Naloxone, meperidine, and shivering

Meperidine, which binds both mu and kappa opioid receptors, is reportedly more effective in treating shivering than are equianalgesic doses of morphine (a nearly pure mu-receptor agonist). Furthermore, butorphanol, a kappa-receptor agonist/antagonist, treats shivering better than does fentanyl, which mostly binds mu receptors. These data indicate that much of meperidine's special antishivering activity may be mediated by its kappa activity. Accordingly, the authors tested the hypothesis that the antishivering activity of meperidine will be minimally impaired by low-dose naloxone (blocking most mu-receptors), but largely prevented by high-dose naloxone (blocking all mu and most kappa receptors).

Twelve volunteers each participated on 2 days. On both days, shivering was induced by central venous infusion of cold fluid. Twenty minutes later, six volunteers were given a placebo infusion of saline on one day, or an infusion of 0.5 microgram.kg-1.min-1 naloxone hydrochloride ("low-dose," designed to block mu receptors) on the other. The second group of six volunteers was given a saline bolus and infusion on one day, or a bolus of 11.5 micrograms/kg naloxone hydrochloride followed by an infusion of naloxone at 5 micrograms.kg-1.min-1 ("high-dose," designed to block both mu and kappa receptors) on the other day. The infusions were continued for the duration of the study. The order of the treatment days (saline vs. naloxone) was randomly assigned, and the study was double blinded. Fifteen minutes after the test infusion was started, all 12 volunteers were given an intravenous bolus of 1 mg/kg meperidine hydrochloride. Pupillary diameter and light reflex amplitude were used to quantify opioid-receptor agonist activity; shivering intensity was evaluated using oxygen consumption.

Administration of naloxone alone did not alter oxygen consumption, pupil size, or the pupillary light reflex. No pupillary constriction was detected in either group when naloxone and meperidine were combined; in contrast, meperidine alone decreased pupil size and amplitude of the light reflex 30%. The meperidine bolus decreased oxygen consumption nearly to control values when the volunteers were given saline placebo. Combined administration of meperidine and low-dose naloxone also significantly reduced oxygen consumption, but the reduction and the duration of the reduction was less than during saline. When the volunteers were given high-dose naloxone, meperidine only slightly reduced oxygen consumption, and the values rapidly returned to premeperidine levels.

These data indicate that the antishivering property of meperidine is not fully mediated by mu-receptors. Although meperidine has well-known nonopioid actions, stimulation of kappa receptors seems a likely alternative explanation for much of the drug's antishivering action.