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ANESTHETIC PHARMACOLOGY

Detection of Acute Tolerance to the Analgesic and Nonanalgesic Effects of Remifentanil Infusion in a Rabbit Model

Masakazu Hayashida, MD PhD^*, Atsuo Fukunaga, MD PhD, and Kazuo Hanaoka, MD PhD^*

*Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and the Department of Anesthesiology, Harbor UCLA Medical Center, Torrance, California

Address correspondence and reprint requests to Masakazu Hayashida, MD, Research Hospital Surgical Center, Institute of Medical Science, The University of Tokyo, 4–6-1 Shiroganedai, Minato-ku, Tokyo, 108–8639, Japan. Address email to hayashida-todai{at}umin.ac.jp

Although acute tolerance to analgesia develops rapidly with remifentanil, it is unknown whether acute tolerance also develops to its nonanalgesic effects. We investigated the analgesic and cardiorespiratory effects of remifentanil during a continuous infusion in a rabbit model. Ten tracheotomized New Zealand White rabbits with arterial and venous accesses were placed on a sling that allowed for reasonably free movement. In spontaneously breathing conscious animals, remifentanil was infused IV at a constant-rate of 0.3 µg · kg^-1 · min^-1 for 360 min. Sedative/analgesic and cardiorespiratory variables were assessed repeatedly during remifentanil infusion, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and subcutaneous electrical stimulation thresholds required to elicit head lift (HLT: pain detection/arousal threshold) and escape movement responses (EMT: pain tolerance threshold). Within 60–120 min of starting the infusion, the number of nonresponders, HLT, EMT, and PaCO₂ increased significantly, whereas blood pressure, heart rate, and respiratory rate decreased. Thereafter, all variables returned towards preinfusion levels despite continuing infusion. These results indicate that during a remifentanil infusion acute tolerance develops for both its analgesic and cardiorespiratory effects.

IMPLICATIONS: Using a new rabbit model, we found that during continuous, constant-rate remifentanil infusion acute tolerance developed within the first few hours, not only to its analgesic but also to its cardiovascular and respiratory effects, albeit in slightly different time courses.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999