Opioid hyperalgesia

Uncontrolled post-operative acute pain, particularly in patients with a history of chronic pain and opioid dependency, can be quickly and effectively relieved by careful and slow titration of intravenous methadone. Similar results maybe achieved in some opioid-naive patients who are refractory to high doses of potent opioids administered in the post-anesthesia care unit (PACU). This author uses 2.5 mg of methadone every 5-10 minutes to extinguish the fire associated with poorly controlled pain, and, once adequate analgesia is obtained, initiates hydromorphone intravenous PCA bolus with or without continuous infusion. It is likely that the intrinsic NMDA antagonistic property of the d-isomer of methadone blunts NMDA receptor activation and spinal sensitization induced by opioids (opioid hyperalgesia) as well as poorly controlled pain. 

Schmidt BL, Tambeli CH, Gear RW, Levine JD (2001) Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens. Neuroscience 106 129-136... 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

In addition to the development of tolerance, persistent administration of opioid analgesics has been observed to increase the sensation of pain leading to a state of hyperalgesia. This phenomenon has been observed with several opioid analgesics, including morphine, fentanyl, and remifentanil. Spinal dynorphin and activation of the bradykinin receptor have emerged as important candidates for the mediation of opioid-induced hyperalgesia. 

Angst MS, Clark JD Opioid-induced hyperalgesia. Anesthesiology 2006 104 570. [PMID 16508405]... 

Chu LF, Angst MS, Clark D Opioid-induced hyperalgesia in humans Molecular mechanisms and clinical considerations. 

King T et al Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain 2005 116 276. [PMID 15964684]... 

We expected that (-)-TAN-67 will be used for the detailed investigation of both the existence and the pharmacological effects of a <5i opioid receptor, and that the (+)-TAN-67-induced nociception may be a unique pharmacological model for the elucidation of pain mechanisms. Moreover, the hyperalgesia produced by (+)-TAN-67 could be one of the neuropathic pain models. We hope that the (+)-TAN-67-induced nociception will be used for the development of analgesics for neuropathic pain, for which morphine indicates little or no effect. 

Hylden, J. L., Thomas, D. A., Iadarola, M. J., Nahin, R. L., and Dubner, R. (1991). Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia Possible involvement of noradrenergic mechanisms. Eur. J. Pharmacol. 194, 135—143. 

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