flurazepam (both statistically significant). For. 0-25 mg of triazolam, despite a reduction in statis- tical power, subjects were still more likely than controls to drop ...
Mr Michael Gerrard is not a board member. He was appointed to his position in the hospital after a normal job application, not as the result of a vacancy being "filled by the board from among their associates." Mr Gerrard was appointed as accountant by the hospital in February this year. Subsequently he was appointed financial controller, and later as director of finance. At all times he has been, and continues to be, employed by the hospital, not by the management company. He is not, and has not been, participating in promoting or managing a company with regard to the Royal Masonic Hospital. Tim Tyndale resigned as a result of disagreements with the then chairman of the board of management, and not over disagreements with members of the board. Justin Gravestock-Bames was appointed acting chief executive for a probationary period by the board of management. He was not "appointed chief executive of a new limited company." There have been no attempts to replace GravestockBarnes immediately. To say that "attempts to replace him have so far failed" is untrue. Grahan Ford is managing director and not acting chief executive. He stepped down as chairman of the board to fulfil this role. The BMY was informed, in response to a question, that the subject matter referred to in the Evening Standard article was not on the agenda for the annual general meeting in December, and that it could only be so if someone were to table it as a resolution. Any company or other concern is likely to discuss future plans at an annual general meeting; the BMJ 's implication is to emphasise this more than the situation actually warrants. Derogatory remarks in the press could certainly be responsible for adversely affecting patient intake. However, with the continued support of our consultants the tradition of The Royal Masonic Hospital, which we are celebrating in this our diamond jubilee year, is being maintained. The management enjoys the total confidence of the staff. E JAMES DAVIES
Royal Masonic Hospital, London W6 OTN 1 Godlee F. Future of Royal Masonic Hospital is in doubt. BMJ
1993;307:467-8. (21 August.)
Triazolam Narrow safety margin is unacceptable EDrIOR,-Jeffrey M Jonas's statement that the Food and Drug Administration (FDA) "reaffirmed that triazolam has an acceptable margin of safety"' is only a fraction of the total story and thus needs to be completed and clarified. Below is information omitted by Dr Jonas. The staff of the FDA Division of Epidemiology and Surveillance has repeatedly documented that triazolam produces extremely high rates of severe neuropsychiatric adverse reactions compared with other benzodiazepines.2 Also, they recently concluded that triazolam is qualitatively different from other benzodiazepines in its capacity to produce neuropsychiatric adverse effects (unpublished data). After drug regulatory actions in France, Italy, and West Germany against 0 5 mg of triazolam, Upjohn lowered the recommended starting dose in the United States to 0-25 mg in 1988. At the most recent FDA hearing on triazolam, FDA staff reported their analysis of 25 of Upjohn's clinical trials of triazolam 0 5 mg and 0-25 mg. For 0 5 mg they noted high rates for "all psychiatric" side effects and high drop out rates for subjects given triazolam for longer than two weeks. These rates were seven times greater than those for placebo and two to three times greater than those for
626
flurazepam (both statistically significant). For 0-25 mg of triazolam, despite a reduction in statistical power, subjects were still more likely than controls to drop out because of psychiatric side effects; there was a nearly sixfold greater risk than for placebo and significantly more (threefold to fourfold) risk for drop outs because of anxiety than for flurazepam (unpublished data). In 1989 the FDA changed triazolam's labelling to reflect a greater risk of amnesia with triazolam. Following the most recent FDA hearing in 1992, it changed the labelling again to reflect a greater risk of daytime anxiety and also to emphasise that triazolam should be used only for a very short period (7-10 days). In summary, FDA staff have presented considerable data showing that triazolam produces high rates of severe neuropsychiatric adverse reactions; expressed many concerns regarding triazolam's safety; approved the reduction of the starting recommended dose from 0 5 mg to 0 25 mg; and initiated a number of labelling changes regarding neuropsychiatric adverse reactions. All of this occurred despite the fact that the final authority for these decisions rested with the Division of Neuropharmacologic Drug Products, whose staff were responsible for originally approving the use of the 0 5 mg dose in the United States-over objections from their own monitors of triazolam. ANTONIO VELA-BUENO
Department of Psychiatry, Autonomous University School of Medicine, 28008 Madrid, Spain 1 JonasJM. Triazolam. BMJ 1993;307:328. (31 July.) 2 Wysowski DK, Barash D. Adverse behavioral reactions attributed to triazolam in the Food and Drug Administration's Spontaneous Reporting System. Arch Intern Med 1991;151: 2003-8.
Small studies miss the difference EDrIOR,-Jeffrey M Jonas of Upjohn touches on an important topic in medical research in his letter on triazolam.' Failure to find is not the same as refutation. It is often a consequence of poor research design, inappropriate study populations, or inadequate statistical power owing to too few subjects being studied. In our research we found that triazolam caused anxiety, panics, depression, paranoid reactions, and weight loss in 40 subjects compared with 40 who received placebo and 40 who received lormetazepam.2 No refereed publication describing research that has repeated the conditions of our research-the design, dose used, subjects averaging mid-50s in age, a trial of over two weeks' duration-has failed to come to conclusions like our own, except a paper by Bliwise et al.3 Bliwise et al studied only seven subjects and the power of the design was only 0-26, which means that, as Raskin (of Upjohn) has testified,4 this research sponsored by Upjohn was three times more likely to miss the truth than to find it. The results of our research were confirmed by the Food and Drug Administration's analysis in 1992 of the unpublished results of Upjohn's own research on triazolam.5 KIRSTINE ADAM IAN OSWALD
Innerleithen, Peeblesshire EH44 6RB
The evidence against is extensive and consistent EDrrOR,-Jeffrey M Jonas, Upjohn's spokesman, again questions the clear cut documentation in our petition to the Food and Drug Administration (FDA).' Our petition requests that triazolam be removed from the market due to an inadequate benefit:risk ratio which is based on high rates of severe psychiatric adverse reactions, narrow margin of safety, and lack of efficacy for the current recommended starting dose (0-25 mg).2 Of the 157 references cited in our petition to the FDA to remove triazolam from the market, 108 references are cited, for a total of 112 citations, to document that triazolam's benefits do not outweigh its risks. These 112 citations include 30 controlled studies by 16 different investigator groups, 13 controlled studies indicating limited efficacy for 0-25 mg of triazolam; 50 case reports, eight reports of postmarketing surveillance data, and 11 published reports of laboratory evidence that explain the mechanisms (very rapid elimination, high affinity for the receptor, and special triazolo properties) for triazolam producing high rates of severe psychiatric and central nervous system adverse reactions. These 108 references do not include four references in the petition that constitute meta-analyses or reviews of different aspects of triazolam's adverse reactions, to which Jonas has repeatedly erroneously referred to as replications of the study by Kales. Jonas also specifically questions the scientific documentation that triazolam produces frequent and severe hyperexcitability states while the drug is taken (daytime anxiety and early morning insomnia). Our petition cites the following references to support this conclusion: eight controlled studies; 12 case reports; data from the FDA's Spontaneous Reporting Sytem showing very high rates of hyperexcitability reactions for triazolam compared with temazepam and flurazepam; and data from a recent FDA review of 25 clinical trials sponsored by Upjohn that showed anxiety as the leading cause of dropping out from using triazolam and led to changes in triazolam's labelling to reflect this side effect. To date there have been 16 regulatory agency actions taken worldwide against triazolam, as the dose has been reduced from 1-0 mg to 0-25 mg or to 0-125 mg. Further, some countries have completely banned triazolam. If it were not for the remarkable consistency and agreement among the extensive, negative scientific data regarding the safety of triazolam, why else would so many regulatory agencies have taken these actions against the drug? ANTHONY KALES EDWARD 0 BIXLER ALEXANDROS N VGONTZAS Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA 1 Jonas JM. Triazolam. BMJ 1993;307:328. (31 July.) 2 Kales A, Bixler EO, Wolfe SM. Public citizen's petition to Food and Drug Administration to withdraw approval of triazolam (Halcion), 22 July 1992. Rockville, Maryland: Freedom of Information Office, Food and DrugAdministration, 1992.
Cardiopulmonary resuscitation Guidelines should be reconsidered
1 JonasJM. Triazolam. BMJ 1993;307:328. (31 July.) 2 Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiaty 1989;22:1 15-9. 3 Bliwise DL, Seidel WF, Cohen SA, Bliwise NG, Dement WC. Profile of mood states changes during and after 5 weeks of nightly triazolam administration. J Clin Psychiany 1988;49: 349-55. 4 Raskin RB. Deposition in Grundberg v Upjohn 1990 April 26. US District Court, District of Utah. (Civil No 89-C-274-W.) 5 Adam K, Oswald I. Triazolam. BMJ 1993;306:1475-6. (29
May.)
ED1TOR,-Douglas Chamberlain and Karl Lindner's reply to my letter on the European guidelines for advanced cardiac life support has not dealt with the hazards of laryngospasm and the stimulation of the discharge of gastric contents into the mouth associated with attempted intubation of patients in ventricular fibrillation due to inhalational agents (substance abuse).' In addition,
BMJ VOLUME 307
4 SEPTEMBER 1993
