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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT05465226
Other study ID # 22-08748-FB
Secondary ID
Status Completed
Phase Phase 4
First received
Last updated
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
Health authority
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

Study Design


Related Conditions & MeSH terms


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

DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physiol. 2007;69:483-510. doi: 10.1146/annurev.physiol.69.022405.154749. — View Citation

DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17. doi: 10.1124/jpet.112.201616. Epub 2013 Jan 8. — View Citation

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

James DL, Jowza M. Principles of Burn Pain Management. Clin Plast Surg. 2017 Oct;44(4):737-747. doi: 10.1016/j.cps.2017.05.005. Epub 2017 Jul 15. — View Citation

Jones LM, Uribe AA, Coffey R, Puente EG, Abdel-Rasoul M, Murphy CV, Bergese SD. Pregabalin in the reduction of pain and opioid consumption after burn injuries: A preliminary, randomized, double-blind, placebo-controlled study. Medicine (Baltimore). 2019 May;98(18):e15343. doi: 10.1097/MD.0000000000015343. — View Citation

Kaul I, Amin A, Rosenberg M, Rosenberg L, Meyer WJ 3rd. Use of gabapentin and pregabalin for pruritus and neuropathic pain associated with major burn injury: A retrospective chart review. Burns. 2018 Mar;44(2):414-422. doi: 10.1016/j.burns.2017.07.018. Epub 2017 Aug 16. — View Citation

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

Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci. 2002 Feb 1;115(Pt 3):455-65. doi: 10.1242/jcs.115.3.455. — View Citation

Ly E, Velamuri S, Hickerson W, Hill DM, Desai J, Tsui B, Herr M, Jones J. Approaching trauma analgesia using prolonged and novel continuous peripheral nerve blocks - A case report. Anesth Pain Med (Seoul). 2022 Jan;17(1):87-92. doi: 10.17085/apm.21029. Epub 2021 Jul 22. — View Citation

MacPherson RD, Woods D, Penfold J. Ketamine and midazolam delivered by patient-controlled analgesia in relieving pain associated with burns dressings. Clin J Pain. 2008 Sep;24(7):568-71. doi: 10.1097/AJP.0b013e31816cdb20. — View Citation

Meyer WJ 3rd, Nichols RJ, Cortiella J, Villarreal C, Marvin JA, Blakeney PE, Herndon DN. Acetaminophen in the management of background pain in children post-burn. J Pain Symptom Manage. 1997 Jan;13(1):50-5. doi: 10.1016/s0885-3924(96)00201-1. — View Citation

Myers R, Lozenski J, Wyatt M, Pena M, Northrop K, Bhavsar D, Kovac A. Sedation and Analgesia for Dressing Change: A Survey of American Burn Association Burn Centers. J Burn Care Res. 2017 Jan/Feb;38(1):e48-e54. doi: 10.1097/BCR.0000000000000423. — View Citation

Nafziger AN, Arscott KA, Cochrane K, Skobieranda F, Burt DA, Fossler MJ. The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Oliceridine. Clin Pharmacol Drug Dev. 2020 Jul;9(5):639-650. doi: 10.1002/cpdd.750. Epub 2019 Nov 7. — View Citation

Pal SK, Cortiella J, Herndon D. Adjunctive methods of pain control in burns. Burns. 1997 Aug;23(5):404-12. doi: 10.1016/s0305-4179(97)00029-6. — View Citation

Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005 Sep;314(3):1195-201. doi: 10.1124/jpet.105.087254. Epub 2005 May 25. — View Citation

Retrouvey H, Shahrokhi S. Pain and the thermally injured patient-a review of current therapies. J Burn Care Res. 2015 Mar-Apr;36(2):315-23. doi: 10.1097/BCR.0000000000000073. — View Citation

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

Thompson EM, Andrews DD, Christ-Libertin C. Efficacy and safety of procedural sedation and analgesia for burn wound care. J Burn Care Res. 2012 Jul-Aug;33(4):504-9. doi: 10.1097/BCR.0b013e318236fe4f. — View Citation

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

Wibbenmeyer L, Eid A, Kluesner K, Heard J, Zimmerman B, Kealey GP, Brennan T. An Evaluation of Factors Related to Postoperative Pain Control in Burn Patients. J Burn Care Res. 2015 Sep-Oct;36(5):580-6. doi: 10.1097/BCR.0000000000000199. — View Citation

Wibbenmeyer L, Eid A, Liao J, Heard J, Horsfield A, Kral L, Kealey P, Rosenquist R. Gabapentin is ineffective as an analgesic adjunct in the immediate postburn period. J Burn Care Res. 2014 Mar-Apr;35(2):136-42. doi: 10.1097/BCR.0b013e31828a4828. — View Citation

Wibbenmeyer L, Oltrogge K, Kluesner K, Zimmerman MB, Kealey PG. An evaluation of discharge opioid prescribing practices in a burn population. J Burn Care Res. 2015 Mar-Apr;36(2):329-35. doi: 10.1097/BCR.0000000000000110. — View Citation

Yang C, Xu XM, He GZ. Efficacy and feasibility of opioids for burn analgesia: An evidence-based qualitative review of randomized controlled trials. Burns. 2018 Mar;44(2):241-248. doi: 10.1016/j.burns.2017.10.012. Epub 2017 Nov 21. — View Citation

* Note: There are 26 references in allClick 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
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