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

Alfonsi, Pascal MD*; Passard, Andrea MD; Guignard, Bruno MD; Chauvin, Marcel MD; Sessler, Daniel I. MD

doi: 10.1213/ANE.0000000000000193
Anesthetic Pharmacology: Research Report

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.

Published ahead of print May 7, 2014

From the *Department of Anesthesia, Hôpital Cochin, AP-HP, Paris, France; Department of Anesthesia, Hôpital Ambroisse Paré, AP-HP, Paris, France; and Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio.

Accepted for publication December 31, 2013.

Published ahead of print May 7, 2014

Funding: Supported by the Medical Research Association (Boulogne, France), Laboratoires Biocodex (Compiègne, France), and the Joseph Drown Foundation (Los Angeles, CA). The sponsors were not involved in subject recruitment, data acquisition, or analysis of results. None of the investigators has a personal financial interest in this research.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the American Society of Anesthesiologists Congress 2005 and French National Congress 2005.

Reprints will not be available from the authors.

Address correspondence to Pascal Alfonsi, MD, Department of Anesthesiology and Intensive Care, Hôpital Cochin, 27, Rue du Faubourg Saint Jacques, Paris, 75014, France. Address e-mail to On the World Wide Web:

© 2014 International Anesthesia Research Society