Cebranopadol
Opioid analgesic drug
From Wikipedia, the free encyclopedia
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]
- Uncontrolled[4]
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| Other names | GRT-6005; GRT6005; PRK-101; PRK101; TRN-228; TRN228 |
| Routes of administration | Oral[1][2][3] |
| Drug class | Non-selective opioid receptor agonist; μ-Opioid receptor agonist; Nociceptin receptor agonist; κ-Opioid receptor agonist; Opioid analgesic |
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| Bioavailability | 40%[3] |
| Onset of action | 4–6 hours (Tmax)[3] |
| Elimination half-life | 62–96 hours[3] |
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| Formula | C24H27FN2O |
| Molar mass | 378.491 g·mol−1 |
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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]
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][17] It has been found to produce less respiratory suppression than other opioid analgesics like oxycodone at equianalgesic doses.[9][6][17]
Misuse potential
Cebranopadol poses misuse potential similarly to other opioid analgesics.[5][11][18] In a misuse liability clinical study however, cebranopadol showed less misuse potential than hydromorphone in recreational opioid users.[5][18] The drug has also shown a low potential for withdrawal symptoms.[6][11]
Pharmacology
Pharmacodynamics
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.[19][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 INN and USAN.[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]
Legal status
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]