What Do We Know About Opioid-Induced Hyperalgesia?

These results indicate that a progressive and lasting reduction of baseline nociceptive threshold, which was referred to as OIH, can result from repeated opioid administration [7–9]. However, different from previous preclinical observations in which a large dose of intrathecal morphine was given, these studies resulted in hyperalgesic response [10,11] in a clinically relevant opioid dose. Of interest is that OIH was observed in animals even when there was continuous opioid infusion via an implanted osmotic pump, suggesting the involvement of active cellular mechanisms in the process [12]. Therefore, prolonged opioid treatment results in not only loss of the opioid analgesic effect (anti-nociceptive effect or desensitization) but also activation of a hyperalgesic effect (a pro-nociceptive effect with reduced nociceptive threshold or increased sensitization). Although both opioid tolerance and OIH are initiated by opioid administration, two opposing cellular mechanisms (ie, desensitization versus sensitization) may be involved in the process. Subsequently, many studies explored the neural and cellular mechanisms underlying the development of OIH and their interaction with the mechanism of opioid tolerance.

Proposed Cellular Mechanisms of OIH

A significant number of recent studies have explored the neurobiological basis of OIH, revealing a divergent range of cellular elements contributory to OIH. These mechanisms include (1) N-methyl-D-aspartate (NMDA) receptor and related intracellular pathways; (2) involvement of G-protein coupled receptors including 5-HT receptors and neurokinin-1 receptors; (3) nitrix oxide and nitric oxide sunthase; (4) TRPV1 receptors; (5) calcium channels; and (6) miscellaneous mechanisms including sex differences [7–9,13–41].

In summary, an increasing number of preclinical studies in the area of OIH indicates that there is enormous interest in understanding the cellular mechanisms of OIH, and the current evidence points to a progressive sensitization process within the central nervous system that involves a constellation of cellular elements such as NMDA receptors, similar to those contributory to the mechanisms of pathological pain.

Evidence of OIH in Human Studies

In animal studies, changes in baseline nociceptive thresholds can be measured in a controlled setting. It is, however, difficult to assess changes in pain threshold in clinical environment following opioid administration [9]. It is often a challenge to distinguish opioid pharmacologic tolerance from OIH because the outcome of opioid therapy is based primarily on subjective pain scores. In the face of these challenges, an increasing number of clinical anecdotal case reports and studies suggest that OIH is likely to be a significant factor in clinical opioid therapy [47–54].

In a study of 1620 patients in which remifentanil was used for general anesthesia, the incidence of postoperative remifentanil-induced hyperalgesia was 16.1%. This study found that age younger than 16 years, male sex, operation duration longer than 2 hours, and remifentanil dose greater than 30 mg/kga were associated with higher rates of OIH [55]. On the other hand, heroin or other opioid addicts not only demonstrated OIH but also had prolonged symptoms of OIH after detoxification from opioids for at least 1 month [56]. In chronic pain patients without opioid dependence, significantly lower pain threshold and tolerance as assessed by pressure pain stimulation were detected [57]. It appears that the sensitivity of detecting OIH in the clinical setting may be influenced by the modality of sensory stimulation [58].