Hyperalgesia in Opioid-Managed Chronic Pain and Opioid-Dependent Patients

Hay, Justin L.; White, Jason M.; Bochner, Felix; Somogyi, Andrew A.; Semple, T.J.; Rounsefell, Bruce

doi:10.1016/j.jpain.2008.10.003

Cited by 136 publications

(101 citation statements)

References 44 publications

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“…This is in agreement with a number of previous studies reporting the development of hypersensitivity following morphine treatment in rodents Liang et al, 2008;Liang et al, 2011;Muscoli et al, 2010;Vera-Portocarrero et al, 2007). Sensory sensitization induced by opioids has also been reported in clinical studies showing an increase in mechanical sensitivity after repeated exposure to morphine (Chu et al, 2006;Hay et al, 2009). The fact that our morphine treatment procedure did not elicit an increase in heat sensitivity is consistent with other reports suggesting that opioids can sensitize the nociceptive pathways activated by mechanical stimuli to a greater extent than those activated by heat stimuli Cabañero et al, 2009).…”

Section: Discussionsupporting

confidence: 92%

Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord

Cabañero

Baker

Zhou

et al. 2013

Neuropsychopharmacol

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Withdrawal from prescribed opioids results in increased pain sensitivity, which prolongs the treatment. This pain sensitivity is attributed to neuroplastic changes that converge at the spinal cord dorsal horn. We have recently reported that repeated morphine administration triggers an insertion of GluA2-lacking (Ca 2 þ -permeable) a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) in the hippocampus. This finding together with the reported involvement of AMPAR in the mechanisms underlying inflammatory pain led us to hypothesize a role for spinal AMPAR in opioid-induced pain behavior. Mice treated with escalating doses of morphine showed hypersensitivity to mechanical stimulation. Intrathecal administration of a Ca 2 þ -permeable AMPAR selective blocker disrupted morphine-induced mechanical sensitivity. Analysis of the expression and phosphorylation levels of AMPAR subunits (GluA1/2/3/4) in homogenates and in postsynaptic density fractions from spinal cord dorsal horns showed an increase in GluA4 expression and phosphorylation in the postsynaptic density after morphine. Co-immunoprecipitation analyses suggested an increase in GluA4 homomers (Ca 2 þ -permeable AMPAR) and immunohistochemical staining localized the increase in GluA4 levels in laminae III-V. The excitatory postsynaptic currents (EPSCs) recorded in laminae III-V showed enhanced sensitivity to Ca 2 þ -permeable AMPAR blockers in morphinetreated mice. Furthermore, current-voltage relationships of AMPAR-mediated EPSCs showed that rectification index (an indicator of Ca 2 þ -permeable AMPAR contribution) is increased in morphine-treated but not in saline-treated mice. These effects could be reversed by infusion of GluA4 antibody through patch pipette. This is the first direct evidence for a role of GluA4-containing AMPAR in morphineinduced pain and highlights spinal GluA4-containing AMPAR as targets to prevent the morphine-induced pain sensitivity.

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Section: Discussionsupporting

confidence: 92%

Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord

Cabañero

Baker

Zhou

et al. 2013

Neuropsychopharmacol

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“…Hyperalgesia and Allodynia Induced by Opioid Analgesics. Opioid-induced hyperalgesia and opioid withdrawal-induced hyperalgesia are paradoxical increases in pain sensitivity that develop after short-and/or longterm opioid exposure, which have clearly been demonstrated in preclinical studies (Ossipov et al, 2004 and have also been reported to occur in several patient populations (Doverty et al, 2001;Angst and Clark, 2006;Pud et al, 2006;Singla et al, 2007;Hay et al, 2009Hay et al, , 2010, although this is not without controversy (for review, see Fishbain et al (2009)). Suggested mechanisms include glutamate-associated NMDA receptor activation, causing spinal neuron sensitization, which is supported by blockade of opioid-induced hyperalgesia after NMDA receptor antagonism Ossipov et al, 2005;Mao, 2006).…”

Section: Central Anatomical Locations Of Opioid Analgesic Action and mentioning

confidence: 99%

“…Central immune signaling and the associated neuronal dysfunction are key participants and mediators of chronic pain conditions (Milligan and Watkins, 2009). Likewise, after opioid exposure, when the pronociceptive mechanisms, including central immune signaling, outweigh the combined antinociceptive actions, a concerning exaggerated pain state is observed, presenting itself as allodynia and/or hyper-798 algesia reported in several disparate patient populations (Doverty et al, 2001;Angst and Clark, 2006;Pud et al, 2006;Singla et al, 2007;Hay et al, 2009Hay et al, , 2010. Proinflammatory central immune signaling (Johnston et al, 2004;Hutchinson et al, 2008a;White and Wilson, 2010) induced by glial reactivity (Raghavendra et al, 2004a;Agostini et al, 2010), causing alterations in glutamate homeostasis (Mao et al, 2002;Ramos et al, 2010) and heterologous desensitization (White and Wilson, 2010), are implicated in this response as well as several other key neuronal adaptations (Ossipov et al, 2004.…”

Section: What Is the Impact Of Proinflammatory Central Immune Signmentioning

confidence: 99%

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

Hutchinson

Shavit

Grace³

et al. 2011

Pharmacological Reviews

347

315

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“…46 The SCD pain stimulus no doubt continues in the face of palliation of pain using opioids. In cancer, this effect is usually short-lived, ending in the death of the patient, so any opioid-generated hyperalgesia is less important; however, in SCD, opioid-induced hyperalgesia could go on for decades, depending on the severity of the pain and the chronicity and intensity of opioid therapy.…”

Section: Neuropathic Pain Mechanisms and Neuroplasticitymentioning

confidence: 99%

Sickle-Cell Pain: Advances in Epidemiology and Etiology

Smith

Scherer

2010

Hematology

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New epidemiological findings recast pain in sickle-cell disease (SCD) as being more often a chronic manifestation than was previously thought, although acute pain is still the hallmark of the disease. SCD pain intensity, the number of painful locations, and the frequency of hospitalizations due to SCD pain may worsen with age. In adults and even in children, the quantity and severity of SCD pain may be vastly underestimated, because most of the "iceberg" of SCD pain is "submerged" at home, and only the tip of the iceberg is seen by health care providers when acute SCD care is rendered in emergency rooms and hospitals. Implications of this "iceberg phenomenon" are significant for clinicians, researchers, employers, policy makers, and the public. Nevertheless, both emergency room and hospital utilization for SCD pain remain prevalent. Often, utilization recurs early, perhaps emblematic of poor acute pain management. New data show the protean impacts of SCD pain on health-related quality of life, sleep, and psychological and social health. The relationship of the severity of SCD pain to the severity of underlying sickle vasculopathy is unclear, but epidemiologic evidence and patient descriptors suggest a temporal evolution of pain mechanisms. At first, increasingly worse nociceptive pain from vaso-occlusion and local lesions may evolve over the first two decades of life. Then, in the third and following decades, central neuropathic pain may also evolve due to past and continuing nociceptive stimuli. New findings confirm environmental contributors to SCD pain, including seasonal (colder) temperatures, barometric pressure, and wind speed.

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Hyperalgesia in Opioid-Managed Chronic Pain and Opioid-Dependent Patients

Cited by 136 publications

References 44 publications

Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord

Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

Sickle-Cell Pain: Advances in Epidemiology and Etiology

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