Clinical Diagnosis of Opioid-Induced Hyperalgesia

Whereas hyperalgesia can be associated with opioid withdrawal in rodents and humans, opioidinduced hyperalgesia (OIH) refers to a progressive decrease of nociceptive threshold after opioid exposure, without overt withdrawal symptoms and signs. Despite evidence of OIH from both preclinical and clinical studies, however, we do not yet have a clinical diagnostic tool for OIH, and the lack of such a tool has led some opinion leaders to conclude that OIH does not exist. In this issue of Regional Anesthesia and Pain Medicine, Wasserman et al offer some insights relevant to the resulting challenge. Since the phenomenon of OIH was reported in rodents exposed to intrathecal morphine at a clinically comparable dose, OIH has been demonstrated in a number of rodent models with intermittent or continuous administration of morphine, fentanyl, heroin, methadone, or buprenorphine. Sensory modalities used to demonstrate OIH in rodents include thermal, mechanical, and viscerosomatic stimulation. For 2 decades, a great number of preclinical studies have also investigated the cellular mechanisms of OIH, including contributions from the glutamatergic system, dynorphin, supraspinal descending facilitation, cytokines, and epigenetic regulation. Collectively, a large body of preclinical evidence supports the notion that opioid exposure can activate a pronociceptive process manifesting itself as OIH and a desensitization process known as opioid tolerance. Emerging evidence suggests that OIH may be present in human subjects as well. For example, 1) the opioid analgesic efficacy was reduced after intraoperative remifentanil infusion, and hyperalgesia induced by remifentanil infusion was similar to that after naloxone-precipitated opioid withdrawal; 2) pain sensitivity was increased in subjects with opioid addiction in response to experimental pain (eg, cold pressor test); 3) opioid exposure diminished diffuse noxious inhibitory control in human subjects, indicating an adverse effect on the endogenous pain modulatory system; and 4) painful response to a needle stick test was exacerbated in patients prescribed opioid therapy. We have also reported that heat pain threshold was reduced, whereas temporal pain summation (a psychophysical correlate of electrophysiological windup) was exacerbated, in a dose-dependent manner in human subjects on chronic opioid therapy. Because OIH is demonstrated in rodent models as the reduced nociceptive threshold, it is reasonable to consider quantitative sensory testing (QST) as a tool to assess OIH in human subjects. Indeed, a variety of QST modalities have been used to assess the validity of QST as a diagnostic tool of OIH. The article by Wasserman et al is an example of this approach. The challenge in clinical diagnosis of OIH is that OIH must be differentiated from opioid tolerance because both conditions can reduce opioid analgesia and increase opioid requirement. For clinicians, differentiating OIH from opioid tolerance provides a critical reference for opioid dose adjustment, such that opioid dose escalation might improve opioid tolerance but would exacerbate OIH. Can QST be used to diagnose OIH? Quantitative sensory testing produces a psychophysical response that can be influenced by an individual's subjective interpretation. Therefore, it is imperative that QST results be interpreted in the context of other clinical findings (Table 1). After all, hyperalgesia refers to an exacerbated response to painful stimulation, which is a subjective experience and likely to be highly individualized. In this regard, several issues should be considered when using QST to assess OIH: (1) Urine drug screen: Several studies have shown that subjects prescribed opioid therapy are more likely to have a substance abuse disorder. Conceivably, the presence of drugs of abuse could influence QSToutcomes. Some studies of OIH included urine drug screening, whereas others, including the article in this issue, did not. (2) Study control: Chronic pain can certainly alter baseline nociceptive threshold detected by QST. Many studies of OIH compared QSToutcomes between pain patients with and without opioid exposure. If preexisting pain has lowered baseline nociceptive threshold, it may be difficult to detect OIH in these subjects. Therefore, adding a naive group (subjects with neither pain nor opioid