BJA Advance Access published September 23, 2014 British Journal of Anaesthesia Page 1 of 3 doi:10.1093/bja/aeu332
EDITORIAL
Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist D. G. Lambert*, M. F. Bird and D. J. Rowbotham Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester Royal Infirmary, Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, UK * E-mail: [email protected]
overlapping expression in the pain pathway,3 including NOP,9 but few molecules are so well characterized as cebranopadol, and there has been significant clinical development of this molecule. Cebranopadol is both a NOP and MOP agonist, a single molecule with affinities for more than one receptor. The benefits of a non-selective drug that combines different modes of action over ‘polypharmacy’ or bivalent compounds (two drug structures joined by a linker molecule) are numerous. The small size of the drug facilitates entry into the central nervous system, an issue raised by the usually bulkier structure of bivalent drugs. Secondly, the pharmacokinetics (distribution, metabolism) of a single drug with different modes of action are more predictable.8 Such compounds have demonstrated synergistic effects and lower side-effect profiles.10 – 12
Cebranopadol In vitro pharmacology Radioligand binding to recombinant human and native rat opioid receptors shows similar nanomolar affinities for NOP and MOP with 3- to 38-fold lower affinity for KOP in the human and rat. Affinity for DOP in humans is 20-fold lower than for NOP or MOP. At recombinant human receptors, cebranopadol is a full agonist at MOP and displays ‘almost full efficacy’ at NOP.
Cebranopadol In vivo pharmacology The in vivo characterization of cebranopadol is particularly thorough, and encompasses a wide range of animal painrelated paradigms along with assessment of typical opioid side-effects. In the tail-flick test in rats (a test of acute antinociception), cebranopadol was effective i.v. (time to peak effect 20 min) and p.o. (time to peak effect 90 min). In comparison with fentanyl (30 min) and morphine (3 h), the antinociceptive effect of an equi-effective dose of cebranopadol lasted 7 h. Cebranopadol is effective i.v. in a range of models of chronic pain including Freund’s adjuvant-induced arthritis (nociceptive), bone cancer pain (nociceptive and neuropathic), diabetic polyneuropathy (neuropathic), and spinal nerve ligationinduced pain (nociceptive and neuropathic). In these models, half-maximal effective doses of between 0.5 and 5.6 mg kg21 were quoted; these are over 2–3 orders of magnitude more
& The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014
Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide agonist for the N/OFQ receptor (NOP).1 NOP is classified as a non-classical member of the opioid family as it shares structural and transduction homology and anatomical localization with the classical m-opioid receptor (MOP), d-opioid receptor (DOP), and k-opioid receptor. However, its actions are not sensitive to the universal opioid antagonist naloxone.2 This peptide receptor system has been implicated in the physiology and pathophysiology of anxiety/depression, learning/memory, feeding, airway disease, immune dysfunction, gastrointestinal motility, urological disease, and pain.1 Modulation of activity at this receptor produces variable effects on the nociceptive (pain) response in laboratory animals, with N/OFQ and NOP agonists in general producing antinociception when given spinally and pro-nociceptive/anti-opioid actions when administered supraspinally in rodents. Spinal administration of N/OFQ or NOP agonists also produces antinociception in nonhuman primates.1 3 The link to the clinic, as is often the case, revolves around discovery and evaluation of novel chemical entities: the pharmaceutical pipeline. The N/OFQ –NOP system is no exception in this regard. Indeed, in 2004, one of us (D.G.L.) wrote an editorial ‘Nociceptin/Orphanin FQ peptide receptor system; are we any nearer the clinic?’.4 At that time, there were some limited studies in urology examining intravesical instillation for bladder instability,5 and a number of simple plasma measurements in patients with a range of clinical diseases.4 We raised several issues including what is the best model/disease to study, and suggested pain. However, all work required development of small non-peptide molecules with good oral bioavailability. Researchers at Grunenthal GmbH recently reported the development and pharmacology of a novel ligand that targets NOP and other members of the opioid receptor family, in particular the MOP receptor.6 7 This molecule, named cebranopadol (trans-6′ -fluoro-4,9′ -dihydro-N,N-dimethyl-4-phenyl-spiro [cyclohexane-1,1′ (3′ H)-pyrano[3,4-b]indol]-4-amine or GRT6005), represents a major development in opioid pharmacology for a number of reasons. In contrast to the accepted norm of designing highly selective ligands for a single target (usually MOP), cebranopadol is a non-selective ligand acting at more than one member of the opioid receptor family. There has been much interest in multi-targeting of opioids,8 due to
BJA
Editorial
Table 1 Registered clinical trials with cebranopadol (GRT6005). Total anticipated enrolment: 2976 patients. CORAL + open label extension, Cebranopadol versus morphine prolonged release in patients with chronic moderate to severe pain related to cancer Details
Status
Pain: Osteoarthritis
Phase IIa; efficacy, safety, tolerability. Random placebo-controlled. Enrolment 207
Completed
Pain: chronic low back
Phase II; efficacy, safety. Random, placebo, and active (Tapentadol) control. Enrolment 1089
Completed
Pain: osteoarthritis
Phase II; safety, efficacy. Random, placebo, and active (oxycodone) control. Enrolment 619
Completed
Pain: diabetic polyneuropathy
Phase II; efficacy, safety, tolerability. Random placebo-controlled. Enrolment 189
Completed
Pain: bunionectomy
Phase IIa; efficacy, safety, tolerability. Random, placebo, and active (morphine) control. Enrolment 258
Completed
Polyneuropathy
Phase IIa; efficacy, safety, tolerability. Random, placebo, and active (morphine) control. Enrolment 90
Completed
Pain: diabetic neuropathy
Phase II; efficacy, safety and tolerability. Random placebo control. Comparison with Lyrica. Enrolment 350
Recruiting
CORAL+open label extension
Phase III; efficacy, safety, tolerability. Random, placebo, and active (morphine) control. Enrolment 524. Extension is open label. Enrolment 220
Recruiting
Cebranopadol Clinical development Cebranopadol is currently being co-developed globally by Gru¨nenthal and Forest Research Institute, Inc. Excluding phase I first in man, publicly available clinical trial databases indicate that there are six completed and one ongoing phase II trials and one ongoing phase III trial in cancer pain (Table 1). All of these studies appear to be based on the preclinical profile already published. The scientific and patient community eagerly await the results of these trials. To return to our 2004 editorial4—are we any nearer the clinic? Ten years on and the answer would seem to be a definite yes with cebranopadol representing a first in class NOP receptor and opioid receptor agonist.
Authors’ contributions D.G.L., D.J.R., and M.F.B. researched material and wrote the editorial.
Declaration of interest potent than the gold standard morphine. Pharmacokinetic analysis in the rat shows rapid absorption and widespread distribution, with oral bioavailability of 13 –23%. Tolerance to opioids is a particularly troublesome side-effect that leads to dose escalation. Dose escalation per se leads to increased tolerance and a vicious cycle ensues.13 There is good evidence that mixed opioids might be beneficial in this regard, with data showing morphine tolerance is reduced in DOP14 and endogenous d-opioid peptide ppENK knockouts,15 and by co-administration of a DOP antagonist.16 From a clinical perspective, the non-selective opioid buprenorphine (acting as a weak partial agonist at MOP and NOP and an antagonist at KOP) displays synergistic antinociceptive effects and reduced onset, but not complete blockade, of tolerance and dependence, making it favourable in the treatment of opioid addiction.17 In the rat, tolerance to morphine develops quickly; in this study, animals were completely tolerant to morphine (8.8 mg kg21 i.p. daily) in 11 days. In contrast, an equi-analgesic dose of cebranopadol (only 0.8 mg kg21 i.p. daily) was still
Page 2 of 3
D.G.L. held a consultancy with Grunenthal GmbH and is a board member and administration director of British Journal of Anaesthesia. D.J.R. is a board member and director of British Journal of Anaesthesia. M.F.B. is a recipient of a PhD studentship funded by British Journal of Anaesthesia and Royal College of Anaesthetists.
References 1 Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 2008; 7: 694– 710 2 Dietis N, Rowbotham DJ, Lambert DG. Opioid receptor subtypes: fact or artifact? Br J Anaesth 2011; 107: 8 –18 3 Schro¨der W, Lambert DG, Ko MC, Koch T. Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol 2014; 171: 3777–800 4 Barnes TA, Lambert DG. Editorial III: Nociceptin/orphanin FQ peptide-receptor system: are we any nearer the clinic? Br J Anaesth 2004; 93: 626–8 5 Lazzeri M, Calo G, Spinelli M, et al. Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014
Indication
effective for a further 15 days, or 26 days in total. For the N/OFQ–NOP system, evidence suggests that NOP antagonism reduces tolerance to morphine,18 19 while NOP activation reduces the manifestations of drug dependence.20 21 This is at variance with data for cebranopadol, but it should be remembered that these studies modulated NOP and MOP simultaneously with two discrete ligands. Typical opioid-induced side-effects include loss of motor co-ordination and respiratory depression. In the rotarod test for motor co-ordination, i.v. doses of cebranopadol that were analgesic were ineffective; morphine (i.v.) at analgesic doses profoundly affected motor co-ordination. Using whole-body plethysmography to assess respiratory function, i.v. doses of cebranopadol that were analgesic produced a transient increase in respiratory rate and tidal volume, while morphine (s.c.) produced a profound depression of respiration.
Editorial
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14 Zhu Y, King MA, Schuller AGP, et al. Retention of supraspinal deltalike analgesia and loss of morphine tolerance in d opioid receptor knockout mice. Neuron 1999; 24: 243–52 15 Nitsche JF, Schuller AGP, King MA, Zengh M, Pasternak GW, Pintar JE. Genetic dissociation of opiate tolerance and physical dependence in d-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 2002; 22: 10906– 13 16 Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 1991; 258: 299–303 17 Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 1978; 35: 501– 16 18 Ueda H, Inoue M, Takeshima H, Iwasawa Y. Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J Neurosci 2000; 20: 7640–7 19 Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK. Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 2006; 318: 262–7 20 Zaveri NT. The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications. Curr Top Med Chem 2011; 11: 1151– 6 21 Kest B, Hopkins E, Palmese CA, Chen ZP, Mogil JS, Pintar JE. Morphine tolerance and dependence in nociceptin/orphanin fq transgenic knock-out mice. Neuroscience 2001; 104: 217–22
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Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014
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randomized, placebo-controlled, double-blind study. Urology 2003; 61: 946–50 Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 2014; 349: 535– 48 Schunk S, Linz K, Hinze C, et al. Discovery of a potent analgesic NOP and opioid receptor agonist: cebranopadol. ACS Med Chem Lett 2014; 5: 857– 62 Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG. Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile. Br J Anaesth 2009; 103: 38 –49 Toll L. The use of bifunctional NOP/mu and NOP receptor selective compounds for the treatment of pain, drug abuse, and psychiatric disorders. Curr Pharm Des 2013; 19: 7451–60 Schiller PW. Bi- or multifunctional opioid peptide drugs. Life Sci 2010; 86: 598–603 Cowan A, Raffa RB, Tallarida CS, et al. Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit. Eur J Pain Advance Access published on February 26, 2014, doi: 10.1002/j.1532-2149.2014.00461.x Schroder W, Tzschentke TM, Terlinden R, et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther 2011; 337: 312–20 Dietis N, Rowbotham DJ, Lambert DG. Controlling cancer pain: is morphine the best we can do? Trends Anaesth Crit Care 2011; 1: 227– 9
BJA
EDITORIAL
Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist D. G. Lambert*, M. F. Bird and D. J. Rowbotham Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester Royal Infirmary, Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, UK * E-mail: [email protected]
overlapping expression in the pain pathway,3 including NOP,9 but few molecules are so well characterized as cebranopadol, and there has been significant clinical development of this molecule. Cebranopadol is both a NOP and MOP agonist, a single molecule with affinities for more than one receptor. The benefits of a non-selective drug that combines different modes of action over ‘polypharmacy’ or bivalent compounds (two drug structures joined by a linker molecule) are numerous. The small size of the drug facilitates entry into the central nervous system, an issue raised by the usually bulkier structure of bivalent drugs. Secondly, the pharmacokinetics (distribution, metabolism) of a single drug with different modes of action are more predictable.8 Such compounds have demonstrated synergistic effects and lower side-effect profiles.10 – 12
Cebranopadol In vitro pharmacology Radioligand binding to recombinant human and native rat opioid receptors shows similar nanomolar affinities for NOP and MOP with 3- to 38-fold lower affinity for KOP in the human and rat. Affinity for DOP in humans is 20-fold lower than for NOP or MOP. At recombinant human receptors, cebranopadol is a full agonist at MOP and displays ‘almost full efficacy’ at NOP.
Cebranopadol In vivo pharmacology The in vivo characterization of cebranopadol is particularly thorough, and encompasses a wide range of animal painrelated paradigms along with assessment of typical opioid side-effects. In the tail-flick test in rats (a test of acute antinociception), cebranopadol was effective i.v. (time to peak effect 20 min) and p.o. (time to peak effect 90 min). In comparison with fentanyl (30 min) and morphine (3 h), the antinociceptive effect of an equi-effective dose of cebranopadol lasted 7 h. Cebranopadol is effective i.v. in a range of models of chronic pain including Freund’s adjuvant-induced arthritis (nociceptive), bone cancer pain (nociceptive and neuropathic), diabetic polyneuropathy (neuropathic), and spinal nerve ligationinduced pain (nociceptive and neuropathic). In these models, half-maximal effective doses of between 0.5 and 5.6 mg kg21 were quoted; these are over 2–3 orders of magnitude more
& The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014
Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide agonist for the N/OFQ receptor (NOP).1 NOP is classified as a non-classical member of the opioid family as it shares structural and transduction homology and anatomical localization with the classical m-opioid receptor (MOP), d-opioid receptor (DOP), and k-opioid receptor. However, its actions are not sensitive to the universal opioid antagonist naloxone.2 This peptide receptor system has been implicated in the physiology and pathophysiology of anxiety/depression, learning/memory, feeding, airway disease, immune dysfunction, gastrointestinal motility, urological disease, and pain.1 Modulation of activity at this receptor produces variable effects on the nociceptive (pain) response in laboratory animals, with N/OFQ and NOP agonists in general producing antinociception when given spinally and pro-nociceptive/anti-opioid actions when administered supraspinally in rodents. Spinal administration of N/OFQ or NOP agonists also produces antinociception in nonhuman primates.1 3 The link to the clinic, as is often the case, revolves around discovery and evaluation of novel chemical entities: the pharmaceutical pipeline. The N/OFQ –NOP system is no exception in this regard. Indeed, in 2004, one of us (D.G.L.) wrote an editorial ‘Nociceptin/Orphanin FQ peptide receptor system; are we any nearer the clinic?’.4 At that time, there were some limited studies in urology examining intravesical instillation for bladder instability,5 and a number of simple plasma measurements in patients with a range of clinical diseases.4 We raised several issues including what is the best model/disease to study, and suggested pain. However, all work required development of small non-peptide molecules with good oral bioavailability. Researchers at Grunenthal GmbH recently reported the development and pharmacology of a novel ligand that targets NOP and other members of the opioid receptor family, in particular the MOP receptor.6 7 This molecule, named cebranopadol (trans-6′ -fluoro-4,9′ -dihydro-N,N-dimethyl-4-phenyl-spiro [cyclohexane-1,1′ (3′ H)-pyrano[3,4-b]indol]-4-amine or GRT6005), represents a major development in opioid pharmacology for a number of reasons. In contrast to the accepted norm of designing highly selective ligands for a single target (usually MOP), cebranopadol is a non-selective ligand acting at more than one member of the opioid receptor family. There has been much interest in multi-targeting of opioids,8 due to
BJA
Editorial
Table 1 Registered clinical trials with cebranopadol (GRT6005). Total anticipated enrolment: 2976 patients. CORAL + open label extension, Cebranopadol versus morphine prolonged release in patients with chronic moderate to severe pain related to cancer Details
Status
Pain: Osteoarthritis
Phase IIa; efficacy, safety, tolerability. Random placebo-controlled. Enrolment 207
Completed
Pain: chronic low back
Phase II; efficacy, safety. Random, placebo, and active (Tapentadol) control. Enrolment 1089
Completed
Pain: osteoarthritis
Phase II; safety, efficacy. Random, placebo, and active (oxycodone) control. Enrolment 619
Completed
Pain: diabetic polyneuropathy
Phase II; efficacy, safety, tolerability. Random placebo-controlled. Enrolment 189
Completed
Pain: bunionectomy
Phase IIa; efficacy, safety, tolerability. Random, placebo, and active (morphine) control. Enrolment 258
Completed
Polyneuropathy
Phase IIa; efficacy, safety, tolerability. Random, placebo, and active (morphine) control. Enrolment 90
Completed
Pain: diabetic neuropathy
Phase II; efficacy, safety and tolerability. Random placebo control. Comparison with Lyrica. Enrolment 350
Recruiting
CORAL+open label extension
Phase III; efficacy, safety, tolerability. Random, placebo, and active (morphine) control. Enrolment 524. Extension is open label. Enrolment 220
Recruiting
Cebranopadol Clinical development Cebranopadol is currently being co-developed globally by Gru¨nenthal and Forest Research Institute, Inc. Excluding phase I first in man, publicly available clinical trial databases indicate that there are six completed and one ongoing phase II trials and one ongoing phase III trial in cancer pain (Table 1). All of these studies appear to be based on the preclinical profile already published. The scientific and patient community eagerly await the results of these trials. To return to our 2004 editorial4—are we any nearer the clinic? Ten years on and the answer would seem to be a definite yes with cebranopadol representing a first in class NOP receptor and opioid receptor agonist.
Authors’ contributions D.G.L., D.J.R., and M.F.B. researched material and wrote the editorial.
Declaration of interest potent than the gold standard morphine. Pharmacokinetic analysis in the rat shows rapid absorption and widespread distribution, with oral bioavailability of 13 –23%. Tolerance to opioids is a particularly troublesome side-effect that leads to dose escalation. Dose escalation per se leads to increased tolerance and a vicious cycle ensues.13 There is good evidence that mixed opioids might be beneficial in this regard, with data showing morphine tolerance is reduced in DOP14 and endogenous d-opioid peptide ppENK knockouts,15 and by co-administration of a DOP antagonist.16 From a clinical perspective, the non-selective opioid buprenorphine (acting as a weak partial agonist at MOP and NOP and an antagonist at KOP) displays synergistic antinociceptive effects and reduced onset, but not complete blockade, of tolerance and dependence, making it favourable in the treatment of opioid addiction.17 In the rat, tolerance to morphine develops quickly; in this study, animals were completely tolerant to morphine (8.8 mg kg21 i.p. daily) in 11 days. In contrast, an equi-analgesic dose of cebranopadol (only 0.8 mg kg21 i.p. daily) was still
Page 2 of 3
D.G.L. held a consultancy with Grunenthal GmbH and is a board member and administration director of British Journal of Anaesthesia. D.J.R. is a board member and director of British Journal of Anaesthesia. M.F.B. is a recipient of a PhD studentship funded by British Journal of Anaesthesia and Royal College of Anaesthetists.
References 1 Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 2008; 7: 694– 710 2 Dietis N, Rowbotham DJ, Lambert DG. Opioid receptor subtypes: fact or artifact? Br J Anaesth 2011; 107: 8 –18 3 Schro¨der W, Lambert DG, Ko MC, Koch T. Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol 2014; 171: 3777–800 4 Barnes TA, Lambert DG. Editorial III: Nociceptin/orphanin FQ peptide-receptor system: are we any nearer the clinic? Br J Anaesth 2004; 93: 626–8 5 Lazzeri M, Calo G, Spinelli M, et al. Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014
Indication
effective for a further 15 days, or 26 days in total. For the N/OFQ–NOP system, evidence suggests that NOP antagonism reduces tolerance to morphine,18 19 while NOP activation reduces the manifestations of drug dependence.20 21 This is at variance with data for cebranopadol, but it should be remembered that these studies modulated NOP and MOP simultaneously with two discrete ligands. Typical opioid-induced side-effects include loss of motor co-ordination and respiratory depression. In the rotarod test for motor co-ordination, i.v. doses of cebranopadol that were analgesic were ineffective; morphine (i.v.) at analgesic doses profoundly affected motor co-ordination. Using whole-body plethysmography to assess respiratory function, i.v. doses of cebranopadol that were analgesic produced a transient increase in respiratory rate and tidal volume, while morphine (s.c.) produced a profound depression of respiration.
Editorial
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14 Zhu Y, King MA, Schuller AGP, et al. Retention of supraspinal deltalike analgesia and loss of morphine tolerance in d opioid receptor knockout mice. Neuron 1999; 24: 243–52 15 Nitsche JF, Schuller AGP, King MA, Zengh M, Pasternak GW, Pintar JE. Genetic dissociation of opiate tolerance and physical dependence in d-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 2002; 22: 10906– 13 16 Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 1991; 258: 299–303 17 Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 1978; 35: 501– 16 18 Ueda H, Inoue M, Takeshima H, Iwasawa Y. Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J Neurosci 2000; 20: 7640–7 19 Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK. Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 2006; 318: 262–7 20 Zaveri NT. The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications. Curr Top Med Chem 2011; 11: 1151– 6 21 Kest B, Hopkins E, Palmese CA, Chen ZP, Mogil JS, Pintar JE. Morphine tolerance and dependence in nociceptin/orphanin fq transgenic knock-out mice. Neuroscience 2001; 104: 217–22
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randomized, placebo-controlled, double-blind study. Urology 2003; 61: 946–50 Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 2014; 349: 535– 48 Schunk S, Linz K, Hinze C, et al. Discovery of a potent analgesic NOP and opioid receptor agonist: cebranopadol. ACS Med Chem Lett 2014; 5: 857– 62 Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG. Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile. Br J Anaesth 2009; 103: 38 –49 Toll L. The use of bifunctional NOP/mu and NOP receptor selective compounds for the treatment of pain, drug abuse, and psychiatric disorders. Curr Pharm Des 2013; 19: 7451–60 Schiller PW. Bi- or multifunctional opioid peptide drugs. Life Sci 2010; 86: 598–603 Cowan A, Raffa RB, Tallarida CS, et al. Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit. Eur J Pain Advance Access published on February 26, 2014, doi: 10.1002/j.1532-2149.2014.00461.x Schroder W, Tzschentke TM, Terlinden R, et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther 2011; 337: 312–20 Dietis N, Rowbotham DJ, Lambert DG. Controlling cancer pain: is morphine the best we can do? Trends Anaesth Crit Care 2011; 1: 227– 9
BJA
