IN 2003, I commented on the decision by the US Food and Drug Administration (FDA) to issue a so-called black box warning on the use of droperidol for antiemetic prophylaxis.1Other authors have also expressed concern regarding what is widely viewed as an inappropriate action by the FDA.2,3The risk of developing ventricular dysrhythmias as a result of the administration of droperidol is again being addressed by two articles in this issue of Anesthesiology. White et al. 4demonstrated a prolongation of QTc when droperidol (either 0.625 or 1.25 mg) is administered intravenously at the beginning of surgery for prophylaxis of postoperative nausea and vomiting (PONV). However, the observed prolongation was not statistically different from that seen in those patients receiving saline placebo. Charbit et al. 5compared QTc prolongation in patients receiving either 0.75 mg droperidol or 4 mg ondansetron for the treatment of PONV in patients experiencing symptoms while in the postanesthesia care unit after surgery. The observed mean maximal prolongation in QTc (17 ± 9 ms for droperidol and 20 ± 13 ms for ondansetron) was consistent with the QTc prolongation reported by White et al. 4(12 ± 35, 15 ± 40, and 22 ± 41 ms for placebo, 0.625 mg droperidol, and 1.25 mg droperidol, respectively).
One must ultimately ask, what do these findings mean? However, an even more fundamental question is, why were these studies undertaken in the first place? QTc prolongation with the administration of droperidol has been known to occur since the drug was approved for use more than 30 yr ago. This phenomena is not unique. Indeed, potent inhalation anesthetics,6thiopental,7propofol,8succinylcholine,9and drugs for reversing neuromuscular blockade10have all been shown to increase QTc. Of particular note is the fact that virtually all of the currently available antiemetics, including phenothiazines, antihistamines, and selective (5-hydroxytryptamine type 3) serotonin receptor antagonists, as reconfirmed by Charbit et al. ,5increase QTc. Why would this journal consume valuable space to apparently restate the obvious?
By applying the black box warning to droperidol, the FDA has essentially removed one of the most effective and cost-efficient antiemetics from clinical use. This decision was based on 273 cases reported to the FDA between November 1, 1997, and January 2, 2002. Of those cases, 127 resulted in serious adverse outcomes. The details of these cases have been extensively reviewed elsewhere.2,11Nevertheless, several points are worth reiterating. Of the 127 cases, 94 were reported from outside the United States. Of all the cases reported, there were only 10 in which serious adverse cardiovascular events were reported when doses of 1.25 mg or less were administered. A careful analysis of those cases did not detect any evidence of a cause-and-effect relation between the arrhythmia observed and the administration of droperidol.2
Since its introduction into clinical practice in 1970, literally hundreds of millions of doses of droperidol have been administered for both the prevention and the treatment of PONV, but there has never been a single case report of dysrhythmia. Both of the studies presented here confirm that the peak QTc prolongation with the administration of droperidol occurs within minutes after administration. If QTc prolongation is indeed the underlying mechanism for dysrhythmias, it is inconceivable that case reports would not have appeared in the literature. It has been argued that a mechanistic basis for droperidol QTc prolongation is sufficient criteria for the action taken by the FDA.12Strict adherence to that mechanistic principle would have interesting and absurdly humorous effects. To reiterate, White et al. 4demonstrated that a saline placebo has QTc prolongation indistinguishable from that of droperidol when administered before general anesthesia. Charbit et al. 5showed that there was no difference in QTc prolongation between droperidol and ondansetron when administered postoperatively for PONV. If the FDA were to be consistent in its application of policy, both general anesthesia (or perhaps all anesthetic agents) and ondansetron (as well as all other selective [5-hydroxytryptamine type 3] serotonin receptor antagonists) should carry the same black box warning. The two studies here seem to indicate that if the decision regarding which antiemetic to use is based on QTc prolongation, the alternatives are no better than droperidol.
In 1992, the Prescription Drug User Fee Act allowed the FDA to augment its budget by charging fees to pharmaceutical firms.13Approximately $825 million have been collected between 1993 and 2001.14It has also been reported that more than half of the members of the FDA expert advisory panels had direct financial interests in the products being evaluated.15In addition, the FDA has been subjected to intense lobbying by the pharmaceutical industry. These facts alone make it impossible not to suspect the possibility of conflict of interest, which is further confirmed by the recent events. For example, it took legal action by the New York Attorney General to bring to light the link between teenage suicide and the use of selective serotonin reuptake inhibitors.16More recently, concerns about the suppression of data regarding increase cardiovascular mortality associated with the use of certain cyclooxygenase-2 inhibitors have been widely publicized. Decisions about frequently prescribed, patent-protected medications have tremendous financial implications for their manufacturers. No such financial incentive exists for inexpensive generic formulations. In fact, it is tempting to speculate that when a generic medication is in direct competition with a more expensive proprietary medication, financial considerations may affect the decision-making process.
No one, save practicing clinicians, speaks for droperidol. In the doses routinely used for the prevention and treatment of PONV, its safety is unparalleled. The argument by the FDA that the minimum approved dose is 2.5 mg and the use of smaller doses is outside the jurisdiction of the FDA is clearly specious and does a tremendous disservice to the American public. The true incidence of dysrhythmias resulting from the administration of “low-dose” droperidol is likely to be vanishingly small. The number of patients necessary to establish the actual incidence is unknown. The cost of the study would be prohibitive and would not be a prudent use of research dollars. Consequently, we are left with studying surrogate endpoints, such as the phenomena of QTc prolongation reported in this issue of Anesthesiology,4,5as an indirect attempt at establishing the “safety” of droperidol. However, the current position adopted by the FDA leaves clinical scientists and practicing physicians with an impossible task—proving a negative. And, as Eger17pointed out more than 25 yr ago, you can’t disprove the existence of dragons.
Wake Forest University School of Medicine, Winston-Salem, North Carolina. email@example.com