Oliceridine in Patients With Acute Burn Injuries

Study Overview
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Brief Summary
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Pain after acute burn injury is complex with much still not understood. The primary mechanism is believed to be nociceptive, but is interwoven with aspects of somatogenic, neuropathic, and psychogenic pathways. As such, opioid receptor agonists are an essential component for pain management after burn injury. The majority of wound care and dressing changes are completed in non-intubated patients and rates of respiratory depression concerning. Oliceridine is a biased, selective MOR agonist approved for treatment of acute pain. To date there is no literature of use in patients with burn injuries. While it should be effective, efficacy and the potential for reduced adverse events need to be quantified. Current practice and guidelines, plead for better analgesia for patients with burn injuries.

Detailed Description
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Pain after acute burn injury is complex with much still not understood. After acute burn injury, both injured tissue and adjacent non-burned tissue, upregulate response to painful and non-painful stimulus (hyperalgesia and allodynia, respectively). The primary mechanism is believed to be nociceptive, but is interwoven with aspects of somatogenic, neuropathic, and psychogenic pathways. As such, opioid receptor agonists are an essential component for pain management after burn injury. Currently, high-dose fentanyl, oxycodone, hydromorphone, and morphine are used at profound doses to mitigate pain associated with daily care of patients with burn injuries. The majority of wound care and dressing changes are completed in non-intubated patients and rates of respiratory depression concerning. High-quality data is controversial or lacking on the best approach for multimodal analgesia. Additionally, limitations exist for prescribing and monitoring some agents. While a multimodal approach may lead to a reduction in acute or chronic pain, adding a handful of medicines to eliminate a single agent leads to exponentially more side effects, risk of adverse effects, drug interactions, and pill burden. Drugs targeting neuropathic pain delay neural processing and are accompanied by cognitive slowing and responsiveness, which increases fall risk and limits rehabilitation participation. Gabapentin and pregabalin efficacies are highly debated with variable dosing recommendations. Side effects are common and include dizziness, somnolence, confusion, vision loss, respiratory dysfunction, peripheral edema, gastrointestinal discomfort or irregularities, or asthenia. If effective, serotonin-norepinephrine reuptake inhibitors response can be delayed by weeks and are known to cause significant weight loss, dizziness, asthenia, sleep disorders, and gastrointestinal dysfunction. Acetaminophen can help reduce background pain, but is hepatotoxic, depletes glutathione, and can mask fever. Nonsteroidal anti-inflammatory drugs carry significant safety concerns, including cardiovascular events, platelet dysfunction, bleeding, gastrointestinal toxicity, and renal failure. Local anesthetics have limited efficacy and dissipate quickly. Peripheral nerve blocks have mostly been studied for donor site pain, and placement requires specialized skills. Ketamine can be extremely helpful, especially in non-naïve patients with high-opioid tolerances but is approved as a moderate sedative and many state laws limit who can prescribe and/or monitor its administration. While ketamine does not depress respiratory drive, it is a hallucinogen, pro-deliriogenic, pro-arrhythmogenic, and carries its own concerns for gastrointestinal irregularities and drug dependence. Opioid agonists bind to the mu opioid receptor (MOR), triggering downstream signaling through either G-protein-coupled or β-arrestin pathways. While the G-protein pathway is primarily involved in analgesia, β-arrestin has been shown responsible for adverse events, especially respiratory depression and gastrointestinal dysfunction. Additionally, the β-arrestin pathway terminates G-protein activation and induces endocytosis of the receptor, which can lead to reduced analgesia or opioid tolerance. Oliceridine is a biased, selective MOR agonist approved for treatment of acute pain. Oliceridine has shown a 3-fold preferential pathway activation of G-protein over β-arrestin. As a result, subsequent clinical trials have resulted in improved analgesia over placebo and morphine, while significantly reducing adverse events. To date there is no literature of use in patients with burn injuries. While it should be effective, efficacy and the potential for reduced adverse events need to be quantified. Current practice and guidelines, plead for better analgesia for patients with burn injuries.

Official Title
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A pRospective, Case-controlled Evaluation of oLIceridine for Moderate or sEVEre Pain in Patients With Acute Burn Injuries. (RELIEVE)

Conditions
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Acute Pain, Burns, Adverse Drug Event, Respiratory Depression, Nausea and Vomiting, Postoperative

Intervention / Treatment
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* Drug: Oliceridine
* Drug: Historical opioid use


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) age ≥ 18 years old, 2) total body surface area (TBSA) burned < 20% 3) deep partial thickness or full thickness burns admitted for possible or definitive surgical needs, 4) moderate or severe pain related to acute burns (NRS ≥ 4 out of 10) Exclusion Criteria: 1) Presence of inhalation injury, 2) Pregnant, 3) Incarcerated, 4) only initial admission, 5) known anaphylaxis to oliceridine or other opioids, 6) Patient or authorized representative unable or unwilling to consent, 7) known cocaine, methamphetamine, or opioid use history, 8) use of numeric rating scale (NRS) would be inaccurate or inappropriate 9) Significant hepatic dysfunction

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will be a single-center, prospective, case-controlled trial. Intervention arm patients will be randomly matched 2:1 to a historical comparator, based on age, TBSA, number of surgeries, and opioid and illicit drug use histories
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oliceridine Arm<br>Initially, patients will receive oliceridine 1-3 mg IVP every 1-3 hours as needed for moderate or severe pain (NRS ≥ 4) with 1-3 mg every 1-3 hours for breakthrough pain. NRS will be assessed every 3-4 hours routinely. Rescue doses will be allowed per clinical discretion as oliceridine 1-3 mg every hour. Doses will be titrated according to patient response and clinical discretion. In settings where rapid analgesia is needed, such as the operating room, post-anesthesia care unit, emergency room, or hydrotherapy, oliceridine will be administered in 0.5-2 mg doses every 5 minutes as needed for moderate or severe pain, according to anesthesiologist or treating physician's discretion. For the purposes of the study oliceridine will not exceed 7 days of administration and patients will be transitioned from intravenous opioids to oral therapy and de-escalated from opioids, as soon as the team deems appropriate. | Drug: Oliceridine<br>* see arm description<br>|
| Active Comparator: Historical control<br>Retrospective, observational, historical control arm matched by age, TBSA, number of surgeries, and opioid and illicit drug use histories | Drug: Historical opioid use<br>* Historical matched, control group in 2:1 ratio<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analyze change in pain scores after initiation of oliceridine in patients with moderate or severe pain after acute burn injury | Change in Numeric Rating Scale (0 - 10 with 10 being the worst) pain scores after initiation | Baseline and every 3-4 hours as standard of care allows or study medication continued, up to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize adverse events associated with administration of oliceridine in patients with acute burn injury | Monitor for adverse events | At least daily while taking study medication, up to 7 days | 
| Establish a burn injury-specific half maximal effective concentration | Plasma samples to measure concentration and pair with numeric pain score captured for Outcome 1 | Sparse sampling strategy with up to 6 samples taken over the 4-hour dosing scheme | 
| Establish a burn injury-specific half-life | Plasma samples to measure concentrations and calculate elimination coefficient | Sparse sampling strategy with up to 6 samples taken over the 4-hour dosing scheme | 
| Establish a burn injury-specific volume of distribution | Plasma samples to measure concentrations and calculate volume of distribution | Sparse sampling strategy with up to 6 samples taken over the 4-hour dosing scheme |