Correspondence
Treatment of Acute Repetitive Seizures
N Engl J Med 1998; 339:1856-1857December 17, 1998
- Article
To the Editor:
The study by Dreifuss et al. (June 25 issue)1 comparing rectal diazepam gel with placebo for the treatment of acute repetitive seizures raises the issue of whether the use of placebos in studies of serious illness for which accepted therapy exists is ethical.2 Apparently, the institutional review boards at the 11 institutions involved believed that “regular review” by an independent monitoring board and a single unblinded interim analysis provided adequate protection for children and adults with recent episodes of acute repetitive seizures who were randomly assigned to receive placebo, even though as the authors point out, “left untreated, acute repetitive seizures can evolve into more serious problems, including status epilepticus.” Fortunately, none of the 91 treated subjects had progression to status epilepticus; however, 13 percent of the subjects in the placebo group did require emergency medical care (as compared with 0 percent of those receiving active treatment), and approximately 75 percent of the subjects in the placebo group had recurrent seizures within 12 hours after the initial dose (as compared with 35 percent of those in the diazepam group). This study was not innocuous for the control subjects.
How many other institutional review boards declined to approve this presumably manufacturer-initiated study? As I have pointed out, there are no agreed-on standards for institutional review boards to use in evaluating proposals that include placebo controls,3 and one would suspect that many institutional review boards would not have approved this proposal.
3 ReferencesRobert D. Orr, M.D.
Loma Linda University Medical Center, Loma Linda, CA 923541
Dreifuss FE ,Rosman NP ,Cloyd JC , et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 1998;338:1869-1875
Full Text | Web of Science | Medline2
Rothman KJ ,Michels KB . The continuing unethical use of placebo controls. N Engl J Med 1994;331:394-398
Full Text | Web of Science | Medline3
Orr RD . Guidelines for the use of placebo controls in clinical trials of psychopharmacologic agents. Psychiatr Serv 1996;47:1262-1264
Web of Science | Medline
To the Editor:
It is incomprehensible how Dreifuss et al. reached their decision to treat a control group of children and adults with seizures with a placebo. The ill effects of nontreatment are well demonstrated in the study.
Instead of placebo, the rectal diazepam gel could have been compared with a parenteral solution of diazepam administered rectally; with oral, sublingual, or nasal medazepam; or even with different doses of the rectal diazepam gel. In addition to being ethically unacceptable, the use of a placebo control meant that a great opportunity was missed to provide more important and practical clinical data than the fact that diazepam can indeed stop seizures.
Quite often, the actual use of a newly approved antiepileptic drug differs from the indication approved by the Food and Drug Administration. It is very likely that rectal diazepam gel will be used extensively for the treatment of status epilepticus by care givers. Because of obvious methodologic and safety issues (e.g., in the event of a single death during an episode of status epilepticus, the trial could have been stopped prematurely), Dreifuss et al. studied a subgroup of patients with a less critical disorder. Therefore, crucial clinical questions, such as the safety and efficacy of rectal diazepam in patients in status epilepticus and the effect of early treatment on the final outcome of an episode of status epilepticus, remain unanswered.
Yuval Shafrir, M.D.
Georgetown University Children's Medical Center, Washington, DC 20007Author/Editor Response
The authors reply:
To the Editor: Orr and Shafrir express concern about whether the use of a placebo control in our study of rectal diazepam gel for the treatment of acute repetitive seizures was ethical. In reply to Orr: no institutional review board (not even those at centers that did not participate) failed to approve our study. There is no consensus on the management of cluster seizures: some practitioners do not intervene; others advise increases in the dose of the patient's usual anticonvulsant; still others send patients to emergency rooms. We conducted a randomized, double-blind, placebo-controlled study of the treatment of acute repetitive seizures. We did not treat “children and adults with seizures,” as Shafrir states, but rather we treated children and adults in whom these seizures were developing on the basis of the opinion of a trained care giver. We did not assess the efficacy of rectal diazepam in patients in status epilepticus. Patients whose acute repetitive seizures habitually progressed to status epilepticus were ineligible for the study, an important safeguard. Each patient had a care giver who was trained to identify, treat, and monitor seizures and to determine whether emergency care was needed. A study nurse spoke with the care giver before and after each study dose was administered. Shafrir states that we could have studied different doses of rectal diazepam gel or compared rectal diazepam gel with a parenteral solution of diazepam given rectally. The placebo-controlled design that we chose, however, avoided the problems of interpreting the results of an active-control trial and increased the likelihood that a treatment difference would be found.
N. Paul Rosman, M.D.
New England Medical Center, Boston, MA 02111James C. Cloyd, Pharm.D.
University of Minnesota, Minneapolis, MN 55455Walter E. Bell, Ph.D.
National Institutes of Health, Bethesda, MD 20892
