Cancer‐related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double‐blind, noninferiority trial

Abstract

Background Cancer‐related pain is a growing health problem given the increasing life expectancy of cancer patients. Opioids are commonly used to treat cancer‐related pain, but carry the risk of severe side effects, limiting their use. Cebranopadol is a first‐in‐class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. This trial examined the analgesic efficacy of cebranopadol compared with morphine prolonged release (PR) in patients with moderate‐to‐severe cancer‐related pain. Methods This double‐blind, parallel‐group, multiple‐dose trial was designed as noninferiority trial for efficacy of cebranopadol versus morphine PR. Planned with 524 patients, finally 126 patients were treated for up to 7 weeks (low accrual). The primary efficacy endpoint was the average amount of daily rescue medication intake (morphine immediate release) over the last 2 weeks of treatment. Results For the primary endpoint, noninferiority of cebranopadol with and superiority over morphine PR were demonstrated (Full Analysis Set: ∆[95%CI] = −7.48 mg [−12.05, −2.92]; Per Protocol Set: ∆[95%CI] = −4.67 mg [−9.25, −0.10]). The vast majority of patients (≥75%, either treatment) had clinically relevant pain reduction, and noninferiority on this secondary endpoint was not shown. Mostly used doses were ≤800 μg cebranopadol or ≤120 mg morphine PR daily. A total of 83.1% of patients on cebranopadol and 82.0% on morphine PR experienced treatment‐emergent adverse events. Conclusions Cebranopadol was effective, safe and well tolerated in the dose range tested (200–1,000 μg) in patients suffering from chronic moderate‐to‐severe cancer‐related pain and was superior to morphine PR on the primary endpoint. Significance Cebranopadol presents a new approach to treat cancer pain. The drug candidate was easy to titrate, safe and well tolerated, and as effective as morphine PR in patients suffering from chronic moderate‐to‐severe cancer‐related pain

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

“…The progressive ratio schedule of reinforcement was used to compare the reinforcing strengths of cebranopadol and fentanyl, which can differentiate reinforcing strengths of abused drugs that function as positive reinforcers. 6,35,36 The ratio progression of the progressive-ratio schedule was from 20 (first injection) to 25, then to 32,40,50,62,77,95,117,144,177,218,267,328, and finally 402 (15th injection). The operant response was maintained at 3 μg/kg per injection of oxycodone until the response was stable (mean ± three injections for three consecutive sessions).…”

Potential innovative targets in the treatment of pain: Combined μ and NOP receptor agonists

“…Early clinical trials suggest safety and efficacy of Cebranopadol for a variety of pain conditions [40][41][42][43][44][45][46] (Table 1). Many of these investigations were designed to assess the tolerability of Cebranopadol and compare its pain mitigating effects against placebo.…”

“…Many of these investigations were designed to assess the tolerability of Cebranopadol and compare its pain mitigating effects against placebo. Although some studies incorporated conventional agents in some arms of the study, 41,43,45,46 the effectiveness of Cebranopadol was never directly compared with those conventional agents. 41,43,46 Some studies were limited by brief duration of investigation, 42,44 small samples, 40,45 and low retention rates.…”

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

“…In turn, some behavioral experiments have revealed that opioid-N/OFQ hybrids such as SR16435, which behaves as a mixed MOP–NOP receptor partial agonist [ 260 ], are highly promising analgesics for the treatment of acute and even neuropathic pain, devoid of respiratory depression [ 261 ]. For example, a mixed opioid/NOP agonist, cebranopadol, is in early phase clinical development in treating diabetic neuropathy, cancer pain, and lower back pain [ 262 , 263 , 264 ].…”