Special Topics in Pain: Opioids

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Cebranopandol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

Author(s): Christoph A, et al.
Journal: Pain. 2017; 158: 1813-1824. 34 references.
Reprint: Annette Christoph, ZieglerstraBe 6, 52078 Aachen Germany. E-mail: Annette.Christoph@grunenthal.com
Faculty Disclosure: Abstracted by N Walea, who has nothing to disclose. Please see original article for disclosures.
Objective: Review and evaluate the latest advances and newest information in the area of Opioids

Editor’s Note: Opioids with multiple mechanisms of action, such as tramadol, tapentadol, and methadone, have the potential benefit of helping with pain beyond that of pure mu agonism.  Neuropathic pain conditions, for example, are difficult to treat with opioids alone.  Cebranopadol has a unique mode of action on the NOP receptor along with opioid receptor agonism, and thus, potentially could treat pain conditions more effectively than traditional opioids.  Interestingly, it seems that opioid withdrawal from abrupt continuation was minimal, though whether this was due to the dosing itself or an inherent property of the drug is unknown.  Although further research is needed, it could be a promising new drug if it progresses to a phase III trial and beyond.

Class: Cebranopadol (opioid)

Cebranopadol is a novel, centrally acting, potent, first-in-class analgesic drug candidate with a unique mode of action that combines nociceptin/orphanin FQ peptide (NOP) receptor and opioid peptide receptor agonism. Preclinical studies demonstrated that, even after doses higher than those required to induce analgesia, cebranopadol affects neither motor coordination nor respiratory function and thus displays a better tolerability profile than opioids.

For this first human phase II drug trial, male and female patients aged 18 to 80 years with a diagnosis of LBP of nonmalignant origin with moderate-to-severe pain present for at least 3 months were recruited. The trial had 3 periods: an enrollment period, a double-blind treatment period and a follow-up period. There were 641 patients enrolled and 360 patients completed the trial. Main reasons for discontinuation were treatment-emergent adverse events (TEAEs) (N=193, most common in the active treatment arms), lack of efficacy (N=35, most common in the placebo arm) and withdrawal of consent (N=29).

Patients were randomized into one of 5 treatment arms: placebo, cebranopadol 200 µg, cebranopadol 400 µg, cebranopadol 600 µg, and tapentadol PR (prolonged release) 200 mg BID. The primary endpoints were changes from baseline pain in the weekly average 24-hour pain and the change from baseline pain to the average 24 hour pain during week 12 of the maintenance phase. Additional endpoints included change from baseline in the Oswestry Disability Index (ODI) score; change from baseline in quality of sleep; the frequency of TEAEs; and frequency of potential withdrawal symptoms using the Clinical Opiate Withdrawal Scale (COWS).

The mean age of patients was 57.5 years and most patients were white (99.7%). No relevant differences in demographic parameters were noted between treatment arms.

  • For the primary endpoints, all 3 cebranopadol arms as well as the tapentadol arm were statistically significantly different from placebo in terms of change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks of the maintenance phase and the change from baseline pain to the average 24-hour pain during week 12 of the maintenance phase. The responder analysis showed a higher percentage of patients in the 3 cebranopadol arms than in the placebo arm reported ≥30% or ≥50% of pain reduction at week 12 of the maintenance phase compared to baseline.

Tapentadol PR was included as an active comparator as it is indicated for the treatment of severe chronic pain, including chronic back pain. The estimated mean on the primary endpoints for tapentadol PR was within that of the 2 higher doses of cebranopadol. Cebranopadol treatment induced a reduction of disability in all active treatment arms compared with placebo, as measured by the ODI. Results of this trial show that cebranopadol treatment improved the overall quality of sleep compared to the placebo arm.

The most frequently reported TEAEs (occurring in at least 5% of patients who took cebranopadol overall) were dizziness, nausea, somnolence, vomiting, constipation, fatigue, headache and hyperhidrosis. Eighteen serious TEAEs were reported in 14 patients (2.2%) during the trial: 3 patients in the tapentadol PR arm, 2 patients in the placebo arm, 3 patients in the cebranopadol 200 µg arm, 4 patients in the cebranopadol 400 µg arm, 2 patients in the cebranopadol 600 µg arm. No deaths occurred during the trial.

In contrast to strong opioids, abrupt discontinuation of cebranopadol intake after up to 14 weeks of treatment did generally not result in withdrawal symptoms, as assessed using the COWS. Therefore, slow tapering off of the cebranopadol treatment seems not required.

Important Points:
This was the first clinical trial to evaluate the analgesic efficacy, safety, and tolerability of cebranopadol taken once daily in patients suffering from moderate-to-severe chronic LBP, with and without a neuropathic pain component. Cebranopandol was effective at all tested doses showing statistically significant differences from placebo for the primary endpoints. Cebranopadol displayed other beneficial effects including improved sleep and functionality. In general, positive responses to treatment with cebranopadol and tapentadol were observed, irrespective of the presence or absence of neuropathic pain components in the chronic LBP. Patients reaching the cebranopadol target doses presented with an acceptable tolerability profile. The incidence rate of most frequently reported TEAEs during the maintenance phase was ≤10%.

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