XANAX - A VOYAGE INTO THE TWILIGHT ZONE
by Max Ricketts
Xanax Does Not Cure Anxiety
by Max Ricketts
Xanax - America's hottest selling tranquilizer - praised by some, condemned by many, has become one of the nation's most controversial drugs as a result of recent approval for use in the treatment of panic disorder - a severe, though not rare, form of anxiety state disorder.
Documents obtained from the Food and Drug Administration (FDA) by this writer under the Freedom of Information Act indicate that no evidence exists that Xanax (a benzodiazepine tranquilizer produced by Upjohn) cures anxiety or panic disorder, nor that it is even safe.
The product does have FDA approval for treating both conditions. However, serious adverse effects were reported even from the short-term clinical trials (less than 10 weeks) that XANAX (alprazolam) was subjected to by Upjohn in order to obtain approval. Panic disorder may be cured naturally without any hazard of adverse drug side effects. The condition is not life threatening, although it leaves its victims often severely disabled in that they often withdraw most activity and live in constant dread of the next panic attack.
Russian Roulette
Xanax is a "therapy" with a great potential for harm. The drug does not effectively resolve the underlying bio-chemical basis of anxiety state disorders. The "evidence" for the FDA approval was obtained from three very short-term studies. Several senior FDA officials have expressed concern that there is no data to suggest that Xanax is safe over a long period or at higher dosages - yet, there are many patients who are being prescribed this drug for months and even years!
Actually, there is compelling evidence that benzodiazepines, particularly XANAX, may be among the most addictive substances in the American drug marketplace. Thomas Temple M.D., Director of the FDA Office of Drug Evaluation, noted that the potential for XANAX withdrawal phenomena was "clearly the area of main concern for two principal reasons. First, there is the matter of seizures. In addition, there is the issue of life-long dependence, i.e. inability to discontinue therapy."
FDA Psychiatric Drug Products group leader Thomas Laughren M.D. agreed that much of Upjohn's information concerning withdrawal events was "often poorly organized and confusing." The official expressed "frustration that so little useful data have emerged".
Yet, the FDA has approved this drug in higher dosages (up to 10 mg per day) for the treatment of panic disorder without evidence that it is safe for long-term prescription! At the highest dosage level (6 mg per day), administered in the short-term studies, subjects were having considerable difficulties with adverse effects.
Unsafe At Any Speed
According to the FDA, applications for XANAX in panic disorder have been turned down by Denmark ("insufficient data to evaluate long term efficacy and safety"), Germany, and Norway "deficiency in long term data to support the safety of XANAX with regard to withdrawal phenomena").
What do quotes from the new XANAX (Upjohn) product labeling reveal? "Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to four months duration for anxiety disorder and four to ten weeks duration for panic disorder."
One may well question the motive for not having longer-term scientific data available on a drug that has been aggressively marketed for a decade and that sells for over $800,000 per kilo.
Upjohn admits, "Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to XANAX. These include a spectrum of withdrawal symptoms; the most important is seizure...studies of patients with panic disorder showed a higher rate of rebound and withdrawal symptoms with XANAX...Other symptoms, such as anxiety and insomnia, were frequently reported during discontinuation"
"The ability of patients to completely discontinue therapy with XANAX after long-term therapy has not been reliably determined...Withdrawal reactions may occur when dosage reduction occurs for any reason...withdrawal symptoms including seizures have been reported after only brief therapy with XANAX at doses within the recommended range for the treatment of anxiety...Death has been reported in association with overdoses in association with overdoses of alprazolam by itself"
Severe Side Effects
"XANAX has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment...The following adverse events have been reported in association with the use of XANAX, seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.
"The necessary duration of treatment for panic disorder victims responding to XANAX is unknown...a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena."
A drug with unknown long-term consequences and potential for addiction has been approved by the FDA for a non-life threatening condition, which may be treated successfully by non-drug means!
XANAX has become a major economic success story for the Upjohn Company. Small wonder with its habituating potential and immediate appeal for sufferers of panic and anxiety disorders desperately seeking relief. In the end, the long benzodiazepine tranquilizer voyage is a journey into the darkest side of the twilight zone - another world's timeless hell for those that are lured there seeking calm, and yet finding unrelenting heightened anxiety and abject misery.
Max Ricketts is a graduate of the US Naval Academy. He is an investigative health writer and the author, with Edwin Bien M.D., of the Great Anxiety Escape, a revolutionary program to escape from anxiety, insomniac, depressive, and drug related disorders. The book is available for $12.45, postage and handling included, from Matulungin Publishing, P.O. Box 2910, La Mesa, CA 91943. California residents, please add $0.72 sales tax or order from amazon.com. © 1991 Max Ricketts
XANAX DOES NOT CURE ANXIETY
by Max Ricketts
Health Store News, April 1991
Documents obtained from the Food and Drug Administration (FDA) by this writer under the Freedom of Information Act indicates that no evidence exists that XANAX (a benzodiazepine tranquilizer produced by Upjohn) cures anxiety or panic disorder. However, the product has FDA approval for treating both conditions. Further, serious adverse effects have been reported even from the dosages administered under the relative short-term clinical trials (less than 10 weeks) that XANAX was subjected to in order to obtain FDA approval.
As one evaluates the memorandums, studies, and statistics purporting to support the safety and efficacy of XANAX, probing questions as to the legitimacy of the direction of the American health care process are inescapable - questions of why we have created financial incentives for sickness, of why we have fostered illogical, self-defeating unnatural pharmaceutical approaches to achieving so-called "health."
Panic disorder, for which XANAX (alprazolam) was recently approved, may be cured by natural holistic means - without any hazard of adverse side effects. On the other hand there is no mention of "cure" in any of the material submitted by the FDA to this writer - not a word about "cure". That may be because XANAX does not cure panic disorder (or any anxiety condition for that matter). XANAX is a "therapy" - yet, a therapy with a great potential for harm. The drug does not effectively resolve the underlying biochemical basis of anxiety state disorders. The "evidence" for the FDA approval was obtained from three short-term studies, the longest being ten weeks. There is no data to suggest that XANAX is safe over a long period or at higher dosages - yet, there are many patients that are being prescribed this drug for months and even years!
Actually, there is compelling evidence that benzodiazepines, including XANAX, may be among the more addictive substances in the American drug marketplace. Certainly, the manufacturer, Upjohn, cannot dismiss such concern based on their own limited studies and data.
In an internal FDA memo (8/21/90) to Paul Leber, M.D., director of the Division of Neuropharmacological Drug Products, Psychiatric Drug Products group leader Thomas Laughren, M.D. agreed that much of Upjohn's information concerning withdrawal events was "often poorly organized and confusing." The official expressed "frustration that so little useful data have emerged..."
An earlier memo (8/6/90) to Dr. Leber from Thomas Temple felt XANAX's effectiveness was "clearly shown", the potential for drug withdrawal phenomena was "clearly the area of main concern for two principal reasons. First, there is the matter of seizures... In addition, there is the issue of lifelong dependence, i.e., inability to discontinue therapy."
The FDA has approved a drug in high dosages (up to 10 mg per day) for the treatment of panic disorder without evidence that it is safe for long-term prescription!
Let's examine the three trials, which were used by quoting a few written comments of FDA consultant Hillary Lee, Ph.D. (Statistical Review and Evaluation of 12/21/88). Keep in mind that, as is the custom, the manufacturer Upjohn sponsored these surveys. The FDA merely reviews their reports: "The trials, studies 4404, 4412, and 4432, were conducted sequentially from April, 1983 to May 1985." Follow-up was ten weeks or less. An initial question you might ask is what happened to the subjects since 1985? - There is no data on this.
Study 4404: A 10-week flexible dose, single-centered, double blind, parallel, placebo controlled multicenter clinical 8-week trial. One comment was, "it is disconcerting to note that the Dupont center, which had the largest sample size (19% of the total sample) and one of the lowest placebo dropout rates, showed a larger decrease in number of panic attacks of the placebo group than for the alprazolam group." In other words, in this center treatment with XANAX was worse than no treatment at all! As to the panic attack effect, the reviewer noted, "only one center showed significant difference..." between alprazolam and placebo. However at the dose of approximately 5 mg alprazolam was judged to be more effective than no treatment at all in the treatment of phobias.
Study 4412: A double blind, parallel, placebo-controlled multicenter clinical 8 week trial. One comment was, "it is disconcerting to note that the Dupont Center, which had the largest sample size (19% of the total sample) and one of the lowest placebo dropout rates, showed a larger decrease in number of panic attacks of the placebo group than for the alprazolam group". In other words, in this center, treatment with XANAX was worse than no treatment at all! As to panic attack effect, the reviewer noted, "...only one center shows a significant difference..." between alprazolam and placebo. However, at a dose of approximately 5 mg alprazolam was judged to be more effective than no treatment at all in treating phobias.
Study 4432: A 6-week double blind, parallel, placebo-controlled muticenter clinical trial. As to phobia ratings, the reviewer noted, "As for the overall phobia scale, the results are not clearly in favor of alprazolam...In conclusion...of concern is the fact that nearly half of the patients dropped out of the 6 mg alprazolam group by the end of the study (the majority due to side effects) suggesting that a dose of 6 mg may be too high."
The criterion by which XANAX effectiveness was judged was mean reduction of panic episodes per week. By that measure, one may reasonably suggest general anesthesia as a method of treatment (e.g., panic attacks would be reduced to zero and the procedure is FDA approved as generally safe). There are many other qualitative and quantitative indicators of reduction of panic attacks over the short term that these studies were conducted.
In a memo (8/11/89) to the FDA Psychopharmacological Drugs Advisory Committee (PDAC), Drs. Leber and Laughren indicated, "the single most significant concern associated with the use of XANAX in the treatment of panic and phobia behaviors is an increased (compared to current recommended uses) risk of dependence and withdrawal phenomena...Information gathered during the eight years of XANAX's domestic marketing for the management of anxiety disorders documents that the use of XANAX is consistently associated with reports of dependence and withdrawal phenomena...we are especially concerned that a recommendation for higher doses...will lead to an increased incidence of these untoward phenomena.
In the same memo the doctors added that HALCION (triazolam), a benzodiazepine sedative/hypnotic of Upjohn's, "continues to exhibit an excess of adverse events..." in spite of lower dose recommendations.
In the same memo the doctors added that HALCION (triazolam), a benzodiazepine sedative/hypnotic of Upjohn's, "continues to exhibit an excess of adverse events..." in spite of lower dose recommendations.
On March 20, Dr. Laughren, in referring to long-term therapy of up to eight months, wrote a memo for the file that mentioned there was no "systematic data to support the effectiveness of alprazolam for such use." The doctor noted, "data on discontinuation from alprazolam in the Upjohn sponsored clinical trials were quite varied...even for controlled trials, seems to me that the design wasn't quite correct to answer the questions of interest." (i.e., withdrawal). He observed that even in the short-term treated patients, "most experienced relapse (a recurrence of their symptoms) and a smaller fraction experienced rebound (a worsening relative to baseline of symptoms already present) or withdrawal (the development of new symptoms)."
Dr. Laughren added, "we already know...many patients have difficulty stopping alprazolam, even with tapering; alprazolam withdrawal symptoms can occur even after low dose and short duration exposure; alprazolam withdrawal can be quite severe; and, at least some patients become tolerant to alprazolam and find it necessary to increase the dose...These data suggest a strikingly higher risk of withdrawal phenomena for alprazolam doses greater than 4 mg/day compared to doses less than 4 mg/day."
According to Dr. Laughren's memo, application for XANAX in panic disorder have been turned down by Denmark ("...insufficient data to evaluate long term efficacy and safety..."), Germany, and Norway ("...deficiency in long term data to support the safety of XANAX with regard to withdrawal phenomena...")
In conclusion, Dr. Laughren indicated that there was strong support for the use of alprazolam "in the short-term treatment of panic disorder. However, there are deficiencies in this application with regard to how best to use XANAX in treating panic disorder; in particular, there was not an adequate exploration of the dose/response relationship or for the duration of effect...there was no systematic attempt by the sponsor to address the issue of maintaining patients who had responded during short-term treatment...There was no systematic attempt to look at withdrawal schedules."
On April 20, 1990, Dr. Leber wrote a memo to the Director of the Office of Drug Evaluation which said, "...it seems likely that the use of XANAX at the doses needed to achieve an anti-panic effect will incidence untoward events substantially greater than that so far observed among patients treated for anxiety."
In discussing the issue of safety of XANAX, Dr. Leber wrote, "The case is, in some ways, a close one...Also contributing to the difficulty of the judgment is the relative sparseness of the evidence...it could be argued that the sponsor has failed to provide sufficient evidence to show that XANAX will be 'safe in use' under the conditions of use recommended."
However, Dr. Leber himself did not accept this assessment; he agreed with FDA advisors that the "public health would be best served by approval..." He added, "currently agency policy holds that effective drugs, even those with a substantive capacity to cause harm, may be approved for use provided that 1) their benefits outweigh their risks for at least some patients and 2) their risks of use are described systematically and accurately in product labeling." Readers, may note that this questionable policy is from the same FDA which hounds holistic practitioners, manufacturers, and retailers who dare make health claims for natural, non-toxic substances such as food constituents.
What do quotes from the new XANAX (Upjohn) product labeling reveal? "Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to four months duration for anxiety disorder and four to ten weeks duration for panic disorder." One may well wonder at the motive for not having longer-term scientific data available on a drug that has been aggressively marketed for a decade and that sells for over $800,000 per kilo.
"Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to XANAX. These include a spectrum of withdrawal symptoms; the most important is seizure... studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms with XANAX...symptoms of withdrawal; heightened sensor perception, impaired concentration, dysosmia, clouded sensorium, paresthesia, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation...The ability of patients to completely discontinue therapy with XANAX after long-term therapy has not been reliably determined...Withdrawal reactions may occur when dosage reduction occurs for any reason...withdrawal symptoms including seizures have been reported after only brief therapy with XANAX at doses within the recommended range for the treatment of anxiety (e.g., 0.75 to 4 mg/day)... Death has been reported in association with overdoses of alprazolam itself..."
"XANAX has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment...The following adverse events have been reported in association with the use of XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice."
"The necessary duration of treatment for panic disorder victims responding to XANAX is unknown...a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena."
A drug with unknown long-term consequences and potential for addiction has been approved by the FDA for a non-life-threatening condition, which may be treated successfully by non-drug means!
XANAX has become a major economic success story for the Upjohn Company. Small wonder with its habituating potential and immediate appeal for sufferers of panic and anxiety disorders desperately seeking relief. In the end, the long benzodiazepine tranquilizer voyage is a journey into the darkest side of the twilight zone - another world's timeless hell for those that are lured there seeking calm. And yet finding - unrelenting heightened anxiety and abject misery.
Max Ricketts is a graduate of the US Naval Academy. He is an investigative health writer and the author, with Edwin Bien M.D., of the Great Anxiety Escape, a revolutionary program to escape from anxiety, insomniac, depressive, and drug related disorders. The book is available for $12.45, postage and handling included, from Matulungin Publishing, P.O. Box 2910, La Mesa, CA 91943. California residents, please add $0.72 sales tax or order from amazon.com. © 1991 Max Ricketts
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