Original articleMechanisms of Opioid-Induced Tolerance and Hyperalgesia
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)
- et al.
Proglumide as a morphine adjunct in cancer pain management
Journal of Pain & Symptom Management
(1998) - et al.
Reduction in opiate receptor reserve in morphine tolerant guinea pig ilea
Life Sciences
(1982) - et al.
Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex
Journal of Pain
(2005) - et al.
Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient
Journal of Pain & Symptom Management
(1995) - et al.
Is disease progression the major factor in morphine “tolerance” in cancer pain treatment?
Pain
(1993) Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status
Journal of Pain & Symptom Management
(1994)- et al.
Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent
Drug & Alcohol Dependence
(2001) - et al.
Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability
Pain
(2000) - et al.
Opioid rotation for toxicity reduction in terminal cancer patients
Journal of Pain Symptom & Management
(1995) - et al.
Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718
European Journal of Pharmacology
(1988)
Hyperalgesic responses in methadone maintenance patients
Pain
Dextromethorphan attenuates and reverses analgesic tolerance to morphine
Pain
Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal
Neuron
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
Opioid receptor–mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery
Neuroscience Letters
Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat
Brain Research
Gabapentin and postoperative pain—a systematic review of randomized controlled trials
Pain
Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications
Trends in Neuroscience
Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy
Pain
Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain
Pain
Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review
Journal of Pain
Unidirectional analgesic cross-tolerance between morphine and levorphanol in the rat
Pain
Incomplete cross tolerance and multiple mu opioid peptide receptors
Trends in Pharmacological Sciences
Arresting developments in heptahelical receptor signaling and regulation
Trends in Cell Biology
Pain, nociception and spinal opioid receptors
Progress in Neuro-psychopharmacology & Biological Psychiatry
Autoradiographic distribution of mu and delta opiate receptors in rat brain using highly selective ligands
Life Sciences
Cholera toxin-A subunit blocks opioid excitatory effects on sensory neuron action potentials indicating mediation by Gs-linked opioid receptors
Brain Research
Proglumide prevents and curtails acute tolerance to morphine in rats
Neuropharmacology
Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains
Pain
Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators
Pain
Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gbetagamma signaling
Neuroscience
Opioid-induced hyperalgesia: a qualitative systematic review
Anesthesiology
Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged mu-opioid receptor expressed in HEK 293 cells
Journal of Neurochemistry
Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain
Cancer
Mu opioid receptor gene variants: lack of association with alcohol dependence
Molecular Psychiatry
Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice
Journal of Neuroscience
Enhanced morphine analgesia in mice lacking beta-arrestin 2
Science
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
Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine
Anesthesiology
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
d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia
Journal of Pharmacol Exp Ther
Opioid rotation in children with cancer
Journal of Palliative Medicine
The effect of intrinsic efficacy on opioid tolerance
Anesthesiology
The reversal of fentanyl-induced tolerance by administration of “small-dose” ketamine
Anesthesia & Analgesia
Opioid rotation in cancer patients: pros and cons
Oncology (Williston Park)
Role of beta-arrestins in the intracellular trafficking of G-protein–coupled receptors
Advances in Pharmacology
Changing concepts of tolerance to opioids: what the cancer patient has taught us
Cited by (129)
Epigenetic regulation in opioid induced hyperalgesia
2023, Neurobiology of PainNeurological complications of steroids and of supportive care
2022, Neurological Complications of Systemic Cancer and Antineoplastic TherapyCurrent research progress in identifying the mechanism of berberine in pain regulation
2021, Pharmacological Research - Modern Chinese MedicineMethadone maintenance patients lack analgesic response to a cumulative intravenous dose of 32 mg of hydromorphone
2021, Drug and Alcohol DependenceDopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges
2020, Neuroscience and Biobehavioral Reviews