Efficacy of Full µ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists – Preclinical and Clinical Evidence

Abstract

Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as µ-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist.

Key words

analgesic drugs - drug research - pharmacology

• References

• 1 Errick JK, Heel RC. Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy. Drugs 1983; 26: 191-211
• 2 Schmidt WK, Tam SW, Shotzberger GS et al. Nalbuphine. Drug and alcohol dependence 1985; 14: 339-362
• 3 Rosow CE. The clinical usefulness of agonist-antagonist analgesics in acute pain. Drug and alcohol dependence 1987; 20: 329-337
• 4 Lasagna L. Benefit-risk ratio of agonist-antagonist analgesics. Drug and alcohol dependence 1987; 20: 385-393
• 5 Hoskin PJ, Hanks GW. Opioid agonist-antagonist drugs in acute and chronic pain states. Drugs 1991; 41: 326-344
• 6 Mercadante S. Efficacy and safety of dual opioid therapy. Expert opinion on drug safety 2014; 13: 1433-1436
• 7 Vissers KCP, Besse K, Hans G et al. Opioid rotation in the management of chronic pain: where is the evidence?. Pain Practice 2010; 10: 85-93
• 8 Jacobs AM, Youngblood F. Opioid receptor affinity for agonist-antagonist analgesics. Journal of the American Podiatric Medical Association 1992; 82: 520-524
• 9 Houlihan KP, Mitchell RG, Flapan AD et al. Excessive morphine requirements after pre-hospital nalbuphine analgesia. Journal of accident & emergency medicine 1999; 16: 29-31
• 10 Yaksh T, Wallace MS. Opioids, Analgesia, and pain management. In: Brunton L, Chabner BA, Knollmann BC. (ed.) Goodman and Gilman’s: The pharmacological basis of therapeutics. 12^th ed 481-525 New York: McGrawHill; 2011
• 11 Gharagozlou P, Demirci H, David Clark J et al. Activity of opioid ligands in cells expressing cloned mu opioid receptors. BMC Pharmacol 2003; 3: 1
• 12 Traynor J, Nahorski SR. Modulation by mu-opioid agonists of guanosine-5'-O-(3-[S-35]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cells. Mol Pharmacol 1995; 47: 848-854
• 13 Bloms-Funke P, Gillen C, Schuettler AJ et al. Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides 2000; 21: 1141-1146
• 14 Feng Y, He X, Yang Y et al. Current research on opioid receptor function. Curr Drug Targets 2012; 13: 230-246
• 15 Reinscheid RK, Nothacker HP, Bourson A et al Orphanin FQ: a neuropeptide that activates an opioid-like G protein-coupled receptor. Science 1995; 270: 792-794
• 16 Blumenthal DK, Garrison JC. Pharmacodynamics: Molecular Mechanisms of Drug Action. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman and Gilman’s: The pharmacological basis of therapeutics. 12^th ed. New York: McGrawHill; 2011: 41-72
• 17 Sora I, Elmer G, Funada M et al. Mu opiate receptor gene dose effects on different morphine actions: evidence for differential in vivo mu receptor reserve. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 2001; 25: 41-54
• 18 Lufty K, Cowan A. Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol 2004; 2: 395-402
• 19 Selley D, Liu Q, Childers SR. Signal transduction correlates of mu opioid agonist intrinsic efficacy: Receptor-stimulated [35S]GTPγS binding in mMOR-CHO cells and rat thalamus. J Pharmacol Exp Ther 1998; 285: 496-505
• 20 Huang PKG, Cowan A, Liu-Chen LY. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther 2001; 297: 688-695
• 21 Volpe DA, McMahon Tobin GA, Mellon RD et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regulatory toxicology and pharmacology: RTP 2011; 59: 385-390
• 22 Toll L, Berzetei-Gurske IP, Polgar WE et al. Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr 1998; 178: 440-466
• 23 Yassen A, Kan J, Olofsen E et al. Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats. The Journal of pharmacology and experimental therapeutics 2007; 321: 598-607
• 24 Christoph T, Kogel B, Schiene K et al. Broad analgesic profile of buprenorphine in rodent models of acute and chronic pain. European journal of pharmacology 2005; 507: 87-98
• 25 Meert TF, Vermeirsch HA. A preclinical comparison between different opioids: antinociceptive versus adverse effects. Pharmacol Biochem Behav 2005; 80: 309-326
• 26 Raffa RBDZ. Examination of the preclinical antinociceptive efficacy of buprenorphine and its designation as full- or partial-agonist. Acute Pain 2007; 9: 145-152
• 27 Koegel B, Christoph T, Strassburger W et al. Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice. European journal of pain 2005; 9: 599-611
• 28 Ambros B. Effect of pretreatment with hydromorphone or buprenorphine on thermal antinociception induced by fentanyl in awake cats. J Feline Med Surg 2015; 1-8
• 29 Dahan AYA, Romberg R, Sarton E et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesthes 2006; 96: 627-632
• 30 Ide S, Minami M, Uhl GR et al. (-)-Pentazocine induces visceral chemical antinociception, but not thermal, mechanical, or somatic chemical antinociception, in μ-opioid receptor knockout mice. Molecular Pain 2011; 7: 23
• 31 Gutstein HB. AH. Opioid analgesics. In: Brunton LLLJ, Parker KL. (ed.). Goodman and Gilman’s: The pharmacological basis of therapeutics. New York: McGrawHill/Hardman; 2006: 547-590
• 32 Shu H, Hayashida M, Arita H et al. Pentazocine-induced antinociception is mediated mainly by mu-opioid receptors and compromised by kappa-opioid receptors in mice. The Journal of pharmacology and experimental therapeutics 2011; 338: 579-587
• 33 Hamura H, Yoshida M, Shimizu K et al. Antinociceptive effect of the combination of pentazocine with morphine in the tail-immersion and scald-pain tests in rats. Jpn J Pharmacol 2000; 83: 286-292
• 34 Obara G, Toyohira Y, Inagaki H et al. Pentazocine inhibits norepinephrine transporter function by reducing its surface expression in bovine adrenal medullary cells. J Pharmacol Sci 2013; 121: 138-147
• 35 Shimada A, Iizuka H, Yanagita T. Agonist-antagonistic interactions of pentazocine with morphine studied in mice. Pharmacol Biochem Behav 1984; 20: 531-535
• 36 Shu H, Wang Z, Ye F et al. High-dose pentazocine antagonizes the antinociception induced by high-dose morphine. Life Sci 2015; 130: 1-6
• 37 Tagashira E, Urano T, Hiramori T et al. Biphasic action of pentazocine in morphine-dependent rats. Jpn J Pharmacol 1982; 32: 523-534
• 38 Preston KL, Bigelow GE. Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers. The Journal of pharmacology and experimental therapeutics 1992; 264: 813-823
• 39 Lamas X, Farre M, Cami J. Acute effects of pentazocine, naloxone and morphine in opioid-dependent volunteers. J Pharmacol Exp Ther 1993; 268: 1485-1492
• 40 Strain EC, Preston KL, Liebson IA et al. Precipitated withdrawal by pentazocine in methadone-maintained volunteers. The Journal of pharmacology and experimental therapeutics 1993; 267: 624-634
• 41 Emmerson PJ, Clark MJ, Mansour A et al. Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor. The Journal of pharmacology and experimental therapeutics 1996; 278: 1121-1127
• 42 Gharagozlou P, Demirci H, Clark JD et al. Activitation profiles of opioid ligands in HEK cells expressing δ opioid receptors. BMC Pharmacology 2002; 3: 19
• 43 Gharagozlou P, Hashemi E, DeLorey TM et al. Pharmacological profiles of opioid ligands at kappa opioid receptors. BMC Pharmacology 2006; 6: 3
• 44 Pick CG, Paul D, Pasternak GW. Nalbuphine, a mixed kappa1 and kappa3 analgesic in mice. The Journal of pharmacology and experimental therapeutics 1992; 262: 1044-1050
• 45 Lee SC, Wang JJ, Ho ST et al. Nalbuphine coadministered with morphine prevents tolerance and dependence. Anesth Analg 1997; 84: 810-815
• 46 DiFazio C, Moscicki JC, Magruder MR. Anesthetic potency of nalbuphine and interaction with morphine in rats. Anesth Analg 2001; 60: 629-633
• 47 Gal TJ, DiFazio CA, Moscicki J. Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine. Anesthesiology 1982; 57: 367-374
• 48 Oifa S, Sydoruk T, White I et al. Effects of intravenous patient-controlled analgesia with buprenorphine and morphine alone and in combination during the first 12 postoperative hours: a randomized, double-blind, four-arm trial in adults undergoing abdominal surgery. Clin Ther 2009; 31: 527-541
• 49 Macintyre PE, Russell RA, Usher KA et al. Pain relief and opioid requirements in the first 24 hours after surgery in patients taking buprenorphine and methadone opioid substitution therapy. Anaesth Intensive Care 2013; 41: 222-230
• 50 Radbruch L. Buprenorphine TDS: use in daily practice, benefits for patients. Int J Clin Pract 2003; 133: 19-22
• 51 Griessinger N, Sittl R, Likar R. Transdermal buprenorphine in clinical practice – a post-marketing surveillance study in 13,179 patients. Curr Med Res Opin 2005; 21: 1147-1156
• 52 Rodriguez-Lopez M . Transdermal buprenorphine in the management of neuropathic pain. Rev Soc Esp Dolor 2004; 11: 11-21
• 53 de Barutell C, González-Escalada JR. Efficacy and safety of buprenorphine TDS in conjunction with oral tramadol or morphine as rescue medication in the treatment of 390 patients with chronic pain: a summary of two retrospective Spanish multicenter studies. J Appl Ther Res 2007; 6: 14-24
• 54 Aurilio B, Pace MC, Passavanti MB. Transdermal buprenorphine combined with spinal morphine and naropine for pain relief in chronic peripheral vasculopathy. Minerva Anestesiol 2005; 71: 445-449
• 55 Pergolizzi J, Aloisi AM, Dahan A et al. Current knowledge of buprenorphine and its unique pharmacological profile. Pain Pract 2010; 10: 428-450
• 56 Levine JD, Gordon NC. Synergism between the analgesic actions of morphine and pentazocine. Pain 1988; 33: 369-372
• 57 Yeh Y, Lin TF, Lin FS et al. Combination of opioid agonist and agonist–antagonist: patient-controlled analgesia requirement and adverse events among different-ratio morphine and nalbuphine admixtures for postoperative pain. Br J Anaesth 2008; 101: 542-548
• 58 Bailey PL, Clark NJ, Pace NL et al. Failure of nalbuphine to antagonize morphine: a double-blind comparison with naloxone. Anesth Analg 1986; 65: 605-611
• 59 Latasch L, Probst S, Dudziak R. Reversal by nalbuphine of respiratory depression caused by fentanyl. Anesth Analg 1984; 63: 814-816
• 60 Gal TJ. Morphine antagonism with nalbuphine. Anesth Analg 1987; 66: 97
• 61 Gear RW, Gordon NC, Hossaini-Zadeh M et al. A subanalgesic dose of morphine eliminates nalbuphine anti-analgesia in postoperative pain. J Pain 2008; 9: 337-341
• 62 Frink MC, Hennies HH, Englberger W et al. Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittel-Forschung 1996; 46: 1029-1036
• 63 Gillen C, Haurand M, Kobelt DJ et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human μ-opioid receptor. Naunyn-Schmiedeberg's Arch Pharmaco1 2000; 362: 116-121