Limited potential of cebranopadol to produce opioid‐type physical dependence in rodents

Tzschentke, Thomas; Kögel, Babette; Frosch, Stefanie; Linz, Klaus

doi:10.1111/adb.12550

Cited by 22 publications

(16 citation statements)

References 31 publications

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“…The incidence rate of the most frequently reported adverse events (constipation, dizziness, fatigue, hyperhidrosis, nausea, vomiting, and somnolence) during maintenance phase was 10%. Interestingly and in line with preclinical findings, 94 discontinuation of cebranopadol after 14 weeks of treatment was not followed by clear withdrawal symptoms, and only a few cases of mild to moderate withdrawal symptoms were reported. Therefore, slow tapering off of the cebranopadol treatment seems not to be required.…”

Section: Cebranopadol Clinical Studiessupporting

confidence: 76%

“…Similar results were obtained in rat studies investigating both spontaneous and naloxone-precipitated withdrawal. 94 These results suggest a lower potential of cebranopadol to produce physical dependence in rodents than morphine, and the authors of the study speculated that this may derive from the ability of cebranopadol to stimulate the NOP receptor. This is certainly an attractive hypothesis that should be validated experimentally by testing cebranopadol in similar experiments in the absence and presence of selective NOP receptor antagonists, in wild type, NOP(e/e) mice or rats, or both.…”

Section: Box 1 Functional Selectivity or Biased Agonismmentioning

confidence: 88%

“…As far as physical dependence is concerned, this aspect has been specifically evaluated in a recent study. 94 In a naloxoneprecipitated withdrawal assay, mice treated with morphine within the analgesic dose range displayed clear withdrawal symptoms whereas animals treated with cebranopadol (even exceeding the analgesic dose range) showed very little withdrawal symptoms. Similar results were obtained in rat studies investigating both spontaneous and naloxone-precipitated withdrawal.…”

Section: Box 1 Functional Selectivity or Biased Agonismmentioning

confidence: 99%

See 2 more Smart Citations

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Calò

Lambert

2018

British Journal of Anaesthesia

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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.

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Section: Cebranopadol Clinical Studiessupporting

confidence: 76%

Section: Box 1 Functional Selectivity or Biased Agonismmentioning

confidence: 88%

Section: Box 1 Functional Selectivity or Biased Agonismmentioning

confidence: 99%

See 1 more Smart Citation

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Calò

Lambert

2018

British Journal of Anaesthesia

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“…Cebranopadol, despite being a potent MOR agonist, produces only little opioid-type physical dependence in mice and rats, potentially due to its NOP receptor agonistic effects [ 141 ]. Linz and coworkers proved in 2017 that cebranopadol limits the respiratory depressant effect of its μ-opioid receptor agonist activity in rats is due to its NOP receptor agonist activity [ 118 ].…”

Section: Biased Agonism On Nop Receptormentioning

confidence: 99%

Biased Opioid Ligands

2020

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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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“…This compound displays analgesic, antiallodynic, and antihyperalgesic properties in several rat models of acute nociceptive, inflammatory, cancer, and neuropathic pain [ 177 , 178 ]. In contrast to classic opioids, it has a higher analgesic potency in models of neuropathic pain than in acute nociceptive pain [ 179 ]. In addition, even at higher doses, cebranopadol does not induce motor coordination deficits or respiratory depression [ 177 ] and has limited potential to produce opioid-type physical dependence in rodents [ 180 ].…”

Section: Anti-opioidsmentioning

confidence: 99%

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

Gibuła‐Tarłowska

Kotlińska

2020

Biomolecules

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Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.

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Limited potential of cebranopadol to produce opioid‐type physical dependence in rodents

Cited by 22 publications

References 31 publications

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Biased Opioid Ligands

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

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