Opioid-Induced Hyperalgesia: Clinically Relevant or Extraneous Research Phenomenon?
First Online: 12 January 2011 DOI:
10.1007/s11916-010-0171-1 Cite this article as: Tompkins, D.A. & Campbell, C.M. Curr Pain Headache Rep (2011) 15: 129. doi:10.1007/s11916-010-0171-1 Abstract
Opioids have become the unequivocal therapy of choice in treating many varieties of chronic pain. With the increased prescription of opioids, some unintended consequences have occurred. After prolonged opioid exposure, opioid-induced hyperalgesia (OIH), the paradoxical effect that opioid therapy may in fact enhance or aggravate preexisting pain, may occur. Over the past several decades, an increasing number of laboratory and clinical reports have suggested lowered pain thresholds and heightened atypical pain unrelated to the original perceived pain sensations as hallmarks of OIH. However, not all evidence supports the clinical importance of OIH, and some question whether the phenomenon exists at all. Here, we present a nonexhaustive, brief review of the recent literature. OIH will be reviewed in terms of preclinical and clinical evidence for and against its existence; recommendations for clinical evaluation and intervention also will be discussed.
Keywords Opioid-induced hyperalgesia Pain hypersensitivity Opioid dependence Chronic pain Individual differences Quantitative sensory testing References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Mendelson J, Flower K, Pletcher MJ, and Galloway GP: Addiction to prescription opioids: characteristics of the emerging epidemic and treatment with buprenorphine. Exp.Clin.Psychopharmacol. 2008, 16:435–441.
Andrews HL: The effect of opiates on the pain threshold in post-addicts. J.Clin.Invest 1943, 22:511–516.
•• Fishbain DA, Cole B, Lewis JE et al.: Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med. 2009, 10:829–839.
This is a comprehensive review on human studies in opioid-induced hyperalgesia. The authors conclude that the strength of the evidence for opioid-induced hyperalgesia is limited but did not refute its existence
Kayan S, Woods LA, and Mitchell CL: Morphine-induced hyperalgesia in rats tested on the hot plate. J.Pharmacol.Exp.Ther. 1971, 177:509–513.
Celerier E, Laulin JP, Corcuff JB et al.: Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J.Neurosci. 2001, 21:4074–4080.
Laulin JP, Celerier E, Larcher A et al.: Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 1999, 89:631–636.
White F and Wilson N: Opiate-induced hypernociception and chemokine receptors. Neuropharmacology 2010, 58:35–37.
Minville V, Fourcade O, Girolami JP, and Tack I: Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine. Br.J.Anaesth. 2010, 104:231–238.
Mert T, Gunes Y, Ozcengiz D, and Gunay I: Magnesium modifies fentanyl-induced local antinociception and hyperalgesia. Naunyn Schmiedebergs Arch.Pharmacol. 2009, 380:415–420.
Chen Y, Yang C, and Wang ZJ: Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia. J.Neurosci. 2010, 30:38–46.
Hay JL, Kaboutari J, White JM et al.: Model of methadone-induced hyperalgesia in rats and effect of memantine. Eur.J.Pharmacol. 2010, 626:229–233.
Waxman AR, Arout C, Caldwell M et al.: Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice. Neurosci.Lett. 2009, 462:68–72.
van Dorp EL, Kest B, Kowalczyk WJ et al.: Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology 2009, 110:1356–1363.
Vorobeychik Y, Chen L, Bush MC, and Mao J: Improved opioid analgesic effect following opioid dose reduction. Pain Med. 2008, 9:724–727.
Guignard B, Bossard AE, Coste C et al.: Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000, 93:409–417.
Compton P, Charuvastra VC, and Ling W: Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend. 2001, 63:139–146.
Compton P, Charuvastra VC, Kintaudi K, and Ling W: Pain responses in methadone-maintained opioid abusers. J.Pain Symptom.Manage. 2000, 20:237–245.
• Compton P, Kehoe P, Sinha K et al.: Gabapentin improves cold-pressor pain responses in methadone-maintained patients. Drug Alcohol Depend. 2010, 109:213–219.
This report describes how one medication may improve opioid-induced hyperalgesia in stable patients on methadone
Ren ZY, Shi J, Epstein DH et al.: Abnormal pain response in pain-sensitive opiate addicts after prolonged abstinence predicts increased drug craving. Psychopharmacology (Berl) 2009, 204:423–429.
Wasan AD, Butler SF, Budman SH et al.: Does report of craving opioid medication predict aberrant drug behavior among chronic pain patients? Clin. J. Pain 2009, 25:193–198.
Chu LF, Clark DJ, and Angst MS: Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J.Pain 2006, 7:43–48.
Chen L, Malarick C, Seefeld L et al.: Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain 2009, 143:65–70.
Reznikov I, Pud D, and Eisenberg E: Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain. Br.J.Clin.Pharmacol. 2005, 60:311–318.
Cortinez LI, Brandes V, Munoz HR et al.: No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br.J.Anaesth. 2001, 87:866–869.
Baron MJ and McDonald PW: Significant pain reduction in chronic pain patients after detoxification from high-dose opioids. J.Opioid.Manag. 2006, 2:277–282.
Koppert W, Sittl R, Scheuber K et al.: Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003, 99:152–159.
Koppert W, Angst M, Alsheimer M et al.: Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans. Pain 2003, 106:91–99.
Schmidt S, Bethge C, Forster MH, and Schafer M: Enhanced postoperative sensitivity to painful pressure stimulation after intraoperative high dose remifentanil in patients without significant surgical site pain. Clin. J. Pain 2007, 23:605–611.
Hood DD, Curry R, and Eisenach JC: Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth.Analg. 2003, 97:810–815.
• Chu LF, Dairmont J, Zamora AK et al.: The endogenous opioid System is not involved in modulation of opioid-induced hyperalgesia. J.Pain 2010.
This report provides evidence that the known opioid receptors are not needed for the development of opioid-induced hyperalgesia.
Fillingim RB: Individual differences in pain responses. Curr.Rheumatol.Rep. 2005, 7:342–347.
Colvin LA and Fallon MT: Opioid-induced hyperalgesia: a clinical challenge. Br.J.Anaesth. 2010, 104:125–127.
Bodnar RJ and Kest B: Sex differences in opioid analgesia, hyperalgesia, tolerance and withdrawal: central mechanisms of action and roles of gonadal hormones. Horm.Behav. 2010, 58:72–81.
Holtman JR, Jr. and Wala EP: Characterization of morphine-induced hyperalgesia in male and female rats. Pain 2005, 114:62–70.
Juni A, Klein G, Kowalczyk B et al.: Sex differences in hyperalgesia during morphine infusion: effect of gonadectomy and estrogen treatment. Neuropharmacology 2008, 54:1264–1270.
Kavaliers M and Choleris E: Sex differences in N-methyl-D-aspartate involvement in kappa opioid and non-opioid predator-induced analgesia in mice. Brain Res. 1997, 768:30–36.
Juni A, Cai M, Stankova M et al.: Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor. Anesthesiology 2010, 112:181–188.
Ram KC, Eisenberg E, Haddad M, and Pud D: Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain—new perspective of opioid-induced hyperalgesia. Pain 2008, 139:431–438.
Jensen KB, Lonsdorf TB, Schalling M et al.: Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism. PLoS.One. 2009, 4:e6016.
Edwards RR, Wasan A, Jamison R. Hyperalgesia in pain patients at elevated risk for opioid misuse. J.Pain 2010, 11:S45.
• Chapman CR, Lipschitz DL, Angst MS et al.: Opioid pharmacotherapy for chronic non-cancer pain in the United States: a research guideline for developing an evidence-base. J.Pain 2010, 11:807–829.
This is a report on the specific research needs for the pain treatment field for the future
• Kapural L, Kapural M, Bensitel T, and Sessler DI: Opioid-sparing effect of intravenous outpatient ketamine infusions appears short-lived in chronic-pain patients with high opioid requirements. Pain Physician 2010, 13:389–394.
This report provides evidence that ketamine infusions can reduce pain and opioid requirements in persons with chronic pain, but the benefits remit 6 months after ending treatment
Angst MS and Clark JD: Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006, 104:570–87.
PubMed CrossRef Copyright information
© Springer Science+Business Media, LLC 2011