Cebranopadol
Cebranopadol (GRT-6005), oral dual nociceptin/orphanin FQ peptide receptor and mu-opioid receptor agonist (a small molecule, not a peptide)
Written by Aaron CuhaReviewed Sep 2026
Also known as: GRT-6005, GRT6005
Not a peptide: a small molecule opioid that also activates the nociceptin peptide receptor. In two head to head healthy volunteer studies it produced less respiratory depression than oxycodone at equal analgesia, and in phase 2 trials it matched or beat morphine and tapentadol. Two phase 3 acute pain trials completed in 2025 and are unpublished. Not approved.
Overview
Cebranopadol is in peptide catalogues by mistake, or by association. It is a synthetic small molecule, not a peptide. The reason for the confusion is its target: alongside the classical mu-opioid receptor it activates the nociceptin/orphanin FQ peptide (NOP) receptor, whose natural ligand is a 17 amino acid peptide. Activating both at once is the idea. NOP receptor activation appears to limit the respiratory depression that mu-opioid agonists cause, so a dual agonist might relieve pain like an opioid with less risk of stopping breathing. Grunenthal developed it as GRT-6005; Tris Pharma now holds it.
The human record is unusually deep for an unapproved drug. In 12 healthy men given a single 600 mcg oral dose, cebranopadol produced typical opioid effects, but the modelled minimum ventilation stayed above zero at 4.9 L/min, a ceiling that full mu agonists do not show; the authors cautioned that this was one dose and needed testing higher. A 2026 randomised, double blind, placebo controlled crossover in 30 healthy volunteers compared 600, 800 and 1,000 mcg with oxycodone 30 and 60 mg: oxygen desaturation to about 80 percent occurred in 65 percent of participants after oxycodone 60 mg and 25 percent after cebranopadol 1,000 mcg, and pharmacokinetic modelling put respiratory depression about 25 percent lower than oxycodone at equal analgesia. In patients, a phase 2 in chronic low back pain (200 to 600 mcg daily for 14 weeks versus tapentadol and placebo) reported statistically significant pain reduction at all doses, with more discontinuations at higher doses during titration; a phase 2a after bunionectomy in 258 patients found 400 and 600 mcg more effective than placebo and than morphine 60 mg on the primary endpoint; a phase 2 in 699 people with painful diabetic neuropathy and one in 619 with osteoarthritis knee pain completed without publication; and a cancer pain non-inferiority trial planned for 524 enrolled 126 because of slow accrual and reported superiority to prolonged release morphine on rescue medication use. The pivotal chronic cancer pain phase 3 (CORAL, NCT01964378) was terminated for low accrual, with the sponsor recording that the decision was unrelated to safety or efficacy. Two phase 3 trials in acute pain after abdominoplasty (279 participants) and bunionectomy (240) completed in December 2024 and January 2025; no results are posted and no publication could be located. Abuse potential studies in recreational opioid users found 200 and 400 mcg indistinguishable from placebo and 800 mcg similar to hydromorphone 8 mg.
Cebranopadol is a mu-opioid agonist and carries the class risks of dependence and overdose. It is not approved anywhere and openFDA holds no application.
Mechanism of action
In people, what is established is that cebranopadol produces miosis, analgesia and respiratory depression like an opioid; that its respiratory depression plateaued above zero ventilation at 600 mcg in 12 men and was about 25 percent less than oxycodone's at equal analgesia in 30 volunteers; that it is far more potent than oxycodone by weight (respiratory EC50 of 0.20 ng/mL versus 36 ng/mL); and that its subjective drug liking in recreational opioid users is lower than hydromorphone at doses up to 400 mcg. Its analgesic effect site equilibration is slow, around 8 hours in the 2017 study, which is why phase 2 trials titrated it over weeks. At the receptor level, established in cells and examined in a 2026 structural paper, cebranopadol is a full agonist at both the NOP receptor and the mu-opioid receptor. The working hypothesis for the respiratory ceiling, supported by the human dose response and by rodent work, is that NOP activation counteracts mu mediated depression of brainstem breathing circuits. In rats, cebranopadol also reduced cocaine self administration through both receptors.
Human evidence
Several thousand people across phase 1 to phase 3. The two head to head respiratory studies against oxycodone and the phase 2 efficacy trials are published; the two recent phase 3 acute pain trials and the two largest phase 2 trials (diabetic neuropathy, 699; osteoarthritis, 619) are not.
- Respiratory pharmacology (2017): 12 healthy men, 600 mcg, ventilation floor of 4.9 L/min; authors caution the ceiling was shown at one dose.
- Head to head versus oxycodone (2026): 30 volunteers, randomised crossover. Desaturation in 25 percent after cebranopadol 1,000 mcg versus 65 percent after oxycodone 60 mg; about 25 percent less respiratory depression at equal analgesia.
- Chronic low back pain phase 2 (2017): 14 weeks, all three doses and tapentadol beat placebo; dose related discontinuations during titration.
- Bunionectomy phase 2a (2018): 258 patients, 400 and 600 mcg beat placebo and morphine 60 mg on the primary endpoint.
- Cancer pain (2019): 126 of a planned 524 enrolled; superior to prolonged release morphine on rescue medication use; non-inferior on pain reduction not shown. CORAL phase 3 (NCT01964378) terminated for low accrual, not safety or efficacy.
- Abuse potential (2019): 42 recreational opioid users; 200 and 400 mcg like placebo, 800 mcg like hydromorphone 8 mg. Two further abuse potential studies (NCT05256108, 38 participants; NCT06453265 intranasal, 48) completed without publication.
- Phase 3 acute pain: NCT06545097 (279, abdominoplasty) and NCT06423703 (240, bunionectomy) completed 2024 to 2025, no results posted.
- Unpublished phase 2: NCT01939366 (699, painful diabetic neuropathy, results posted 2019) and NCT01709214 (619, osteoarthritis knee pain, no results posted).
What this does not tell you: The respiratory ceiling has been shown in 42 healthy volunteers at doses up to 1,000 mcg, once, in a laboratory. It has not been shown in patients, in combination with sedatives or alcohol, or at the overdose level exposures where it would matter most, and the 2017 authors' caveat that it might not hold at higher doses still stands. Cebranopadol is a full mu agonist: at 800 mcg its drug liking matched hydromorphone, and lower abuse potential is not no abuse potential. The efficacy trials are mostly 12 to 14 weeks or single dose; the chronic pain phase 3 never finished; and the two completed acute pain phase 3 trials that would decide approval are unreported. There is no data on long term use, tolerance or withdrawal.
Reading the research record
Cebranopadol has been in clinical development since at least 2012 under two owners, and its record shows what a large opioid programme looks like when the sponsor changes and the regulatory climate for new opioids changes with it. Grunenthal ran the phase 2 programme, most of which is published, and started the chronic cancer pain phase 3, which could not recruit; the reason is recorded on the registry as feasibility, unrelated to safety or efficacy, and the truncated trial that was published favoured cebranopadol. Tris Pharma took over and pivoted to acute postoperative pain, the regulatory path most new analgesics have used, and completed two phase 3 trials in early 2025. Eighteen months later neither has posted results, which is within the range of normal for a sponsor preparing a filing and is also the interval in which readers should not assume an outcome.
The respiratory data are the interesting science here and they come from an academic anaesthesiology group with a long record in opioid respiratory pharmacology, working in the 2026 study with Tris Pharma co-authors. The finding that a NOP and mu dual agonist has a ventilation floor is real in healthy volunteers and would matter enormously if it held in the situations where people die of opioids. That has not been tested and cannot be tested ethically in the same way. As for the peptide catalogues, cebranopadol's presence there is a category error: it is a synthetic small molecule that happens to act at a peptide receptor. Any powder sold under the name is an unapproved, highly potent opioid measured in micrograms, which is its own hazard.
The evidence, charted
Fig. 1 · evidence composition
7of 7 citations (100%) are in people
Every citation cited here is Human work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2017 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2026
Respiratory and Antinociceptive Effects of Nociceptin Receptor-mu-Opioid Receptor Agonist Cebranopadol versus Full Opioid Receptor Agonist Oxycodone: A Comparison in Healthy Volunteers
Randomised, double blind, placebo controlled partial crossover in 30 healthy volunteers: oral cebranopadol 600, 800 or 1,000 mcg, oxycodone 30 or 60 mg, or placebo. Oxygen desaturation to about 80 percent in 65 percent of participants after oxycodone 60 mg versus 25 percent after cebranopadol 1,000 mcg; cebranopadol 600 mcg produced less respiratory depression than oxycodone 30 mg (p = 0.022); modelled respiratory depression about 25 percent lower at equal analgesia. Three authors work for Tris Pharma, the developer.
Anesthesiology - Human2017
Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers
Phase 1, 12 healthy men, single 600 mcg oral dose. Modelled minimum ventilation stayed above zero at 4.9 L/min (95% CI 3.5 to 6.6), a ceiling not seen with full mu agonists. Effect site half-lives 1.2 hours for respiratory depression and 8.1 hours for analgesia. The authors state that further studies are needed to see whether the ceiling holds at higher doses. Funding not stated in the abstract.
Anesthesiology - Human2017
Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial
Phase 2, randomised, double blind, 14 weeks: cebranopadol 200, 400 or 600 mcg once daily, tapentadol 200 mg twice daily, or placebo in moderate to severe chronic low back pain. All cebranopadol doses and tapentadol improved 24 hour pain versus placebo on the primary endpoints; higher doses had more discontinuations for adverse events during titration. Developer funded (Grunenthal).
Pain - Human2018
Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain
258 patients after bunionectomy randomised to a single oral dose of cebranopadol 200, 400 or 600 mcg, morphine controlled release 60 mg, or placebo. On the primary endpoint (summed pain intensity 2 to 10 hours), 400 and 600 mcg beat placebo and beat morphine, whose effect emerged later; 200 mcg did not differ from placebo. Adverse events rose with dose and were highest on morphine. Developer funded.
Pain Physician - Human2019
Cancer-related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial
Planned for 524, enrolled 126 because of low accrual; up to 7 weeks of cebranopadol (200 to 1,000 mcg) versus prolonged release morphine. On the primary endpoint, daily rescue morphine use, cebranopadol was non-inferior and superior (difference -7.48 mg, 95% CI -12.05 to -2.92). Non-inferiority on pain reduction itself was not shown. Adverse events in 83 versus 82 percent. Developer funded; corresponds to the terminated CORAL trial NCT01964378.
European Journal of Pain - Human2019
Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study
Double blind crossover, 42 completers. Cebranopadol 200 and 400 mcg did not differ from placebo on peak drug liking and scored below hydromorphone; 800 mcg was similar to hydromorphone 8 mg and below 16 mg, with peak liking delayed to 3 hours. Developer funded.
Journal of Clinical Psychopharmacology - Human2024
A Study of Cebranopadol for the Treatment of Acute Pain After Abdominoplasty (NCT06545097)
Phase 3, 279 participants, completed December 2024. No results posted and no publication located as of September 2026. A companion phase 3 after bunionectomy (NCT06423703, 240 participants) completed January 2025 and is in the same position. Sponsor funded.
ClinicalTrials.gov, Tris Pharma
Frequently asked questions
Is cebranopadol a peptide?
No. It is a synthetic small molecule. It appears in peptide catalogues because one of its two targets is the nociceptin/orphanin FQ receptor, whose natural ligand is a peptide. The drug itself is not.
Is it safer than other opioids?
On respiratory depression, in healthy volunteers, the data say yes so far: minimum ventilation stayed above zero at 600 mcg in 12 men, and in 30 volunteers it caused about 25 percent less respiratory depression than oxycodone at equal analgesia, with desaturation in 25 versus 65 percent of participants at the top doses. That has not been shown in patients, with other sedatives, or at overdose exposures. It is a full mu-opioid agonist and at 800 mcg its drug liking matched hydromorphone.
Does it relieve pain?
In phase 2 trials, yes: 14 weeks of 200 to 600 mcg daily beat placebo in chronic low back pain, single doses of 400 and 600 mcg beat placebo and morphine 60 mg after bunionectomy, and it reduced rescue medication use more than prolonged release morphine in cancer pain. Two phase 3 acute pain trials completed in 2025 have not reported.
Why is it not approved?
The chronic cancer pain phase 3 could not recruit enough patients and was terminated; the sponsor recorded that the reason was unrelated to safety or efficacy. The two acute pain phase 3 trials that could support a filing completed in December 2024 and January 2025 and have no posted results as of September 2026. No application appears in openFDA.