Advertisement

Der Anaesthesist

, Volume 59, Issue 11, pp 983–993 | Cite as

Induzieren Opioide Hyperalgesie?

  • C. ZöllnerEmail author
Leitthema

Zusammenfassung

Opioide stellen bis heute die potentesten Medikamente zur Therapie akuter und chronischer Schmerzen dar. Die paradoxe Beobachtung einer Hyperalgesie unter Opioidtherapie wurde in den zurückliegenden Jahren intensiv diskutiert. Diese sog. opioidinduzierte Hyperalgesie (OIH) ist als eine Sensitivierung nozizeptiver Signaltransduktionswege durch Opioide definiert. Sie resultiert in einer Abnahme der Schmerzschwelle für schmerzhafte Stimuli und zeigt sich klinisch durch einen gesteigerten Schmerzmittelbedarf oder eine gesteigerte Schmerzempfindlichkeit des Patienten. Über die genauen molekularen Mechanismen gibt es eine Vielzahl unterschiedlicher Hypothesen. Auch die klinische Relevanz der OIH wird unterschiedlich bewertet. Einzelne Berichte deuten bereits nach akuter, einmaliger intraoperativer Gabe eines Opioids auf einen vermehrten postoperativen Verbrauch von Schmerzmitteln hin. Auch bei chronischen Erkrankungen und Opioiddauertherapie wird in Einzelfällen über eine paradoxe Zunahme von Schmerzen berichtet, die nicht auf eine Progression der Grundkrankheit zurückzuführen ist. Im vorliegenden Beitrag werden die molekularen Mechanismen der Opioidtoleranz, des Opioidentzugs und andere Applikationsformen von Opioiden, die zur Hyperalgesie beim Patienten führen können, vorgestellt. Diese Arbeit soll einen Überblick geben, unter welchen Bedingungen die Applikation von Opioiden zu einer Hyperalgesie beim Patienten führen kann und welche klinische Bedeutung diese Hyperalgesie für die klinische Praxis hat.

Schlüsselwörter

Opioide Schmerz Entzugssymptome Allodynie Hyperalgesie Opioidinduzierte Hyperalgesie 

Do opioids induce hyperalgesia?

Abstract

Opioids are the most potent drugs for treatment of acute and chronic pain. However, accumulating evidence suggests that opioids may paradoxically also enhance pain, often referred to as opioid-induced hyperalgesia. Opioid-induced hyperalgesia is defined as an increased sensitivity to pain or a decreased pain threshold in response to opioid therapy. Several mechanisms have been proposed to support opioid-induced hyperalgesia. However, it remains unclear whether opioid-induced hyperalgesia develops during continuous chronic application of opioids or on their withdrawal. This review provides a comprehensive summary of clinical research concerning opioid-induced hyperalgesia and the molecular mechanisms of opioid withdrawal and opioid tolerance and other potential mechanisms which might induce hyperalgesia during opioid therapy will be discussed. The status quo of our knowledge will be summarized and the clinical relevance of opioid-induced hyperalgesia will be discussed.

Keywords

Opioids Pain Withdrawal symptoms Allodynia Hyperalgesia Opioid induced hyperalgesia 

Notes

Interessenkonflikt

Es besteht kein Interessenkonflikt

Literatur

  1. 1.
    Schmitz R (1985) Friedrich Wilhelm Serturner and the discovery of morphine. Pharm Hist 27:61–74PubMedGoogle Scholar
  2. 2.
    Nestler EJ, Aghajanian GK (1997) Molecular and cellular basis of addiction. Science 278:58–63CrossRefPubMedGoogle Scholar
  3. 3.
    Bie B, Peng Y, Zhang Y, Pan ZZ (2005) cAMP-mediated mechanisms for pain sensitization during opioid withdrawal. J Neurosci 25:3824–3832CrossRefPubMedGoogle Scholar
  4. 4.
    Bie B, Pan ZZ (2003) Presynaptic mechanism for anti-analgesic and anti-hyperalgesic actions of kappa-opioid receptors. J Neurosci 23:7262–7268PubMedGoogle Scholar
  5. 5.
    Mao J, Price DD, Mayer DJ (1995) Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 62:259–274CrossRefPubMedGoogle Scholar
  6. 6.
    Mayer DJ, Mao J, Holt J, Price DD (1999) Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci U S A 96:7731–7736CrossRefPubMedGoogle Scholar
  7. 7.
    Mao J, Sung B, Ji RR, Lim G (2002) Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 22:8312–8323PubMedGoogle Scholar
  8. 8.
    Mao J, Sung B, Ji RR, Lim G (2002) Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 22:7650–7661PubMedGoogle Scholar
  9. 9.
    Celerier E, Rivat C, Jun Y et al (2000) Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 92:465–472CrossRefPubMedGoogle Scholar
  10. 10.
    Laulin JP, Larcher A, Celerier E et al (1998) Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur J Neurosci 10:782–785CrossRefPubMedGoogle Scholar
  11. 11.
    Aley KO, Green PG, Levine JD (1995) Opioid and adenosine peripheral antinociception are subject to tolerance and withdrawal. J Neurosci 15:8031–8038PubMedGoogle Scholar
  12. 12.
    Aley KO, Levine JD (1997) Dissociation of tolerance and dependence for opioid peripheral antinociception in rats. J Neurosci 17:3907–3912PubMedGoogle Scholar
  13. 13.
    Celerier E, Gonzalez JR, Maldonado R et al (2006) Opioid-induced hyperalgesia in a murine model of postoperative pain: role of nitric oxide generated from the inducible nitric oxide synthase. Anesthesiology 104:546–555CrossRefPubMedGoogle Scholar
  14. 14.
    Colpaert FC, Fregnac Y (2001) Paradoxical signal transduction in neurobiological systems. Mol Neurobiol 24:145–168CrossRefPubMedGoogle Scholar
  15. 15.
    Laulin JP, Maurette P, Corcuff JB et al (2002) The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg 94:1263–1269CrossRefPubMedGoogle Scholar
  16. 16.
    Colpaert FC, Niemegeers CJ, Janssen PA, Maroli AN (1980) The effects of prior fentanyl administration and of pain on fentanyl analgesia: tolerance to and enhancement of narcotic analgesia. J Pharmacol Exp Ther 213:418–424PubMedGoogle Scholar
  17. 17.
    Angst MS, Clark JD (2006) Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104:570–587CrossRefPubMedGoogle Scholar
  18. 18.
    Koppert W, Sittl R, Scheuber K et al (2003) Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 99:152–159CrossRefPubMedGoogle Scholar
  19. 19.
    Angst MS, Koppert W, Pahl I et al (2003) Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 106:49–57CrossRefPubMedGoogle Scholar
  20. 20.
    Hood DD, Curry R, Eisenach JC (2003) Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 97:810–815CrossRefPubMedGoogle Scholar
  21. 21.
    Compton P, Athanasos P, Elashoff D (2003) Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain 4:511–519CrossRefPubMedGoogle Scholar
  22. 22.
    Joly V, Richebe P, Guignard B et al (2005) Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 103:147–155CrossRefPubMedGoogle Scholar
  23. 23.
    Guignard B, Bossard AE, Coste C et al (2000) Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 93:409–417CrossRefPubMedGoogle Scholar
  24. 24.
    Lee LH, Irwin MG, Lui SK (2005) Intraoperative remifentanil infusion does not increase postoperative opioid consumption compared with 70% nitrous oxide. Anesthesiology 102:398–402CrossRefPubMedGoogle Scholar
  25. 25.
    Cortinez LI, Brandes V, Munoz HR et al (2001) No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 87:866–869CrossRefPubMedGoogle Scholar
  26. 26.
    Ren ZY, Shi J, Epstein DH et al (2009) Abnormal pain response in pain-sensitive opiate addicts after prolonged abstinence predicts increased drug craving. Psychopharmacology (Berl) 204:423–429Google Scholar
  27. 27.
    Hay JL, White JM, Bochner F et al (2009) Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J Pain 10:316–322CrossRefPubMedGoogle Scholar
  28. 28.
    Dyer KR, Foster DJ, White JM et al (1999) Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships. Clin Pharmacol Ther 65:685–694CrossRefPubMedGoogle Scholar
  29. 29.
    King CD, Rios GR, Assouline JA, Tephly TR (1999) Expression of UDP-glucuronosyltransferases (UGTs) 2B7 and 1A6 in the human brain and identification of 5-hydroxytryptamine as a substrate. Arch Biochem Biophys 365:156–162CrossRefPubMedGoogle Scholar
  30. 30.
    Andersen G, Christrup L, Sjogren P (2003) Relationships among morphine metabolism, pain and side effects during long-term treatment: an update. J Pain Symptom Manage 25:74–91CrossRefPubMedGoogle Scholar
  31. 31.
    Abbott FV, Palmour RM (1988) Morphine-6-glucuronide: analgesic effects and receptor binding profile in rats. Life Sci 43:1685–1695CrossRefPubMedGoogle Scholar
  32. 32.
    Lewis SS, Hutchinson MR, Rezvani N et al (2010) Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience 165:569–583CrossRefPubMedGoogle Scholar
  33. 33.
    Bartlett SE, Cramond T, Smith MT (1994) The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex. Life Sci 54:687–694CrossRefPubMedGoogle Scholar
  34. 34.
    Bartlett SE, Dodd PR, Smith MT (1994) Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites. Pharmacol Toxicol 75:73–81CrossRefPubMedGoogle Scholar
  35. 35.
    Hemstapat K, Monteith GR, Smith D, Smith MT (2003) Morphine-3-glucuronide’s neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: mechanistic studies in embryonic cultured hippocampal neurones. Anesth Analg 97:494–505CrossRefPubMedGoogle Scholar
  36. 36.
    Komatsu T, Sakurada S, Katsuyama S et al (2009) Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice. Int Rev Neurobiol 85:207–219CrossRefPubMedGoogle Scholar
  37. 37.
    Komatsu T, Sasaki M, Sanai K et al (2009) Intrathecal substance P augments morphine-induced antinociception: possible relevance in the production of substance P N-terminal fragments. Peptides 30:1689-1696CrossRefPubMedGoogle Scholar
  38. 38.
    Andersen G, Christrup LL, Sjogren P et al (2002) Changing M3G/M6G ratios and pharmacodynamics in a cancer patient during long-term morphine treatment. J Pain Symptom Manage 23:161–164CrossRefPubMedGoogle Scholar
  39. 39.
    Klepstad P, Borchgrevink PC, Dale O et al (2003) Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients. Palliat Med 17:679–687PubMedGoogle Scholar
  40. 40.
    Klepstad P, Dale O, Kaasa S et al (2003) Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand 47:725–731CrossRefPubMedGoogle Scholar
  41. 41.
    Chen XY, Zhao LM, Zhong DF (2003) A novel metabolic pathway of morphine: formation of morphine glucosides in cancer patients. Br J Clin Pharmacol 55:570–578CrossRefPubMedGoogle Scholar
  42. 42.
    Quigley C, Joel S, Patel N et al (2003) Plasma concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain. Palliat Med 17:185–190CrossRefPubMedGoogle Scholar
  43. 43.
    Sjogren P, Jonsson T, Jensen NH et al (1993) Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 55:93–97CrossRefPubMedGoogle Scholar
  44. 44.
    Rozan JP, Kahn CH, Warfield CA (1995) Epidural and intravenous opioid-induced neuroexcitation. Anesthesiology 83:860–863CrossRefPubMedGoogle Scholar
  45. 45.
    Smith MT (2000) Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 27:524–528CrossRefPubMedGoogle Scholar
  46. 46.
    Chen JJ, Dymshitz J, Vasko MR (1997) Regulation of opioid receptors in rat sensory neurons in culture. Mol Pharmacol 51:666–673PubMedGoogle Scholar
  47. 47.
    Sim LJ, Selley DE, Dworkin SI, Childers SR (1996) Effects of chronic morphine administration on mu opioid receptor-stimulated [35S] GTPgammaS autoradiography in rat brain. J Neurosci 16:2684–2692PubMedGoogle Scholar
  48. 48.
    Zhang J, Ferguson SS, Barak LS et al (1998) Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness. Proc Natl Acad Sci U S A 95:7157–7162CrossRefPubMedGoogle Scholar
  49. 49.
    Bruggemann I, Schulz S, Wiborny D, Hollt V (2000) Colocalization of the mu-opioid receptor and calcium/calmodulin-dependent kinase II in distinct pain-processing brain regions. Brain Res Mol Brain Res 85:239–250CrossRefPubMedGoogle Scholar
  50. 50.
    Bohn LM, Gainetdinov RR, Lin FT et al (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408:720–723CrossRefPubMedGoogle Scholar
  51. 51.
    Law PY, Wong YH, Loh HH (2000) Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 40:389–430CrossRefPubMedGoogle Scholar
  52. 52.
    Eisinger DA, Ammer H, Schulz R (2002) Chronic morphine treatment inhibits opioid receptor desensitization and internalization. J Neurosci 22:10192–10200PubMedGoogle Scholar
  53. 53.
    Sternini C, Spann M, Anton B et al (1996) Agonist-selective endocytosis of mu opioid receptor by neurons in vivo. Proc Natl Acad Sci U S A 93:9241–9246CrossRefPubMedGoogle Scholar
  54. 54.
    Koch T, Widera A, Bartzsch K et al (2005) Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol 67:280–287CrossRefPubMedGoogle Scholar
  55. 55.
    Stein C, Pfluger M, Yassouridis A et al (1996) No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest 98:793–799CrossRefPubMedGoogle Scholar
  56. 56.
    Zollner C, Mousa SA, Fischer O et al (2008) Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest 118:1065–1073PubMedGoogle Scholar
  57. 57.
    Mao J, Price DD, Mayer DJ (1994) Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 14:2301–2312PubMedGoogle Scholar
  58. 58.
    Vanderah TW, Gardell LR, Burgess SE et al (2000) Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 20:7074–7079PubMedGoogle Scholar
  59. 59.
    Aley KO, Levine JD (1997) Multiple receptors involved in peripheral alpha 2, mu, and A1 antinociception, tolerance, and withdrawal. J Neurosci 17:735–744PubMedGoogle Scholar
  60. 60.
    Mercadante S, Bruera E (2006) Opioid switching: a systematic and critical review. Cancer Treat Rev 32:304–315CrossRefPubMedGoogle Scholar
  61. 61.
    Mitra S, Sinatra RS (2004) Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 101:212–227CrossRefPubMedGoogle Scholar
  62. 62.
    Leon-Casasola OA de, Myers DP, Donaparthi S et al (1993) A comparison of postoperative epidural analgesia between patients with chronic cancer taking high doses of oral opioids versus opioid-naive patients. Anesth Analg 76:302–307PubMedGoogle Scholar
  63. 63.
    Stein C, Zollner C (2009) Opioids and sensory nerves. Handb Exp Pharmacol 495–518Google Scholar
  64. 64.
    Savage SR (1996) Long-term opioid therapy: assessment of consequences and risks. J Pain Symptom Manage 11:274–286CrossRefPubMedGoogle Scholar
  65. 65.
    Brodner RA, Taub A (1978) Chronic pain exacerbated by long-term narcotic use in patients with nonmalignant disease: clinical syndrome and treatment. Mt Sinai J Med 45:233–237PubMedGoogle Scholar
  66. 66.
    Davis MP, Shaiova LA, Angst MS (2007) When opioids cause pain. J Clin Oncol 25:4497–4498CrossRefPubMedGoogle Scholar
  67. 67.
    Singla A, Stojanovic MP, Chen L, Mao J (2007) A differential diagnosis of hyperalgesia, toxicity, and withdrawal from intrathecal morphine infusion. Anesth Analg 105:1816–1819CrossRefPubMedGoogle Scholar
  68. 68.
    Baron MJ, McDonald PW (2006) Significant pain reduction in chronic pain patients after detoxification from high-dose opioids. J Opioid Manag 2:277–282PubMedGoogle Scholar
  69. 69.
    Zech DF, Grond S, Lynch J et al (1995) Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain 63:65–76CrossRefPubMedGoogle Scholar
  70. 70.
    Ballantyne JC, Shin NS (2008) Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 24:469–478CrossRefPubMedGoogle Scholar
  71. 71.
    Williams JT, Christie MJ, Manzoni O (2001) Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 81:299–343PubMedGoogle Scholar
  72. 72.
    Gutstein HB (1996) The effects of pain on opioid tolerance: how do we resolve the controversy? Pharmacol Rev 48:403–407PubMedGoogle Scholar
  73. 73.
    Jensen KB, Lonsdorf TB, Schalling M et al (2009) Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism. PLoS One 4:e6016CrossRefPubMedGoogle Scholar
  74. 74.
    Tan HY, Chen Q, Goldberg TE et al (2007) Catechol-O-methyltransferase Val158Met modulation of prefrontal-parietal-striatal brain systems during arithmetic and temporal transformations in working memory. J Neurosci 27:13393–13401CrossRefPubMedGoogle Scholar
  75. 75.
    Drabant EM, Hariri AR, Meyer-Lindenberg A et al (2006) Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. Arch Gen Psychiatry 63:1396–1406CrossRefPubMedGoogle Scholar
  76. 76.
    Diatchenko L, Nackley AG, Slade GD et al (2006) Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 125:216–224CrossRefPubMedGoogle Scholar
  77. 77.
    Zubieta JK, Heitzeg MM, Smith YR et al (2003) COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299:1240–1243CrossRefPubMedGoogle Scholar
  78. 78.
    Kim H, Neubert JK, San Miguel A et al (2004) Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109:488–496CrossRefPubMedGoogle Scholar
  79. 79.
    Mao J (2002) Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 100:213–217CrossRefPubMedGoogle Scholar
  80. 80.
    Simonnet G, Rivat C (2003) Opioid-induced hyperalgesia: abnormal or normal pain? Neuroreport 14:1–7CrossRefPubMedGoogle Scholar
  81. 81.
    Koppert W (2004) Opioid-induced hyperalgesia. Pathophysiology and clinical relevance. Anaesthesist 53:455–466CrossRefPubMedGoogle Scholar
  82. 82.
    Ossipov MH, Lai J, King T et al (2004) Antinociceptive and nociceptive actions of opioids. J Neurobiol 61:126–148CrossRefPubMedGoogle Scholar
  83. 83.
    King T, Ossipov MH, Vanderah TW et al (2005) Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals 14:194–205CrossRefPubMedGoogle Scholar
  84. 84.
    Chu LF, Angst MS, Clark D (2008) Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain 24:479–496CrossRefPubMedGoogle Scholar
  85. 85.
    Fishbain DA, Cole B, Lewis JE et al (2009) Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med 10:829–839CrossRefPubMedGoogle Scholar
  86. 86.
    Wilder-Smith OH, Arendt-Nielsen L (2006) Postoperative hyperalgesia: its clinical importance and relevance. Anesthesiology 104:601–607CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Klinik und Poliklinik für Anästhesiologie, Zentrum für Anästhesiologie und IntensivmedizinUniversitätsklinikum Hamburg EppendorfHamburgDeutschland

Personalised recommendations