Relieving Acute Pain (RAP) Study: A Pilot Study

NCT03426137 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: HP-00078742
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

The United States (US) faces a crisis of pain management. According to the 2012 National Health Interview Survey, almost 50 million adults in the US reported having significant chronic or severe pain (Nahin 2015). Doctors in the US still prescribe opioids across the board for pain despite a growing recognition of an epidemic of opioid overdose and use disorder. Few solutions have been successfully proposed and implemented. Placebos represent a novel and potentially fruitful means of addressing this issue. However, clinicians often use placebos deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Recently, we reviewed a database of placebo studies including 22 studies in both animals and humans hinting of evidence that placebos may work as a dose extender of active painkillers. Placebos given after repeated administration of active treatments can acquire medication-like effects based on learning mechanisms. Here, we will test if dose-extending placebos are effective in relieving clinical acute pain in opioid patients with traumatic pain. Patients will be randomized to three arms. Arm 1 will be a Full Dose (FD) group, which will receive all NSAIDs as described in the Guidelines for NSAID use in Orthopedic Patients and Oxycodone (5mg). Arm 2 will be a Partial Reinforcement (PR) group, which will receive NSAIDs, Oxycodone (5mg), and placebos to reach a 50% reduction of the total intake of opioids. Finally, Arm 3 will be a Control (C) group receiving NSAIDs and placebos. Patients will be assigned to one of three arms according to a 1:1:1 schedule of randomization. Study IDs will be generated by the pharmacy and blinding will occur by ensuring that oxycodone and placebos look, smell, and taste identical. Rescue therapy will be provided as needed. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated.

Conditions

Trauma; Opioid Use; Spine Fusion

Keywords

Oxycodone; Placebo; Expectancy Induced Analgesia; NSAID

Outcome Measures

Primary Outcomes (1)

• Pain Self-reports

  Collected on a visual analogue scale, with 0 being "no pain" and 100 being "maximum pain tolerable"

  Day 1-7, Week 2, Months 1, 3 and 6

Study Arms (3)

Full Dose (FD)

ACTIVE COMPARATOR

Participants in the FD arm will receive NSAIDs and Oxycodone (5mg).dosed in accordance with the Guidelines for Use from University of Maryland Shock Trauma Center.

Drug: Oxycodone; Drug: Ketorolac

PR (Partial Reinforcement)

PLACEBO COMPARATOR

Participants in this group will receive NSAIDs, Oxycodone (5mg), and placebo pills to reach a 50% reduction of the total intake of opioids.

Drug: Oxycodone; Drug: Ketorolac; Other: Placebo

C (Control)

PLACEBO COMPARATOR

Participants in this group will receive NSAIDs and placebo pills

Drug: Ketorolac; Other: Placebo

Interventions

Oxycodone DRUG

5mg Oxycodone in oral solution given every 3 hours

Also known as: Oxycodone Hydrochloride

Full Dose (FD); PR (Partial Reinforcement)

Ketorolac DRUG

toradol intravenous (IV) 30mg. Maintain toradol IV every 8 hours, round the clock. For patients with renal insufficiency, decrease toradol dose to 15mg every 8 hours. For patients over 65 years old, decrease toradol dose to 15 mg every 8 hours. After 24 hours, start oral NSAIDS every 8 hours round the clock when tolerating pain.

Also known as: Toradol

C (Control); Full Dose (FD); PR (Partial Reinforcement)

Placebo OTHER

Oral solutions containing only the carrier vehicle - a flavored syrup called OraSweet

Also known as: OraSweet

C (Control); PR (Partial Reinforcement)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65
• Admission to The Shock Trauma Center within 72 hrs
• Any trauma requiring inpatient opioid medication
• Plan by primary service to follow the Shock Trauma Guidelines for Acute Pain in Orthopedic Injury
• Predicted length of stay greater than or equal to 2 days

You may not qualify if:

• Non English speaking
• Spine cord injury
• Severe Traumatic brain injury (based on a Glascow Coma Scale of 8 or less)
• Patient-controlled analgesia
• Admission Creatinine \> 1.4
• History of chronic kidney disease
• Heroin use in the 3 months prior to admission (patient self-report)
• Severe psychiatric condition (e.g. schizophrenia, bipolar disorders, mania, autism) and /or psychiatric condition leading to treatment and/or hospitalization within the last 1 year.
• Positive toxicology screen for methadone not prescribed during current hospitalization
• Pregnancy or breast feeding
• Contraindication to NSAIDs, including high risk of bleeding or known severe coronary artery disease
• Injuries deemed non survival.

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

University of Maryland

Baltimore, Maryland, 21201-1512, United States

Location

Related Publications (6)

• Chen EY, Marcantonio A, Tornetta P 3rd. Correlation Between 24-Hour Predischarge Opioid Use and Amount of Opioids Prescribed at Hospital Discharge. JAMA Surg. 2018 Feb 21;153(2):e174859. doi: 10.1001/jamasurg.2017.4859. Epub 2018 Feb 21.

  PMID: 29238810 BACKGROUND

• Hah J, Mackey SC, Schmidt P, McCue R, Humphreys K, Trafton J, Efron B, Clay D, Sharifzadeh Y, Ruchelli G, Goodman S, Huddleston J, Maloney WJ, Dirbas FM, Shrager J, Costouros JG, Curtin C, Carroll I. Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. JAMA Surg. 2018 Apr 1;153(4):303-311. doi: 10.1001/jamasurg.2017.4915.

  PMID: 29238824 BACKGROUND

• Howard R, Waljee J, Brummett C, Englesbe M, Lee J. Reduction in Opioid Prescribing Through Evidence-Based Prescribing Guidelines. JAMA Surg. 2018 Mar 1;153(3):285-287. doi: 10.1001/jamasurg.2017.4436.

  PMID: 29214318 BACKGROUND

• Zelcer S, Kolesnikov Y, Kovalyshyn I, Pasternak DA, Pasternak GW. Selective potentiation of opioid analgesia by nonsteroidal anti-inflammatory drugs. Brain Res. 2005 Apr 8;1040(1-2):151-6. doi: 10.1016/j.brainres.2005.01.070.

  PMID: 15804436 BACKGROUND

• Vanegas H, Vazquez E, Tortorici V. NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System. Pharmaceuticals (Basel). 2010 Apr 29;3(5):1335-1347. doi: 10.3390/ph3051335.

  PMID: 27713305 BACKGROUND

• Colloca L, Lee SE, Luhowy MN, Haycock N, Okusogu C, Yim S, Raghuraman N, Goodfellow R, Murray RS, Casper P, Lee M, Scalea T, Fouche Y, Murthi S. Relieving acute pain (RAP) study: a proof-of-concept protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2019 Nov 11;9(11):e030623. doi: 10.1136/bmjopen-2019-030623.

  PMID: 31719077 BACKGROUND

Related Links

• Dr. Luana Colloca is the Principle Investigator for this research study. More information about her background and other research can be found at this link.

MeSH Terms

Conditions

Wounds and Injuries

Interventions

Oxycodone; Ketorolac; Ketorolac Tromethamine

Intervention Hierarchy (Ancestors)

Codeine; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Indomethacin; Indoles; Heterocyclic Compounds, 2-Ring

Limitations and Caveats

Early termination due to logistical and funding issues, which lead to no analyzable data. A protocol paper has been published should other investigators wish to use the study design (DOI: 10.1136/bmjopen-2019-030623).

Results Point of Contact

• Title: Research Coordinator
• Organization: University of Maryland School of Nursing

NRSCollocaLab@umaryland.edu

410-706-5975

Study Officials

• Luana Colloca, MD/PHD/MS

  University of Maryland Baltimore School of Nursing

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Oxycodone and Placebo will be identical in terms of appearance, taste, and smell so as to keep the investigators, care providers, and participants blind to their treatment allocation. Oxycodone and placebo oral suspensions will be manufactured and dispensed by the pharmacy at University of Maryland Medical Center. All research personnel, aside from the pharmacists and team members responsible for final review and write-up of the study, will be blinded to participants' treatment groups. For participants in the Partial Reduction group (Arm 2), the pharmacy will dispense the study drug such that participants in Arm 2 will receive four doses of Oxycodone (5mg) followed by one of four repeating schedules of administration alternating between Oxycodone (5mg) and placebo.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Patients will be randomized to three arms. Arm 1 will be a Full Dose (FD) group, which will receive all NSAIDs will be dosed in accordance with the STC Guidelines for NSAID use and Oxycodone (5mg). Arm 2 will be a Partial Reinforcement (PR) group, which will receive NSAIDs, Oxycodone (5mg), and placebo pills to reach a 50% reduction of the total intake of opioids. Finally, Arm 3 will be a Control (C) group receiving NSAIDs and placebos.

Study Record Dates

• First Submitted: January 16, 2018
• First Posted: February 8, 2018
• Study Start: September 17, 2018
• Primary Completion: March 30, 2019
• Study Completion: January 21, 2020
• Last Updated: April 27, 2021
• Results First Posted: March 16, 2020

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)