Relieving Acute Pain (RAP) Study



Status:Recruiting
Conditions:Hospital, Orthopedic, Gastrointestinal
Therapuetic Areas:Gastroenterology, Orthopedics / Podiatry, Other
Healthy:No
Age Range:18 - 65
Updated:3/28/2019
Start Date:September 17, 2018
End Date:June 15, 2020
Contact:Research Coordinator, MS
Email:nrscollocalab@umaryland.edu
Phone:410-706-5975

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Relieving Acute Pain (RAP): A Pilot Study

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.

Overview:

We will screen 500 patients from the Shock Trauma Center to recruit a total of 159 (53 per
arm) to participate in a pilot study aimed at reducing use of opioids. Participants will meet
all of the eligibility criteria and none of the exclusion criteria. After enrollment,
participants will be blindly allocated to one of three randomization arms by means of
de-identified Study IDs corresponding to treatment arms. Study IDs will be generated by the
pharmacy and blinding will be ensured by creating study drugs that look, smell, and taste
identical. The pharmacy will create and dispense identical study drugs in terms of
appearance, smell, and taste. Only the blinding coordinator will know the identity of
patients in each treatment arm. Arm 1 will be a Full Dose (FD) group, which will receive
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), dosed in accordance with the University of
Maryland Shock Trauma Center (STC) Guidelines for NSAIDs 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 these three arms
according to a 1:1:1 schedule of randomization. The patient will start receiving study
medication as part of his or her pain management as soon as possible after admission to the
hospital and enrollment in the study (ideally as their first dose of pain-management
medication). Rescue therapy will be provided as needed.

All enrolled patients will receive an Adult Pain Management Service (APMS) consult. APMS will
work with the study and clinical teams to ensure that all treatment protocols are met, and be
available to address any issues that may arise. The APMS provider will work with the primary
service to determine the most effective NSAID as described in their guidelines.

Other than the study medication (Oxycodone and placebo), all participants will be treated in
accordance with the current standard of care at the University of Maryland Shock Trauma
Center. This includes intravenous Toradol every 8 hours for 24 hours followed by oral NSAIDs
round the clock until pain is minimal. The timing of administration will be the same for
participants in all three arms - they will receive their arm's treatment (Oxycodone,
Oxycodone alternating with placebo, or no additional medication beyond standard of care
NSAIDs) round the clock for the first 24 hours followed by every hours for the remainder of
hospitalization. All patients will receive intravenous Dilaudid every hour for rescue or
break through pain. In addition, all patients will be discharged on Oxycodone tablets (5mg)
every 3 hours as needed.

In Arm 2, the first four doses of study drug will be Oxycodone (5mg) to condition them to its
effects. Afterwards, they will receive alternating Oxycodone (5mg) and placebo according to
one of four repeating sequences. During data analysis, we will test whether the sequence of
administration has an effect on outcomes. Participants in Arm 2 will never receive more than
2 doses of placebo in a row. This administration schedule will be repeated for the remainder
of hospitalization.

Prior to patients' enrollment:

The intent of this study is to enroll 159 patients with trauma into this study to compare
strategies to reduce opioid use during the management of acute pain. Patients will be
screened on admission to the Shock Trauma Center. Eligible patients will meet all of the
inclusion criteria and none of the exclusion criteria. Patients with trauma will be
considered for enrollment and be flagged for screening. A plan by the primary service to
adhere to The Shock Trauma Protocol for NSAID use is also a requirement for enrollment.
Eligible participants will be informed and have the opportunity to discuss the nature of the
study, potential for treatment allocation, and risk/benefits. For those who agree to
participate, the approved Informed Consent Form and HIPAA authorization form will be signed.
The research staff will explain to the participant what tasks they are expected to complete
during this study, answer any questions they may have, and ensure comprehension by completing
the Informed Consent Checklist, which asks participants to verbally report their
understanding of the study purpose and procedures, among other key points.

Allocation to treatment group:

After the participant discusses and signs the consent form, a staff member will call the
pharmacy to inform them of the participant's de-identified Screening number. The pharmacy
will then randomly assign that participant a Study ID corresponding randomly to one of the
three treatment groups and handle drug logistics (sourcing, processing, and administration)
for the remainder of Phase I. The patient will start receiving the study drug within 24 hours
of being able to take narcotics, ideally as his/her first narcotic medication. All staff
involved with the protocol will be fully trained on it and will be given study team member
emergency contacts in case of incident.

Blinding:

Oxycodone and Placebo will be identical in terms of appearance, taste, and smell so as to
keep both the investigators and participants blind to their treatment allocation. Oxycodone
and placebo oral suspensions will be manufactured by the IDS. Oxycodone solution will be made
from tablets to ensure blinding. In this way, both Oxycodone and placebo will look identical
for taste, color, and smell. This will help not only to blind the study, but also facilitate
study drug administration given that patients may be intubated. 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. The pharmacy will dispense medications for
each participant that will correspond with their allocated treatment group. For participants
in the Partial Reduction group (Arm 2), the pharmacy will dispense the study drug. In
summary, 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.

Hospitalization window (Enrollment - End of Hospitalization):

Pain ratings will be recorded as usual within 20 to 90 minutes after each study drug
administration. Also, participants will be given the option to complete a set of
psychological questionnaires during the time in the hospital or by the time of their first
follow-up visit. Questionnaires unrelated to pain will be optional. Although we cannot change
the wording of our validated pain questionnaires, staff will be trained to use the phrasing
such as "how well they are able to perform their daily activities, how well they are able to
interact with visitors/family, and how well they are sleeping" whenever possible, and that
surveys andquestions during the follow-up phase will also take this non-pain-centric
approach.

Discharge:

Participants will be monitored for subsequent use of opioids at the first post-discharge
visit (at approximately 2 weeks) and within month 1, 3, and 6 for follow-ups. The research
team via calls, letters, emails, or texts. REDCap, Qualtrics / MetricWire will be used to
facilitate the communication via text and emails. The team member will ask the participant
questions about their health and medication use. In addition, a phone application may be
developed or the data collection system Qualtrics used to gather information about
participants' medication use and health during the follow-up period. Although the wording of
the validated Pain Questionnaires we will use during hospitalization cannot be changed,
during the follow-up phase we will aim to frame questions about pain intensity and
interference with function in such a way as to avoid nocebo effects (i.e. asking how well
they are able to perform their daily activities, how well they are able to interact with
visitors/family, and how well they are sleeping instead of how much pain are they
experiencing).

Duration of the clinical trial:

Hospitalization window (starting as soon after admission as possible for a projected minimum
of 2 days), with follow-up at approximately 2 weeks (coinciding with their first
post-discharge visit with their clinician), and months 1, 3, and 6.

Rescue plan:

All patients will have the same rescue medicine available for break through pain; intravenous
Dilaudid every hour.

Participants in each of the three randomization arms will have access to opioid rescue
medication (Dilaudid) as needed via a standing order for breakthrough pain rated as Severe.
The rate of use pf rescue therapy will be evaluated as a primary endpoints. Participants who
request more than 3 doses of rescue medication in a row will be withdrawn from the study and
referred to APMS for further pain management.

Primary and secondary outcomes. To be measured daily during hospitalization

1.) Acute clinical and functional pain / acute pain improvement; opioid intake; rate of
request of rescue therapies.

Primary and secondary outcomes. To be measured daily during the follow-up.

1. Use (frequency and intensity) of opioid prescriptions

2. Development of dependence and/or addiction problems

Inclusion Criteria:

- 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

Exclusion Criteria:

- 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.
We found this trial at
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Baltimore, Maryland 20742
(301) 405-1000
Phone: 301-364-8089
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