Nefopam and Alfentanil Additively Reduce the Shivering Threshold in Humans whereas Nefopam and Clonidine Do Not

Background: Induction of therapeutic hypothermia is often complicated by shivering. Nefopam, reduces the shivering threshold with minimal side effects. Consequently, nefopam is an attractive component for induction of therapeutic hypothermia. However, nefopam alone is insufficient; it will thus need to be combined with another drug. Clonidine and alfentanil each reduce the shivering threshold. This study, therefore, tested the hypothesis that nefopam, combined either with clonidine or alfentanil, synergistically reduces the shivering threshold. Methods: For each combination, ten volunteers were studied on 4 days. Combination 1: (1) control (no drug); (2) nefopam (100 ng/ml); (3) clonidine (2-5 mu g/kg); and (4) nefopam plus clonidine (100 ng/ml and 2.5 mu g/kg, respectively). Combination 2: (1) control (no drug); (2) nefopam (100 ng/ml); (3) alfentanil (150 ng/rid); and (4) nefopam plus alfentanil (100 ng/ml and 150 ng/ml, respectively). Lactated Ringer's solution. (approximately 4 degrees C) was infused to decrease core temperature. Mean skin temperature was maintained at 31 degrees C. The core temperature that increased oxygen consumption to more than 25% of baseline identified the shivering threshold. Results: With nefopam and clonidine, the shivering thresholds were significantly lower than on the control day. The shivering threshold decreased significantly less than would be expected on the basis of the individual effects of each drug (P = 0.034). In contrast, the interaction between nefopam and alfentanil on shivering was additive, meaning that the combination reduced the shivering threshold as much as would be expected by the individual effect of each drug. Conclusions: Nefopam and alfentanil additively reduce the shivering threshold, but nefopam and clonidine do not.