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

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.

Efficacy and safety of multiple doses of tapentadol oral solution in the treatment of moderate to severe acute pain in children aged 2 to <18 years - a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Well-controlled trials of analgesics in the pediatric population are scarce. Tapentadol is a strong centrally acting analgesic which has undergone a pediatric development program investigating its suitability for treating moderate to severe acute pain across the entire pediatric age range from birth to adolescence. Here, we report data from a pivotal Phase III trial performed as part of this development program. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled, multicenter clinical trial investigated efficacy and safety/tolerability of multiple tapentadol oral solution doses (OS; target dose 1.25 mg/kg) in the treatment of postsurgical acute pain. Data for patients aged 2 to <18 years are reported here. The main objective of the trial was to investigate if oral tapentadol administration compared to placebo reduces the use of supplemental opioid analgesic medication within the first 24 hrs of treatment. Other investigated parameters included taste and palatability of the trial medication, adverse events (AEs), vital signs, and laboratory parameters. RESULTS: A total of 160 patients were included (placebo n=52, tapentadol n=108). It was shown that the total amount of supplemental opioid analgesic medication used in the first 24 hrs was significantly lower in tapentadol patients than placebo patients (p=0.0154). Taste and palatability of tapentadol OS was well perceived by most patients. Treatment-emergent AEs were reported in 50% of patients treated with placebo vs 57.4% in those exposed to tapentadol, most commonly vomiting, nausea, and constipation in both treatment groups. CONCLUSION: Tapentadol OS was effective and generally well tolerated in children (≥2 years) for the treatment of moderate to severe acute pain. Across all age groups, palatability and acceptability of tapentadol OS were sufficient to ensure intake compliance. This trial provides evidence that tapentadol OS can be effectively used to treat pain in young patients for whom currently limited labelled treatment options are available.

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

Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 µg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (≥30% or ≥50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ≤10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.