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Department of Anesthesia and Intensive Care, University of Rome "La Sapienza", Rome, Italy
To the Editor:
We question why in their study investigating drugs for preventing postanesthetic shivering Piper et al compared placebo with dolasetron and clonidine (1). We also wonder why they state that "a dose-response study would be scientifically important and economically justified only if its side-effect profile were significantly superior to that of established drugs."
In a similar study conducted in 1999, Piper et al compared placebo with nefopam and clonidine (2). Despite showing a significantly lower incidence of postanesthetic shivering in patients treated with nefopam (0.15 mg/kg IV) or clonidine (3 µg/kg) than placebo (5% vs. 15% vs. 60% ), they showed that nefopam and clonidine are both effective in the prevention of postanesthetic shivering and that neither drug induces significant adverse effects, concluding that ". . .nefopam is probably a better drug to use than clonidine for the prevention of postanesthetic shivering (2)."
The nonopioid analgesic nefopam is also effective in preventing the hemodynamic and metabolic demands of shivering while inducing practically no adverse reactions (3). Why did Piper et al. in this study therefore compare dolasetron with clonidine? What is the point of seeking a possible antishivering effect in dolasetron, when nefopam, a less costly drug, is effective and induces practically no adverse reactions?
References
Department of Anesthesiology, Klinikum Ludwigshafe, Ludwigshafen, Germany, wolfgang_maleck@hotmail.com
In Response:
Thank you for the opportunity to answer to the letter of Bilotta and Rosa concerning our publication in Anesthesia & Analgesia (1). Bilotta and Rosa have two main points where they argue with our study.
First, they ask why we compared the experimental drug (dolasetron) with clonidine rather than nefopam. They base their suggestion to use nefopam on two studies by Rosa et al. (2) and our group (3) that in their opinion showed an advantage of nefopam over clonidine. In Rosa’s study in neurosurgical patients (n = 20 per group), comparing 20 mg of nefopam with 150 µg of clonidine, a lower rate of shivering after nefopam was indeed shown. In our study (also n = 20 per group) comparing 0.15 mg/kg of nefopam versus 3 µg/kg clonidine in abdominal and orthopedic surgery, there was no significant difference in the incidence of shivering after clonidine and nefopam, although there was a trend favoring nefopam. Our recommendation to prefer nefopam was based on the slightly (about 4 min) but significantly prolonged time to extubation in the clonidine group. In any case, these are the only studies known to us that directly compared the efficacy of nefopam and clonidine as antishivering agents, and two studies with 20 patients per group each are, in our opinion, not enough to show a clear advantage of one of these drugs over the other. More importantly, an ad hoc Medline search [www.ncbi.nlm.nih.gov/Pubmed, accessed Friday, March 29, 2002; search item: (clonidin* OR nefopam*) AND shiver*] as well as three recent reviews on shivering (4–6) identified some 30 original papers on clonidine as a perianesthetic antishivering agent (including six reports on its use after epidural or spinal anesthesia, but excluding studies in volunteers), whereas only seven original papers on the use of nefopam to treat or prevent postanesthetic shivering were found. In addition, the papers on nefopam originated from only two countries (Italy and Germany), whereas the clonidine papers, albeit showing a continental European dominance, were from seven different countries. Finally, nefopam is to our knowledge not available in North America. Consequently, we consider clonidine, but not nefopam, to be an internationally established antishivering drug against which new drugs can be tested.
Second, Bilotta and Rosa argue that a dose-response study with dolasetron would not be justified considering the high cost of dolasetron, as nefopam is cheaper. Although economic aspects have rightfully achieved high importance in modern medicine, it should be kept in mind that such arguments are highly variable in space and time. The availability and cost of drugs vary between countries, and often within countries, as hospitals may get drugs below list prices. Also, prices vary over time, and as some of the older "setrons" are approaching the end of patent protection, it is likely that their prices will decline soon. The advantage of ondansetron (7) or dolasetron (8) as antishivering agents would be that they solve two problems–shivering and postoperative nausea and vomiting (PONV)–with one drug, whereas most other antishivering agents (including nefopam) are mildly proemetic. Consequently, a study to determine the minimum effective dose of dolasetron for prevention of shivering would be scientifically and ethically sound, and its results might even save money at least in patients who receive dolasetron anyway for prevention of PONV.
References
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