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Preclinical and clinical evidence indicates that locally administered opioid agonists produce an antihyperalgesic effect through peripheral opioid receptors in inflamed tissue. Loperamide, a [micro sign] opioid agonist, does not cross the blood-brain barrier and therefore lacks central effects after systemic administration. The authors defined the effects of topical loperamide on a thermal injury-induced hyperalgesia.In halothane-anesthetized rats, thermal injury was induced by placing the plantar surface of a hindpaw on a hot plate (52.0 +/− 1 [degree sign]C) for 45 s. Loperamide was prepared in a cream emulsion (ADL 2-1294B, 0.5%, 1.7%, and 5.0%). The drug was applied as follows: before or after injury on the injured paw and on a normal paw and after injury on the injured paw of morphine-tolerant rats. Paw withdrawal latency to a radiant heat source was measured to determine the nociceptive threshold. A pharmacokinetic study was performed with the use of14 C-labeled drug.Thermal injury yielded a significant thermal hyperalgesia. Loperamide, but not the vehicle, posttreatment on the injured paw resulted in a dose-dependent antihyperalgesic effect, which was reversible with naloxone (1 mg/kg given intraperitoneally). Treatment with loperamide on the normal paw produced short-lasting hypoalgesia, but the effect was not reversible with naloxone. Pretreatment at 1 and 2 but not 4 h with loperamide was effective. A rightward shift of the dose-response curve was observed in rats made tolerant to systemic morphine with subcutaneous morphine pellets. No rats with drug treatment displayed any evident behavior changes (e.g., loss of corneal or pinna reflexes or change in ambulation). Drug activity in the tissue revealed an elimination half life of 2.3 h and negligible concentration in the blood.Loperamide, a peripherally acting [micro sign] opioid agonist, applied topically at the site of inflammation possesses a significant antihyperalgesic action without any systemic side effects.