Immediate and Delayed Remifentanil-Induced Hypersensitivity

To the Editor Recently, Ishida et al.1 reported that IV infusions of remifentanil induced transient withdrawal hyperalgesia in uninjured rats, its magnitude dependent on duration but not on the dose of the opioid administered. In their model, 120-minute remifentanil infusions (0.1, 1, or 3 μg/kg/min) induced hyperalgesia from 5 to 60 minutes after infusion. They did not detect hyperalgesia after 10-minute (30 μg/kg/min) or 30-minute infusions (0.1, 1, or 10 μg/kg/min). The authors compare their findings with those from previously published reports including results reported in mice by our group,2–4 consistently showing delayed remifentanil-induced hypersensitivity after 30-minute infusions, lasting up to 7 days, its extent and duration depending on the dose administered. These factors, together with the rapid onset and short duration of remifentanil-induced hypersensitivity observed by Ishida et al. suggest that 2 different phenomena are being investigated. The different time(s) of nociceptive evaluation after the remifentanil infusions in the study by Ishida et al. makes the comparison with other results difficult. In our work, we consider that the first time-point regarded sufficiently reliable to determine opioid-induced hyperalgesia is 4 hours after infusion; we think that it is important to avoid potential residual effects of the opioid such as antinociception, sedation, motor impairment, and especially opiate withdrawal. Thus, it is not known from the results by Ishida et al. whether delayed opioid-induced hyperalgesia might have been present. Numerous publications support the development of long-lasting remifentanil-induced hypersensitivity after a single dose or infusion. We have recently reported in rats with incisional injury5 that similar doses of IV remifentanil (6.67 μg/kg/min) as those used by Ishida et al., induce significant mechanical hypersensitivity 4 hours, 1 and 2 days after a 30-minute infusion. Heinl et al.6 also demonstrated protracted mechanical hyperalgesia from 4 hours to >7 days with similar doses (7.5 μg/kg/ min, 60 minutes). Remifentanil long-lasting hyperalgesia was also observed after single intraperitoneal injections in a different rat model of postoperative pain.7 It could be claimed that transient withdrawal remifentanil hyperalgesia is not dose-dependent, even if Kiss et al.8 reported dose-dependent remifentanil-induced acute and short-lived hyperalgesia in the rat; in humans, the clinical effect of this phenomenon is small and is probably masked/ prevented by the administration of analgesia on emergence from general anesthesia. Collectively, preclinical data are supported by clinical studies reporting that remifentanil hyperalgesia is (a) dose-dependent and long-lasting, and (b) significant particularly in the setting of incisional injury.9,10 Thus, based both on preclinical and clinical data, it can be concluded that a reduction in the doses of intraoperative remifentanil must be considered to decrease postoperative pain hypersensitivity in humans. David Cabañero, DVM, PhD Department of Anesthesiology Columbia University College of Physicians and Surgeons New York, New York Margarita M. Puig, MD, PhD Department of Anaesthesiology Hospital del Mar Universitat Autònoma de Barcelona Barcelona, Spain [email protected]