Cebranopadol: Side Effects
Known side effects, contraindications, and interactions
📌TL;DR
- •7 known side effects documented
- •4 mild, 3 moderate, 0 severe
- •3 contraindications listed
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Side Effects Severity Chart
Most common adverse event across all trials. Reported in approximately 29.4% of patients in the chronic LBP Phase 2 trial. Also the most frequent adverse event in Phase 3 acute pain trials. Usually occurs during titration and decreases during maintenance.
Reported in approximately 35.8% of cebranopadol-treated patients in the chronic LBP trial vs 8.7% placebo. Most frequent during titration phase; incidence drops to 10% or less during maintenance.
Reported in approximately 18.2% of cebranopadol-treated patients vs 4.8% placebo. Related to CNS depressant effects of opioid receptor activation. Usually resolves with continued treatment.
Reported in approximately 17.9% of patients during the chronic LBP trial vs 1.6% placebo. More common during titration phase.
Reported in approximately 16.1% of patients vs 4.8% placebo. Expected pharmacological effect of opioid receptor activation on gastrointestinal motility.
Reported in approximately 14.3% of patients vs 6.3% placebo. Related to CNS effects. Usually self-limiting.
Reported in approximately 10.4% of patients. Mild severity in most cases.
⛔Contraindications
- •Known hypersensitivity to cebranopadol or any excipient
- •Severe respiratory depression or severe bronchial asthma in unmonitored settings
- •Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation (theoretical, based on opioid class precautions)
⚠️Drug Interactions
- •CNS depressants (benzodiazepines, alcohol, other sedatives) may potentiate sedation and respiratory depression. Combined use should be avoided or carefully monitored.
- •Other opioid agonists may produce additive effects. Combination use requires careful dose adjustment.
- •CYP enzyme inhibitors or inducers may alter cebranopadol metabolism and plasma levels. Specific interaction studies are pending.
Community-Reported Side Effects
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Based on 10+ community reports
View community protocolsSafety Overview#
Cebranopadol has been evaluated for safety across more than 33 clinical trials in over 2,300 participants. The safety profile is characterized by typical opioid-class adverse events (nausea, dizziness, somnolence, constipation) that are most prominent during the titration phase and decrease substantially during maintenance treatment. Notably, the NOP receptor component of cebranopadol's mechanism contributes to reduced respiratory depression risk and lower abuse potential compared to pure mu-opioid agonists.
Adverse Events by Treatment Phase#
An important distinction in cebranopadol's safety profile is the difference between titration and maintenance phases:
Titration Phase#
During the initial dose titration period, adverse events were common:
| 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% |
| Headache | 10.4% | 7.9% |
| Hyperhidrosis | 9.9% | 0.8% |
Higher cebranopadol doses (600 mcg) were associated with more treatment discontinuations during titration. Most adverse events resolved with continued treatment.
Maintenance Phase#
Once patients reached and stabilized at their target dose, the incidence of individual adverse events dropped to 10% or less, indicating significant adaptation.
Acute Pain Phase 3 Trials#
In the ALLEVIATE-1 and ALLEVIATE-2 Phase 3 trials for acute pain:
- Safety profile comparable to placebo
- Most common adverse event was nausea
- No serious adverse events related to cebranopadol
- Well tolerated at the fixed 400 mcg dose without titration
Abuse Potential and Respiratory Depression#
Reduced Abuse Liability#
The Phase 1 abuse liability study (PMID 30531478) demonstrated:
- At clinical doses (200-400 mcg): no difference from placebo on drug-liking assessments
- At supratherapeutic dose (800 mcg): abuse signals similar to hydromorphone 8 mg but lower than hydromorphone 16 mg
- Delayed onset of drug-liking effects (3 hours vs 1.5 hours for hydromorphone), further reducing abuse potential
Respiratory Safety#
Preclinical data indicate that NOP receptor activation ameliorates the respiratory depression associated with MOP receptor agonism. No serious respiratory adverse events have been reported in clinical trials.
Comparison with Opioid Safety Profile#
| Safety Parameter | Cebranopadol | Traditional Opioids |
|---|---|---|
| Abuse potential | Low (at clinical doses) | High |
| Respiratory depression | Reduced risk | Significant risk |
| GI effects (nausea, constipation) | Present | Present |
| CNS effects (dizziness, somnolence) | Present (mostly titration) | Present |
| Physical dependence | Under investigation | Well established |
| Tolerance development | Under investigation | Well established |
Contraindications#
- Hypersensitivity: Known allergy to cebranopadol or any formulation component
- Severe respiratory depression: As with all opioid receptor agonists, use in patients with severe respiratory compromise should be avoided
- Concurrent CNS depressants: Combined use with benzodiazepines, alcohol, or other sedatives increases the risk of respiratory depression and excessive sedation
Drug Interactions#
- CNS depressants: Benzodiazepines, alcohol, muscle relaxants, and other sedatives may potentiate cebranopadol's sedative effects
- Other opioid agonists: Additive opioid effects may occur
- CYP enzyme modulators: As cebranopadol is hepatically metabolized, strong CYP inhibitors or inducers may alter plasma levels; specific interaction data are pending
Related Reading#
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