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Context: Pain is one of the most prevalent symptoms associated with cancer. Strong opioids are commonly used in the analgesic management of the disease, but carry the risk of severe side effects. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. For cancer patients, frequently experiencing multimorbidities and often exposed to polypharmacy, cebranopadol is easy to handle given its once-daily dosing, the small tablet size that enables swallowing, and the option to flexibly titrate to an effective dose.Objectives: We assessed the safety and tolerability of prolonged treatment with oral cebranopadol for up to 26 weeks in patients suffering from chronic moderate-to-severe cancer-related pain.Methods: This was a non-randomized, multi-site, open-label, single-arm clinical trial with patients who had completed a double-blind trial comparing morphine prolonged release with cebranopadol. In this extension trial, patients were treated with oral cebranopadol for up to 26 weeks.Results: Cebranopadol was safe and well tolerated in patients with chronic moderate-to-severe pain related to cancer in the dose range tested (200-1000 μg once daily). The median and mean pain levels remained in the range of mild pain during the treatment period.Conclusion: Our data suggest that cebranopadol was safe and well tolerated when administered for up to 26 weeks in patients with chronic cancer-related pain who were previously treated with cebranopadol or morphine prolonged release. [ABSTRACT FROM AUTHOR]

Highlights • Cebranopadol is an innovative analgesic acting as mixed NOP/opioid receptor agonist. • Cebranopadol evoked a stronger withdrawal syndrome in NOP(-/-) than NOP(+/+) mice. • NOP signaling counteracts opioid-like physical dependency. Abstract Cebranopadol is a mixed NOP/opioid receptor agonist currently under development as innovative analgesic. In this study the liability of cebranopadol to produce opioid-type physical dependence has been evaluated in comparison with morphine in wild type mice and in mice knockout for the NOP receptor gene (NOP(-/-)). Mice were treated twice a day for 5 days with increasing doses of cebranopadol or morphine (cumulative doses 10.2 and 255 mg/kg, respectively) and the number of jumping in response to naloxone 10 mg/kg were measured after 2 h from the last injection. In wild type mice naloxone evoked a similar withdrawal jumping behavior in animal pretreated with morphine or cebranopadol. In NOP(-/-) mice morphine treatment produced the same signs of withdrawal as in NOP(+/+) animals, while cebranopadol treatment elicited a stronger withdrawal syndrome in NOP(-/-) than of NOP(+/+) mice. These results demonstrated that the activation of the NOP receptor reduces the liability of cebranopadol to produce opioid-like physical dependence. Thus, the simultaneous activation of NOP and opioid receptors can be an effective pharmacological strategy to counteract physical dependence to opioid drugs. [ABSTRACT FROM AUTHOR]

Opioids are characterised as classical (mu, delta, and kappa) along with the non-classical nociceptin/orphanin FQ (N/OFQ) receptor or NOP. Targeting NOP has therapeutic indications in control of the cardiovascular and respiratory systems and micturition, and a profile as an antidepressant. For all of these indications, there are translational human data. Opioids such as morphine and fentanyl (activating the mu receptor) are the mainstay of pain treatment in the perioperative period, despite a challenging side-effect profile. Opioids in general have poor efficacy in neuropathic pain. Moreover, longer term use is associated with tolerance. There is good evidence interactions between opioid receptors, and receptor co-activation can reduce side-effects without compromising analgesia; this is particularly true for mu and NOP co-activation. Recent pharmaceutical development has produced a mixed opioid/NOP agonist, cebranopadol. This new chemical entity is effective in animal models of nociceptive and neuropathic pain with greater efficacy in the latter. In animal models, there is little evidence for respiratory depression, and tolerance (compared with morphine) only develops after long treatment periods. There is now early phase clinical development in diabetic neuropathy, cancer pain, and low back pain where cebranopadol displays significant efficacy. In 1996, N/OFQ was formally identified with an innovative analgesic profile. Approximately 20 yr later, cebranopadol as a clinical ligand is advancing through the human trials process. [ABSTRACT FROM AUTHOR]

Cebranopadol is a novel, first-in-class analgesic with agonist activity at the nociceptin/orphanin FQ opioid peptide (NOP) receptor as well as the classical opioid peptide receptors. This study investigated the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain. Selective antagonists were used to probe the involvement of the NOP receptor and the µ-opioid peptide (MOP) receptors. Experimental mono-arthritis was induced by intra-articular injection of complete Freund's adjuvant into the left hind knee joint. Intravenous (i.v.) administration of cebranopadol 0.8–8.0 µg/kg to rats 5 days after induction of arthritis elicited dose-dependent increases in weight bearing on the affected limb. The quarter-maximal effective dose (ED 25 ) for this anti-hypersensitive effect of cebranopadol was 1.6 µg/kg i.v. (95% confidence interval [CI]: 0.8, 1.6). The ED 25 increased to 3.2 µg/kg i.v. (95% CI: 2.4, 4.0) following pretreatment with the selective NOP receptor antagonist J-113397 and to 18.3 µg/kg i.v. (95% CI: 9.6, 146.0) following pretreatment with the MOP receptor antagonist naloxone (at intraperitoneal antagonist doses of 4.64 mg/kg and 1.0 mg/kg, respectively). The MOP receptor agonist morphine and the NOP receptor agonist Ro65–6570 also elicited increases in weight bearing on the affected limb. The anti-hypersensitive effect of morphine 2.15 mg/kg i.v. was inhibited by naloxone but not by J-113397. Conversely, the anti-hypersensitive effect of Ro65–6570 0.464 mg/kg i.v. was inhibited by J-113397 but not by naloxone. In conclusion, cebranopadol evoked potent anti-hypersensitive efficacy in a rat model of arthritic pain, and this involved agonist activity at both the NOP and MOP receptors. [ABSTRACT FROM AUTHOR]

There has been significant research to develop an ideal synthetic opioid. Opioids with variable properties possessing efficacy and with reduced side effects have been synthesized when compared to previously used agents. An opioid modulator is a drug that can produce both agonistic and antagonistic effects by binding to different opioid receptors and therefore cannot be classified as one or the other alone. These compounds can differ in their structures while still possessing opioid-mediated actions. This review will discuss TRV130 receptor modulators and other novel opioid receptor modulators, including Mitragyna "Kratom," Ignavine, Salvinorin-A, DPI-289, UFP-505, LP1, SKF-10,047, Cebranopadol, Naltrexone-14-O-sulfate, and Naloxegol. In summary, the structural elucidation of opioid receptors, allosteric modulation of opioid receptors, new opioid modulators and agonists, the employment of optogenetics, optopharmacology, and next-generation sequencing of opioid receptor genes and related functionality should create exciting new avenues for research and therapeutic development to treat conditions including pain, opioid abuse, and addiction. [ABSTRACT FROM AUTHOR]

Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1–1 mg kg −1 ) and morphine (0.1–10 mg kg −1 ) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01–0.1 mg kg −1 ) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory. [ABSTRACT FROM AUTHOR]

As a novel first-in-class potent analgesic acting as an agonist of multiple opioid receptors, cebranopadol showed high efficacy and good tolerability in a broad range of preclinical models and clinical trials related to pain. In the present study, to evaluate the efficacy and safety of cebranopadol as a potential treatment of cocaine dependence, we tested the effects of cebranopadol with single and repeated doses (25, 50, 75, or 100 μg/kg, oral gavage) using rat models of cocaine fixed-ratio (FR) self-administration (SA), cocaine progressive-ratio (PR) SA, and sucrose pellet SA. In single-dosing treatment paradigm, cebranopadol significantly and dose-dependently reduced cocaine SA under FR and PR schedules and suppressed food intake under FR schedule without causing apparent side effects. In repeated-dosing treatment scheme, i.e. daily administration of 25, 50, 75, or 100 μg/kg cebranopadol for a week, the similar reduction in cocaine intake was detected, while non-negligible complications/side effects were observed at repeated high doses (75 and 100 μg/kg). The observed side effects were similar to the common toxic signs elicited by heroin at high doses, although cebranopadol did not fully substitute heroin's discriminative stimulant effects in our drug discriminative tests. These results demonstrated that the most appropriate oral dose of cebranopadol to balance the efficacy and safety is 50 μg/kg. Collectively, although cebranopadol may serve as a new treatment for cocaine dependence, more consideration, cautiousness, and a clear optimal dose window to dissociate its therapeutic effects from opioid side effects/complications in male and female subjects will be necessary to increase its practical clinical utility. • Cebranopadol is known as a candidate for treatment of pain and cocaine dependence. • Administration of cebranopadol dose-dependently reduced cocaine self-administration. • Repeated high doses (≥75 μg/kg) of cebranopadol led to significant adverse effects. • Cebranopadol-induced adverse effects were similar to classic opioid adverse effects. • Cebranopadol did not fully substitute heroin's discriminative stimulant effects. [ABSTRACT FROM AUTHOR]