Cebranopadol (developmental code TRN-228 and formerly GRT-6005) is an investigational opioid analgesic currently under development internationally by Tris Pharma,[1][2] a private pharmaceutical company in the United States. The drug was originally discovered and developed by Grünenthal, a German pharmaceutical company and was formerly developed by Park Therapeutics and Depomed (now Assertio Terapeutics), pharmaceutical companies in the United States, for the treatment of a variety of different acute and chronic pain states.[3][4][5] As of June 2025, phase III clinical trials have been completed for acute pain with positive results.[6]
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| Routes of administration | Oral |
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| Elimination half-life | ~24 hours |
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| Formula | C24H27FN2O |
| Molar mass | 378.491 g·mol−1 |
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Like most opioid analgesics, cebranopadol is an agonist of the μ-opioid receptor but unlike most other opioid analgesics it also acts as an agonist of the nociceptin receptor.
Receptor Binding Profile
editCebranopadol acts as a full agonist at two key receptors:[citation needed]
- μ-opioid receptor (MOP): Ki = 0.7 nM; Intrinsic Activity (IA) = 104%
- Nociceptin/orphanin FQ peptide receptor (NOP): Ki = 0.9 nM; IA = 89%
The drug also binds to other opioid receptors with lower affinity and are not believed to contribute materially to its activity:
- δ-opioid receptor: Ki = 18 nM; IA = 105%
- κ-opioid receptor: Ki = 2.6 nM; IA = 67% (partial agonist)
Cebranopadol is unusual among analgesics in being a dual NOP-MOP (dual NMR) receptor agonist. While opioids like morphine, oxycodone, and fentanyl act primarily through MOP receptors with no significant NOP activity, cebranopadol activates both systems.
Pharmacokinetics
editCebranopadol demonstrates distinctive pharmacokinetic properties that differentiate it from other analgesic compounds. After oral administration of the immediate-release formulation, cebranopadol exhibits a single dose half-life of 24 hours and a steady state half-life ranging from 62-96 hours.[7] The time to reach maximum plasma concentration occurs 4–6 hours after oral administration, with a long half-value duration of 14–15 hours.[8] The time to reach steady state is approximately 2 weeks, with an accumulation factor of approximately 2 and low peak-trough fluctuation (70–80%).[9] Clinical studies suggest that cebranopadol's pharmacokinetics remain unaffected by hepatic or renal impairment.[10]
Research and Development History
editCebranopadol, originally developed by Grünenthal, has undergone extensive clinical evaluation with more than 33 trials encompassing over 2,300 participants. In 2015, Depomed (which later became Assertio Therapeutics) acquired licensing rights for the United States and Canada prior to Park Therapeutics acquiring worldwide rights in 2020. Park was then acquired by Tris in 2021.
As of 2025, both Phase 3 pivotal trials (ALLEVIATE-1 and ALLEVIATE-2) for acute pain have been completed with positive results:
ALLEVIATE-1 studied Cebranopadol in patients following abdominoplasty surgery
ALLEVIATE-2 studied Cebranopadol in patients following bunionectomy surgery
Both trials demonstrated statistically significant pain reduction compared to placebo with favorable safety profiles.[citation needed]
The FDA granted Fast Track Designation to cebranopadol for chronic low back pain in 2017. Tris Pharma plans to submit their NDA to the FDA in 2025 based on the completed Phase 3 acute pain studies. The company has announced plans to conduct cebranopadol studies in multiple chronic pain indications beginning in the second half of 2025.
Cebranopadol has been awarded a five-year grant of up to $16.6 million from the National Institute of Drug Abuse (NIDA), a division of NIH, to study the drug for the treatment of opioid use disorder (OUD).
See also
editReferences
edit- ^ Inc TP. "Tris Pharma® Announces Acquisition of Park Therapeutics - Pain Company with First-In-Class, Phase III-Ready New Chemical Entity (NCE)". www.prnewswire.com (Press release). Retrieved 2025-03-28.
- ^ "Our Pipeline". Tris Pharma. Retrieved 2025-03-28.
- ^ Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, et al. (June 2014). "Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist". The Journal of Pharmacology and Experimental Therapeutics. 349 (3): 535–548. doi:10.1124/jpet.114.213694. PMID 24713140. S2CID 6942770.
- ^ Schunk S, Linz K, Hinze C, Frormann S, Oberbörsch S, Sundermann B, et al. (August 2014). "Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol". ACS Medicinal Chemistry Letters. 5 (8): 857–862. doi:10.1021/ml500117c. PMC 4137374. PMID 25147603.
- ^ Lambert DG, Bird MF, Rowbotham DJ (March 2015). "Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist". British Journal of Anaesthesia. 114 (3): 364–366. doi:10.1093/bja/aeu332. PMID 25248647.
- ^ rajeshlohakare@sambrown.com (2025-03-06). "Tris Pharma Announces Positive Results from ALLEVIATE-2 Phase 3 Pivotal Trial for Cebranopadol, an Investigational First-in-Class Oral Dual-NMR Agonist, for the Treatment of Moderate-to-Severe Acute Pain". Tris Pharma. Retrieved 2025-08-01.
- ^ Kleideiter E, Piana C, Wang S, Nemeth R, Gautrois M (January 2018). "Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic". Clinical Pharmacokinetics. 57 (1): 31–50. doi:10.1007/s40262-017-0545-1. ISSN 1179-1926. PMC 5766727. PMID 28623508.
- ^ Ziemichod W, Kotlinska J, Gibula-Tarlowska E, Karkoszka N, Kedzierska E (2022-06-21). "Cebranopadol as a Novel Promising Agent for the Treatment of Pain". Molecules. 27 (13). Basel, Switzerland: 3987. doi:10.3390/molecules27133987. ISSN 1420-3049. PMC 9268744. PMID 35807228.
- ^ [1], KLEIDEITER, Elke; CHRISTOPH, Annette & FUSSEN, Rene et al., "Cebranopadol for treating pain in subjects with impaired hepatic and/or impaired renal function", issued 2018-07-17
- ^ [2], KLEIDEITER, Elke; CHRISTOPH, Annette & FUSSEN, Rene et al., "Cebranopadol for treating pain in subjects with impaired hepatic and/or impaired renal function", issued 2018-07-17