Factors influencing opioids tolerance
W. Koppert
Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both, pain inhibitory and pain facilitatory systems (1-3). Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) -receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia (4-9). Interestingly, the same mechanisms were identified to play a major role in the development of tolerance, leading to the suggestion that tolerance results from a pain sensitization prozess more than from a decrease in the opioid effectiveness (10-12).
Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models (13-18). Brief exposures to m-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large-doses of intraoperative m-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, a2-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity (19-26).
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