Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects

Abstract

Background: The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering. Methods: Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34°C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response. Results: Nefopam did not significantly modify the slopes for sweating (0.0 ± 4.9°C · μg -1 · ml; r 2 = 0.73 ± 0.32) or vasoconstriction (-3.6 ± 5.0°C · μg -1 · ml; r 2 = -0.47 ± 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 ± 9.3°C · μg -1 · ml; r 2 = 0.92 ± 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 ± 0.4°C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds. Conclusions: Most drugs with thermoregulatory actions-including anesthetics, sedatives, and opioids-synchronously reduce the vasoconstriction and shivering thresholds. However, nefopam reduced only the shivering threshold. This pattern has not previously been reported for a centrally acting drug. That pharmacologic modulations of vasoconstriction and shivering can be separated is of clinical and physiologic interest.