Cebranopadol

Cebranopadol
Clinical data
Other namesGRT-6005; GRT6005; PRK-101; PRK101; TRN-228; TRN228
Routes of
administration		Oral[1][2][3]
Drug classNon-selective opioid receptor agonist; μ-Opioid receptor agonist; Nociceptin receptor agonist; κ-Opioid receptor agonist; Opioid analgesic
Legal status
Legal status
  • Uncontrolled[4]
Pharmacokinetic data
Bioavailability40%[3]
Onset of action4–6 hours (TmaxTooltip time to peak levels)[3]
Elimination half-life62–96 hours[3]
Identifiers
  • 6-fluoro-N,N-dimethyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H27FN2O
Molar mass378.491 g·mol−1
3D model (JSmol)
  • CN(C)C1(CCC2(CC1)C3=C(CCO2)C4=C(N3)C=CC(=C4)F)C5=CC=CC=C5
  • InChI=1S/C24H27FN2O/c1-27(2)23(17-6-4-3-5-7-17)11-13-24(14-12-23)22-19(10-15-28-24)20-16-18(25)8-9-21(20)26-22/h3-9,16,26H,10-15H2,1-2H3
  • Key:CSMVOZKEWSOFER-UHFFFAOYSA-N

Cebranopadol, also known by its developmental code names TRN-228 and formerly GRT-6005, is an experimental atypical opioid analgesic which is under development for the treatment of various types of pain as well as for treatment of substance-related disorders.[5][1] It is taken orally.[1][2][3]

Side effects of cebranopadol include nausea, vomiting, constipation, somnolence, euphoria, and respiratory depression, among others.[5][6][7] The drug acts as a non-selective opioid receptor agonist, including as a dual μ-opioid receptor and nociceptin receptor full agonist and to a lesser extent as a κ-opioid receptor partial agonist.[8] In relation to its multi-target profile, namely its nociceptin receptor agonism, cebranopadol shows atypical effects and certain potential advantages compared to selective μ-opioid receptor agonists like morphine, such as less misuse potential and respiratory depression.[5][9][8] On the other hand, it has a long half-life in humans and still carries risk of misuse similarly to other opioids.[10][5][11]

Cebranopadol was first described in the patent literature by 2002[12] and in the scientific literature by 2013.[13][14] As of August 2025, it has completed multiple phase 3 clinical trials for treatment of pain.[1][2] According to its developer, a New Drug Application (NDA) is to be submitted in the near future.[15][16] As a dual μ-opioid and nociceptin receptor agonist, cebranopadol is a potential first-in-class medication.[6][5] Cebranopadol is not yet a controlled substance as of 2022.[4] It either has been encountered or could be encountered as a novel opioid recreational designer drug as of 2019.[17]

Medical uses

Cebranopadol remains investigational and is not yet approved for any medical use.[1][2][4]

Side effects

Side effects of cebranopadol include nausea, vomiting, pupil constriction, constipation, somnolence, euphoria, indigestion, and respiratory depression, among others.[5][6][7][18] It has been found to produce less respiratory suppression than other opioid analgesics like oxycodone at equianalgesic doses.[9][6][18]

Misuse potential

Cebranopadol poses misuse potential similarly to other opioid analgesics.[5][11][19] In a misuse liability clinical study however, cebranopadol showed less misuse potential than hydromorphone in recreational opioid users.[5][19] The drug has also shown a low potential for withdrawal symptoms.[6][11]

Pharmacology

Pharmacodynamics

Cebranopadol activities[11][8]
Target KiTooltip Inhibitor constant (nM) EC50Tooltip Half-maximal effective concentration (nM) EmaxTooltip maximal efficacy (%)
MORTooltip μ-Opioid receptor 0.7 1.2 104%
NOPTooltip Nociceptin receptor 0.9 13 89%
KORTooltip κ-Opioid receptor 2.6 17 67%
DORTooltip δ-Opioid receptor 18 110 105%
Notes: Proteins are human. The smaller the value, the more avidly the drug interacts with the site.

Cebranopadol acts as a non-selective opioid receptor agonist, including as a dual μ-opioid receptor (MOR) and nociceptin receptor (NOP) full agonist and to a lesser extent as a κ-opioid receptor partial agonist.[8] It is also a δ-opioid receptor full agonist to a much lesser extent.[8]

The drug shows antinociceptive and antihypertensive effects in a variety of different animal models of pain.[8] It has analgesic ED50 values in animals of 0.5 to 5.6 μg/kg intravenously and 25 μg/kg orally.[8] The drug has been found to be more effective in models of chronic neuropathic pain than acute nociceptive pain compared to selective MOR agonists.[8] Relative to morphine, tolerance to the analgesic effects of cebranopadol has been found to be delayed (26 days versus 11 days for complete tolerance).[8] In addition, unlike morphine, cebranopadol has not been found to affect motor coordination or reduce respiration in animals at doses within or above the dose range for analgesia.[8] As such, it might have improved efficacy and greater tolerability in comparison to existing opioid analgesics.[8]

As an agonist of the KOR, cebranopadol may have the capacity to produce hallucinogenic effects, dysphoria, and other adverse reactions at sufficiently high doses, a property which could potentially limit its practical clinical dose range.[17][20]

Pharmacokinetics

The oral absorption of cebranopadol is thought to be complete, while its oral bioavailability is approximately 40%.[6][3] Relatedly, the drug is thought to undergo substantial first-pass metabolism.[3] The time to peak levels of cebranopadol is 4 to 6 hours.[6][3] Cebranopadol shows high permeability into the central nervous system.[5] Its half-value duration (HVD) is 14 to 15 hours, while its terminal elimination half-life is in the range of 62 to 96 hours.[6][3] Cebranopadol with once-daily administration reaches steady-state levels after approximately 2 weeks, with an accumulation ratio of about 2 and a low peak-to-trough fluctuation (PTF) of about 70 to 80%.[6][3]

Chemistry

Cebranopadol is a spiro[cyclohexane-dihydropyrano[3,4-b]indole] derivative of the benzenoid class.[5][21] It is somewhat similar in chemical structure to other indoles with opioid receptor modulator activity like noribogaine and mitragynine.[9][22]

Synthesis

The chemical synthesis of cebranopadol has been described.[23][24]

Analogues

A notable analogue of cebranopadol is lexanopadol (GRT-6006).[25][26]

History

Cebranopadol was originated by Grunenthal and has been subsequently developed by Grunenthal, Park Therapeutics, and Tris Pharma.[1][27] It was first described in a patent in 2002[12] and was first mentioned in the scientific literature by 2013, by which point multiple phase 2 clinical trials had been completed and phase 3 trials were started.[13][14][28][29] Subsequently, several dedicated journal articles on cebranopadol were published in 2014 and 2015.[8][30][31][32]

Society and culture

Names

Cebranopadol is the generic name of the drug and its INNTooltip International Nonproprietary Name and USANTooltip United States Adopted Name.[33] It is also known by its developmental code names GRT-6005 (Grünenthal), PRK-101 (Park Therapeutics), and TRN-228 (Tris Pharma).[1][27][2]

Cebranopadol is not yet a controlled substance as of 2022.[4]

Research

Cebranopadol is under development for the treatment of acute pain, back pain, postoperative pain, cancer pain, neuropathic pain, and substance-related disorders.[1][27] As of August 2025, it is in phase 3 trials for acute pain, back pain, and postoperative pain, phase 2 trials for cancer pain and neuropathic pain, and phase 1 trials for substance-related disorders.[1] Phase 3 trials for postoperative pain have been completed and data released.[1][2][15][16] According to Tris Pharma, a New Drug Application (NDA) of cebranopadol would be submitted in 2025.[15][16]

See also

References

  1. ^ a b c d e f g h i j "Cebranopadol". AdisInsight. Springer Nature Switzerland AG. 28 August 2025. Retrieved 7 January 2026.
  2. ^ a b c d e f "Cebranopadol Drug Profile". Ozmosi. Retrieved 7 March 2026.
  3. ^ a b c d e f g h i j 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. PMC 5766727. PMID 28623508.
  4. ^ a b c d Pergolizzi J, Magnusson P, Coluzzi F, Breve F, LeQuang JA, Varrassi G (June 2022). "Multimechanistic Single-Entity Combinations for Chronic Pain Control: A Narrative Review". Cureus. 14 (6) e26000. doi:10.7759/cureus.26000. PMC 9286298. PMID 35855248. Since cebranopadol is not yet approved for market release, it has not yet been scheduled by the DEA as a controlled substance.
  5. ^ a b c d e f g h i j Edinoff AN, Flanagan CJ, Roberts LT, Dies RM, Kataria S, Jackson ED, et al. (October 2023). "Cebranopadol for the Treatment of Chronic Pain". Curr Pain Headache Rep. 27 (10): 615–622. doi:10.1007/s11916-023-01148-9. PMID 37556044.
  6. ^ a b c d e f g h i Qiu Q, Chew JC, Irwin MG (November 2022). "Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain". Expert Opin Pharmacother. 23 (16): 1831–1843. doi:10.1080/14656566.2022.2141566. PMID 36302462.
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  9. ^ a b c Grundmann O, Henderson A (28 February 2026). "Indole Alkaloids as Biased Opioid Receptor Modulators". Pharmaceuticals. 19 (3): 397. doi:10.3390/ph19030397. ISSN 1424-8247. An indole derivative itself, cebranopadol is currently in phase 3 clinical trials and did not indicate substantial respiratory depression in animals and lower respiratory depression in healthy human volunteers, which has been attributed to its biased activity at opioid receptors [65].
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  12. ^ a b "Spirocyclic cyclohexane compounds". Google Patents. 11 May 2005. Retrieved 7 March 2026.
  13. ^ a b Toll L, Khroyan TV, Polgar WE, Husbands SM, Zaveri NT (2013). "Pharmacology of Mixed NOP/Mu Ligands". ACS Symposium Series. Vol. 1131. Washington, DC: American Chemical Society. pp. 369–391. doi:10.1021/bk-2013-1131.ch017. ISBN 978-0-8412-2782-8. Retrieved 7 March 2026. More recently Grunenthal, together with Forest Labs, has taken GRT 6005 into Phase IIb clinical trials. This compound has equal affinity and equal and full efficacy at NOP and mu opiate receptors. Although there is no animal data available in the literature, this compound has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with initial Phase II clinical trials.
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  19. ^ a b Göhler K, Sokolowska M, Schoedel KA, Nemeth R, Kleideiter E, Szeto I, et al. (2019). "Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study" (PDF). J Clin Psychopharmacol. 39 (1): 46–56. doi:10.1097/JCP.0000000000000995. PMC 6319565. PMID 30531478.
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  21. ^ Catalano A, Iacopetta D, Ceramella J, Saturnino C, Sinicropi MS (2022). "A Comprehensive Review on Pyranoindole-containing Agents" (PDF). Curr Med Chem. 29 (21): 3667–3683. doi:10.2174/0929867328666211206111058. PMID 34872472. Cebranopadol (4f, Fig. 17) is a spiro[cyclohexane-dihydropyrano[3,4-b]indole], which functions as an opioid analgesic of the benzenoid class [43].
  22. ^ Kalita RC, Sharma S, Samanta S, Patle D (July 2025). "Narcotics through time: exploring historical origins, synthetic advances, and clinical progress". Future Med Chem. 17 (13): 1587–1599. doi:10.1080/17568919.2025.2527606. PMID 40621822. Cebranopadol, a novel analgesic, targets both opioid and nociceptin receptors. It has shown strong efficacy in pain management with a reduced risk of tolerance and abuse, positioning it as a promising alternative for chronic pain treatment [101].
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