg 2020 -06;88(6):816-824. 
8. Reagan KML, O'Sullivan DM, Gannon R, Steinberg AC. Decreasing postoperative 
narcotics in reconstructive pelvic surgery: a randomized controlled trial. Am J Obstet 
Gynecol 2017 -09;217(3):325.e1-325.e10. 


9. Rafiq S, Steinbrüchel DA, Wanscher MJ, Andersen LW, Navne A, Lilleoer NB, Olsen, 
PS. Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, 
a randomized controlled trial. J Cardiothorac Surg 2014 -03-20;9:52. 
10. Sim V, Hawkins S, Gave AA, Bulanov A, Elabbasy F, Khoury L, Panzo M, Sim E, Cohn 
S. How low can you go: Achieving postoperative outpatient pain control without opioids. 
J Trauma Acute Care Surg 2019 -07;87(1):100-103. 
11. Pitchon DN, Dayan AC, Schwenk ES, Baratta JL, Viscusi ER. Updates on Multimodal 
Analgesia for Orthopedic Surgery. Anesthesiol Clin 2018 -09;36(3):361-373. 
12. Wick EC, Grant MC, Wu CL. Postoperative Multimodal Analgesia Pain Management 
With Nonopioid Analgesics and Techniques: A Review. JAMA Surg 2017 -07- 
01;152(7):691-697. 
13. Schneider-Smith E, Salottolo K, Swartwood C, Melvin C, Madayag RM, Bar-Or D. 
Matched pilot study examining cannabis-based dronabinol for acute pain following 
traumatic injury. Trauma Surg Acute Care Open. 2020 Feb 9;5(1):e000391. doi: 
10.1136/tsaco-2019-000391. 
14. Team, R.C., R: A Language and Environment for Statistical Computing. 2017, R 
Foundation for Statistical Computing: Vienna, Austria. 
15. Assmann, S.F., et al., Subgroup analysis and other (mis)uses of baseline data in clinical 
trials. Lancet, 2000. 355(9209): p. 1064-9. 
 
16. Pocock, S.J., et al., Subgroup analysis, covariate adjustment and baseline comparisions 
in clinical trial reporting: Current practice and problems. Statistics in Medicine, 2002. 
21: p. 2917-2930. 
 
17. Best, N. and A.E.p.-. Thomas, Bayeisan Graphical Models and Software for GLMs, in 
Generalized Linear Models: A Bayesian Perspective, D. Dey, S.K. Ghosh, and B.K. 
Mallick, Editors. 2000, Marcel Dekker, Inc.: New York. 
 
18. Fitzmaurice, G.M. and N.M. Laird, Generalized linear mixture models for handling 
nonignorable dropouts in longitudinal studies. Biostatistics, 2000. 1: p. 141-156. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0499 
IRB APPROVAL DA1T0E: 04/24/2023