Elsevier

Pain Management Nursing

Volume 8, Issue 3, September 2007, Pages 113-121
Pain Management Nursing

Original article
Mechanisms of Opioid-Induced Tolerance and Hyperalgesia

https://doi.org/10.1016/j.pmn.2007.02.004Get rights and content

Abstract

Opioid tolerance and opioid-induced hyperalgesia are conditions that negatively affect pain management. Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a decrease of the drug’s effects over time. Opioid-induced hyperalgesia occurs when prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus. Complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying opioid tolerance. Pain facilitatory mechanisms in the central nervous system are known to contribute to opioid-induced hyperalgesia. Recent research indicates that there may be overlap in the two conditions. This article reviews known and hypothesized pathophysiologic mechanisms surrounding these phenomena and the clinical implications for pain management nurses.

Section snippets

Opioid Receptor Physiology

A discussion of opioid tolerance is best prefaced with a review of opioid receptor physiology. Researchers have identified three types of opioid receptors: mu, delta, and kappa receptors. These receptors are distributed in various locations within the spinal cord and brain structures. Figure 1 shows the distribution of opioid receptors in the brain of a guinea pig. Mu opioid receptors are highly concentrated in the outer laminae of the dorsal horn of the spinal cord, whereas delta opioid

Opioid Tolerance

Opioid-induced tolerance is described in the simplest pharmacologic terms as a shift to the right in the dose-response curve; in other words, a higher dose is required over time to maintain the same level of analgesia. At times, progressive disease is the reason for higher opioid requirements (Collin et al 1993, Foley 1993). Other causes of increased opioid needs are pharmacokinetic or pharmacodynamic changes. Pharmacokinetic changes occur, for example, if the drug up-regulates the activity of

Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia is a condition manifested clinically as hyperesthesia (i.e., dramatically increased sensitivity to painful stimuli) and/or allodynia (i.e., pain elicited by a normally nonpainful stimulus). It occurs in some patients (and, in laboratory studies, animals) receiving chronic opioid therapy; the abnormal pain often arises from an anatomically distinct region and is of a different quality than the original pain problem (Ossipov et al., 2005). Clinical reports dating back

Opioid-Induced Tolerance and Hyperalgesia: Two Sides of the Same Coin?

The major clinical manifestation of opioid-induced tolerance and that of hyperalgesia are the same; that is, increasing opioid doses are necessary to achieve adequate analgesia (Angst & Clark 2006, King et al 2005, Mao 2006). Moreover, there are similarities in the mechanisms that cause tolerance and hyperalgesia. For example, CCK-mediated changes in the descending modulatory pathways appear to contribute to both opioid-induced tolerance and hyperalgesia (King et al., 2005). There also is

Clinical Implications

Pain management specialists are frequently called to consult on cases involving opioid tolerance or toxicities. Strategies for clinical management must be based on the current understanding of the complex mechanisms underlying these problems. Some strategies, such as the use of opioid-sparing therapies and opioid rotation, are currently used to prevent and treat tolerance and hyperalgesia, although the evidence supporting these practices is lacking. Other strategies such as the use of

Future Directions and Summary

The molecular mechanisms underlying opioid tolerance and opioid-induced hyperalgesia are being investigated in research laboratories throughout the world. Based on the research accomplished to date, it appears that these two phenomena may be related but also have distinct features. Future scientific efforts will be directed at deepening our understanding of how adaptive responses by multiple neural systems work together to counteract the analgesic efficacy of commonly used opioids. Future

References (94)

  • M. Doverty et al.

    Hyperalgesic responses in methadone maintenance patients

    Pain

    (2001)
  • K. Elliott et al.

    Dextromethorphan attenuates and reverses analgesic tolerance to morphine

    Pain

    (1994)
  • A.K. Finn et al.

    Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal

    Neuron

    (2001)
  • B.S. Galer 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)
  • L.R. Gardell et al.

    Opioid receptor–mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery

    Neuroscience Letters

    (2006)
  • J.E. Haley et al.

    Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat

    Brain Research

    (1990)
  • K.Y. Ho et al.

    Gabapentin and postoperative pain—a systematic review of randomized controlled trials

    Pain

    (2006)
  • A. Mansour et al.

    Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications

    Trends in Neuroscience

    (1995)
  • J. Mao

    Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy

    Pain

    (2002)
  • J. Mao et al.

    Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain

    Pain

    (1995)
  • E. McNicol et al.

    Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review

    Journal of Pain

    (2003)
  • D.E. Moulin et al.

    Unidirectional analgesic cross-tolerance between morphine and levorphanol in the rat

    Pain

    (1988)
  • G.W. Pasternak

    Incomplete cross tolerance and multiple mu opioid peptide receptors

    Trends in Pharmacological Sciences

    (2001)
  • S.J. Perry et al.

    Arresting developments in heptahelical receptor signaling and regulation

    Trends in Cell Biology

    (2002)
  • R. Quirion

    Pain, nociception and spinal opioid receptors

    Progress in Neuro-psychopharmacology & Biological Psychiatry

    (1984)
  • R. Quirion et al.

    Autoradiographic distribution of mu and delta opiate receptors in rat brain using highly selective ligands

    Life Sciences

    (1983)
  • K.F. Shen et al.

    Cholera toxin-A subunit blocks opioid excitatory effects on sensory neuron action potentials indicating mediation by Gs-linked opioid receptors

    Brain Research

    (1990)
  • J. Tang et al.

    Proglumide prevents and curtails acute tolerance to morphine in rats

    Neuropharmacology

    (1984)
  • J.M. Terner et al.

    Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains

    Pain

    (2006)
  • A. Vigano et al.

    Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators

    Pain

    (1996)
  • H.Y. Wang et al.

    Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gbetagamma signaling

    Neuroscience

    (2005)
  • M.S. Angst et al.

    Opioid-induced hyperalgesia: a qualitative systematic review

    Anesthesiology

    (2006)
  • J.R. Arden et al.

    Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged mu-opioid receptor expressed in HEK 293 cells

    Journal of Neurochemistry

    (1995)
  • M.A. Benitez del Rosario et al.

    Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain

    Cancer

    (2004)
  • A.W. Bergen et al.

    Mu opioid receptor gene variants: lack of association with alcohol dependence

    Molecular Psychiatry

    (1997)
  • L.M. Bohn et al.

    Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice

    Journal of Neuroscience

    (2002)
  • L.M. Bohn et al.

    Enhanced morphine analgesia in mice lacking beta-arrestin 2

    Science

    (1999)
  • C. Bond et al.

    Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction

    Proceeding of the National Academies of Science of the United States of America

    (1998)
  • E. Celerier et al.

    Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine

    Anesthesiology

    (2000)
  • C. Chavkin et al.

    Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus

    Proceeding of the National Academies of Science of the United States of America

    (1984)
  • A.M. Davis et al.

    d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia

    Journal of Pharmacol Exp Ther

    (1999)
  • R. Drake et al.

    Opioid rotation in children with cancer

    Journal of Palliative Medicine

    (2004)
  • A. Duttaroy et al.

    The effect of intrinsic efficacy on opioid tolerance

    Anesthesiology

    (1995)
  • H. Eilers et al.

    The reversal of fentanyl-induced tolerance by administration of “small-dose” ketamine

    Anesthesia & Analgesia

    (2001)
  • B. Estfan et al.

    Opioid rotation in cancer patients: pros and cons

    Oncology (Williston Park)

    (2005)
  • S.S. Ferguson et al.

    Role of beta-arrestins in the intracellular trafficking of G-protein–coupled receptors

    Advances in Pharmacology

    (1998)
  • K. Foley

    Changing concepts of tolerance to opioids: what the cancer patient has taught us

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