To the Editor:—
We would like to address several points raised by Dr. Scuderi in his recent editorial entitled “Droperidol: Many questions, few answers.”1
Dr. Scuderi rightfully points out that the recent Food and Drug Administration (FDA) “black box” warning on droperidol may “overshadow” many other important issues involving the treatment of postoperative nausea and vomiting (PONV). Indeed, as Dr. Scuderi has suggested, the power of the black box warning is so great that many clinicians are now reluctant to use droperidol because of medicolegal concerns, despite its long and successful track record. The FDA-imposed black box warning on droperidol has rendered the results of numerous, placebo-controlled, comparative clinical trials practically moot.
An important question that remains unanswered relates to how the FDA make its assessment that a black box warning—its most serious “indictment”—is merited? To date, we, as well as other experts in the field (personal written communications with Tong J. Gan, M.B, Department of Anesthesiology, Duke University, Durham, North Carolina, and Mehernoor F. Watcha, M.D., Department of Anesthesiology & Critical Care Medicine, Children's Hospital of Philadelphia, Philadephia, Pennsylvania, on May 25, 2003), remain totally unconvinced that the process is objective, adequate, or even rational. Indeed, the database summarizing the “reported” adverse events with droperidol is seriously flawed. 2Furthermore, it is unclear whether any effort was made by the FDA to validate the “sources” of these alleged adverse events? The attention given the FDA black box warning by anesthesiologists is very surprising in light of the extensive peer-reviewed literature on the safety and efficacy of low-dose droperidol. 3
Previous experience with other often-used “generic” anesthetic drugs (e.g. , succinylcholine) has demonstrated that the FDA black box process is less than perfect. 4Interestingly, somewhere between 10 and 20% of all FDA-approved drugs eventually receive some sort of black box warning. 5The popular sedative-anxiolytic drug midazolam (Versed®; Roche Laboratories, Nutley, New Jersey) received a black box warning regarding respiratory depression because a large number of patients died from iatrogenic “overdosing” of the drug by nonanesthesiologists (e.g. , gastroenterologists, pulmonary specialists). Did anesthesiologists stop administering midazolam to their patients in the wake of that black box warning? Obviously not. What would be the impact if clinicians believed that they could no longer administer otherwise useful drugs that have received black box warnings (e.g. , cyclosporine, atenolol, metoprolol, or ketorolac)? At both of our teaching institutions, droperidol remains approved by the hospital pharmacy and therapeutics committees for the prophylaxis and treatment of PONV. Although droperidol remains in widespread clinical use, Dr. Scuderi's recent editorial will make some anesthesia providers less comfortable about using this cost-effective antiemetic drug in the future.
Dr. Scuderi also implies that in keeping with the notion of primum non nocere (first, do no harm), perhaps the benefits of prophylaxis against PONV are outweighed by the risks of these therapies. He further states that we have insufficient data to address this matter and, thus, we cannot make a rational decision. We strongly disagree! First, very good data exist documenting the cost-effectiveness 6,7and safety of droperidol, 8as well as the patient concerns regarding PONV 9and its impact on patient satisfaction. 10These facts, combined with our knowledge of the mechanisms of PONV and its effective pharmacologic treatment, has led most experts to conclude that low-dose droperidol (0.625–1.25 mg IV) is the most rational choice for prophylaxis in patients at risk of developing PONV. Does Dr. Scuderi really believe that there may be less risk in allowing these patients to vomit compared to administering antiemetic prophylaxis with low-dose droperidol? When our patients express concerns regarding PONV, are we supposed to tell them, “Oh don't worry, a little throwing up won't hurt you!”
As noted by Dr. Scuderi, many different types of drugs prolong the electrocardiographic QT interval (including the popular antiemetic drugs dolasetron [Anzemet®; Abbott Laboratories, Chicago, Illinois] and ondansetron [Zofran®; Glaxo Smith Kline, Research Triangle Park, New Jersey]).There are no data demonstrating that these 5-HT3antagonists are any safer than droperidol with respect to adverse cardiac events. The two frequently cited studies of QT prolongation by droperidol involved large (0.1–0.25 mg/kg) doses of the drug. 11,12The question of QT prolongation with low-dose droperidol is a red herring. As Dr. Scuderi concluded in his recent editorial, questioning the safety of droperidol is about “as productive as arguing about how many angels can dance on the head of a pin.” What funding agency would be willing to pay for additional prospective studies involving a generic drug with a well-established safety and efficacy profile? The FDA has already declined! More important, what truly informed patient would consent to participate in a placebo-controlled study involving an antiemetic drug with proven efficacy in preventing this common postoperative side effect?
With patient safety at the top of everyone's list of concerns, we should be devoting our attention to addressing important healthcare issues. It is time for the FDA, along with experts in the field, to resolve that a “mountain has been made of a mole hill” in the case of droperidol's safety when administered in appropriate doses for antiemetic prophylaxis and treatment. We maintain that the FDA-mandated black box warning on droperidol is not only undeserved but also detrimental to the provision of cost-effective patient care. The FDA black box warning and the consequences of this dubious act may very well cause more harm than good to our patients!
