Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.


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Literature Cited

  1. Baron R, Hans G, Dickenson AH. 1.  2013. Peripheral input and its importance for central sensitization. Ann. Neurol. 74:630–36 [Google Scholar]
  2. Basbaum AI, Bautista DM, Scherrer G, Julius D. 2.  2009. Cellular and molecular mechanisms of pain. Cell 139:267–84 [Google Scholar]
  3. Stein C, Hassan AH, Przewlocki R. 3.  et al. 1990. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. PNAS 87:5935–39 [Google Scholar]
  4. Stein C, Machelska H. 4.  2011. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol. Rev. 63:860–81 [Google Scholar]
  5. Rittner HL, Brack A, Stein C. 5.  2008. Pain and the immune system. Br. J. Anaesthesia 101:40–44 [Google Scholar]
  6. Herz A, Millan MJ, Stein C. 6.  1989. Arthritic inflammation in rats as a model of chronic pain: role of opioid systems. NIDA Res. Monogr. 95:110–15 [Google Scholar]
  7. Cheng HY, Pitcher GM, Laviolette SR. 7.  et al. 2002. DREAM is a critical transcriptional repressor for pain modulation. Cell 108:31–43 [Google Scholar]
  8. Stein C. 8.  2013. Opioids, sensory systems and chronic pain. Eur. J. Pharmacol. 716:179–87 [Google Scholar]
  9. Zöllner C, Stein C. 9.  2007. Opioids. Handb. Exp. Pharmacol. 177:31–63 [Google Scholar]
  10. Cox BM. 10.  2013. Recent developments in the study of opioid receptors. Mol. Pharmacol. 83:723–28 [Google Scholar]
  11. Law PY, Reggio PH, Loh HH. 11.  2013. Opioid receptors: toward separation of analgesic from undesirable effects. Trends Biochem. Sci. 38:275–82 [Google Scholar]
  12. Katritch V, Cherezov V, Stevens RC. 12.  2013. Structure-function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53:531–56 [Google Scholar]
  13. Schmidt Y, Gaveriaux-Ruff C, Machelska H. 13.  2013. mu-Opioid receptor antibody reveals tissue-dependent specific staining and increased neuronal mu-receptor immunoreactivity at the injured nerve trunk in mice. PLoS ONE 8e79099
  14. Wang HB, Zhao B, Zhong YQ. 14.  et al. 2010. Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons. PNAS 107:13117–22 [Google Scholar]
  15. Bradbury A, Pluckthun A. 15.  2015. Reproducibility: standardize antibodies used in research. Nature 518:27–29 [Google Scholar]
  16. Tedford HW, Zamponi GW. 16.  2006. Direct G protein modulation of Cav2 calcium channels. Pharmacol. Rev. 58:837–62 [Google Scholar]
  17. Luscher C, Slesinger PA. 17.  2010. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat. Rev. Neurosci. 11:301–15 [Google Scholar]
  18. Nockemann D, Rouault M, Labuz D. 18.  et al. 2013. The K channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol. Med. 5:1263–77 [Google Scholar]
  19. Endres-Becker J, Heppenstall PA, Mousa SA. 19.  et al. 2007. Mu-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol. Pharmacol. 71:12–18 [Google Scholar]
  20. Spahn V, Fischer O, Endres-Becker J. 20.  et al. 2013. Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner. Pain 154:598–608 [Google Scholar]
  21. Cai Q, Qiu CY, Qiu F. 21.  et al. 2014. Morphine inhibits acid-sensing ion channel currents in rat dorsal root ganglion neurons. Brain Res. 1554:12–20 [Google Scholar]
  22. Ingram SL, Williams JT. 22.  1994. Opioid inhibition of Ih via adenylyl cyclase. Neuron 13:179–86 [Google Scholar]
  23. Gold MS, Levine JD. 23.  1996. DAMGO inhibits prostaglandin E2-induced potentiation of a TTX-resistant Na+current in rat sensory neurons in vitro. Neurosci. Lett. 212:83–86 [Google Scholar]
  24. Waldhoer M, Bartlett SE, Whistler JL. 24.  2004. Opioid receptors. Annu. Rev. Biochem. 73:953–90 [Google Scholar]
  25. Williams JT, Ingram SL, Henderson G. 25.  et al. 2013. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 65:223–54 [Google Scholar]
  26. Pradhan AA, Smith ML, Kieffer BL, Evans CJ. 26.  2012. Ligand-directed signalling within the opioid receptor family. Br. J. Pharmacol. 167:960–69 [Google Scholar]
  27. McPherson J, Rivero G, Baptist M. 27.  et al. 2010. Mu-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol. Pharmacol. 78:756–66 [Google Scholar]
  28. Walwyn W, Evans CJ, Hales TG. 28.  2007. Beta-arrestin2 and c-Src regulate the constitutive activity and recycling of mu opioid receptors in dorsal root ganglion neurons. J. Neurosci. 27:5092–104 [Google Scholar]
  29. Mohr K, Schmitz J, Schrage R. 29.  et al. 2013. Molecular alliance—from orthosteric and allosteric ligands to dualsteric/bitopic agonists at G protein coupled receptors. Angew. Chem. Int. Ed. Engl. 52:508–16 [Google Scholar]
  30. Walwyn W, John S, Maga M. 30.  et al. 2009. Delta receptors are required for full inhibitory coupling of mu-receptors to voltage-dependent Ca2+ channels in dorsal root ganglion neurons. Mol. Pharmacol. 76:134–43 [Google Scholar]
  31. Berg KA, Rowan MP, Gupta A. 31.  et al. 2012. Allosteric interactions between delta and kappa opioid receptors in peripheral sensory neurons. Mol. Pharmacol. 81:264–72 [Google Scholar]
  32. Stein C, Clark JD, Oh U. 32.  et al. 2009. Peripheral mechanisms of pain and analgesia. Brain Res. Rev. 60:90–113 [Google Scholar]
  33. Tabas I, Glass CK. 33.  2013. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339:166–72 [Google Scholar]
  34. Stein C. 34.  1993. Peripheral mechanisms of opioid analgesia. Anesth. Analg. 76:182–91 [Google Scholar]
  35. Stein C. 35.  1995. The control of pain in peripheral tissue by opioids. N. Engl. J. Med. 332:1685–90 [Google Scholar]
  36. Busch-Dienstfertig M, Stein C. 36.  2010. Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain—basic and therapeutic aspects. Brain Behav. Immun. 24:683–94 [Google Scholar]
  37. Hassan AHS, Ableitner A, Stein C, Herz A. 37.  1993. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 55:185–95 [Google Scholar]
  38. Zöllner C, Shaqura MA, Bopaiah CP. 38.  et al. 2003. Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol. Pharmacol. 64:202–10 [Google Scholar]
  39. Mousa SA, Cheppudira BP, Shaqura M. 39.  et al. 2007. Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain. Brain 130:502–13 [Google Scholar]
  40. Jeanjean AP, Moussaoui SM, Maloteaux JM, Laduron PM. 40.  1995. Interleukin-1 beta induces long-term increase of axonally transported opiate receptors and substance P. Neuroscience 68:151–57 [Google Scholar]
  41. Zhou L, Zhang Q, Stein C, Schäfer M. 41.  1998. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J. Pharmacol. Exp. Ther. 286:1000–6 [Google Scholar]
  42. Antonijevic I, Mousa SA, Schäfer M, Stein C. 42.  1995. Perineurial defect and peripheral opioid analgesia in inflammation. J. Neurosci. 15:165–72 [Google Scholar]
  43. Rittner HL, Amasheh S, Moshourab R. 43.  et al. 2012. Modulation of tight junction proteins in the perineurium to facilitate peripheral opioid analgesia. Anesthesiology 116:1323–34 [Google Scholar]
  44. Patwardhan AM, Berg KA, Akopain AN. 44.  et al. 2005. Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors. J. Neurosci. 25:8825–32 [Google Scholar]
  45. Berg KA, Patwardhan AM, Sanchez TA. 45.  et al. 2007. Rapid modulation of mu-opioid receptor signaling in primary sensory neurons. J. Pharmacol. Exp. Ther. 321:839–47 [Google Scholar]
  46. Bao L, Jin SX, Zhang C. 46.  et al. 2003. Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 37:121–33 [Google Scholar]
  47. Gendron L, Lucido AL, Mennicken F. 47.  et al. 2006. Morphine and pain-related stimuli enhance cell surface availability of somatic delta-opioid receptors in rat dorsal root ganglia. J. Neurosci. 26:953–62 [Google Scholar]
  48. Zhang N, Rogers TJ, Caterina M, Oppenheim JJ. 48.  2004. Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons. J. Immunol. 173:594–99 [Google Scholar]
  49. Rowan MP, Ruparel NB, Patwardhan AM. 49.  et al. 2009. Peripheral delta opioid receptors require priming for functional competence in vivo. Eur. J. Pharmacol. 602:283–87 [Google Scholar]
  50. Cayla C, Labuz D, Machelska H. 50.  et al. 2012. Impaired nociception and peripheral opioid antinociception in mice lacking both kinin B1 and B2 receptors. Anesthesiology 116:448–57 [Google Scholar]
  51. Rasenick MM, Childers SR. 51.  1989. Modification of Gs-stimulated adenylate cyclase in brain membranes by low pH pretreatment: correlation with altered guanine nucleotide exchange. J. Neurochem. 53:219–25 [Google Scholar]
  52. Selley DE, Breivogel CS, Childers SR. 52.  1993. Modification of G protein-coupled functions by low-pH pretreatment of membranes from NG108-15 cells: increase in opioid agonist efficacy by decreased inactivation of G proteins. Mol. Pharmacol. 44:731–41 [Google Scholar]
  53. Vetter I, Cheng W, Peiris M. 53.  et al. 2008. Rapid, opioid-sensitive mechanisms involved in transient receptor potential vanilloid 1 sensitization. J. Biol. Chem. 283:19540–50 [Google Scholar]
  54. Andreev N, Urban L, Dray A. 54.  1994. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 58:793–98 [Google Scholar]
  55. Wenk HN, Brederson JD, Honda CN. 55.  2006. Morphine directly inhibits nociceptors in inflamed skin. J. Neurophysiol. 95:2083–97 [Google Scholar]
  56. Moshourab R, Stein C. 56.  2012. Fentanyl decreases discharges of C and A nociceptors to suprathreshold mechanical stimulation in chronic inflammation. J. Neurophysiol. 108:2827–36 [Google Scholar]
  57. Schmidt Y, Labuz D, Heppenstall PA, Machelska H. 57.  2012. Cutaneous nociceptors lack sensitisation, but reveal mu-opioid receptor-mediated reduction in excitability to mechanical stimulation in neuropathy. Mol. Pain 8:81 [Google Scholar]
  58. Machelska H. 58.  2011. Dual peripheral actions of immune cells in neuropathic pain. Arch. Immunol. Ther. Exp. 59:11–24 [Google Scholar]
  59. Hall KE, Liu J, Sima AA, Wiley JW. 59.  2001. Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy. J. Neurophysiol. 86:760–70 [Google Scholar]
  60. Mousa SA, Shaqura M, Khalefa BI. 60.  et al. 2013. Rab7 silencing prevents mu-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy. Diabetes 62:1308–19 [Google Scholar]
  61. Labuz D, Machelska H. 61.  2013. Stronger antinociceptive efficacy of opioids at the injured nerve trunk than at its peripheral terminals in neuropathic pain. J. Pharmacol. Exp. Ther. 346:535–44 [Google Scholar]
  62. Wei LN. 62.  2011. The RNA superhighway: axonal RNA trafficking of kappa opioid receptor mRNA for neurite growth. Integr. Biol. 3:10–16 [Google Scholar]
  63. Stein C, Küchler S. 63.  2012. Non-analgesic effects of opioids: peripheral opioid effects on inflammation and wound healing. Curr. Pharm. Des. 18:6053–69 [Google Scholar]
  64. Picard PR, Tramer MR, McQuay HJ, Moore RA. 64.  1997. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 72:309–18 [Google Scholar]
  65. Stein C, Pflüger M, Yassouridis A. 65.  et al. 1996. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J. Clin. Invest. 98:793–99 [Google Scholar]
  66. Likar R, Mousa SA, Philippitsch G. 66.  et al. 2004. Increased numbers of opioid expressing inflammatory cells do not affect intra-articular morphine analgesia. Br. J. Anaesth. 93:375–80 [Google Scholar]
  67. Zöllner C, Mousa SA, Fischer O. 67.  et al. 2008. Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J. Clin. Invest. 118:1065–73 [Google Scholar]
  68. Roques BP, Fournie-Zaluski MC, Wurm M. 68.  2012. Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nat. Rev. Drug Discov. 11:292–310 [Google Scholar]
  69. Schreiter A, Gore C, Labuz D. 69.  et al. 2012. Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J. 26:5161–71 [Google Scholar]
  70. Whiteside GT, Adedoyin A, Leventhal L. 70.  2008. Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology 54:767–75 [Google Scholar]
  71. Woolf CJ. 71.  2010. Overcoming obstacles to developing new analgesics. Nat. Med. 16:1241–47 [Google Scholar]
  72. Galer BS, Lee D, Ma T. 72.  et al. 2005. 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 115:284–95 [Google Scholar]
  73. Berge OG. 73.  2011. Predictive validity of behavioural animal models for chronic pain. Br. J. Pharmacol. 164:1195–206 [Google Scholar]
  74. Mogil JS, Davis KD, Derbyshire SW. 74.  2010. The necessity of animal models in pain research. Pain 151:12–17 [Google Scholar]
  75. Lee MC, Wanigasekera V, Tracey I. 75.  2012. Imaging opioid analgesia in the human brain. Trends Anaesth. Crit. Care 2:244–48 [Google Scholar]
  76. Davis KD, Racine E, Collett B. 76.  2012. Neuroethical issues related to the use of brain imaging: Can we and should we use brain imaging as a biomarker to diagnose chronic pain?. Pain 153:1555–59 [Google Scholar]
  77. Roberts NJ, Vogelstein JT, Parmigiani G. 77.  et al. 2012. The predictive capacity of personal genome sequencing. Sci. Transl. Med. 4:133ra58 [Google Scholar]
  78. Stein C. 78.  2013. Towards safer and more effective analgesia. Vet. J. 196:6–7 [Google Scholar]
  79. Mousa SA, Shakibaei M, Sitte N. 79.  et al. 2004. Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology 145:1331–41 [Google Scholar]
  80. Sitte N, Busch M, Mousa SA. 80.  et al. 2007. Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and beta-endorphin during painful inflammation in vivo. J. Neuroimmunol. 183:133–45 [Google Scholar]
  81. Busch-Dienstfertig M, Labuz D, Wolfram T. 81.  et al. 2012. JAK-STAT1/3-induced expression of signal sequence-encoding proopiomelanocortin mRNA in lymphocytes reduces inflammatory pain in rats. Mol. Pain 8:83 [Google Scholar]
  82. Rittner HL, Hackel D, Voigt P. 82.  et al. 2009. Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathog. 5:e1000362 [Google Scholar]
  83. Stein C, Hassan AHS, Lehrberger K. 83.  et al. 1993. Local analgesic effect of endogenous opioid peptides. Lancet 342:321–24 [Google Scholar]
  84. Mousa SA, Straub RH, Schäfer M, Stein C. 84.  2007. Beta-endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis. Ann. Rheum. Dis. 66:871–79 [Google Scholar]
  85. Likar R, Mousa SA, Steinkellner H. 85.  et al. 2007. Involvement of intraarticular corticotropin-releasing hormone in postoperative pain modulation. Clin. J. Pain 23:136–42 [Google Scholar]
  86. Sharp BM. 86.  2006. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behavior Immun. 20:9–14 [Google Scholar]
  87. Brack A, Rittner HL, Stein C. 87.  2011. Immunosuppressive effects of opioids—clinical relevance. J. Neuroimmune Pharmacol. 6:490–502 [Google Scholar]
  88. Ekholm O, Kurita GP, Hojsted J. 88.  et al. 2014. Chronic pain, opioid prescriptions, and mortality in Denmark: a population-based cohort study. Pain 155:2486–90 [Google Scholar]
  89. Lin JG, Chen WL. 89.  2008. Acupuncture analgesia: a review of its mechanisms of actions. Am. J. Chin. Med. 36:635–45 [Google Scholar]
  90. Kim W, Kim SK, Min BI. 90.  2013. Mechanisms of electroacupuncture-induced analgesia on neuropathic pain in animal model. Evid. Based Complement. Alternat. Med. 2013:436913 [Google Scholar]
  91. Schumacher MA, Basbaum AI, Way WL. 91.  2009. Opioid analgesics and antagonists. Basic and Clinical Pharmacology BG Katzung, SB Masters, AJ Trevor 531–52 New York: McGraw-Hill Med. [Google Scholar]
  92. Kalso E, Smith L, McQuay HJ, Moore RA. 92.  2002. No pain, no gain: clinical excellence and scientific rigour—lessons learned from IA morphine. Pain 98:269–75 [Google Scholar]
  93. Graham T, Grocott P, Probst S. 93.  et al. 2013. How are topical opioids used to manage painful cutaneous lesions in palliative care? A critical review. Pain 154:1920–28 [Google Scholar]
  94. Zeng C, Gao SG, Cheng L. 94.  et al. 2013. Single-dose intra-articular morphine after arthroscopic knee surgery: a meta-analysis of randomized placebo-controlled studies. Arthroscopy 29:1450–58 [Google Scholar]
  95. Mesgarpour B, Griebler U, Glechner A. 95.  et al. 2014. Extended-release opioids in the management of cancer pain: a systematic review of efficacy and safety. Eur. J. Pain 18:605–16 [Google Scholar]
  96. Drewes AM, Jensen RD, Nielsen LM. 96.  et al. 2013. Differences between opioids: pharmacological, experimental, clinical and economical perspectives. Br. J. Clin. Pharmacol. 75:60–78 [Google Scholar]
  97. Jagla CA, Martus P, Stein C. 97.  2014. Peripheral opioid receptor blockade increases postoperative morphine demands—a randomized, double-blind, placebo-controlled trial. Pain 155:2056–62 [Google Scholar]
  98. Stein C, Comisel K, Haimerl E. 98.  et al. 1991. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N. Engl. J. Med. 325:1123–26 [Google Scholar]
  99. Valverde A, Gunkel CI. 99.  2005. Pain management in horses and farm animals. J. Vet. Emerg. Crit. Care 15:295–307 [Google Scholar]
  100. Wei J, Lei GH, Gao SG. 100.  et al. 2014. Single-dose intra-articular bupivacaine versus morphine after arthroscopic knee surgery: a meta-analysis of randomized-controlled studies. Clin. J. Pain 30:630–38 [Google Scholar]
  101. Kivell B, Prisinzano TE. 101.  2010. Kappa opioids and the modulation of pain. Psychopharmacology 210:109–19 [Google Scholar]
  102. Stein C, Küchler S. 102.  2013. Targeting inflammation and wound healing by opioids. Trends Pharmacol. Sci. 34:303–12 [Google Scholar]
  103. Dahan A, van Dorp E, Smith T, Yassen A. 103.  2008. Morphine-6-glucuronide (M6G) for postoperative pain relief. Eur. J. Pain 12:403–11 [Google Scholar]
  104. Vadivelu N, Mitra S, Hines RL. 104.  2011. Peripheral opioid receptor agonists for analgesia: a comprehensive review. J. Opioid Manag. 7:55–68 [Google Scholar]
  105. 105. US Securities and Exchange Commission 2014. Cara Therapeutics, Inc., 2013 Annual Report. http://secfilings.nasdaq.com/edgar_conv_html%2f2014%2f03%2f28%2f0001193125-14-119005.html#FIS_BUSINESS
  106. Machelska H, Schroff M, Oswald D. 106.  et al. 2009. Peripheral non-viral MIDGE vector-driven delivery of beta-endorphin in inflammatory pain. Mol. Pain 5:72 [Google Scholar]
  107. Raja SN. 107.  2012. Modulating pain in the periphery: gene-based therapies to enhance peripheral opioid analgesia: Bonica lecture, ASRA 2010. Reg. Anesth. Pain Med. 37:210–14 [Google Scholar]
  108. 108. Coxib and Traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. 2013. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382:769–79 [Google Scholar]
  109. Charfi I, Audet N, Bagheri Tudashki H, Pineyro G. 109.  2015. Identifying ligand-specific signalling within biased responses: focus on delta opioid receptor ligands. Br. J. Pharmacol. 172:435–48 [Google Scholar]
  110. White KL, Scopton AP, Rives ML. 110.  et al. 2014. Identification of novel functionally selective kappa-opioid receptor scaffolds. Mol. Pharmacol. 85:83–90 [Google Scholar]
  111. DeWire SM, Yamashita DS, Rominger DH. 111.  et al. 2013. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344:708–17 [Google Scholar]
  112. Soergel DG, Subach RA, Burnham N. 112.  et al. 2014. Biased agonism of the mu-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain 155:1829–35 [Google Scholar]
  113. van Rijn RM, Defriel JN, Whistler JL. 113.  2013. Pharmacological traits of delta opioid receptors: pitfalls or opportunities?. Psychopharmacology 228:1–18 [Google Scholar]
  114. Raffa RB, Taylor R Jr, Pergolizzi JV Jr. 114.  2014. Sequestered naltrexone in sustained release morphine or oxycodone—a way to inhibit illicit use?. Expert Opin. Drug Saf. 13:181–90 [Google Scholar]
  115. Alexander L, Mannion RO, Weingarten B. 115.  et al. 2014. Development and impact of prescription opioid abuse deterrent formulation technologies. Drug Alcohol. Depend. 138:1–6 [Google Scholar]
  116. Kruger R, Meissner W, Zimmer A. 116.  2014. [Misuse of opioid analgesics. An internet analysis]. Schmerz 28:473–82 In German [Google Scholar]
  117. Passik SD. 117.  2014. Tamper-resistant opioid formulations in the treatment of acute pain. Adv. Ther. 31:264–75 [Google Scholar]
  118. Holzer P. 118.  2009. Opioid receptors in the gastrointestinal tract. Regul. Pept. 155:11–17 [Google Scholar]
  119. Diego L, Atayee R, Helmons P. 119.  et al. 2011. Novel opioid antagonists for opioid-induced bowel dysfunction. Expert Opin. Invest. Drugs 20:1047–56 [Google Scholar]
  120. Mura E, Govoni S, Racchi M. 120.  et al. 2013. Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?. J. Pain Res. 6:331–53 [Google Scholar]
  121. Walter C, Doehring A, Oertel BG, Lötsch J. 121.  2013. Mu-opioid receptor gene variant OPRM1 118 A>G: a summary of its molecular and clinical consequences for pain. Pharmacogenomics 14:1915–25 [Google Scholar]
  122. Busch-Dienstfertig M, Roth CA, Stein C. 122.  2013. Functional characteristics of the naked mole rat mu-opioid receptor. PLoS ONE 8:e79121 [Google Scholar]
  123. Bruehl S, Apkarian AV, Ballantyne JC. 123.  et al. 2013. Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges. J. Pain 14:103–13 [Google Scholar]
  124. Collett BJ. 124.  1998. Opioid tolerance: the clinical perspective. Br. J. Anaesth. 81:58–68 [Google Scholar]
  125. McNicol E. 125.  2008. Opioid side effects and their treatment in patients with chronic cancer and noncancer pain. J. Pain Pall. Care Pharmacother. 22:270–81 [Google Scholar]
  126. Schneider JP, Kirsh KL. 126.  2010. 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. 6:385–95 [Google Scholar]
  127. Fishbain DA, Cole B, Lewis JE. 127.  et al. 2009. Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med. 10:829–39 [Google Scholar]
  128. Reinecke H, Weber C, Lange K. 128.  et al. 2015. Analgesic efficacy of opioids in chronic pain: recent meta-analyses. Br. J. Pharmacol. 172:324–33 [Google Scholar]
  129. Paulozzi LJ. 129.  2012. Prescription drug overdoses: a review. J. Saf. Res. 43:283–89 [Google Scholar]
  130. Vowles KE, McEntee ML, Julnes PS. 130.  et al. 2015. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain 156:569–76 [Google Scholar]
  131. Chou R, Cruciani RA, Fiellin DA. 131.  et al. 2014. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J. Pain 15:321–37 [Google Scholar]
  132. Eriksen J, Sjogren P, Bruera E. 132.  et al. 2006. Critical issues on opioids in chronic non-cancer pain: an epidemiological study. Pain 125:172–79 [Google Scholar]
  133. Noble M, Treadwell JR, Tregear SJ. 133.  et al. 2010. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst. Rev. 1:CD006605 [Google Scholar]
  134. Gustavsson A, Bjorkman J, Ljungcrantz C. 134.  et al. 2012. Pharmaceutical treatment patterns for patients with a diagnosis related to chronic pain initiating a slow-release strong opioid treatment in Sweden. Pain 153:2325–31 [Google Scholar]
  135. Schiltenwolf M, Akbar M, Hug A. 135.  et al. 2014. Evidence of specific cognitive deficits in patients with chronic low back pain under long-term substitution treatment of opioids. Pain Phys. 17:9–20 [Google Scholar]
  136. Rhodin A, Stridsberg M, Gordh T. 136.  2010. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin. J. Pain 26:374–80 [Google Scholar]
  137. Stein C. 137.  1997. Opioid treatment of chronic nonmalignant pain. Anesth. Analg. 84:912–14 [Google Scholar]
  138. Fordyce WE. 138.  1991. Opioids and treatment targets. Am. Pain Soc. Bull. 1:1–4 [Google Scholar]
  139. Rubelt MS, Amasheh S, Grobosch T, Stein C. 139.  2012. Liquid chromatography-tandem mass spectrometry for analysis of intestinal permeability of loperamide in physiological buffer. PLoS ONE 7:e48502 [Google Scholar]

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