Nefopam and Meperidine Are Infra-Additive on the Shivering Threshold in Humans

BACKGROUND: Induction of therapeutic hypothermia is often complicated by shivering. Nefopam, a nonsedative benzoxazocine analgesic, reduces the shivering threshold (triggering core temperature) with minimal side effects. Consequently, nefopam is an attractive drug for inducing therapeutic hypothermia. However, nefopam alone is insufficient and thus needs to be combined with another drug. Meperidine also reduces the shivering threshold. We therefore determined whether the combination of nefopam and meperidine is additive, infra-additive, or synergistic on the shivering threshold. METHODS: Ten volunteers were each studied on 4 randomly assigned days. In random order, they were given the following treatments: (1) control, no drug; (2) nefopam to a target concentration of 0.1 μg/mL; (3) meperidine to a target concentration of 0.1 μg/mL; and (4) both nefopam and meperidine at target concentrations of 0.1 μg/mL each. Lactated Ringer's solution at 4°C was infused to decrease core temperature while mean skin temperature was kept near 30.5°C. The core temperature that increased oxygen consumption >25% defined the shivering threshold. RESULTS: Nefopam reduced the shivering thresholds by 0.7°C ± 0.3°C compared with no drug. Meperidine reduced the shivering thresholds by 0.4°C ± 0.3°C compared with no drug. When combined, the shivering threshold decreased by only 0.6°C ± 0.4°C, which was about half what would have been expected based on the individual effects of each drug (P < 0.001). The effect of combined nefopam and meperidine on the shivering threshold was thus infra-additive. CONCLUSIONS: The combination of nefopam and meperidine should be avoided for induction of therapeutic hypothermia. Better options would be combinations of drugs that are at least additive or even synergistic.