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Opioid-Induced Hyperalgesia

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Cancer Pain

Abstract

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitisation caused by exposure to opioids. The condition is characterised by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain.

Observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilising former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, cancer patients on opioids, and healthy human volunteers after acute opioid exposure using human experimental pain testing.

There are several proposed mechanisms for OIH; among these mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms.

Clinicians should suspect OIH when opioid treatment’s effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor inhibitors.

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References

  1. Eriksen J, Sjøgren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on opioids in chronic non-­malignant pain: an epidemiological study. Pain. 2006;125:172–9.

    Article  PubMed  CAS  Google Scholar 

  2. Chou R, Fanciullo GJ, Fine PG, Miaskowski C, Passik S, Portnoy RK. Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain. 2009;10(2):131–46.

    Article  PubMed  CAS  Google Scholar 

  3. Kayan S, Woods LA, Mitchell CL. Morphine-induced hyperalgesia in rats tested on the hot plate. J Pharmacol Exp Ther. 1971;177(3):509–13.

    PubMed  CAS  Google Scholar 

  4. Andrews HL. The effect of opiates on the pain threshold in post-addicts. J Clin Invest. 1943;22:511–6.

    Article  PubMed  CAS  Google Scholar 

  5. De Conno F, Caraceni A, Martini C, Spoldi E, Salvetti M, Ventafridda V. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine. Pain. 1991;47:337–9.

    Article  PubMed  Google Scholar 

  6. Sjøgren P, Jonsson T, Jensen NH, Drenck NE, Jensen TS. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain. 1993;55:93–7.

    Article  PubMed  Google Scholar 

  7. Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain. 2001;90:91–6.

    Article  PubMed  CAS  Google Scholar 

  8. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93:409–17.

    Article  PubMed  CAS  Google Scholar 

  9. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain. 2006;7:43–8.

    Article  PubMed  CAS  Google Scholar 

  10. Woolf CJ. Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res. 1981;209(2):491–5.

    Article  PubMed  CAS  Google Scholar 

  11. Cérèlier E, Rivat C, Jun Y, et al. Long lasting hyperalgesia induced by fentanyl in rats. Anesthesiology. 2000;92:465–72.

    Article  Google Scholar 

  12. Célèrier E, Laulin J-P, Corcuff J-B, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001;21(11):4074–80.

    PubMed  Google Scholar 

  13. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase c. J Neurosci. 1994;14(4):2301–12.

    PubMed  CAS  Google Scholar 

  14. Vanderah TW, Ossipov MH, Lai J, Malan Jr TP, Porreca F. Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin. Pain. 2001;92:5–9.

    Article  PubMed  CAS  Google Scholar 

  15. Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Mol Brain Res. 2001;86:56–62.

    Article  PubMed  CAS  Google Scholar 

  16. Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg. 2001;93: 204–9.

    Article  PubMed  CAS  Google Scholar 

  17. Chia Y-Y, Liu K, Wang J-J, Kuo M-C, Ho S-T. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999;46(9):872–7.

    Article  PubMed  CAS  Google Scholar 

  18. Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103:147–55.

    Article  PubMed  CAS  Google Scholar 

  19. Crawford MW, Hickey C, Zaarour C, Howard A, Naser B. Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth Analg. 2006;102:1662–7.

    Article  PubMed  CAS  Google Scholar 

  20. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the μ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003;106:49–57.

    Article  PubMed  CAS  Google Scholar 

  21. Koppert W, Sitti R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by s-ketamine and clonidine in humans. Anesthesiology. 2003;99:152–9.

    Article  PubMed  CAS  Google Scholar 

  22. Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg. 2003;97:810–5.

    Article  PubMed  CAS  Google Scholar 

  23. Chen L, Malarick C, Seefeld L, Wang S, Houghton M, Mao J. Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain. 2009;143:65–70.

    Article  PubMed  CAS  Google Scholar 

  24. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain – new perspective of opioid-induced hyperalgesia. Pain. 2009;139:431–8.

    Article  Google Scholar 

  25. Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend. 2001;63:139–46.

    Article  PubMed  CAS  Google Scholar 

  26. Compton P, Kehoe P, Sinha K, Torrington MA, Ling W. Gabapentin improves cold-pressure pain responses in methadone-maintained patients. Drug Alcohol Depend. 2010;109:213–9.

    Article  PubMed  CAS  Google Scholar 

  27. Pud D, Cohen D, Lawental E, Eisenberg E. Opioids and abnormal pain perception: new evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend. 2006;82:218–23.

    Article  PubMed  CAS  Google Scholar 

  28. Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J Pain 2009;10(3): 316–22.

    Article  PubMed  CAS  Google Scholar 

  29. Mercadante S, Ferrera P, Villari P, Arcuri E. Hyperalgesia: an emerging iatrogenic syndrome. J Pain Symptom Manage. 2003;26(2):769–75.

    Article  PubMed  Google Scholar 

  30. Wilson GR, Reisfield GM. Morphine hyperalgesia: a case report. Am J Hosp Palliat Care. 2003;20:459–61.

    Article  PubMed  Google Scholar 

  31. Davis MP, Shaiova LA, Angst MS. When opioids cause pain. J Clin Oncol. 2007;25(28):2297–8.

    Article  Google Scholar 

  32. Vorobeychik Y, Chen L, Bush MC, Mao J. Improved opioid analgesic effect following opioid dose reduction. Pain Med. 2008;9(6):724–7.

    Article  PubMed  Google Scholar 

  33. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991;251:85–7.

    Article  PubMed  CAS  Google Scholar 

  34. Marek P, Ben Eliyahu S, Gold M. Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat. Brain Res. 1991;547:81–8.

    Article  Google Scholar 

  35. Mao J, Price DD, Mayer DJ. Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain. Pain. 1995;61:353–64.

    Article  PubMed  CAS  Google Scholar 

  36. Mao J. NMDA and opioid receptors: their interactions in anti-nociception tolerance and neuroplasticity. Brain Res Rev. 1999;30:289–304.

    Article  PubMed  CAS  Google Scholar 

  37. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci. 2002;22:8312–23.

    PubMed  CAS  Google Scholar 

  38. Narita M, Mizoguchi H, Nagase M, Suzuki T, Tseng LF. Involvement of spinal protein kinase C gamma in the attenuation of opioid-mu-receptor mediated G-protein activity after chronic intrathecal administration of [D-Ala2, N-Mephe4, Gly-Ol5] enkephalin. J Neurosci. 2001;21:3715–20.

    PubMed  CAS  Google Scholar 

  39. Zeitz KP, Malmberg AB, Gilbert H, Basbaum AL. Reduced development of tolerance to the analgesic effect of morphine and clonidine in PKC gamma mutant mice. Pain. 2002;94:245–53.

    Article  Google Scholar 

  40. Mao J, Sung B, Ru Rong J, Grewo L. Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci. 2002;22:7650–61.

    PubMed  CAS  Google Scholar 

  41. Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers. 2005;80:319–24.

    Article  PubMed  CAS  Google Scholar 

  42. Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM, et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci. 2000;20:7074–9.

    PubMed  CAS  Google Scholar 

  43. Campillo A, González-Cuello A, Cabañero D, Garcia-Nogales P, Asunción R, Milanés MV, et al. Increased spinal dynorphin levels and phosphor-extracellular signal-regulated kinases 1 and 2 and c-fos immunoreactivity after surgery under remifentanil anesthesia in mice. Mol Pharmacol. 2010;77(2):185–94.

    Article  PubMed  CAS  Google Scholar 

  44. Chu LF, Dairmont J, Zamora AK, Young CA, Angst MS. The endogenous opioid system is not involved in modulation of opioid-induced hyperalgesia. J Pain. 2011;12(1):108–11.

    Article  PubMed  CAS  Google Scholar 

  45. Barbaro NM, Heinricher MM, Fields HL. Putative pain modulating neurons in the rostral ventral medulla: reflex-related activity predicts effects of morphine. Brain Res. 1986;366:203–10.

    Article  PubMed  CAS  Google Scholar 

  46. Heinricher MM, Morgan MM, Fields HL. Direct and indirect actions of morphine on medullary neurons that modulate nociception. Neuroscience. 1992;48:533–43.

    Article  PubMed  CAS  Google Scholar 

  47. Morgan MM, Heinricher MM, Fields HL. Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla. Neuroscience. 1992;47(4):863–71.

    Article  PubMed  CAS  Google Scholar 

  48. Vanderah TW, Suenaga NMH, Ossipov MH, Malan Jr TP, Lai J, Porreca F. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci. 2001;21(1):279–86.

    PubMed  CAS  Google Scholar 

  49. Gardell LR, Wang R, Burgess SE, et al. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci. 2002;22(15):6747–55.

    PubMed  CAS  Google Scholar 

  50. King T, Gardell LR, Wang R, Vardanyan A, Ossipov MH, Malan TP, et al. Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain. 2005;116:276–88.

    Article  PubMed  CAS  Google Scholar 

  51. White F, Wilson N. Opiate-induced hypernociception and chemokine receptors. Neuropharmacology. 2010;58:35–7.

    Article  PubMed  CAS  Google Scholar 

  52. Gris P, Gauthier J, Cheng P, Gibson DG, Gris D, Laur O, et al. A novel alternative spliced isoform of the mu-opioid receptor: functional antagonism. Mol Pain. 2010;6:33–42.

    Article  PubMed  Google Scholar 

  53. Waxman AR, Arout C, Caldwell M, Dahan A, Kest B. Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice. Neurosci Lett. 2009;462(1):68–72.

    Article  PubMed  CAS  Google Scholar 

  54. Van Dorp ELA, Kest B, Kowalczyk WJ, Morariu AM, Waxman AR, Arout CA, et al. Morphine-­­6­b-glcoronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 2009;110:1356–63.

    Article  PubMed  Google Scholar 

  55. Juni A, Klein G, Kest B. Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or ­tolerance: evidence for multiple diverse hyperalgesic systems. Brain Res. 2006;1070:35–44.

    Article  PubMed  CAS  Google Scholar 

  56. Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, et al. Evidence that intrathecal morphine-3-glucoronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β. Neuroscience. 2010;165(2):569–83.

    Article  PubMed  CAS  Google Scholar 

  57. Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after detoxification from high dose opioids. J Opioid Manag. 2006;2:277–82.

    PubMed  Google Scholar 

  58. Mercadante S, Arcuri E. Hyperalgesia and opioid switching. Am J Hosp Palliat Care. 2005;22(4):291–4.

    Article  PubMed  Google Scholar 

  59. Okon TR, George ML. Fentanyl-induced neurotoxicity and paradoxic pain. J Pain Symptom Manage. 2008;35(3):327–33.

    Article  PubMed  CAS  Google Scholar 

  60. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev. 2006;32:304–15.

    Article  PubMed  CAS  Google Scholar 

  61. Ebert B, Thorkildsen C, Andersen S, Christru LL, Hjeds H. Opioid analgesics as noncompetetive N-methyl_D-aspartate (NMDA) antagonists. Biochem Pharmacol. 1998;56:553–9.

    Article  PubMed  CAS  Google Scholar 

  62. Blackburn D, Somerville E, Squire J. Methadone: an alternative conversion regime. Eur J Palliat Care. 2002;9(3):93–6.

    Google Scholar 

  63. Axelrod DJ, Reville B. Using methadone to treat opioid-induced hyperalgesia and refractory pain. J Opioid Manag. 2007;3(2):113–4.

    PubMed  Google Scholar 

  64. Richebé P, Rivat C, Laulin J-P, Maurette P, Simonnet G. Ketamine improves the management of exaggerated postoperative pain observed in perioperative fentanyl-treated rats. Anesthesiology. 2005;102:421–8.

    Article  PubMed  Google Scholar 

  65. Minville V, Fourcade O, Girolami J-P, Tack I. Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine. Br J Anaesth. 2010;104(2):231–8.

    Article  PubMed  CAS  Google Scholar 

  66. Forero M, Chan PSL, Restrepo-Garces CE. Successful reversal of hyperalgesia/myoclonus complex with low-dose ketamine infusion. Pain Pract. 2011. doi:10.1111/j.1533-2500.2011.00475.x.

    PubMed  Google Scholar 

  67. Van Elstraete AC, Sitbon P, Mazoit J-X, Benhamou D. Gabapentin prevents delayed and long-lasting hyperalgesia induced by fentanyl in rats. Anesthesiology. 2008;108:484–94.

    Article  PubMed  Google Scholar 

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Correspondence to Per Sjøgren MDSci .

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Sørensen, J., Sjøgren, P. (2013). Opioid-Induced Hyperalgesia. In: Hanna, M., Zylicz, Z. (eds) Cancer Pain. Springer, London. https://doi.org/10.1007/978-0-85729-230-8_10

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