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The Effects of Nefopam on the Gain and Maximum Intensity of Shivering in Healthy Volunteers

BACKGROUND: Mild hypothermia has been shown to improve neurologic outcome after cardiac arrest. Nefopam, a centrally acting, nonsedative analgesic, decreases the threshold of shivering, but not vasoconstriction, and thus might be a suitable drug for induction of therapeutic hypothermia. However, not only the threshold but also the gain and maximum intensity of shivering define the thermoregulatory properties of a drug and thus are clinically important. Therefore, we evaluated the gain and maximum intensity of shivering at 2 different doses of nefopam and placebo. METHODS: Seven healthy volunteers were randomly assigned to 3 study days: (1) control (saline), (2) small-dose nefopam (50 ng/mL), and (3) large-dose nefopam (100 ng/mL). On all study days volunteers were cooled using central venous infusion of cold IV fluid while mean skin temperature was maintained at 31°C. Core temperature was recorded at the tympanic membrane. Threshold, gain, and maximum intensity of shivering were evaluated using oxygen consumption. RESULTS: Both 50 and 100 ng/mL nefopam significantly reduced the shivering threshold as well as the gain of shivering: shivering threshold: 35.6°C ± 0.2°C (control); 35.2°C ± 0.3°C (small dose); 34.9°C ± 0.5°C (large dose), P = 0.004; gain of shivering: 597 ± 235 mL · min−1 · °C−1 (control); 438 ± 178 mL · min−1 · °C−1 (small dose); 301 ± 134 mL · min−1 · °C−1 (large dose), P = 0.028. Maximum intensity of shivering did not differ among the 3 treatments. CONCLUSIONS: Nefopam significantly reduced the gain of shivering. This reduction, in combination with a reduced shivering threshold, will allow clinicians to cool patients even further when therapeutic hypothermia is indicated.