2,363
Views
4
CrossRef citations to date
0
Altmetric
Review

New concepts in opioid analgesia

ORCID Icon
Pages 765-775 | Received 09 May 2018, Accepted 22 Aug 2018, Published online: 07 Sep 2018

References

  • Stein C. Opioids, sensory systems and chronic pain. Eur J Pharmacol. 2013;716:179–187.
  • Basbaum AI, Bautista DM, Scherrer G, et al. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267–284.
  • Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol. 2013;74(5):630–636.
  • Richards N, McMahon SB. Targeting novel peripheral mediators for the treatment of chronic pain. Br J Anaesth. 2013;111(1):46–51.
  • Stein C, Hassan AH, Przewlocki R, et al. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA. 1990;87(15):5935–5939.
  • Przewlocki R, Hassan AHS, Lason W, et al. Gene expression and localization of opioid peptides in immune cells of inflamed tissue. Functional role in antinociception. Neuroscience. 1992;48:491–500.
  • Stein C, Hassan AHS, Lehrberger K, et al. Local analgesic effect of endogenous opioid peptides. Lancet. 1993;342:321–324.
  • Schreiter A, Gore C, Labuz D, et al. Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J. 2012;26(12):5161–5171.
  • Machelska H. Dual peripheral actions of immune cells in neuropathic pain. Arch Immunol Ther Exp (Warsz). 2011;59(1):11–24.
  • Stein C, Machelska H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev. 2011;63:860–881.
  • Basso L, Bourreille A, Dietrich G. Intestinal inflammation and pain management. Curr Opin Pharmacol. 2015;25:50–55.
  • Rittner HL, Brack A, Stein C. Pain and the immune system. Br J Anaesth. 2008;101(1):40–44.
  • Roques BP, Fournie-Zaluski MC, Wurm M. Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nat Rev Drug Discov. 2012;11(4):292–310.
  • Piomelli D, Sasso O. Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci. 2014;17(2):164–174.
  • Schumacher MA, Basbaum AI, Naidu RK. Opioid agonists and antagonists. In: Katzung BG, Trevor AJ, editors. Basic and clinical pharmacology. 13th ed. New York: McGraw-Hill Medical; 2015. p. 531–551.
  • Fordyce WE. Opioids, pain and behavioral outcomes. APS Journal. 1992;1(4):282–284.
  • Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain–United States, 2016. JAMA. 2016;315(15):1624–1645.
  • Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131–157.
  • Stein C. Opioid receptors. Annu Rev Med. 2016;67:433–451.
  • Cox BM. Recent developments in the study of opioid receptors. Mol Pharmacol. 2013;83(4):723–728.
  • Stevens CW. Bioinformatics and evolution of vertebrate nociceptin and opioid receptors. Vitam Horm. 2015;97:57–94.
  • Law PY, Reggio PH, Loh HH. Opioid receptors: toward separation of analgesic from undesirable effects. Trends Biochem Sci. 2013;38(6):275–282.
  • Wacker D, Stevens RC, Roth BL. How ligands illuminate GPCR molecular pharmacology. Cell. 2017;170(3):414–427.
  • Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a concept. Pharmacol Rev. 2013;65(4):1257–1317.
  • Bradbury A, Pluckthun A. Reproducibility: standardize antibodies used in research. Nature. 2015;518(7537):27–29.
  • Livingston KE, Traynor JR. Allostery at opioid receptors: modulation with small molecule ligands. Br J Pharmacol. 2018 Jul;175(14):2846–2856.
  • Zamponi GW, Currie KP. Regulation of Ca(V)2 calcium channels by G protein coupled receptors. Biochim Biophys Acta. 2013;1828(7):1629–1643.
  • Lüscher C, Slesinger PA. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci. 2010;11(5):301–315.
  • Wang HB, Zhao B, Zhong YQ, et al. Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons. Proc Natl Acad Sci USA. 2010;107(29):13117–13122.
  • Stein C, Küchler S. Targeting inflammation and wound healing by opioids. Trends Pharmacol Sci. 2013;34(6):303–312.
  • Nockemann D, Rouault M, Labuz D, et al. The K channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol Med. 2013;5(8):1263–1277.
  • Dembla S, Behrendt M, Mohr F, et al. Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels. Elife. 2017;6:pii:e26280.
  • Endres-Becker J, Heppenstall PA, Mousa SA, et al. Mu-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol Pharmacol. 2007;71(1):12–18.
  • Spahn V, Fischer O, Endres-Becker J, et al. Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner. Pain. 2013;154(4):598–608.
  • Quallo T, Alkhatib O, Gentry C, et al. G protein betagamma subunits inhibit TRPM3 ion channels in sensory neurons. Elife. 2017;6:pii:e26138.
  • Zöllner C, Stein C. Opioids. Handb Exp Pharmacol. 2007;31–63. 2006/ 11/08ed.
  • Williams JT, Ingram SL, Henderson G, et al. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev. 2013;65(1):223–254.
  • Vadivelu N, Mitra S, Hines RL. Peripheral opioid receptor agonists for analgesia: a comprehensive review. J Opioid Manag. 2011;7(1):55–68.
  • Graham T, Grocott P, Probst S, et al. How are topical opioids used to manage painful cutaneous lesions in palliative care? A critical review. Pain. 2013;154(10):1920–1928.
  • Zeng C, Gao SG, Cheng L, et al. Single-dose intra-articular morphine after arthroscopic knee surgery: a meta-analysis of randomized placebo-controlled studies. Arthroscopy. 2013;29(8):1450–8 e2.
  • Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology. 2015;122(3):659–665.
  • Spahn V, Stein C. Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development. Expert Opin Investig Drugs. 2017;26(2):155–160.
  • Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747–758.
  • Li Y, van den Pol AN. Mu-opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system. J Neurosci. 2008;28(11):2814–2819.
  • McNicol E. Opioid side effects and their treatment in patients with chronic cancer and noncancer pain. J Pain Palliat Care Pharmacother. 2008;22(4):270–281.
  • Imam MZ, Kuo A, Ghassabian S, et al. Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. Neuropharmacology. 2018;131:238–255.
  • Stein C. Pain. In: Cavaillon J-M, Singer M, editors. Inflammation: from molecular and cellular mechanisms to the clinic. Weinheim, Germany: Wiley-VCH; 2018. p. 891–914.
  • Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science (80- ). 2013;339(6116):166–172.
  • Herz A, Millan MJ, Stein C. Arthritic inflammation in rats as a model of chronic pain: role of opioid systems. NIDA Res Monogr. 1989;95:110–115.
  • Stein C, Millan MJ, Shippenberg TS, et al. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther. 1989;248(3):1269–1275.
  • Stein C, Comisel K, Haimerl E, et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med. 1991;325(16):1123–1126.
  • Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg. 1993;76:182–191.
  • Hassan AHS, Ableitner A, Stein C, et al. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience. 1993;55:185–195.
  • Antonijevic I, Mousa SA, Schäfer M, et al. Perineurial defect and peripheral opioid analgesia in inflammation. J Neurosci. 1995;15(1):165–172.
  • Zöllner C, Shaqura MA, Bopaiah CP, et al. Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol. 2003;64(2):202–210.
  • Spahn V, Del Vecchio G, Labuz D, et al. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science (80- ). 2017;355(6328):966–969.
  • Spahn V, Del Vecchio G, Rodriguez-Gaztelumendi A, et al. Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist. Sci Rep. 2018;8:8965.
  • Celik MO, Labuz D, Henning K, et al. Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides. Brain Behav Immun. 2016;57:227–242.
  • Stein C, Pflüger M, Yassouridis A, et al. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest. 1996;98:793–799.
  • Mousa SA, Straub RH, Schäfer M, et al. Beta-endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):871–879.
  • Likar R, Mousa SA, Philippitsch G, et al. Increased numbers of opioid expressing inflammatory cells do not affect intra-articular morphine analgesia. Br J Anaesth. 2004;93(3):375–380.
  • Zöllner C, Mousa SA, Fischer O, et al. Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest. 2008;118(3):1065–1073.
  • Jagla CA, Martus P, Stein C. Peripheral opioid receptor blockade increases postoperative morphine demands - a randomized, double-blind, placebo-controlled trial. Pain. 2014;155:2056–2062.
  • Collett BJ. Opioid tolerance: the clinical perspective. Br J Anaesth. 1998;81(1):58–68.
  • Rozen D, Grass GW. Perioperative and intraoperative pain and anesthetic care of the chronic pain and cancer pain patient receiving chronic opioid therapy. Pain Pract. 2005;5(1):18–32.
  • Hill R, Disney A, Conibear A, et al. The novel mu-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception. Br J Pharmacol. 2018;175(13):2653–2661.
  • Galer BS, Lee D, Ma T, et al. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain. 2005;115(3):284–295.
  • Schneider JP, Kirsh KL. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. J Opioid Manag. 2010;6(6):385–395.
  • Collin E, Poulain P, Gauvain-Piquard A, et al. Is disease progression the major factor in morphine ‘tolerance’ in cancer pain treatment? Pain. 1993;55(3):319–326.
  • Smith SM, Dart RC, Katz NP, et al. Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. Pain. 2013;154(11):2287–2296.
  • Compton P, Miotto K, Elashoff D. Precipitated opioid withdrawal across acute physical dependence induction methods. Pharmacol Biochem Behav. 2004;77(2):263–268.
  • Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4):569–576.
  • Schuchat A, Houry D, Guy GP Jr. New data on opioid use and prescribing in the United States. JAMA. 2017;318(5):425–426.
  • Psaty BM, Merrill JO. Addressing the opioid epidemic - opportunities in the postmarketing setting. N Engl J Med. 2017;376(16):1502–1504.
  • Szigethy E, Knisely M, Drossman D. Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nat Rev Gastroenterol Hepatol. 2018;15(3):168–180.
  • Haffajee RL, Mello MM. Drug companies’ liability for the opioid epidemic. N Engl J Med. 2017;377(24):2301–2305.
  • Fishbain DA, Cole B, Lewis JE, et al. Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med. 2009;10(5):829–839.
  • Comelon M, Raeder J, Stubhaug A, et al. Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia. Br J Anaesth. 2016;116(4):524–530.
  • Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth. 2014;112(6):991–1004.
  • Angst MS. Intraoperative use of remifentanil for TIVA: postoperative pain, acute tolerance, and opioid-induced hyperalgesia. J Cardiothorac Vasc Anesth. 2015;29(Suppl 1):S16–22.
  • Eriksen J, Sjogren P, Bruera E, et al. Critical issues on opioids in chronic non-cancer pain: an epidemiological study. Pain. 2006;125(1–2):172–179.
  • Reinecke H, Weber C, Lange K, et al. Analgesic efficacy of opioids in chronic pain: recent meta-analyses. Br J Pharmacol. 2015;172(2):324–333.
  • Stein C. Opioid treatment of chronic nonmalignant pain. Anesth Analg. 1997;84(4):912–914.
  • Mura E, Govoni S, Racchi M, et al. Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside? J Pain Res. 2013;6:331–353.
  • Walter C, Doehring A, Oertel BG, et al. Mu-opioid receptor gene variant OPRM1 118 A>G: a summary of its molecular and clinical consequences for pain. Pharmacogenomics. 2013;14(15):1915–1925.
  • Matic M, De Wildt SN, Tibboel D, et al. Analgesia and opioids: a pharmacogenetics shortlist for implementation in clinical practice. Clin Chem. 2017;63(7):1204–1213.
  • Hauser AS, Chavali S, Masuho I, et al. Pharmacogenomics of GPCR drug targets. Cell. 2018;172(1–2):41–54 e19.
  • Busch-Dienstfertig M, Roth CA, Stein C. Functional characteristics of the naked mole rat mu-opioid receptor. PloS One. 2013;8(11):e79121.
  • Chan HCS, McCarthy D, Li J, et al. Designing safer analgesics via mu-opioid receptor pathways. Trends Pharmacol Sci. 2017;38(11):1016–1037.
  • Vardy E, Sassano MF, Rennekamp AJ, et al. Single amino acid variation underlies species-specific sensitivity to amphibian skin-derived opioid-like peptides. Chem Biol. 2015;22(6):764–775.
  • Fidecka S, Malec D, Langwinski R. Central action of narcotic analgesics. II. Locomotor activity and narcotic analgesics. Pol J Pharmacol Pharm. 1978;30(1):5–16.
  • Noble F, Cox BM. Differences among mouse strains in the regulation by mu, delta 1 and delta 2 opioid receptors of striatal adenylyl cyclases activated by dopamine D1 or adenosine A2a receptors. Brain Res. 1996;716(1–2):107–117.
  • Noble F, Cox BM. Differential regulation of D1 dopamine receptor- and of A2a adenosine receptor-stimulated adenylyl cyclase by mu-, delta 1-, and delta 2-opioid agonists in rat caudate putamen. J Neurochem. 1995;65(1):125–133.
  • Huang P, Chen C, Liu-Chen LY. Detection of mu opioid receptor (MOPR) and its glycosylation in rat and mouse brains by western blot with anti-muC, an affinity-purified polyclonal anti-MOPR antibody. Methods Mol Biol. 2015;1230:141–154.
  • Sirohi S, Aldrich JV, Walker BM. Species differences in the effects of the kappa-opioid receptor antagonist zyklophin. Alcohol. 2016;51:43–49.
  • Kruegel AC, Gassaway MM, Kapoor A, et al. Synthetic and receptor signaling explorations of the mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulators. J Am Chem Soc. 2016;138(21):6754–6764.
  • Rowan MP, Szteyn K, Doyle AP, et al. Beta-arrestin-2-biased agonism of delta opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) in primary sensory neurons. Mol Pain. 2014;10:50.
  • Corder G, Tawfik VL, Wang D, et al. Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med. 2017;23(2):164–173.
  • Albert-Vartanian A, Boyd MR, Hall AL, et al. Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential? J Clin Pharm Ther. 2016;41(4):371–382.
  • Becker WC, Fiellin DA. Abuse-deterrent opioid formulations - putting the potential benefits into perspective. N Engl J Med. 2017;376(22):2103–2105.
  • Yekkirala AS, Roberson DP, Bean BP, et al. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov. 2017;16(8):545–564.
  • Raffa RB, Taylor R Jr., Pergolizzi JV Jr. Sequestered naltrexone in sustained release morphine or oxycodone - a way to inhibit illicit use? Expert Op Drug Safety. 2014;13(2):181–190.
  • Bonnard E, Poras H, Nadal X, et al. Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain. Pharmacol Res Perspect. 2015;3(2):e00116.
  • Basso L, Boue J, Auge C, et al. Mobilization of CD4+ T lymphocytes in inflamed mucosa reduces pain in colitis mice: toward a vaccinal strategy to alleviate inflammatory visceral pain. Pain. 2018 Feb;159(2):331–341.
  • Schmid CL, Kennedy NM, Ross NC, et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell. 2017;171(5):1165–75 e13.
  • Montandon G, Ren J, Victoria NC, et al. G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids. Anesthesiology. 2016;124(3):641–650.
  • Soergel DG, Subach RA, Sadler B, et al. First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol. 2014;54(3):351–357.
  • Charfi I, Audet N, Bagheri Tudashki H, et al. Identifying ligand-specific signalling within biased responses: focus on delta opioid receptor ligands. Br J Pharmacol. 2015;172(2):435–448.
  • Altarifi AA, David B, Muchhala KH, et al. Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents. J Psychopharmacol. 2017;31(6):730–739.
  • Viscusi ER, Webster L, Kuss M, et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain. 2016;157(1):264–272.
  • Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–779.
  • Valverde A, Gunkel CI. Pain management in horses and farm animals. J Vet Emerg Crit Care. 2005;15(4):295–307.
  • Wei J, Lei GH, Gao SG, et al. Single-dose intra-articular bupivacaine versus morphine after arthroscopic knee surgery: a meta-analysis of randomized-controlled studies. Clin J Pain. 2014;30(7):630–638.
  • Machelska H, Schroff M, Oswald D, et al. Peripheral non-viral MIDGE vector-driven delivery of beta-endorphin in inflammatory pain. Mol Pain. 2009;5:72.
  • Raja SN. Modulating pain in the periphery: gene-based therapies to enhance peripheral opioid analgesia: bonica lecture, ASRA 2010. Reg Anesth Pain Med. 2012;37(2):210–214.
  • Binder W, Machelska H, Mousa S, et al. Analgesic and antiinflammatory effects of two novel kappa-opioid peptides. Anesthesiology. 2001;94(6):1034–1044.
  • Machelska H, Pflüger M, Weber W, et al. Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans. J Pharmacol Exp Ther. 1999;290(1):354–361.
  • Dahan A, Van Dorp E, Smith T, et al. Morphine-6-glucuronide (M6G) for postoperative pain relief. Eur J Pain. 2008;12(4):403–411.
  • Gonzalez-Rodriguez S, Quadir MA, Gupta S, et al. Polyglycerol-opioid conjugate produces analgesia devoid of side effects. Elife. 2017;6:e27081.
  • Del Vecchio G, Spahn V, Stein C. Novel opioid analgesics and side effects. ACS Chem Neurosci. 2017;8(8):1638–1640.
  • Rodriguez-Gaztelumendi A, Spahn V, Labuz D, et al. Analgesic effects of a novel pH-dependent mu-opioid receptor agonist in models of neuropathic and abdominal pain. Pain. 2018. In press.
  • Li JG, Chen C, Yin J, et al. ASP147 in the third transmembrane helix of the rat mu opioid receptor forms ion-pairing with morphine and naltrexone. Life Sci. 1999;65(2):175–185.
  • Dosen-Micovic L, Ivanovic M, Micovic V. Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor. Bioorg Med Chem. 2006;14(9):2887–2895.
  • Mogil JS, Davis KD, Derbyshire SW. The necessity of animal models in pain research. Pain. 2010;151(1):12–17.
  • Davis KD, Flor H, Greely HT, et al. Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations. Nat Rev Neurol. 2017;13(10):624–638.
  • Berge OG. Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol. 2011;164(4):1195–1206.
  • Wieschowski S, Chin WWL, Federico C, et al. Preclinical efficacy studies in investigator brochures: do they enable risk-benefit assessment? PLoS Biol. 2018;16(4):e2004879.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.