Administrative information
Title {1} | The Opioid Analgesic Reduction Study (OARS): A comparison of opioid vs. non-opioid combination analgesics for management of post-surgical pain study protocol for a double-blind randomized multi-center clinical trial. |
Trial registration {2a and 2b}. | ClinicalTrials.gov NCT04452344. Registered on June 20, 2020 |
Protocol version {3} | Version 5.0; July 30, 2021 |
Funding {4} | Supported by National Institute of Dental and Craniofacial of the National Institutes of Health awards under award numbers UG3DE028860 and UH3DE028860. |
Author details {5a} | Primary and Corresponding Author Cecile A. Feldman, DMD, MBA Dean and Professor Rutgers University – School of Dental Medicine and Professor Rutgers University – School of Public Health 110 Bergen Street Newark, NJ. 07103 Phone: 973-972-4634 e-mail: feldman@rutgers.edu Additional Contributors to the Protocol Janine Fredericks-Younger, DMD Rutgers University, School of Dental Medicine 110 Bergen Street, Room D813 Newark, NJ 07101 Phone: (973) 972-1679 frederja@sdm.rutgers.edu Paul J. Desjardins, DMD, Ph.D. Rutgers University, School of Dental Medicine 110 Bergen Street, Room B815 Newark, NJ 07101 Phone: (973) 762-4430 paul.j.desjardins@gmail.com Shou-En Lu, PhD Rutgers University, School of Public Health 683 Hoes Lane Piscataway, NJ 08854 Phone: (732) 235-5764 sl1020@sph.rutgers.edu Hans Malmstrom, DDS University of Rochester, Eastman Institute for Oral Health 625 Elmwood Ave. Rochester, NY 14620 Phone: (585) 273-5087 hans_malmstrom@urmc.rochester.edu Michael Miloro, DMD, MD University of Illinois, College of Dentistry 801 S Paulina St, Room 110 (MC 835) Chicago, IL 60612 Phone: (312) 996-1052 mmiloro@uic.edu Gary Warburton, MD, DDS University of Maryland, School of Dentistry 650 W Baltimore St, Room 1209 Baltimore, MD 2120 Phone: (410) 706-7060 gwarburton@umaryland.edu Brent Ward, DDS, MD University of Michigan, School of Dentistry 1515 E. Hospital Drive Ann Arbor, MI 48109 Phone: (734) 936-5950 bward@med.umich.edu Vincent Ziccardi, DDS, MD Rutgers University, School of Dental Medicine 110 Bergen St., Room B854 Newark, NJ 07101 Phone: (973) 972-7462 ziccarvb@sdm.rutgers.edu Daniel Fine, DMD Rutgers University, School of Dental Medicine 110 Bergen St., Room B854 Newark, NJ 07101 Phone: (973) 972-3728 finedh@sdm.rutgers.edu |
Name and contact information for the trial sponsor {5b} | Rutgers, The State University of New Jersey, Rutgers School of Dental Medicine, 110 Bergen Street, Newark, New Jersey, USA |
Role of sponsor {5c} | The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. |
Introduction
Background and rationale {6a}
Description of health problem
Previous study weaknesses
Importance of the study
Objectives {7}
Aim 1—Pain management and patient satisfaction
Aim 2—Adverse events, daily function, and opioid-seeking behavior
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Adverse effects: (i.e., constipation, diarrhea, dizziness/light headedness, euphoria, headache, nausea, tired/sleepy, vomiting, itching, and urinary retention) by patient reports in their electronic diaries and emergency call/visit logs
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Daily function: ability to carry out their normal activities (determined by the mean normal-daily-function rating) by patient rating in their daily diary
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Sleep quality: sleep quality either from data obtained by an electronic sleep monitor device or by patient rating in their daily diary
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Future opioid-seeking behavior: number of NON-OPIOID patients filling an opioid prescription within 6 months following the study post-operative period by querying Prescription Database Monitoring Program databases
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Diversion: number of doses remaining return bottles at the time of the post-operative visit or by electronic medical bottle monitoring, which is normally well past the time period in which patients require analgesics.
Aim 3—Clinical protocol/decision support tool
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
Inclusion criteria
Exclusion criteria
Who will perform the informed consent procedure? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Brief description/justification of outcome measure | Outcome measured by | Timing |
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Primary outcome measures | ||
Pain: For pain level, Brief Pain Inventory (BPI) using the Numerical Rating Scale (NRS) was chosen because: • BPI with NRS is widely used and accepted • Reliability and validity for BPI and NRS have been established • BPI with NRS is clinically relevant (patients want to minimize pain experienced after surgery) • BPI with NRS is a sensitive measure • BPI with NRS allows for direct comparisons across studies Satisfaction: For satisfaction, overall satisfaction questions from the Pain Treatment Satisfaction Scale (PTSS) were chosen because: • While patients want to minimize pain, patients are willing to tradeoff some pain relief to minimize side effects, maintain their ability to sleep, maintain their ability to engage in normal activities, and minimize exposure to opioids • PTSS has been shown to be valid and reliable | Pain: NRS is used on a scale of 0 to 10 where 0 = no pain and 10 = worst imaginable pain for average pain level, pain at its worst, pain at its least, pain experiencing now. Satisfaction (measures from PTSS): • How satisfied are you with the time that it takes your pain medication to work? (scale: 1 = very satisfied, 2 = satisfied, 3 = neither satisfied nor dissatisfied, 4 = dissatisfied, 5 = very dissatisfied) • How satisfied are you with the level of amount of pain relief provided by your pain medication? (scale: 1 = very satisfied, 2 = satisfied, 3 = neither satisfied nor dissatisfied, 4 = dissatisfied, 5 = very dissatisfied) • How satisfied are you with the duration of pain relief provided by your pain medication? (scale: 1 = very satisfied, 2 = satisfied, 3 = neither satisfied nor dissatisfied, 4 = dissatisfied, 5 = very dissatisfied) • Overall, how satisfied are you with your pain medication? (scale: 1 = very satisfied, 2 = satisfied, 3 = neither satisfied nor dissatisfied, 4 = dissatisfied, 5 = very dissatisfied) • Overall, how does your level of pain relief meet your expectations of pain relief? (scale: 1 = greatly exceeds my expectations, 2 = somewhat exceeds my expectations, 3 = meets my expectations, 4 = does not quite meet my expectations, 5 = does not meet my expectations at all) • Do you think that your pain medication could be more effective in relieving your pain? (scale: 1 = yes, definitely, 2 = probably yes, 3 = I do not know, 4 = probably not, 5 = definitely not) Participants report their pain experience and rate their overall satisfaction using a REDCap application developed for electronic phones and tablets. | Pain: • Visit 1 (in the last 24 h) • Each morning days 2 to 8 • Each evening days 1 to 7 • Visit 2 (in the last 24 h) Satisfaction: Satisfaction recorded during post-op visit (visit 2) |
Secondary outcome measures | ||
Adverse events: As medications have side effects, a list of possible adverse events (side effects) related to the intervention has been developed, and participants are asked if they are experiencing any of them. (This is separate from serious adverse events which are captured. Serious adverse events result in a participant being exited from the study. An analysis of serious adverse events is included in the study analysis.) Sleep quality: • Pain and Sleep Questionnaire 3-item index (PSQ-3) was selected because it is a validated measure and because of its ease of use for the eDiary on a smart phone. • A question from the PTSS was selected because it provides an overall rating of the quality of sleep. Pain interference (daily function): The PROMIS Short 6b was selected because it is a standard NIH measure of pain interference and can be recorded during the post-operative visit. Future opioid-seeking behavior: The PDMP is accessed; 6 months was selected because it is the maximum follow-up time which could be completed within the study time frame. Potential diversion: Participants are instructed to bring the pill bottle and unused capsules to the follow-up appointment. | Adverse events: • Adverse events include excessive fatigue or drowsiness, inability to concentrate, nausea, diarrhea, dizziness, constipation, skin rashes, stomach aches, heartburn, vomiting, euphoria, headache, urinary retention, and unintentional weight gain with a binary yes/no scale. Self-reported binary response (yes/no) is ascertained. If yes, was the adverse event bothersome to a minor or major extent? o For visit 1, participants are asked how much were you bothered by … over the last 24 h. o At the time of getting up in the morning, participants are asked how much were you bothered with …. during the night o Right before going to sleep at night, participants are asked how much they were bothered by … during the day. o For visit 2, participants are asked how much were you bothered by … over the last 24 h. Sleep ability: • From the PSQ-3: (a) Last night did you have trouble falling asleep? (b) Last night were you awakened by pain during the night? (c) Were you awakened by pain this morning? {binary yes/no scale during the post-operative period; NRS scale where 0 = never, 10 = always at visits 1 and 2} • From PTSS: rating the overall quality of last night’s sleep {NRS where 0 = excellent and10 = very poor} • From ActiGraph: Sleep quality is monitored, and data collected Pain interference: • PROMIS Short 6b: During the post-operative period, how much did pain interfere with your day to day activities, work around the home, ability to participate in social activities, enjoyment of life, the things you usually do for fun, enjoyment of social activities, household chores, family life, your ability to concentrate, enjoyment of recreational activities, tasks away from home {scale: 1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit, 5 = very much} and how often did pain keep you from socializing with others? {scale: 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = always} Future opioid-seeking behavior: • # of new opioid prescriptions recorded in the Prescription Monitoring Database Program at approximately 6 months following the surgical procedure Potential diversion: • # returned capsules at visit 2 determined by counting the returned capsules or via electronic monitoring device • # unaccounted for capsules at visit 2 (not recorded as used and not returned) Participants report whether they have experienced each adverse event and rate their sleep ability and pain interference in a daily electronic diary using a REDCap application developed for electronic phones and tablets. | Adverse events: • Visit 1 • Each night for days 2–8 • Each day for days 1–7 • Visit 2 Ability to sleep: • Visit 1 • Each morning on days 2 thru 8 and • Visit 2 (in the last 24 h) Pain interference: • Visit 1 • Each evening on days 1 through 7 • Visit 2 Future drug-seeking behavior: • Opioid prescriptions filled within 6 months after visit 2 Potential diversion: • Visit 2 |
Participant timeline {13}
Expected duration of subject participation
Sequence of procedures and duration of study period
Post-Operative Period | |||||||||
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Procedures | Screening (Visit 0) | Study Visit 1: Surgery (Day 1) | Upon Waking in the Morning (Days 2 to 10 +/-5) | When taking Pain Meds (Days 1 to 10 +/-5) | Before Going to Sleep in the Evening (Days 1 to 9 +/-5) | Intermediate Visit / Hospitalization or Fatality Days 1 to 10 (+/- 5) | Post Operative Visit Study Visit 2 (Day 10 +/-5) | Withdrawal or Termination | PDMP Query (Visit 2 plus 186 days +/- 14 days) |
Signed Consent Form | X | ||||||||
Assessment of Eligibility Criteria (including review of medical history and concomitant medications) | X | X | |||||||
Study Intervention | X | X | X | X | |||||
Pain Assessment | X | ||||||||
Pain Interference Assessment | X | X | |||||||
Sleeping Quality | X | X | |||||||
Assessment of Adverse Events | X | X | X | X | |||||
Adverse Events and Serious Adverse Event Reporting | X | ||||||||
Obtain Satisfaction | X | ||||||||
Determination of Tablets for Diversion | X | ||||||||
Premature Exit study Documentation | X | ||||||||
PDMP Inquiry | X |
Sample size {14}
Sample size and power
Consideration of within-site correlation
Recruitment {15}
Recruitment strategies
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Capsule number | OPIOID content | NON-OPIOID content | Quantity for a dose | Total dispensed | Capsule size | Color |
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1 | Hydrocodone 5 mg/acetaminophen 300 mg | Ibuprofen 400 mg | 1 | 20 | AA | Brown |
2 | Placebo | Acetaminophen 500 mg | 1 | 20 | 00 | White |
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Plans to promote participant retention and complete follow-up {18b}
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An electronic message is sent to the participant each morning and each evening with a link to the eDiary and a reminder to complete their eDiary entry.
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If the eDiary entry is not made within 2 h, an automatic text message reminder is sent up to two times.
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Research coordinators contact participants by phone to reinforce adherence to study protocol.
Data management {19}
REDCap
SMRxT
ActiGraph
Barcoding
Data validation
Stopping logic
Calculation aids
Confidentiality {27}
Deletion of identifying information
Database for public release
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Aim 1—Pain experience and patient satisfaction
Aim 2—Adverse effects, daily function and sleep quality, and opioid-seeking behavior
Aim 3—Clinical protocol/decision support tool
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Heterogeneity and subgroup analyses
Sensitivity analyses—site effect
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant-level data, and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
Composition of the data monitoring committee, its role, and reporting structure {21a}
Adverse event reporting and harms {22}
Frequency and plans for auditing trial conduct {23}
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}
Dissemination plans {31a}
Dissemination at scientific meetings
Publication and authorship policies
NIH Public Access Policy
Discussion
Clinical situation | Intervention | Outcomes (important to providers and patients) |
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• Examines gender differences • Allows for extraction of any number of 3rd molars during the surgical visit • Can use any type of anesthesia • Can use post-operative steroids | • Uses medication protocols which can be followed with existing over-the-counter and prescription formularies • Follows decreased FDA-recommended doses for acetaminophen • Allows patients to “get ahead of the pain” | • Follows patients over entire post-operative period (10 days ±5 days) • Primary outcome is pain experience rather than pain relief • Assesses ability to sleep and perform daily activities • Tracks adverse effects • Explores left-over medication which can be diverted • Explores future opioid-seeking behavior |