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No drugs are more obviously brain-disabling and spellbinding than the benzodiazepines (BZs). They produce a continuum of central nervous system (CNS) effects that begins with a feeling of relaxation, progresses toward somnolence, and, in sufficient doses, causes a coma deep enough to use as anesthesia in major surgery. The continuum of effects is very similar to alcohol, but the BZs can suppress the CNS without producing as much drunkenness (slurred speech and ataxia) and can more effectivelyy produce the depth of coma necessary for surgery.
Experts who advocate the use of BZs for the control of anxiety want to believe that these drugs produce a specific antianxiety or anxiolytic effect, but there is no reason to believe this. The continuum of CNS supression is smooth, and anxiety reduction is one of the brain-disabling effects of gradually shutting down the brain.
Because they have no ax to grind about treating anxiety with BZs and other CNS depressants, anesthesiologists have been more honest in evaluating their effects. All currently used forms of anesthesia work by enhancing the effect of the neurotransmitter system receptors known as gamma-aminobutyric acid (GABA), in particular the receptor subtype A, or GABAA. All BZs enhance GABA, including the long-acting diazepam (Valium) used to treat anxiety and the ultra-short-acting midazollam. (Versed) used intravenously to produce anesthesia.
GABAA receptors exist throughout the brain and can be found on the great majority of neurons. This system dampens neuronal activities, regulating the overalllevel of CNS activity. When stimulated by drugs, GABA produces the continuum of CNS depression leading to coma.
The subtype GABAA has at least 19 subtypes of its own, and most of those subtypes have subtypes, producing a dizzying array of receptor subtypes (Hemmings et al., 2005 [613]; Orser, 2007 [1013]). In addition, recent research has demonstrated that GABAA receptors are not limited, as originally thought, to the synapse. They line the outside of neurons as well, where they regulate neurotransmission by potentially inhibiting their capacity to become excited. Of course, this effect is so generalized that it cannot possibly be specific for one aspect of consciousness, the generation of anxiety.
In evaluating the latest advances in anesthesiology, Beverley Orser (2007) [1013], Professor of Anesthesiology and Physiology at the University of Toronto, discussed the mechanism of action of anesthetics, including BZs. Her description confirmed the brain-disabling principle in regard to these drugs:
"Because consciousness is a complex experience whose defining properties are still hotly debated by neuroscientists, it is not as easy to pinpoint a single anatomical source of unconsciousness during anesthesia. One leading theory holds that it is simply the result of `cognitive unbinding' - a severing of communication between the many brain regions that usually cooperate in higher cognitive processing. Even at the local level, if one imagines groups of neurons as forming lines in a vast telephone network, the effect of general anesthesia is analogous to pulling out the plugs at the switchboard."
This kind of general disruption of brain function and consciousness takes place when an individual undergoes anesthesia - or takes a BZ to relieve anxiety. Unfortunately, Dr. Orser's (2007) [1013] level of sophistication about the brain-disabling effects of BZs is sorely missing among psychiatric drug experts who persist in believing that their chemicals treat specific psychiatric disorders similar to the way insulin treats diabetes.
Since the days when Valium was the most prescribed drug in America, doctors have become more cautious about prescribing addictive BZs. According to the Drug Enforcement Administration (DEA, 2006) [377], in 1999, there were about 100 million prescriptions written. According to IMS Health (2007) [648], they have not yet fallen off the charts. The BZs were 10th in the nation in sales, with over 80 million prescriptions written. Antianxiety agents (anxiolytics or minor tranquilizers) remain among the most commonly used drugs in both medicine and psychiatry.
I could not locate any reliable recent estimates for the number of patients taking BZs. More than a decade ago, it was estimated that 15% of American adults used these or similar sedative/hypnotic agents during any given year, usually through a physician's prescription (Gold et al., 1995 [535]). Almost 2% of the population was using BZs more or less chronically (DuPont, 1986 [386]). In 1993, Xanax topped the list for frequency of use, followed by Klonopin.
Moore and Jones (1985) [944] performed a review of all adverse drug reactions reported to the Food and Drug Administration (FDA) from 1968 to 1982 (see chapter 13 for an analysis of the FDA's system). Antibiotics ranked first with 33,959 reported adverse reactions, but so-called tranquilizers were neck and neck with 33,720. The BZs are frequently prescribed for anxiety or panic and for sleep. They are also given to counteract the stimulating effects of the antidepressants, especially Prozac, Paxil, and other SSRIs. Most of the antianxiety agents, including the more potent ones, are BZs. This chapter will focus on the brain-disabling effects of BZs, especially the short-acting, high-potency drugs alprazolam (Xanax) and triazolam (Halcion). Because they produce more frequent and intensive adverse drug reactions, Xanax and Halcion provide a magnifying glass for investigating the more general impact of all BZs.
With their trade names and half-lives in parentheses (the units are hours), current BZs include the following: alprazolam (Xanax, 6-20), chlordiazepoxide (Librium, 30-100), clonazepam (Klonopin, 18-50), clorazepate (Tranxene, 30-100 or 200), diazepam (Valium, 30-100), estazolam (ProSom, 10-24), flurazepam (Dalmane, 50-160), lorazepam (Ativan, 10-20), midazolam (Versed, 2-3), oxazepam (Serax, 3-21), prazepam (Centrax, 30-100), quazepam (Doral, 50-160), temazepam (Restoril, 8-20), and triazolam (Halcion, 1.5-5)21. The appendix contains a more complete list.
Some BZs have been marketed as hypnotics or sleeping medications, or are more frequently prescribed for this purpose by physicians, without being substantially different in their characteristics from other BZs marketed for anxiety. As Ashton (1995) [70] remarked, "The pharmacological actions of all benzodiazepines are similar; the distinction between tranquilizers and hypnotic preparations is based on commercial, not pharmacological grounds" (p. 159, note on chart). Flurazepam, for example, is sold as a sleeping medication, but its rather lengthy half-life will produce hangover effects the following day. Xanax, and to an even greater extent, Halcion, do have a significantly different profile due to a greater capacity to bind to receptors and a shorter half-life. Halcion's very short half-life led to the hope that it would make a particularly good sleeping medication because its effects presumably would wear off by the morning. Instead, it has proven relatively ineffective and especially dangerous, often causing withdrawal reactions the following morning.
The brain-disabling or toxic effects of the BZs can be divided into several somewhat overlapping categories:
As much as any psychiatric drugs, the brain-disabling effects of the BZs (or any sedative-hypnotic, including alcohol) are readily apparent. Much as for alcohol, there is a continuum of CNS depression from relaxation through sleep, and, in the extreme, coma. Prescribing is a matter of giving enough of the medication to the point where the patient experiences a desired effect without becoming too heavily sedated or comatose.
Neurophysiological studies show that the BZs potentiate the neuronal inhibition that is mediated by GABA. In doses used clinically, this results in a generalized suppression of both spontaneous and evoked electrical activity of the large neurons throughout all regions of the brain and spinal cord (Ballenger, 1995 [94]).
The binding of BZs to the GABA receptors is most intense in the cerebral cortex. Some BZs, such as Xanax and Halcion, bind especially tightly, increasing their tendency to produce more intense sedation and hypnosis, and also more severe cognitive deficits, behavioral abnormalities, rebound, and withdrawal.
People who use BZs to calm their anxiety will frequently use alcohol and other sedatives interchangeably for the same purpose, either in conbination or at different times. As they switch from drug to drug, they tend to find little or no difference in the antianxiety effect. This confirms that BZs have no specificity for anxiety in comparison to other sedative/hypnotic agents.
There are at least two causes for the abnormal behavior produced by BZs. One mechanism is direct intoxication, resulting in impaired executive and cognitive function, including reduced judgment and impulse control. Fogel and Stone (1992) [453] observed, "Benzodiazepines, given to reduce arousal or possibly to treat a hypomanic state, may aggravate impulsive behavior by impairing the inhibition mechanism of the frontal lobes. Barbiturates may have similar effects" (p. 341).
Especially in regard to the BZs, a second mechanism, withdrawal or rebound, can also cause severe psychiatric reactions. These discontinuation symptoms occur when the BZs are withdrawn or when they begin to lose their effectiveness (American Psychiatric Association [APA], 1990a [39]). When exposed to BZs, the brain compensates by reducing the activity of the GABA system. The GABA receptors become down-regulated (less sensitive). The GABA system, in effect, becomes sluggish. There may also be a reduction in GABA itself to compensate for the drug effect, once again leaving the natural GABA system relatively inactive. In short, the natural inhibitory mechanism of the brain becomes relatively disabled and ineffective in the presence of BZs. When the BZs are then withdrawn, the brain is left with an ineffective or sluggish inhibitory system, resulting in anxiety, agitation, behavioral disinhibition, and loss of control.
BZ disinhibition differs in some ways from alcohol disinhibition. It can occur without a noticeable sedative intoxication, such as slurred speech, lack of coordination, or impaired consciousness. Furthermore, the BZs are prescribed by a physician, often without providing the patient a warning about possible disinhibition. Unlike the experienced alcohol user, the trusting BZ user has little reason to anticipate losin control. Expecting to be helped, and not harmed, by the drug, the patient is less able to understand or manage potentially overwhelming feelings of anger or violence or other untoward emotional responses. Also, unlike with alcohol, some of the worst BZ behavioral reactions occur during withdrawal or in between doses, adding to the patient's confusion concerning what is happening. At the time, the patient may have little idea what is driving the unfamiliar behavior, and in retrospect, it may seem like a fragmented, poorly recalled nightmare. In addition, the BZs are very spellbinding, so individuals often suffer toxic effects on their brains and minds without appreciating or recognizing them.
The FDA-approved label for Xanax XR, the long-acting preparation of the drug, listed the following "psychiatric disorders" caused by the drug in short-term placebo-controlled clinical trials: depression, decreased libido, disorientation, confusion, depressed mood, and anxiety. It lists additional psychiatric symptoms under the rubric of "nervous system disorders," including sedation, somnolence, memory impairment, mental impairment, and hypersomnia (Physicians' Desk Reference, 2006, p. 2658 [1036]). Memory impairment is listed as one of the reasons that patients stopped taking the drug. It is unusual for so many adverse psychiatric symptoms to surface in short-term placebo-controlled clinical trials, indicating that Xanax XR has an unusual capacity to cause them. The label for Xanax (not the XR preparation) indicated that it caused "disinhibition," even in the short-term placebo-controlled clinical trials (Physicians' Desk Reference, 2005 [1036], p. 2766).
Standard textbooks and reviews spanning more than two decades as well as a variety of clinical studies confirm widespread recognition of BZ-induced behavioral abnormalities (Arana et al., 1991 [65]; Ashton, 1995 [69]; DiMascio et al., 1970 [363]; Kochansky et al., 1975 [772]; Maxmen, 1991 [891]; Rosenbaum et al., 1984 [1104]; Shader et al., 1977 [1159]). My 1998(b) [201] review titled "Analysis of Adverse Behavioral Effects of Benzodiazepines with a Discussion of Drawing Scientific Conclusions From the FDA's Spontaneous Reporting System" probably remains one of the most complete reviews in the scientific literature.
Salzman et al. (1974) [1122], in a placebo-controlled study, showed that volunteers taking chlordiazepoxide became more hostile when confronted with a situation of interpersonal frustration. Salzman (1992) [1121] also reviewed the literature. He pointed out the then controversial nature of BZ-induced violence but went on to assert, "Recent observations, however, have confirmed that hostility can be seen with all benzodiazepines, including alprazolam and clonazepam".
Writing in The Pharmacological Basis of Therapeutics, Rall (1990) [1068] summarized:
"Adverse psychological effects: Benzodiazepines may cause paradoxical effects. Nitrazepam frequently and flurazepam occasionally increase the incidence of nightmares, especially during the first week of use. Flurazepam occasionally causes garrulousness, anxiety, irritability, tachycardia, and sweating. Euphoria, restlessness, hallucinations, and hypomanic behavior have been reported to occur during the use of various benzodiazepines. Antianxiety benzodiazepines have been reported to release bizarre uninhibited behavior in some users with low levels of anxiety; hostility and rage may occur in others. Paranoia, depression, and suicidal ideation occasionally also accompany the use of these agents." (p. 355)
Rall believed that "the incidence of such paradoxical reactions is extremely small". Whether or not that is true, they are extremely hazardous. They are more common in regard to the short-acting BZs.
Drug-induced disinhibition or loss of impulse control can cause serious harm to self and to others. I have evaluated in depth cases in which only one or two doses of a BZ such as alprazolam or clonazepam have led to suicidal or homicidal outbursts.
As the above observations confirm, reactions to BZs can reach psychotic proportions. As noted in Drug Facts and Comparisons (2003-2007), [379], the BZs in general can cause serious psychiatric problems, including psychosis. They can disrupt CNS function, producing, among other things, "disorientation ... confusion ... delirium ... euphoria ... agitation". A special Precautions section noted "paradoxical reactions," including "excitement, stimulation and acute rage" and "hyperexcited states, anxiety, hallucinations".
Mania is a special danger in regard to Xanax. Unlike any other benzodiazepine, the FDA-approved label for Xanax, as found in the 2007 Physicians' Desk Reference [1036], specifically mentioned the risk of mania. Drug Facts and Comparisons (2007) [379] also made a specific reference to Xanax under "Precautions," stating that "anger, hostility and episodes of mania and hypomania have been reported with alprazolam" (p. 1199). As another example, Maxmen and Ward's (1995) [892] Psychotrapic Drug Fast Facts stated that "manic reactions" are "most often reported with alprazolam" (p. 287). It also stated that "rage reactions" and "violent episodes" have especially been observed with Xanax and Valium. Yet another example is the Handbook of Psychiatric Drug Therapy by Hyman et al. (1995) [644]. It singled out Xanax to observe that "increased impulsiveness, euphoria, and frank mania have been reported with alprazolam" (p. 177).
As already noted, there are reports in the clinical literature indicating that the BZs can cause depression. Some reviews mention the phenomenon but express skepticism, while nonetheless declaring that it should be taken seriously. Arana and Hyman (1991) [65], for example, stated:
"Depression: All benzodiazepines have been associated with the emergence or worsening of depression; whether they were causative or only failed to prevent the depression is unknown. When depression occurs during the course of benzodiazepine treatment, it is prudent to discontinue the benzodiazepine."
Ashton (1995) [69] observed that BZs can blunt the emotions in general, producing "emotional anesthesia". He reported, "Former long-term benzodiazepine users often bitterly regret their lack of emotional response to family events during the period that they were taking the drugs". Ashton also observed that BZs can precipitate suicide in already depressed patients.
The APA (1990a) [39] task force report on BZs, in a discussion of toxicity, also observed that
"benzodiazepines have also been reported to cause or to exacerbate symptoms of depression. This, too, is not a frequent side effect, although the depressive symptoms may be potentially serious." (p. 41)
Great Britain's Committee on Safety of Medicines (CSM; 1988) [305] recommended that "benzodiazepines should not be used alone to treat depression or anxiety associated with depression. Suicide may be precipitated in such patients".
Some psychiatrists believe that there is usually a predisposition toward depression and suicidality in the affected individual, but this position lacks evidence. As a medical expert, I have extensively evaluated cases of depression and suicide induced by benzodiazepines in individuals with no prior history of these emotional problems.
Several studies have demonstrated rebound phenomena the same night or the day following the ingestion of the short-acting BZ triazolam (Halcion). In a controlled study, Moon et al. (1985) [943] found that "the results support previous reports that early insomnia and an increase in daytime anxiety are problems associated with short acting benzodiazepines, such as triazolam".
De Tullio et al. (1989) [340] reviewed the charts of 72 adult male patients taking triazolam for sleep through an ambulatory Veterans Administration (VA) clinic. Thirty-nine of the patients were available for telephone interviews. Most of the patients were elderly (age 60 or older). Of the 39 patients interviewed, only 4 reported no adverse effects, and 23 experienced more than one. The most common were dizziness, rebound insomnia, and nightmares. "Rebound insomnia was defined as waking during the night or waking too early in the morning, and having trouble falling back to sleep." As a result of the study, the VA facility modified its policies on triazolam administration: "For outpatients on chronic triazolam therapy, a switch to a longer-acting benzodiazepine was instituted with tapering if therapy was not to be continued."
Public and professional awareness of the special dangers of Halcion began in 1978. At that time, C. van der Kroef (as cited in Dukes, 1980 [382]), a psychiatrist in The Hague, Netherlands, noticed abnormal reactions to Halcion in 4 of 11 patients he treated with the drug. Following is van der Kroef's description of one of his patients:
"The insomnia improved at once, but psychically she rapidly went downhill. Progressively she became paranoid. Several times she asked me what the hypnotic contained - LSD perhaps? - for she felt that she was bordering on psychosis. She felt shut off from the world; it was as if she no longer belonged to society. Her friends asked her what was happening to her, so strangely was she behaving After two months I too began to suspect, particularly in light of experience with an earlier patient, that all this might be a consequence of her taking triazolam. The drug was withdrawn and replaced with nitrazepam. Within a day she felt herself again. The people around her noticed the difference and recognized her old self again. The paranoid traits, the hypermotility urge and the hyperaesthesia disappeared in the course of two days."
Dukes (1980) [382], a physician with considerable regulatory experience, commented on van der Kroef's findings. He observed that all of the BZs, including those used to induce sleep (hypnotics), have been known to produce reactions that are "frankly psychotic". While not common, according to Dukes, "virtually every known drug in this class" has produced "hallucinations, delusions, paranoia, amnesia, delirium, hypomania - almost every conceivable symptoms of psychotic madness".
According to Dukes (1980) [382], all the BZs used for the control of anxiety were also implicated in causing violence:
"If one - to begin at an arbitrary point - looks to the literature for evidence that the benzodiazepines can unleash aggression then one will find it. More than a dozen papers in the literature speak of irritability, defiance, hostility, aggression, rage or a progressive deve10pment of hates and dislikes in certain patients treated with benzodiazepine tranquilizers; all those products which are widespread have been incriminated at one time or another. The phenomenon has been demonstrated in animal studies and it has even been proved possible to show in human volunteers that these drugs can release pent-up hostility, particularly in highly anxious or action-oriented individuals."
Until the advent of Halcion, according to Dukes (1980) [382], the older BZs commonly used to induce sleep were not known to cause violence. We shall find his observations confirmed later on by in - house studies at the FDA indicating that Halcion - but not the older hypnotics, Dalmane or Restoril - caused a vastly increased rate of violent activities.
I have been a medical expert in criminal cases involving abnormal behavior, including theft and violence, related to Xanax intoxication. I have also been an expert in civil suits involving suicide related to Halcion.
It is, of course, extremely difficult to demonstrate drug-induced behavioral abnormalities in highly selective, short, controlled clinical trials (see chapter 13 for a detailed analysis of why this is so). Nonethless, several studies have confirmed some of the hazards associated Halcion.
Gardner and Cowdry (1985) [504] found an increase in dyscontrol in borderline patients taking alprazolam in a double-blind, placebo-controlled cross-over study. The dyscontrol included the following: "Overdose, severe"; "Overdose, moderate"; "Deep neck cuts"; "Transverse wrist cuts"; "Tried to break own arm"; "Threw chair at child"; and "Arm and head banging; jumped in front of car".
Gardner and Cowdry (1985) [504] pointed out that there are some reports of borderline patients also improving on alprazolam. They concluded, "Caution should, however, be exercised, particularly in treating individuals with a substantial history of dyscontrol."
Bayer et al. (1986) [113] conducted a 9-week, double-blind controlled study of triazolam and another hypnotic, chlormethiazole, in the elderly with sleep disturbances. They found daytime withdrawal effects from triazolam but not chlormethiazole. At week 3, significantly more triazolam patients were rated as more restless during the day, "and they also appeared more hostile, less relaxed, more irritable and more anxious". Patients on triazolam also had more adverse events related to the CNS, requiring 4 of 22 patients to withdraw from the study; 3 of those withdrawn recovered after terminating the medication. One patient felt that the tablets were making him nervous. The others individually developed paranoid delusions, "increasing confusion and irritability," and irrational, irritable, and uncooperative behavior.
Adam and Oswald (1989) [11], in a double-blind, placebo-controlled study of triazolam and lormetazepam with 40 subjects in each of the three groups, found that "triazolam takers became more anxious on self-ratings, were judged more often to have had a bad response by an observer, more often wrote down complaints of distress, and suffered weight loss. After about 10 days of regular triazolam they tended to develop panics and depression, felt unreal, and sometimes paranoid". According to the authors,
"Subjects' written comments suggested that from about 10 days after starting triazolam, they became liable to panic attacks, feelings of despair and derealization. There were descriptions of panic episodes in public places in seven subjects during triazolam intake, but none during placebo or lormetazepam. ... Several reported their family relationships were changed. A number of triazolam subjects became paranoid. ... Two men developed paranoid psychoses. [During the withdrawal period, the anxiety of the triazolam patients] fell quickly to normal levels."
Soldatos et al. (1986) [1201] reported on serious adverse drug reactions in all five psychiatric inpatients during a clinical trial of 0.5 mg triazolam and placebo. The patients and nurses were blind in the study, but not the physician with medical responsibility for the patients. The study consisted of 1 week of placebo baseline, 2 weeks of triazolam administration, and 1 week of withdrawal on placebo. All five patients developed severe reactions to triazolam. Case 1 developed "anxiety and hallucinations on the last two days of triazolam administration and the first withdrawal day". Case 2 had a sudden increase in anxiety and became "irritable, uncooperative, and depressed". She became withdrawn and cried, and showed "considerable impairment of memory and orientation". On withdrawal of triazolam, "she became more incoherent, expressing paranoid ideas of persecution that persisted about a week". She required Haldol to control her delusions. Case 3 developed severe insomnia during withdrawal and "reported considerable anxiety and irritability along with an uncontrollable fear of death, which persisted to the next day when she additionally manifested a marked degree of memory impairment". Case 4, by the end of the second week of triazolam administration, "became more depressed and manifested increasingly irritability and hostility". Case 5, on the second week of triazolam administration, "experienced increasing daytime anxiety and he became, for the first time since admission, irritable, hostile, and somewhat guarded and paranoid towards the unit staff". The authors suggested that some of the symptoms may have been related to disinhibition. They warned that these serious side effects "may not be rare when triazolam is used in patients ... [with] major psychiatric conditions".
Rosenbaum et al. (1984) [1104] found that 8 of 80 patients treated with alprazolam in an outpatient clinical setting developed extreme anger or hostile behavior.
In 1987 [144], Bixler et al. reviewed adverse reactions to BZs recorded in the FDA's spontaneous reporting system (SRS). They compared triazolam with two other BZs commonly used to induce sleep: temazepam (Restoril) and flurazepam (Dalmane). They controlled the reports for the number and size of prescriptions for each of the three drugs. In regard to psychiatric adverse reactions, they found:
"in general, triazolam had much higher overall rates than did the other two drugs. Hyperexcitability and withdrawal effects were greatest for triazolam and least for flurazepam. Amnesia was reported almost exclusively with triazolam. Rates for other cognitive as well as affective and other behavior effects were also much greater for triazolam and about equal for the other two drugs."
The affective and other behavioral disturbances category of adverse drug reactions included "Depression, Psychotic Depression, Emotional lability, Euphoria, Hostility, Personality disorder, and Decreased libido".
Epidemiological studies at the FDA have consistently shown that alprazolam and, especially, triazolam produce more frequent and more serious adverse CNS effects, including drastic and life-threatening behavioral changes, than any other BZs. I have reviewed the in-house memos with detailed analyses generated by the Division of Epidemiology and Surveillance, which is responsible for the SRS. This divisian has consistently shown more concern about triazolam than has Paul Leber's Division of Neuropharmacological Drug Products, which originally approved the drug (see subsequent discussion; see chapter 13 for more about Leber and the FDA [819]). In the earlier edition of this book, the data from the epidemiology studies were described in detail for the first time in the literature.
Robert "Bob" Wise (1989) [1351], in a working paper for the FDA's Division of Epidemiology and Surveillance, made an executive summary concerning reports of hostility on triazolam. Wise addressed a syndrome that consists of "anger or rage, aggression, and some actual assaults and murders". He stated:
"More such reports of this type have been received by the FDA for triazolam and alprazolam than for any other drug product regulated by the Agency. Reporting rates, which adjust for differences in the extent of each drug's utilization, reveal much higher ratios of hostility reports to drug sales for both triazolam and alprazolam than for other benzodiazepines with similar indications."
"The public health importance of these reactions lies in their severity, with occasionally lethal behavior unleashed, in the context of large population exposures as the popularity of both drugs continues to rise."
After a brief history of the FDA's increased focus on BZ-induced hostility, Wise explained:
"Our concern with such reactions then broadened to the class of triazolobenzodiazepines, when another Increased Frequency Report included a reaction in which a 57 year old woman fatally shot her mother two hours after taking one-half milligram of triazolam. When we looked at reports received during 1988, we found that triazolam's 1988 reporting rate for hostility reactions was more than twice as high as alprazolam's."
"In the entire SRS ... during early August, 1989, triazolam was the suspect drug in 113 reports coded as hostility, more than any other medication. It was followed by alprazolam, which accounted for 78 reports. Only nine other drugs were suspected in more than ten cases each. Another 318 drug products had fewer hostility reports, most often one (60.4 percent of 318) or two (14.8 percent)."
Three fatalities were reported to the SRS for triazolam and one for alprazolam. Five reports of alprazolam overdose were associated with assaults, including two murders. Reactions were reported across the dose range. Men (29) and women (26) were almost evenly distributed.
Four alprazolam cases showed a reduction in hostility and rage reactions after a reduction in dose (dechallenge), confirming the drug's role in producing the behavior.
Wise (1989) [1350] summarized, "This apparently excessive number of rage and similar reports with triazolam and alprazolam, after adjusting the differences in frequency of drug use, provides strong suspicion that a causal relationship may obtain". It should be added that the relationship to increased dosage seen in several cases further confirms causation. Wise concluded that these reports cannot "prove the presence of a causal relationship" to the drug but that they do "imply a substantial public health importance for the potential hostility syndrome".
Wise (1989) [1350] missed an extremely important aspect of his own data. Not only were Halcion and Xanax first and second in total reports of hostility, midazolam (Versed) was third in order. Versed, like Halcion and Xanax, is a very short-acting, tightly binding BZ. It is used exclusively as an intravenous injection for preoperative sedation and memory impairment. The total numbers of reports were Halcion (112), Xanax (77), and Versed (46). Valium (34 reports) was fourth. They were followed by Symmetrel (22) and Prozac (20).
Thus the data base for all drugs in the SRS of the FDA - which includes all prescription drugs in the United States - showed that three short - acting, tightly binding BZs came in first, second, and third for reports of hostility as an adverse drug reaction. Furthermore, the three drugs are typically used under very different clinical conditions: Halcion orally, with one daily dose at night for sleep; Xanax orally, with several daily doses for daytime anxiety; and Versed intravenously, for preoperative purposes, usually on one occasion only. Despite the different uses, dosage schedules, and even routes of administration, they cluster at the very top of the list for producing hostility. This is convincing and seemingly irrefutable evidence that these kinds of agents can cause violence22.
On April 21, 1989 [1350], Wise wrote an increased frequency report for the FDA on the subject of alprazolam and rage. Wise explained that the analysis was undertaken because "over a 12 month period, Upjohn received six reports of rage, agitation, anger, aggression, and similar behavioral and emotional symptoms after exposures to alprazolam". All but one involved "manifested or verbalized murderous impulses". According to Wise:
"From spontaneous reports alone, we cannot estimate the acrual incidence of alprazolam-induced rage reactions. But in light nf the widely acknowledged, substantial underreporting to spontaneous surveillance systems in general and to the FDA's SRS in particular, ir is entirely possible that six reports of this kind of reaction within a single year might reflect sixty or more in reality."
After reviewing all reports made to Upjohn and the FDA, Wise concluded:
"An increase in annual frequency of `rage' reports with alprazolam prompted us to compare hostility reports more generally across several anxiolytic benzodiazepines. Alprazolam appears to have an excessive reporting rate for events coded with `hostility,' even after adjusting for differences in the extent of each drug's utilization. The numbers and potential gravity of these reactions and their possible relationship to dos age all appear to conflict with current labeling's brief description of `paradoxical effects' that occur only `in rare instances and in a random fashion'."
On October 17, 1988 [51], Charles Anello, Deputy Director of the Office of Epidemiology and Biostatistics, referred to an earlier FDA comparison of spontaneous reports concerning triazolam to two other BZs used to treat insomnia, temazepam (Restoril) and flurazepam (Dalmane). Anello stated that there was a proportionately increased number of reports concerning abnormal behavior in regard to triazolam. Anello reported on a further analysis comparing triazolam and temazepam, showing that for triazolam, the FDA received proportionally more adverse drug reaction reports (ADRs), more serious ADRs, and more reports of five selected behavioral drug reactions.
On September 12, 1989 [52], Anello reported within the FDA on "Triazolam and Temazepam-Comparison Reporting Rates". He found that adverse drug reactions were reported 11 times more frequently with triazolam than with temazepam. The rei ative reporting rate was 46 to 1 for amnesia, 9 to 1 for "agitation, anxiety and nervousness," 16 to 1 for psychosis ("psychosis, hallucinations, paranoid reaction, and acute brain syndrome"), and 19 to 1 for "hostility and intentional injury".
Anello's (1989) [52] analysis indicated that there were no convincing explanations for these differences other than actual drug effects, but he did not make a formal determination of causality. However, in a handwritten analysis attached to the document, obtained through the Freedom of Information Act, there is a summary titled "Other Evidence in Favor of Effect of Triazolam," which I quote in full:
The above note indicates some of the logical, scientific steps by which data from spontaneous reporting were used by an unidentified FDA official to confirm causality in regard to Halcion and adverse behavioral effects. (For a further discussion of the scientific process in epidemiological studies, see chapter 13.)
In 1991 [1366], Diane Wysowski and David Barash, also from the FDA's Division of Epidemiology and Surveillance, published a report in the Archives of Internal Medicine. A footnote stated, "This article contains the professional views of the authors and does not constitute the official position of the Food and Drug Administration". Using the FDA's SRS, the authors compared triazolam and temazepam through 1985 for "confusion, amnesia, bizarre behavior, agitation, and hallucinations". They concluded, "Considering the extent of use, reporting rates for triazolam were 22 to 99 times those for temazepam, depending upon the reaction". Echoing the handwritten remarks appended to Anello's (1989) [52] in-house report, the authors summarized:
"Factors that indicate a causal association between triazolam and ad. verse behavioral reactions include corroborating case reports and sleep laboratory studies in the literature, reports of reactions in otherwise normal persons, acute onset and temporal relationship to reactions with initial dose, spontaneous recoveries and return to normalcy with drug discontinuation, and occurrences of positive rechallenge. Also, the high benzodiazepine receptor affinity with triazolam has been postulated as a possible biological mechanism."
While unable to "completely exclude the possibility that some selection factors are operating to produce higher reporting rates for triazolam," nonetheless, Wysowski and Barash (1991) [1366] found that the evidence suggested a greater occurrence with triazolam than with temazepam. Andreadis and Schrimer (1992) [47] responded critically for Upjohn with a letter, and Wysowski and Barash (1992) [1367] were given the opportunity to try to answer their objections.
Finally, in November 1991, the FDA approved new labeling for Halcion (Food and Drug Administration, 1992 [461]). The new label emphasizes that triazolam is indicated for short-term use and specifies 7-10 days. Treatment lasting longer than 2-3 weeks requires a complete reevaluation of the patient. In addition, the label emphasizes the use of the lowest possible dose.
Following is the new warning on the Halcion label as found, for example, in the 1995 Physicians' Desk Reference [1036]:
"A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics, including HALCION. Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Other kinds of behavioral changes have been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines."
The warning concludes with the following:
"As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of HALCION. Data from several sources suggest that anterograde amnesia may occur at a higher rate with HALCION than with other benzodiazepine hypnotics."
The final label change was negotiated and approved under the authority of Paul Leber, Director of the Division of Neuropharmacological Drug Products, the division responsible for Halcion's original approval. In several ways, the label seems to fall far short of conclusions generated by both the literature and the division responsible for postmarketing surveillance.
The FDA label does mention the disproportionate reporting of amnesia, but by omission, it leads the reader to believe that the behavioral effects did not occur with increased frequency. Instead of linking directly to Halcion the enormously increased risk for violence, psychosis, and other extremely hazardous behavioral abnormalities, the label notes that these changes have been "reported in association with the use of benzodiazepine hypnotics, including triazolam". As we documented earlier in this chapter, Charles Anello, Deputy Director of the Office of Epidemiology and Biostatistics, compared adverse drug reaction reports for Halcion and Restoril. For Halcion versus Restoril, the relative reporting rate for "agitation, anxiety and nervousness" was 9-1; for psychosis, 16-1; and for "hostility and intentional injury," 19-1.
Great Britain took a stronger stand and ended up banning Halcion. On October 1, 1991 [306], the CSM gave notice of the withdrawal of Halcion from the market because of concerns about safety, especially in regard to causing memory loss and depression (Asscher, 1991 [71]; Brahams, 1991 [167]). On December 9, 1991, the CSM (1991) [306] responded to Upjohn's appeal with a definitive scientific conclusion about the dangers of Halcion. It found what it called a clearly established causal relationship between Halcion and adverse psychiatric effects. These adverse effects occurred, in the CSM's opinion, far more frequently with Halcion than with other BZs. The CSM declared that the SRS data from the United States and England confirmed or strengthened the connection between Halcion and various psychiatric side effects. Concerning the FDA epidemiological data, the CSM observed that despite differences of opinion within the FDA, the U.S. data provided a signal requiring further investigation.
Why would Great Britain take a tougher stand against Halcion? The answer lies partly in the greater power of the psychopharmaceutical complex in America and, in particular, the lavish spending of Upjohn in the maintenance of its self-avowed partnership with the APA. In response to my criticism in a letter to The New York Times (Breggin, 1992c [193]), the medical director of the APA (Sabshin, 1992 [1114]) defended taking a gift in the form of a check for $1.5 million from Upjohn on the grounds that the drug company and the psychiatric association have a "responsible, ethical partnership". Upjohn confirmed the so-called partnership in a letter of its own to Clinical Psychiatry News (Jonas, 1992 [699]). (Even after the controversy, the APA continued the theme of "our partners in industry" in a mass mailing to its membership (Benedek, 1993 [125]).
The manufacturer of Halcion, Upjohn, has been criticized in the media and in court for allegedly withholding from the FDA and the profession damaging evidence concerning the drug. Upjohn has denied allegations of intentional wrongdoing and has attributed errors in reporting adverse effects to innocent mistakes. The controversy continues in the FDA, the media, and the courts (Breggin, 1996 [197]; Carey et al., 1996 [258]; Kolata, 1992 [776]; controversy summarized from a legal viewpoint in Moch et al., 1995 [937]).
Some of the tricyclic antidepressants and barbiturates are probably more lethal than BZs taken alone. But when BZs are combined with other drugs, such as alcohol, their lethality is increased. Overall, the BZs account for many more suicides than most physicians probably realize.
A survey in Britain covering the decade of the 1980s demonstrated large numbers of successful suicides using BZs, either alone or in combination with alcohol (Serfaty et al., 1993 [1157]; see also Buckley et al., 1995 [238]). Serfaty and Masterton (1993) [1157] found 891 fatalities with BZs alone and 591 in combination with alcohoI. The total of all poisonings attributed to BZs was 1,576 during the 10-year period, putting them ahead of aspirin/salicylates at 1,308 as well as amitriptyline (1,083) and dothiepin at 981. (The latter two drugs accounted for over half the fatal poisonings attributed to antidepressants.)
Among the BZs, two commonly prescribed for sleep, flurazepam (Dalmane) and temazepam (Restoril), had the most deaths per million prescriptions (15.0 and 11.9, respectively). They were more dangerous than about half the antidepressants surveyed by the same methods. Triazolam (Halcion) had far fewer deaths per million prescriptions (5.1) than Dalmane or Restoril, but it was still above the mean for anxiolytic BZs (3.2).
In estimated deaths per million patients, the rank order among all BZs in Britain was dominated by the hypnotics. Dalmane (90 per million) was first, Restoril (71) was second, the British hypnotic flunitrazepam (Rohypnol; 49) was third, and Halcion (30) was fourth. Another British hypnotic, nitrazepam (Mogadon and others; 26) was fifth.
In deaths per million patients, among the antianxiety drugs, prazepam (Centrax; 25) and alprazolam (Xanax; 24) were close behind triazolam and nitrazepam.
BZs are often taken to induce sleep, but in reality, they cause a disturbed sleep pattern. Disturbances in sleep pattems are a major source of abnormal emotional and behavioral reactions.
The effects of the BZs on the electroencephalogram (EEG) resemble those of other sedative/hypnotic agents, including decreased alpha activity and increased low-voltage fast activity, especially beta activity (Rall, 1990 [1068]). Their effects on sleep are also similar to those of other CNS depressants and provide a window into the dysfunctions they produce (Rall, 1990 [1068]).
Before the brain rebounds after one or more doses, the BZs decrease sleep latency (the time it takes to fall asleep) and reduce the number of awakenings. The overall time in REM sleep is usually shortened, but the number of cycles of REM may be increased later in sleep. Total sleep durarion is usually increased. There are complex effects on the dream process.
Within a short time of starting Halcion, rebound begins to dominate the clinical picture, and insomnia worsens. Nishino et al. (1995) [991] observed that short-acting BZs were initially preferred for elderly patients. They remarked, "However, it has since been found that short-acting BZs induce rebound insomnia (a worsening of sleep beyond baseline levels on discontinuation of a hypnotic), rebound anxiety, anterograde amnesia, and even paradoxical rage."
In general, the usefulness of BZs in insomnia is temporary at best. They do not provide for normal sleep, but rather for a disruption in various aspects of the normal cycle.
Many physicians seem unaware that the BZs and other sedative drugs can cause persistent or irreversible harm to the brain in the form of persisting memory dysfunction and dementia. The failure to appreciate these adverse drug reactions occurs despite clear confirmatory diagnoses in the consensus document, the APA (2000) [44] Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). In the DSM-IV-TR, the BZ-induced disorders are included in the category of sedative-, hypnotic-, or anxiolytic-induced disorders. The BZs, such as Valium, Ativan, and Xanax, meet all three criteria; they are sedative, hypnotic, and anxiolytic. The DSM-IV-TR [44] stated, "The sedative-, hypnotic- and anxiolytic (antianxiety) substances include the BZs, BZ-like drugs such as zolpidem and zaleplon, the carbamates (e.g., glutethimide, meprobamate), the barbiturates (e.g., secobarbital), and the barbiturate-like hypnotics (e.g. glutethimide, methaqualone)" (p. 284).
The DSM-IV-TR [44] offers specific diagnostic categories for persistent disorders resulting from tranquilizing and sedating agents, including sedative-, hypnotic-, and anxiolytic-induced persisting dementia and sedative-, hypnotic-, and anxiolytic-induced persisting amnestic disorder.
In discussing the meaning of the diagnosis of substance-induced persisting dementia, the DSM-IV (APA, 1994 [43]) stated that
"this disorder is termed `persisting' because the dementia persists long after the individual has experienced the effects of the Substance Intoxication or Substance Withdrawal." (p. 169)
In the preceding discussion, the DSM-IV [43] is very specific, as it is elsewhere, that "Substance-Induced Dementia can occur in association with the following classes of substances: alcohol; inhalants; sedatives, hypnotics, and anxialytics" (p. 169, emphasis added).
Confirmation of BZ-induced dementia is also reconfirmed in the DSM-IV-TR [44] in its Table I: Diagnosis Associated with Class of Substances. Among 12 classes of substances, only 3 are indicated as causing persisting dementia: alcohol, inhalants, and sedatives, hypnotics, or anxiolytics. Only two are associated with amnestic (memory) disorders: alcohol and sedatives, hypnotics, or anxiolytics. The table indicates that BZs are in fact associated with the whole range of disorders that are also associated with alcohol, including dementia.
Thus the APA's committee of experts confirmed a scientific consensus in the field that the BZ drugs can cause dementia and that the dementia, by definition, persists long after the exposure to the drug. I stress this point because so many prescribing health care providers fail to understand the long-term risk of BZ-induced dementia and because I have extensively evaluated several tragic cases of BZ-induced dementia that could have been avoided had the physicians been alert to the risk and stopped the medication.
A number of studies have demonstrated that long-term exposure to BZs can produce persistent memory and cognitive dysfunction, including dementia (e.g., Ashton, 1984 [69], 1995 [70]; Barker et al., 2004 [98]; Bergman al., 1989 [131]; Berzele, 1992 [136]; Golombok et al., 1988 [542]; Lagnaoui et al., 2002 [804]; Petursson et al., 1983 [1031]; Rickels et al., 1999 [1085]; Tata et al., 1994 [1240]).
Barker et al. (2004) [98] found and evaluated 13 studies that employed neuropsychological tests to evaluate cognitive performance after longterm BZ use. Despite the limitations of the studies, they concluded, "The observation that long-term benzodiazepine use leads to a generalised effect on cognition has numerous implications for the informed and responsible prescription of these drugs." The study did not address the potential persistence of these negative effects following termination of drug exposure.
Tata et al. (1994) [1240] used psychometric tests to follow up 21 patients 6 months after abstinence from long-term therapeutic doses of prescribed BZs. They also examined 21 normal matched controls. Pre- and post-withdrawal and 6 months afterward, "the results demonstrated significant impairment in patients in verbal learning and memory, psychomotor, visuo-motor and visuo-conceptual abilities, compared with controls". Lagnaoui et al. (2002) [804] found increased dementia in elderly patients treated with BZs in a community setting.
Several studies demonstrated brain dysfunction and damage in association with the use of BZs, usually in the form of enlarged cerebral ventricles associated with shrinkage or atrophy of the brain substance, sometimes in association with neuropsychological deficits (Bergman et al., 1989 [131]; Lader et al., 1984 [801]; Schmauss et al., 1987 [1135]; Uhde et al., 1987 [1273]). Schmauss and Krieg (1987) [1135] gave CT scans to 17 BZ-dependent in-patients and recorded a dose-dependent enlargement of cerebral ventricles. Bergman et al. (1989) [131] found an increased frequency of dilated cerebral ventricles and intellectual impairments: "The results suggest that despite some neuropsychological improvement cerebral disorder diagnosed in patients abusing sedative or hypnotics is often permanent through the years and that neuropsychological status is linked to long-term prognosis." Several mechanisms are involved in causing persistent changes in mental function from BZs, including reduced cerebral blood flow and reduced utilization of glucose, atrophy of the brain, and down-regulation of the receptors (Buchsbaum et al., 1992 [236]; Mathew et al., 1985 [886]; Mathew et al., 1991 [885]).
Although many health care providers have been misled by drug company promotional efforts, the great majority of sleep aids share the same risks as the BZs (see the appendix for a list). Almost all are placed in Schedule IV by the DEA to indicate a risk of abuse and dependence. According the DEA (2006) [377], Ambien and Sonata (zaleplon) are "benzodiazepine-like CNS depressants".
For example, Ambien differs in chemical structure from the BZs but affects the same neurotransmitter system, GABA. The 2007 FDA-approved label for Ambien CR, available in the Physicians' Desk Reference [1036], warns that
"a variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to the effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavior changes such as bizarre behavior, agitation, and depersonalization. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thinking, has been reported in association with the use of sedative/hypnotics."
Also according to the drug label, in brief, 3-week controlled clinical trials, patients developed hallucinations, disorientation, anxiety, depression, psychomotor retardation (mental and physical slowing), depersonalization, disinhibition, euphoric mood, mood swings, and stress symptoms. Hallucinations were reported in 4% of the Ambien patients and none of the placebo patients.
The label for Ambien CR also describes separate subheadings for the discussion of memory problems, tolerance, dependence, and withdrawl. Another subhead, "Changes in Behavior and Thinking," lists the following bulleted drug reactions:
Many health care providers probably have little idea about the range of psychiatric risks associated with these drugs or their powerful tendency to become spellbinding. On March 14, 2007, the FDA (2007c) [476] issued a new warning for a broad range of sleep medications, including all those in the appendix: "complex sleep-related behaviors which may include sleep-driving, making phone calls, and preparing and eating food (while asleep)". Sleepwalking in some ways epitomizes spellbinding; the individual is wholly unaware of carrying out potentially dangerous activities.
ln recent years, the FDA-approved labels for Xanax and Xanax XR have carried extensive warnings about dependence (addiction) and withdrawal. The Xanax XR label found in the 2006 Physicians' Desk Reference [1036] warned that dependence occurs in small doses over short periods of time. The label described both withdrawal and rebound symptoms, with interdose withdrawal occurring when the effect of each dose wears off during the day or on awakening in the morning. It reported a broad array of withdrawal reactions based on controlled clinical trials: heightened sensory perception, impaired smell, impaired concentration, clouded sensorium [mind], parethesias, muscle cramps, muscle twitch, diarrhea, blurred vision, decreased appetitive, and insomnia. Anxiety and insomnia were also reported as withdrawal symptoms, but the label suggests that these were difficult to separate from the patients' original psychiatric disorders. In reality, the abrupt surfacing of anxiety and insomnia on withdrawal from BZs is commonplace and well established by clinical experience and a variety of studies (e.g., Marks et al., 1989 [877]).
The label reported that severe withdrawal reactions made it impossible for many patients to stop taking the medication after the termination of controlled clinical trials. In two clinical trials of only 6 and 8 weeks duration, 7% and 19%, respectively, of patients were unable to withtaw. These are very high rates for the inability to withdraw from a drug after very short exposures.
Earlier in the chapter 1 pointed out that the Xanax label also carried many warnings about adverse psychiatric effects such as disinhibition, depression, and mania. I suspect that many physicians reading these new labels would think twice about prescribing the medication. The manufacturer, Pharmacia & Upjohn, apparently came to the same conclusio because they decided not to include any information about Xanax or Xanax XR in the 2007 Physicians' Desk Reference [1036] (PDR). The PDR is the major source of data for health care providers concerning medication adverse effects. As a result of removing Xanax and Xanax XR from the PDR, the drug company protected its valuable products from medical scrutiny, leaving many prescribing physicians to fly blind, guided only by vaguely recalled older misinformation about the relative safety of Xanax.
Among the BZs used primarily for the treatment of anxiety or panic, alprazolam has an especially bad record. In the field of drug addiction, Xanax is the most frequently implicated psychiatric drug (Breggin, 1991b [189]). Often, it occurs in cross-addiction with alcohol and other sedatives. Withdrawal problems and rebound increases in anxiety and panic were so extreme in key studies used for FDA approval of Xanax for panic disorder that many or most patients had more frequent or severe symptoms at the end of the studies than before they took the drug, and many had trouble withdrawing (Marks et al., 1989 [877]; reviewed in Breggin, 1991b [189]).
In regard to short-acting BZs such as Xanax and Halcion, the American Psychiatric Association (1990a) [39] Task Force task force report on BZs made the following observations:
"Abrupt discontinuation of short half-life benzodiazepines leads to rapid drug removal from the blood and brain, rapid uncovering of the receptor site, and relatively rapid onset of post-drug discontinuation syndromes. Because of the severity of symptoms related to its halflife, short half-life benzodiazepines given for anxiety are frequently implicated in intense discontinuation syndromes With very short half-life drugs such as triazolam, rebound symptomatology has actually been described during the period of ingestion, especially when it is given nightly." (pp. 39-40)
Although Xanax is among the worst offenders, all BZs can cause serious withdrawal problems. The APA (1990a) [39] task force presented a table of discontinuation symptoms. The complete list of frequent discontinuation symptoms includes "anxiety, insomnia, restlessness, agitation, irritability, muscle tension" (p. 18). Among many symptoms that are comon but less frequent, it lists "depression" and "nightmares" as well as "lethargy" (p. 18). Clinical experience indicates that the combination of anxiety, insomnia, restlessness, agitation, irritability, nightmares, and depression can produce a spectrum of behavioral abnormalities, including suicide and violence. Adding to the dangers, the task force's complete list of uncommon symptoms includes "psychosis, seizures, persistent tinnitus, confusion, paranoid delusions, hallucinations" (p. 18). There are estimates that 50% or more of patients taking BZs in therapeutic doses over a year will become physically dependent, developing withdrawal symptoms on abrupt cessation (Ashton, 1995 [70]; Noyes, 1992 [997]).
Abrupt withdrawal from BZs can be extremely painful, both emotionally and physically, and even lethal in the case of uncontrolled seizures. It is unclear if gradual withdrawal merely extends the process over time, rather than avoiding it (Noyes, 1992 [997]); but gradual withdrawal does help to protect against severe seizures.
Many symptoms can take weeks or months to fully subside, leaving the patient with prolonged anxiety or depression (Ashton, 1995 [70]). Sometimes the withdrawal symptoms never completely subside. I have treated patients who have not regained their predrug condition many years after stopping BZs. Some have suffered from permanent memory problems, difficulties with concentration, and other cognitive impairments. They have felt depressed and emotionally unstable. Some have continued to suffer from poor fine motor coordination, muscle cramps, and parethesias. A few cases have suffered from a little-known long-term effect, peripheral neuritis with extreme pain, especially in the feet (for descriptions of severe BZ withdrawal and lasting aftereffects, see Breggin, in press). These effects are more accurately viewed as irreversible effects of BZ toxicity rather than as withdrawal reactions.
Severe withdrawal can occur after relatively short exposures to BZs. I have treated patients who have suffered from severe withdrawal problems after only 2 weeks of low-dose exposure to prescribed alprazolam and clonazepam. Lader (1984) [799] and the APA (1990a) [39] task force confirmed that therapeutic doses commonly produce severe withdrawal symptoms.
Kales et al. (1991) [720], in a placebo-controlled sleep lab study, showed that even under "brief, intermittent administration and withdrawal" of triazolam (and, to a lesser extent, temazepam), patients experienced rebound insomnia, "thereby predisposing to drug-taking behavior and increasing the potential for drug dependence".
Some patients can find it difficult to withdraw from as little as 0.5 mg clonazepam each night for sleep. Even motivated patients have sometimes developed such a fear of trying to go to sleep without BZs that they cannot undertake a serious effort. The fear is usually based on previous disturbing experiences of rebound insomnia.
Physicians erroneously prescribe BZs in ever-increasing doses, mistakenly thinking that their patients' anxiety was spontaneously increasing, rather than rebounding from the drug. Even if the ultimate dose remains within the recommended range, patients can roller coaster with anxiety or other mental aberrations through each day between doses. The patients' lives can become devoted to finding the right drug and taking it at the right time.
It requires a physician's patience and understanding, and often a period of many months, to wean some indi-iiduals from the BZs. At the end of the weaning, patients may discover that nearly all of their supposedly psychiatric symptoms were in fact drug induced. The general principles of drug withdrawal in outpatient practice are discussed in greater detail in chapter 15. Patients taking large doses of BZs may need detoxification in a hospital setting.
Patients who have not been properly monitored by physicians may end up taking large doses of BZs for prolonged periods of times. Their daily lives may cycle from periods of excessive sedation, when they appear drunk, to periods of hyperarousal and anxiety as they undergo partial withdrawal. Friends and family may attribute their symptoms to mental illness until, for example, the patient begins to stumble about in a drunken manner or collapses in a stupor after only one alcoholic drink during a holiday dinner. In retrospect, it will be apparent that the patient was medication spellbound for months, too intoxicated to properly evaluate his or her own condition or to exercise judgment in regard to the drug's effects. Often, the patient's memory for the period of time will be severely impaired. Sometimes he or she will have committed irresponsible and even illegal acts (Breggin, in press).
The BZs are frankly brain-disabling drugs. Much like alcohol, their clinical effect is no different from their toxic effect-a continuum of suppression of neuronal function, leading eventually to sleep or coma. The sought-after reduction of anxiety or induction of sleep is the direct result of impaired central nervous system function.
These drugs are also extremely spellbinding so that individuals frequently become mentally and even physically disabled without fully recognizing their deterioration and without attributing it to the medication. Instead, they feel compelled to take more and more psychiatric drugs in a fruitless, self-defeating effort to end their suffering.
BZs can produce a wide variety of abnormal mental responses and very hazardous behavioral abnormalities: rebound anxiety, insomnia, psychosis, paranoia, violence, antisocial acts, depression, and suicide. They impair cognition, especially memory, and can cause confusion. There is strong evidence that they produce persisting memory dysfunction, dementia, and shrinkage of brain tissue reflected in ventricular dilation.
These drugs commonly cause abuse and dependence (addiction), and even in relatively short-term use at relatively small doses, they can produce severe withdrawal syndromes. Because the withdrawal symptoms are so distressing, many patients cannot stop taking these drugs. After stopping the medication, some individuals never fully recover from their toxic effects, including memory and cognitive problems, impaired fine motor coordination, emotional instability, fatigue, and painful cramps or peripheral neuritis.
Mixed with alcohol and other sedatives, their hazards multiply, and unintentional fatalities are possible. Successful suicides involving BZs, especially those drugs prescribed as sleeping medications - Halcion, Dalmane, and Restoril - are much more frequent than commonly realized by physicians.
Although the shorter-acting BZs such as Xanax (alprazolam) and Halcion (triazolam) seem to be the most toxic and most prone to cause dependence, any BZ can cause these untoward effects, including the commonly used Klonopin (clonazepam) and Ativan (lorazepam). Overall, the BZs and many related medications used to treat anxiety and insomnia are potentially very brain disabling and spellbinding, and entail much graver risks than commonly recognized by health care providers and their patients.