Opioid analgesics hyperalgesia

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. 

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. 

The recognition and control of nociceptor transduction and development of primary hyperalgesia are key to reducing the intensity and duration of acute pain. Nociceptor sensitization leads to reductions in noxious thresholds, increased pain disability, and delayed rehabilitation. The physiological response to transduction and the initiation of nociception can be limited or eliminated by peri operative administration of non-opioid analgesics and anti-inflammatory agents (e.g. NS AIDS, steroids). Although opioids can inhibit... 

A second clinical alteration observed in patients treated with opioids is termed opioid induced hyperalgesia [11]. This phenomenon is characterized by paradoxical increases in pain intensity (hyperesthesia), the development of new pain complaints, and alterations in pain characteristics (allodynia) in response to continued administration or increased dosing of opioid analgesics. 

Ziconotide provides powerful and prolonged analgesia for patients suffering chronic intractable pain that is poorly responsive to conventional opioid and nonopioid analgesics. An important advantage of ziconotide is the avoidance of opioid-induced adverse events such as GI issues, pruritus, decreased testosterone levels, opioid-induced hyperalgesia, as well as behavioral issues. 

Pharmacological tolerance of analgesic effects, symptoms of withdrawal, opioid-induced hyperalgesia, and psychological factors have been reported as contributing... 

Chu LF, D Arcy N, Brady C, Zamora AK, Young CA, KimJE, et al. Analgesic tolerance without demonstrable opioid-induced hyperalgesia a double-blinded, randomized, placebo-controUed trial of sustained-release morphine for treatment of chronic nonradicular low-back pain. Pain August 2012 153(8) 1583-92. 

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. 

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. 

Ziconotide is neuroprotective in rat models of ischemic neuronal damage and after intrathecal administration, antinociception is observed in rats with limited toxicity. The neuroprotective effects observed in rat models are thought to be due to a reduction in body temperature. Analgesic effects are observed in cancer and AIDS patients whose pain was not relieved after opioid administration and in neuropathic conditions. Intrathecal administration of ziconotide prevents mechanical and cold allodynia and heat hyperalgesia " in neuropathic rats. The use of N-type VSCC inhibitors in both ischemic brain injury and pain treatment is complicated by their important role in the synapse. Adverse effects are observed in patients but they are managed through dose reduction or symptomatic treatment, although serious supraspinal and systemic adverse effects have been seen. ... 

Ketamine, a non-opioid, inhibits the excitatory effects of the endogenous excitatory amino acid neurotransmitter glutamate upon the NMDA receptor. The NMDA receptor plays a key role in the development of sensitization, hyperalgesia, and tolerance to the analgesic effects of opioids, as well as in certain preclinical models of neurotoxicity. We have demonstrated that... 

---