When Similar Is Not Alike

Abstract

To the Editor Recently, Ishida et al.1 reported decreased sensory thresholds after 120-minute, but not after 30-minute remifentanil infusions in rats. Although these data seem to support the existence of opioid-induced hyperalgesia, a closer look at the methodology points to other factors that must be considered before ascribing the observed hypersensitivity to a direct pronociceptive effect of remifentanil. First, the authors used 2 stimulation modalities, thermal and mechanical, to determine pain thresholds. Application of heat may result in burns when protective responses are abolished by opioids. This is usually avoided by establishing cutoff points,2 but there is always a risk of cumulative injury with repeated stimulation. During the 30-minute remifentanil infusions, thermal thresholds were taken at 0, 5, 10, 20, and 30 minutes. It seems that in the case of the 120-minute infusions, measurements at every 30 minutes were preceded with measurements at 0, 5, 10, and 20 minutes, although only the first (0-minute) data from the latter 4 were presented on their graph. With the greater number of heat exposures during 120-minute infusions, there is a possibility of burn injury emerging as hyperalgesia after the infusion. Second, the authors did not describe how and which parts of the tail were stimulated. In rats, the reaction time decreases when the stimulus is applied to increasingly distal parts of the tail.3 If, to avoid cumulative injury, the authors altered the stimulation sites from more proximal to more distal, such testing would appear as false hyperalgesia on their graph. Third, the rat tail is a richly vascularized thermoregulatory organ and vasodilators can increase tail skin temperature.2 This results in decreased tail withdrawal latencies, which again can be falsely interpreted as hyperalgesia.4,5 Because the ability of remifentanil to cause vasodilatation is well known,6,7 the longer exposure to remifentanil could be responsible for decreased thresholds in the 120-minute groups. Fourth, the authors also reported decreased mechanical thresholds after remifentanil infusion. Their baseline von Frey thresholds are equal to or in the vicinity of the cutoff value of 15 g. This is evidence of animal stress and anxiety or of an inadequately chosen testing method. Also, saline controls seemed to be better responders than any of the remifentanil-treated groups, suggesting some differences in animal handling between the groups. Finally, if mechanical and thermal thresholds were measured simultaneously in the same animals, it is possible that tail skin sensitized by repeated thermal stimulation also became sensitive to mechanical stimulation that manifested as decreased von Frey thresholds. Also, if mechanical thresholds were measured not on the tail as we are presuming but on the rat hindpaws, there is still a possibility that the observed hypersensitivity was due to thermal injury of the tail, because the injury to the tail can cause hyperalgesia in the hindpaws.8,9 Opioid-induced hyperalgesia is a topic about which there is some disagreement in the analgesia research community.10 Most evidence supporting its existence comes from behavioral studies in rodents. To have any clinical implications, these studies must be based on reliable methodology. Andrey B. Petrenko, MD, PhD Hideaki Ishii, MD, PhD Tatsuro Kohno, MD, PhD Hiroshi Baba, MD, PhD Division of Anesthesiology Niigata University Graduate School of Medical and Dental Sciences Niigata, Japan [email protected]