Oliceridine in Patients With Acute Burn Injuries

Acute Pain Clinical Trial

— RELIEVE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05465226
• Other study ID #: 22-08748-FB
• Status: Completed
• Phase: Phase 4
• Start date: April 1, 2023
• Est. completion date: October 24, 2023

Study information

• Verified date: October 2023
• Source: University of Tennessee
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: October 24, 2023
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Pain
• Adverse Drug Event
• Burns
• Drug-Related Side Effects and Adverse Reactions
• Nausea and Vomiting, Postoperative
• Postoperative Nausea and Vomiting
• Respiratory Depression
• Respiratory Insufficiency
• Vomiting

Intervention

Drug:
• Oliceridine
see arm description
• Historical opioid use
Historical matched, control group in 2:1 ratio

Locations

Country	Name	City	State
United States	Regional One Health	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
University of Tennessee

Country where clinical trial is conducted

United States, 

References & Publications (26)

Bergese SD, Brzezinski M, Hammer GB, Beard TL, Pan PH, Mace SE, Berkowitz RD, Cochrane K, Wase L, Minkowitz HS, Habib AS. ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The micro-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy. J Pain Res. 2019 Nov 14;12:3113-3126. doi: 10.2147/JPR.S217563. eCollection 2019. — View Citation

Brennan PG, Landry JK, Miles MVP, Lintner AC, McGinn KA, Kahn SA. Intravenous Ketamine as an Adjunct to Procedural Sedation During Burn Wound Care and Dressing Changes. J Burn Care Res. 2019 Feb 20;40(2):246-250. doi: 10.1093/jbcr/iry044. — View Citation

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Fossler MJ, Sadler BM, Farrell C, Burt DA, Pitsiu M, Skobieranda F, Soergel DG. Oliceridine (TRV130), a Novel G Protein-Biased Ligand at the mu-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model. J Clin Pharmacol. 2018 Jun;58(6):750-761. doi: 10.1002/jcph.1076. Epub 2018 Feb 7. — View Citation

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Lintner AC, Brennan P, Miles MVP, Leonard C, Alexander KM, Kahn SA. Oral Administration of Injectable Ketamine During Burn Wound Dressing Changes. J Pharm Pract. 2021 Jun;34(3):423-427. doi: 10.1177/0897190019876497. Epub 2019 Sep 19. — View Citation

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Romanowski KS, Carson J, Pape K, Bernal E, Sharar S, Wiechman S, Carter D, Liu YM, Nitzschke S, Bhalla P, Litt J, Przkora R, Friedman B, Popiak S, Jeng J, Ryan CM, Joe V. American Burn Association Guidelines on the Management of Acute Pain in the Adult Burn Patient: A Review of the Literature, a Compilation of Expert Opinion and Next Steps. J Burn Care Res. 2020 Nov 30;41(6):1152-1164. doi: 10.1093/jbcr/iraa120. No abstract available. — View Citation

Singla NK, Skobieranda F, Soergel DG, Salamea M, Burt DA, Demitrack MA, Viscusi ER. APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the mu-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty. Pain Pract. 2019 Sep;19(7):715-731. doi: 10.1111/papr.12801. Epub 2019 Jun 24. — View Citation

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Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N. APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the micro-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy. J Pain Res. 2019 Mar 11;12:927-943. doi: 10.2147/JPR.S171013. eCollection 2019. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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