Cebranopadol: Research & Studies
Scientific evidence, clinical trials, and research findings
📌TL;DR
- •5 clinical studies cited
- •Overall evidence level: moderate-high
- •5 research gaps identified
Research Studies
Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial
Christoph T, Eerdekens MH, Kok M, et al. (2017) • Pain
Phase 2, randomized, double-blind, placebo- and active-controlled trial evaluating cebranopadol in moderate-to-severe chronic low back pain across 79 sites in 11 European countries. Patients treated for 14 weeks with cebranopadol 200, 400, or 600 mcg once daily, tapentadol 200 mg BID, or placebo.
Key Findings
- All cebranopadol doses showed statistically significant and clinically relevant improvements over placebo
- Responder analysis confirmed results at both 30% and 50% pain reduction thresholds
- Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality
- Adverse events during titration were most common; maintenance phase incidence was 10% or less for individual events
Limitations: Phase 2 trial; higher doses led to more discontinuations during titration; 14-week duration limits long-term safety assessment
Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study
Goehler K, Sokolowska M, Schoedel KA, et al. (2019) • Journal of Clinical Psychopharmacology
Phase 1, single-dose, randomized, double-blind crossover study in 42 nondependent recreational opioid users evaluating abuse potential of cebranopadol relative to hydromorphone IR and placebo.
Key Findings
- Cebranopadol 200 and 400 mcg did not differentiate from placebo on abuse potential assessments
- Cebranopadol 800 mcg responses were similar to hydromorphone 8 mg and lower than hydromorphone 16 mg
- Peak drug-liking was delayed (3 hours) vs hydromorphone (1.5 hours)
- Confirmed lower abuse potential than pure mu-opioid agonist
Limitations: Single-dose study in nondependent users; may not reflect real-world chronic use patterns
Cebranopadol: A Novel First-in-Class Potent Analgesic Acting via NOP and Opioid Receptors
Tzschentke TM, Linz K, Koch T, Christoph T. (2019) • Handbook of Experimental Pharmacology
Comprehensive review of cebranopadol preclinical and clinical pharmacology covering receptor binding, in vivo efficacy models, mechanism of action, and Phase 2 clinical results.
Key Findings
- Sub-nanomolar affinity for NOP and MOP receptors; 20-fold lower affinity for DOP and KOP
- NOP receptor activity ameliorates opioid-type side effects including respiratory depression and abuse potential
- Highly potent across broad range of acute, chronic, and neuropathic pain models
- Phase 2 clinical trials demonstrated efficacy and good tolerability in acute and chronic pain
Limitations: Review article; clinical data limited to Phase 2 at time of publication
Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain
Scholz A, Bothmer J, Kok M, et al. (2018) • Pain Physician
Phase 2a, randomized, double-blind, placebo- and active-controlled trial in 258 patients following bunionectomy. Single oral doses of cebranopadol 200, 400, or 600 mcg compared to morphine CR 60 mg and placebo.
Key Findings
- Cebranopadol 400 and 600 mcg more effective than placebo from 2 to approximately 22 hours post-dose
- Single-dose cebranopadol 400 mcg better tolerated than morphine CR 60 mg
- Duration of analgesic effect supported once-daily dosing potential
Limitations: Phase 2a single-dose study; limited assessment of repeat dosing and chronic use
Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol
Schunk S, Linz K, Hinze C, et al. (2014) • ACS Medicinal Chemistry Letters
Original discovery paper describing the medicinal chemistry optimization that led to cebranopadol, developed at Grunenthal GmbH in Aachen, Germany. Reports structure-activity relationships and receptor binding profiles.
Key Findings
- Identified cebranopadol as a potent dual NOP and opioid receptor agonist from spiro[cyclohexane-pyrano-indol] scaffold
- Demonstrated potent in vivo analgesic activity in multiple pain models
- Characterized unique receptor binding profile combining NOP and opioid activity
Limitations: Preclinical discovery paper; no clinical data included
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🔍Research Gaps & Future Directions
- •Phase 3 chronic pain data not yet available (trials planned for late 2025)
- •Long-term safety and efficacy data beyond 14 weeks in chronic pain settings
- •Comparative efficacy against newer analgesics and non-opioid alternatives
- •Real-world abuse liability in populations with opioid use disorder
- •Optimal dosing for specific chronic pain conditions (neuropathic, cancer, osteoarthritis)
Research Overview#
Cebranopadol (GRT-6005) has been evaluated in a comprehensive clinical program spanning more than 33 clinical trials with over 2,300 participants. The evidence base includes preclinical pharmacology, Phase 1 pharmacokinetic and abuse liability studies, Phase 2 trials in acute and chronic pain, and two completed Phase 3 pivotal trials for acute pain.
The compound's unique dual NOP/opioid receptor mechanism has been extensively characterized in preclinical studies, and the clinical program has progressively confirmed both efficacy and the expected safety advantages over pure mu-opioid agonists.
Phase 3 Program: ALLEVIATE Trials#
ALLEVIATE-1 (Acute Pain Following Abdominoplasty)#
The ALLEVIATE-1 trial (NCT06545097) was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating cebranopadol for moderate-to-severe acute pain following full abdominoplasty.
Key Results:
- Primary endpoint met: statistically significant reduction in pain intensity (NRS AUC4-48) with cebranopadol 400 mcg once daily for two days vs placebo (LS Mean difference [SE] of 59.2 [14.36]; p<0.001)
- Cebranopadol-treated patients required significantly fewer rescue medication doses than placebo (LS mean difference 2.2; p<0.001)
- No serious adverse events related to cebranopadol; most common adverse event was nausea
- Safety profile comparable to placebo
ALLEVIATE-2 (Acute Pain Following Bunionectomy)#
The ALLEVIATE-2 trial (NCT06423703) was a Phase 3, multicenter, randomized, double-blind, placebo- and active-controlled study in 240 patients following primary unilateral bunionectomy with first metatarsal osteotomy.
Key Results:
- Primary endpoint met: statistically significant pain reduction (NRS AUC2-48) with cebranopadol 400 mcg once daily vs placebo (LS Mean difference 56.1; p<0.001)
- Oxycodone IR 10 mg (four times daily) showed more pain relief than placebo but lower mean activity than cebranopadol
- Well tolerated; most common adverse event was nausea; no serious adverse events reported
Tris Pharma plans to submit a New Drug Application (NDA) based on these results in 2025.
Phase 2: Chronic Low Back Pain#
Christoph et al., Pain 2017 (PMID 28644196)#
The first Phase 2 trial evaluating cebranopadol in chronic pain was a randomized, double-blind, placebo- and active-controlled parallel group study conducted at 79 sites across 11 European countries from November 2012 to July 2014.
Study Design:
- Patients with moderate-to-severe chronic LBP with or without neuropathic component
- Treatment for 14 weeks (titration + maintenance)
- Cebranopadol 200, 400, or 600 mcg once daily vs tapentadol 200 mg twice daily vs placebo
Key Results:
- All cebranopadol doses showed statistically significant improvements over placebo
- Responder analysis (30% and 50% pain reduction thresholds) confirmed clinical relevance
- Beneficial effects on sleep quality and physical function
- During maintenance phase, individual adverse event incidence was 10% or less
Adverse Event Profile During Titration:
| Adverse Event | Cebranopadol (pooled) | Placebo |
|---|---|---|
| Dizziness | 35.8% | 8.7% |
| Nausea | 29.4% | 6.3% |
| Somnolence | 18.2% | 4.8% |
| Vomiting | 17.9% | 1.6% |
| Constipation | 16.1% | 4.8% |
| Fatigue | 14.3% | 6.3% |
Phase 2a: Postoperative Acute Pain#
Scholz et al., Pain Physician 2018 (PMID 29871387)#
A Phase 2a single-dose study in 258 patients following bunionectomy compared cebranopadol 200, 400, and 600 mcg to morphine CR 60 mg and placebo.
- Cebranopadol 400 and 600 mcg were more effective than placebo from 2 to approximately 22 hours
- Duration of effect supported once-daily dosing
- Cebranopadol 400 mcg was better tolerated than morphine CR 60 mg
Abuse Liability Assessment#
Goehler et al., J Clin Psychopharmacol 2019 (PMID 30531478)#
A Phase 1, randomized, double-blind, crossover study assessed abuse potential in 42 nondependent recreational opioid users.
| Treatment | Drug Liking vs Placebo | Key Finding |
|---|---|---|
| Cebranopadol 200 mcg | Not different from placebo | No abuse signal |
| Cebranopadol 400 mcg | Not different from placebo | No abuse signal |
| Cebranopadol 800 mcg | Similar to hydromorphone 8 mg | Lower than hydromorphone 16 mg |
| Hydromorphone 8 mg | Significantly above placebo | Active comparator |
| Hydromorphone 16 mg | Significantly above placebo | Active comparator |
The delayed onset of drug-liking effects (3 hours for cebranopadol vs 1.5 hours for hydromorphone) further reduces abuse potential, as rapid onset is a key driver of subjective reward.
Evidence Quality Assessment#
| Criterion | Assessment | Details |
|---|---|---|
| Study design | Phase 3 RCTs + Phase 2 | Two positive pivotal trials; multiple Phase 2 studies |
| Sample size | >2,300 across program | Adequate for regulatory submission |
| Primary endpoints | Met in all key trials | Pain NRS AUC consistently significant (p<0.001) |
| Safety profile | Favorable | Lower abuse potential than comparator opioids |
| Regulatory pathway | FDA Fast Track | NDA submission planned 2025 |
| Peer-reviewed publications | Yes (Phase 2) | Phase 3 data presented at conferences; publications pending |
Key Research Gaps#
-
Chronic pain Phase 3 data: Despite FDA Fast Track for chronic LBP, Phase 3 chronic pain trials have not yet been conducted; planned for late 2025.
-
Long-term safety: Available chronic pain data are limited to 14 weeks. Long-term safety, tolerance development, and physical dependence profiles need characterization.
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Comparative studies: No head-to-head trials against newer non-opioid analgesics or mixed mechanism agents.
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Real-world abuse liability: Abuse potential data are from controlled laboratory settings in nondependent users; real-world data in at-risk populations are needed.
-
Special populations: Limited data on efficacy and safety in elderly patients, those with hepatic or renal impairment, and patients with prior opioid exposure.
Related Reading#
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