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Opioid analgesics are among the most powerful pain medications used to treat a variety of pain conditions. Activation of opioid receptors produces analgesia, euphoria, respiratory depression, decreased gastrointestinal motility, and cardiovascular effects. Exposure to opioids also can lead to opioid tolerance and opioid-induced hyperalgesia (OIH). The concept of OIH refers to a pronociceptive state induced by exposure to opioids with a paradoxical increase in nociceptive sensitization through changes at the cellular and system level. This chapter will review evidence of OIH from preclinical and clinical studies and discuss the issues relevant to clinical diagnosis and management of OIH.


An original preclinical study by Mao et al. showed that baseline nociceptive threshold was progressively reduced, assessed by using a foot-withdrawal test, in rats receiving repeated intrathecal morphine administration (10-20 μg) over a 7-day period.1 This finding was later supported by a series of animal studies. For example, 1) the reduced baseline nociceptive threshold was observed in animals receiving subcutaneous fentanyl boluses using the Randall-Sellitto test in which a constantly increasing pressure was applied to a rat's hindpaw. The decreased baseline nociceptive threshold lasted 5 days after the cessation of four fentanyl bolus injections;2 2) the reduced baseline nociceptive threshold was detected in animals with repeated heroin administration as well;3 3) rats exposed to morphine also developed a latent sensitization of visceral hyperalgesia with a shift of the morphine dose-response curve to the right;4 4) exposure to methadone induced hyperalgesia in rats, which was not prevented by a weak NMDA receptor antagonist (memantine);5 and 5) a partial µ-receptor agonist buprenophine produced a dose-related OIH.6

These findings indicate that repeated opioid administration can lead to a progressive and lasting reduction of baseline nociceptive threshold, referred as OIH.7-9 This phenomenon differs from previous preclinical observations in which a large dose of intrathecal morphine resulted in hyperalgesic response10,11 because OIH developed in response to a clinically relevant dose. It is of interest to note that OIH was observed in animals even when an opioid infusion continues via an implanted osmotic pump, suggesting the involvement of active cellular mechanisms in the process.12 Therefore, a prolonged opioid treatment can result in not only a loss of the opioid antinociceptive effect, a negative sign of system adaptation (desensitization), but also activation of a pronociceptive system manifested as the reduced nociceptive threshold, a positive sign of system adaptation (sensitization).


A considerable number of recent studies have explored the neurobiological basis of OIH, revealing a divergent range of cellular elements contributory to OIH. For example, N-methyl-D-aspartate (NMDA) receptors have long been implicated in the cellular mechanism of OIH.7-9,13 A recent study indicates that the periaqueductal gray may be a site ...

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