Review of Behavioral Effects of Benzodiazepines

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Review of Behavioral Effects of Benzodiazepines

 

copyright by Peter R. Breggin, M.D.

 

The following material is excerpted and revised from Peter R. Breggin, M.D.,

Brain-Disabling Treatments in Psychiatry: Drugs, Electroshock and the Role of

the FDA, Springer Publishing Company (1997).

Presented here with the permission of Springer Publishing Company

536 Broadway, New York, NY 10012-3955.

Review of Behavioral Effects of Benzodiazepines With an Appendix on Drawing

Scientific Conclusions from the FDA's Spontaneous Reporting System (MedWatch)

By Peter R. Breggin, M.D.

The benzodiazepines (BZs) have for several decades been recognized in the

literature and clinical practice for their capacity to cause mental and

behavioral abnormalities. Xanax (alprazolam), and to an even greater extent,

Halcion (triazolam), have a significantly different profile from other

benzodiazepines due to their greater capacity to bind to receptors and their

shorter half-life. Halcion's very short half-life led to the hope that it would

make a particularly good sleeping medication but it has proven especially

dangerous.

The brain-disabling or toxic effects of the Bzs in general can be divided into

several somewhat overlapping categories:

(1) The primary clinical effect of inducing sedation (tranquility) or hypnosis

(sleep), which is indistinguishable from a toxic effect except in degree;

(2) Cognitive dysfunction, ranging from short-term memory impairment and

confusion to delirium;

(3) Disinhibition and other behavioral aberrations-- including extreme

agitation, psychosis, paranoia, and depression, sometimes with violence toward

self or others;

(4) Withdrawal, in which the individual experiences a continuum of symptoms from

anxiety and insomnia after routine use to psychosis and seizures after the

abrupt termination of long-term, larger doses;

(5) Rebound, an aspect of withdrawal, in which the individual develops anxiety,

insomnia, or other serious emotional reactions that are more intense than before

drug treatment began. Withdrawal can take place between doses during the routine

administration of Bzs, especially the short-acting ones. (6) Habituation and

addiction, along a continuum from feeling dependent on the drug to compulsively

organizing one's behavior in a self-destructive manner around obtaining large

amounts of the agent.

The Mechanism of Brain-Disability

Neurophysiological studies show that the BZs potentiate the neuronal inhibition

that is mediated by gamma-aminobutyric acid (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). 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. Some advocates of the BZs have argued for a specific

anti-anxiety effect separate from the general sedative effect, but there's no

substantial evidence for this. Rall (1990) concludes " The question whether the

so-called antianxiety effects of the benzodiazepines are the same or different

from the sedative and hypnotic effects has not been resolved. "

People who use BZs to calm their anxiety will frequently use alcohol and other

sedatives interchangeably for the same purpose, either in combination or at

different times. As they switch from drug to drug, they tend to find little or

no difference in the anti-anxiety effect. This confirms the brain-disabling

principle that BZs have no specificity for anxiety in comparison to other

sedative/hypnotic agents. The Mechanism for Producing Behavioral Abnormalities

There are at least two probable 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, p. 341) observe " 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. "

Especially in regard to the BZs, a second mechanism, rebound, has been

demonstrated, and is a probable cause of many more severe reactions. Rebound or

discontinuation symptoms occur when the BZs are withdrawn or when they begin to

lose their effectiveness (American Psychiatric Association, 1990). As the BZ

disappears from the GABA receptor sites, the receptors may have become

down-regulated (less sensitive). Or there may be a reduction in GABA itself in

response to the drugs, once again leaving the GABA system relatively inactive.

Without the inhibiting effects of the GABA system, the " disinhibited " brain

over-reacts. The American Psychiatric Association (1990) task force report,

Benzodiazepine Dependence, Toxicity, and Abuse, theorized that discontinuation

symptoms arise from the abrupt withdrawal of BZs from their receptor sites.

Before GABA can retake these positions, there is an acute reduction of GABA, and

a loss of GABA inhibitory tone.

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 " losing 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 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.

Adverse Reactions to the BZs as a Group

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 (DiMascio and Shader, 1970; Kochansky, Salzman, Shader,

Harmatz, and Ogeltree, 1975; Shader and DiMascio, 1977; Rosenbaum, Woods,

Groves, et al., 1984; Arana and S. Hyman, 1991; Maxmen, 1991; Maxmen and Ward,

1994; Ashton, 1995).

Salzman, Kochansky, Shader, Porrino, Harmatz, and Swett (1974), in a placebo

controlled study, showed that volunteers taking chlordiazepoxide became more

hostile when confronted with a situation of interpersonal frustration. In 1988,

Dietch and Jennings reviewed the literature concerning reports about

disinhibition whose " Manifestations range from irritability to increased verbal

hostility and frank assault. " They found a variety of studies that demonstrate

an increase in feelings of hostility or in verbal hostility. They did not come

to a definitive conclusion concerning the existence of the phenomenon, but

estimated it was probably rare. Salzman (1992) reviewed the literature. He too

pointed out the 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 " (citations

omitted). Writing in Goodman and Gilman's The Pharmacological Basis of

Therapeutics, Rall (1990) summarized:

AAdverse 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 hypomania 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.@

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. The APA task force report on BZs

(1990, p. 18) presents a table of discontinuation symptoms. The complete list of

frequent discontinuation symptoms includes " anxiety, insomnia, restlessness,

agitation, irritability, muscle tension. " Among many symptoms that are common

but less frequent, it lists " depression " and " nightmares, " as well as

" lethargy. " 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. "

The Production of Mania and Rage

As the above observations confirm, reactions to Xanax and other benzodiazepines

can reach psychotic proportions. As noted in the 1996 edition of Drug Facts and

Comparisons, the BZs in general can cause serious psychiatric problems,

including " psychosis. " They can disrupt central nervous system function,

producing, among other things, " disorientation... confusion... delirium....

euphoria... agitation. " A special Precautions section notes " Paradoxical

reactions, " including " excitement, stimulation and acute rage " and " hyperexcited

states, anxiety, hallucinations... "

Mania, a psychosis, is a special danger in regard to Xanax. The Drug Facts and

Comparisons (p. 1440) makes a specific reference to Xanax in this regard,

stating that " Anger, hostility and episodes of mania and hypomania have been

noted with alprazolam. " The fact that mania is a particular risk with Xanax is

generally recognized. As another example, Maxmen and Ward's Psychotropic Drug

Fast Facts (1995, p. 287) states that " manic reactions " are " Most often reported

with alprazolam. " It also states that " rage reactions " and " violent episodes "

have especially been observed with Xanax and Valium. Yet another example is The

Handbook of Psychiatric Drug Therapy (Third edition, 1995, p. 177) by Hyman,

Arana, and Rosenbaum. It singles out Xanax to observe " Increased impulsiveness,

euphoria, and frank mania have been reported with alprazolam. " Drug Facts and

Comparisons, Psychotropic Drug Fast Facts and the Handbook of Psychiatric Drug

therapy are intended for ready reference for physicians for the purpose of

alerting them to adverse drug reactions they need to be aware of. That all three

indicate that mania and uncontrollable rage are special problems with Xanax

confirms my own clinical observations that this medication is more apt than many

others to produce these hyper-excited, aggressive psychotic states.

The FDA's " Safety Review and Evaluation of Clinical Data " by J. Knudsen (1989)

for Xanax for panic disorder once again highlighted its tendency to produce

mania. It included a review of Xanax-induced mania from the literature. It

described several cases of mania produced in the panic disorder clinical studies

and offered two tables described 14 cases of hypomania and one of mania. Several

attacks developed during the first week of treatment at relatively small doses.

The Production of Depression and Suicide

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 it should be taken seriously. Arana and

Hyman, for example, stated:

ADepression: 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) observed that benzodiazepines 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 task fore

report on BZs (1990), in a discussion of toxicity, also observed:

ABenzodiazepines 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 (citation omitted)@ Great Britain's

Committee on Safety of Medicines (1988) recommended that " benzodiazepines should

not be used alone to treat depression or anxiety associated with depression.

Suicide may be precipitated in such patients. " Due to the action of the BZs on

gamma-aminobutyric acid (GABA) receptors, as well as to research in depression,

there is growing interest in the role of a GABAergic systems in mood disorders

(Kalpana, Musselman, Schatzberg & Nemeroff, 1995; also see Bartholini, Lloyd &

Morselli, 1986). GABA systems have also been associated with the production of

anxiety and anger. Cognitive, Emotional and Behavioral Abnormalities Caused by

Halcion and Xanax 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, Ankier and Hayes (1985) found " 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, Kirking, Zacardelli and Kwee (1989) reviewed the charts of 72 adult

male patients taking triazolam for sleep through an ambulatory Veterans

Administration clinic. Thirty-nine of the patients were available for telephone

interviews. Most of the patients were elderly (aged 60 or older) and almost all

received 0.25 mg. Of the thirty-nine 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. " We have already note that the APA task

force (1990) on BZs described a variety of symptoms, including depression,

anxiety, hostility, and paranoia, and attribute them in part at least to

discontinuation or withdrawal. In regard to short-acting BZs, the task force

made the following observations:

AAbrupt 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 half-life, 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. p. 39-40 (citations omitted)@

Public and professional awareness of the special dangers of Halcion began in

1978. At that time, C. van der Kroef--a psychiatrist in the Hague,

Netherlands--noticed abnormal reactions to Halcion in four of eleven patients he

treated with the drug. Here is van der Kroef's description in one of his

patients (quoted in Dukes, 1980):

AThe 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...@

M. N. G. Dukes (1980), 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, all the BZs used for the control of anxiety were also

implicated in causing violence:

AIf 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 development 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, the 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. It is, of course, extremely difficult to demonstrate drug-induced

behavioral abnormalities in highly selective, short, controlled clinical trials

(see chapter 11 for detailed analysis of why this is so). Nonetheless, several

studies have confirmed some of the hazards associated with Halcion. Gardner and

Cowdry (1985) found an increase in " dyscontrol " in borderline patients taking

alprazolam in a double-blind, placebo-controlled crossover 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 heading banging; jumped in front of car. "

Gardner and Cowdry 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, Bayer, Pathy and Stoker (1986) 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 three, 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 central nervous system, requiring four of

twenty-two patients to withdraw from the study, three of whom recovered after

terminating the medication. One patient felt 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), in a double blind, placebo controlled study of triazolam

and lormetazepam with forty 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, Sakkas,

Bergiannaki, and Stefanis (1986) 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 one week of

placebo baseline, two weeks of triazolam administration, and one 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 suggest that some of

the symptoms may be related to disinhibition. They warn that these serious side

effects " may not be rare when triazolam is used in patients " with " major

psychiatric conditions. "

Rosenbaum, Woods, Groves et al (1994) found that 8 of 80 (10%) of patients

treated with alprazolam in an outpatient clinical setting developed extreme

anger or hostile behavior.

In the FDA's " Safety and Review Evaluation of Clinical Data " by J. Knudsen

(1989) of Xanax for panic disorder, the issue of disinhibition from Xanax was

addressed. It stated " The emergence of the rather paradoxical reaction of

disinhibition often characterized by agitating, aggressive behavior, rage,

hostility has been reported in patients treated with alprazolam. Knudsen

described several reports of adverse drug reactions described as " disinhibition,

rage, hostility " occurring early in treatment at relatively low doses. One

physician reported three different patients as suffering from these attacks.

Evidence from the FDA's Spontaneous Reporting System (SRS)

In 1987, Bixler, Kales, Brubaker and Kales, from the Sleep Research and

Treatment Center and Department of Psychiatry at the Pennsylvania State

University College of Medicine, reviewed adverse reactions to BZs recorded in

the FDA's spontaneous reporting system. 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. They found:

AIn 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 central

nervous system 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 division has consistently shown more concern about

triazolam than has Paul Leber's Division of Neuropharmacological Drug Products,

which originally approved the drug (see below; see chapter 11 for more about

Leber and the FDA). The data from the epidemiology studies will now be described

in detail for the first time in the literature. Robert " Bob " Wise (1989), in a

working paper for the FDA's Division of Epidemiology and Surveillance, made an

" executive summary " of reports of hostility associated with exposure to

triazolam. Wise addresses a syndrome that " consists of anger or rage,

aggression, and some actual assaults and murders. " He stated:

AMore 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

explains " 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. "

According to Wise (1989):

AIn the entire SRS (spontaneous reporting system) 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.

Males (29) and females (26) were almost evenly distributed. Four alprazolam

cases showed a reduction in hostility and rage reactions with a reduction in

dose, confirming the drug's role in producing the behavior. Wise 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, the

dose dependency 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. "

On April 21, 1989, 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: AFrom spontaneous reports alone, we

cannot estimate the actual incidence of alprazolam-induced rage reactions. But

in light of the widely acknowledged, substantial under-reporting to spontaneous

surveillance systems in general and the to the FDA's SRS in particular, it 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:

AAn increase in annual frequency of " rage " reports with alprazolam promoted 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 dosage all appear to conflict with

current labelling's brief description of " paradoxical effects " that occur only

" in rare instances and in a random fashion. "

On October 17, 1988, Charles Anello, Deputy Director of the Office of

Epidemiology & 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 receives

proportionally more adverse drug reaction reports (ADRs), more serious ADRs, and

more reports of five selected " behavioral " drug reactions.

On September 12, 1989, Anello reported within the FDA on " Triazolam and

Temazepam--Comparison Reporting Rates. " He found that adverse drug reactions

were reported eleven times more frequently with triazolam than with temazepam.

The relative 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 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 the document that was obtained through the Freedom of Information Act,

there is a summary entitled " Other Evidence in Favor of Effect of Triazolam "

which we produce in full:

A1) Temporal relationship of reactions to initial dose

2) Large proportion of spontaneous resolution with drug withdrawal pos[itive]

dechallenge [in dechallenge, a drug is withdrawn to see if an adverse reactions

then stops, confirming that it was drug induced.]

3) a few reports of positive rechallenges [in rechallenge, after an adverse drug

effect disappears upon withdrawal of the drug, the drug is given again to see if

the reaction can be repeated and reconfirmed.]

4) reports of reactions in otherwise normal individuals

5) corroborating reports in literature (including WHO data--similar magnitude of

reactions in Canada in data through 3/87)@

Their analysis 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 regard to epidemiological studies, see

appendix).

In an August 11, 1989 in-house FDA memo from Paul Leber and Thomas Laughren to

an upcoming Psychopharmacological Drugs Advisory Committee Meeting (PDAC), the

FDA officials commented that " Spontaneous reporting of adverse events in the

United States subsequent to the marketing of Halcion has consistently revealed a

pattern of excess reporting of events for Halcion compared to the two other

marked benzodiazepine hypnotics. " He brought up the earlier hope that the

recommendations to reduce the dose of Halcion would result in a reduction of the

high rates of reported adverse behavioral reactions. However, this proved to be

a false hope. Leber observed, Halcion continues to exhibit an excess of adverse

events reported compared to one comparitor agent [Restoril] " in regard to " the

cluster of behavioral adverse reactions. " In 1991, 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

spontaneous report system, they 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 the in-house report by Anello (1990), the

authors summarize:

AFactors that indicate a causal association between triazolam and adverse

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.@

[citations omitted]

While unable to " completely exclude the possibility that some selection factors

are operating to produce higher reporting rates for triazolam, " nonetheless they

find that the " evidence suggests " a greater occurrence with triazolam and than

with temazepam. Andreadis and Schirmer (1992) responded critically for Upjohn

with a letter and Wysowski and Barash (1992) then tried to answer their

objections. American and British Responses Diverge

Finally, in November 1991, the FDA approved new labelling for Halcion (Food and

Drug Administration, April 1992). The new label emphasizes that triazolam is

indicated for short-term use, and specifies 7-10 days. Treatment lasting longer

than 2 to 3 weeks requires a complete reevaluation of the patient. In addition,

the label emphasizes the use of the lowest possible dose.

Here is the new warning in the Halcion label as found, for example, in the 1994

Physicians' Desk Reference:

AA 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, eg,

aggressiveness and extroversion that seem excessive, similar to that seen with

alcohol and other CNS depressants (eg, 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:

AAs 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 behavioral extremely hazardous abnormalities,

label notes 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 &

Biostatistics, reported on a comparison of 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 to 1; and

for " hostility and intentional injury, " 19-1. Great Britain took a stronger

stand and ended up banning Halcion. On October 1, 1991, the Committee on the

Safety of Medicines (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 (Brahams, 1991; Asscher, 1991). On December 9, 1991, the

Committee on Safety of Medicines (1991) responded to Upjohn's appeal with a

definitive scientific conclusion about the dangers of Halcion (p. 1). 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 than with other BZs. The CSM declared that the

spontaneous reporting system data from the US 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 US data provided a signal requiring

further investigation (p. 10).

Other Risks of Benzodiazepine Use

BZs As Instruments of Suicide

Some of the tricyclic antidepressants and barbiturates are probably more toxic

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, alone and in combination with alcohol (Serfaty

and Masterton, 1993; also see Buckley, et al. 1995). Serfaty and Masterton found

891 fatalities with BZs alone and 591 in combination with alcohol. The total of

all poisonings attributed to BZs was 1576 during the ten year period, putting

them ahead of aspirin/salicylates at 1308 as well as amitriptyline (1083) and

dothiepin at 981. That 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 was fourth (30). Another

British hypnotic, nitrazepam (Mogadon and others) (26) was fifth. In death per

million patients, among the anti-anxiety drugs, prazepam (Centrax) (25 estimated

deaths per million patients) and alprazolam (Xanax) (24) were close behind

triazolam and nitrazepam.

BZ-Induced Cognitive Dysfunction

Cognitive impairment, including memory impairment and confusion, is a well-known

phenomenon in association with BZs (Ashton, 1995; APA, 1990; Golombok, Moodley

and Lader, 1988; Hommer, 1991). Xanax and Halcion are especially prone to

produce cognitive deficits. Individuals who take Halcion to sleep on an airplane

may end with a blank in their memories for the period surrounding the trip.

Students who take BZs before exams in order to relax or to get sleep are in

danger of losing some of the material they have been studying. Triazolam

produced more sedation and greater impairment of psychomotor performance at the

same dose in healthy elderly persons than in healthy young persons (Greenblatt

et al., 1991).

Effects on Sleep and the EEG

The effects of the BZs on the EEG resemble those of other sedative-hypnotic

agents, including decreased alpha activity and increased low-voltage fast

activity, especially beta activity (Rall, 1990). Their effects on sleep are also

similar to those other CNS depressants, and provide a window into the

dysfunctions they produce (Rall, 1990). 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 duration is usually increased. There are complex effects on the

dream process.

Within a short time of starting Halcion, rebound begins to the dominate the

clinical picture, and insomnia worsens. Nishino, Mignot and Dement (1995)

observe that short-acting BZs were initially preferred for elderly patients.

They remark, " However, it has since been found that short-acting benzodiazepines

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.

The Probability of Permanent Brain Damage

There have been relatively few studies on the persistence of cognitive deficits

following termination of BZ treatment. Despite the analogy with alcohol-induced

cognitive dysfunction and dementia, most review articles and book chapters do

not raise the issue. As I have previously noted (1991), patients on high doses

of BZs develop chronic cognitive impairments (Golombok, Moodley, and Lader,

1988; Lucki, Rickels, and Geller, 1986). There is little literature concerning

these effects. At least two reports indicate brain atrophy in association with

long-term BZ use (Lader and Petursson, 1984; Schmauss and Krieg, 1987). There

seem to be no follow up studies concerning these critical questions. Ashton

(1995) is among the few reviewers to show concern about the possibility of

BZ-induced persistent cognitive deficits or brain damage. He notes the lack of

studies and comments, " It remains possible that subtle, perhaps reversible,

structural changes may underlie the neuropsychological impairments shown in

long-term benzodiazepine users. "

Dependence and Withdrawal

Alcohol-like withdrawal symptoms from the long-term use of excessively high

doses of BZs is well-established. Withdrawal can take two to twenty days to

develop after abrupt termination of the drug, depending on the half-life of the

particular BZ. The first signs may be insomnia, irritability, and nervousness.

This can progress to a state that includes abdominal cramps, muscle cramps,

nausea or vomiting, trembling, sweats, hyperarousal and hypersensitivity to

environmental stimuli, confusion, depersonalization, anxiety and obsessional

states, psychosis and organic brain syndrome, and seizures. Occasional case

reports suggest that even slow withdrawal may not obviate serious withdrawal

symptoms. It is unclear if gradual withdrawal merely extends the process over

time rather than avoiding it (Noyes, 1992). Many symptoms can take weeks or

months to fully subside, leaving the patient with prolonged anxiety or

depression (Ashton, 1995). I have seen patients who felt they had not regained

their pre-drug condition many months or years later. Kales, Manfredi, Vgontzas,

Bixler, Vela-Bueno, and Fee (1991), 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. "

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 (Noyes, 1992; Ashton, 1995). Among the BZs used primarily for

the treatment of anxiety or panic, alprazolam seems to have an especially bad

record. In the field of drug addiction, Xanax is the most frequently implicated

psychiatric drug (Breggin, 1991). 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 (reviewed in

Breggin, 1991).

Some patients can find it difficult to withdraw from as little as 0.5 clonazepam

each night for sleep. Even motivated patients have sometimes developed such a

fear of trying to sleep without BZs that they cannot undertake a serious effort.

The fear is in part psychological. But it is also based on the frightening

experiencing rebound insomnia. Physicians erroneously prescribe BZs in

ever-increasing doses, mistakenly thinking that their patient's 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, in order to wean some individuals off the BZs. At the

end of the weaning, patients may discover that nearly all of their symptoms were

drug-induced. I discuss the general principles of drug withdrawal in outpatient

practice in greater detail in Talking Back to Prozac. Patients taking large

doses of BZs need detoxification in a hospital setting.

Where patients have not been properly monitored by physicians, they may end up

taken 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 one

alcoholic drink during a holiday dinner. In retrospect, it will be apparent that

the patient was, for months, too intoxicated to properly evaluate his or her own

condition or to exercise judgment in regard to the drug effects. Often the

patient's memory for the period of time will be severely impaired. Sometimes

they will have committed irresponsible and even illegal acts. In summary, the

benzodiazepines can produce a wide variety of abnormal mental responses and

hazardous behavioral abnormalities, including rebound anxiety and insomnia,

psychosis, paranoia, violence, antisocial acts, depression, and suicide. The BZs

impair cognition, especially memory, and can cause confusion. They probably can

cause brain atrophy. They are habit-forming and addictive, and when taken in

large doses for a period of time, severe withdrawal syndromes can develop on

termination of the drug. Mixed with alcohol and other sedatives, their hazards

multiply. Halcion and Xanax so commonly produce a variety of potentially

disastrous adverse reactions that they should not be prescribed by physicians.

If a physician or patient decides to use another of the BZs, the drug should be

prescribed in the smallest possible dose for the shortest possible time, usually

no more than a week at a time. The physician, the patient, and the family or

close friends should be alert for possible adverse drug reactions. Appendix

Drawing Scientific Conclusions from the FDA's Spontaneous Reporting System

(MedWatch)

There are a number of approaches that can be used to confirm from spontaneous

reports that a drug is actually causing a particular adverse reaction with which

it has been associated in the reports. This paper described how FDA officials

went about confirming for themselves a possible or probable causal relationship

between Halcion (and Xanax) and various behavioral abnormalities, including

violence. These principles will now be elaborated upon. To confirm causality,

some of the following factors are useful:

(1) a disproportionately high frequency of reporting or disproportionately large

number of reports in comparison to other drugs, especially in the same or

similar class of drugs;

(2) a meaningful or strong enough association as reflected in epidemiological

and clinical data;

(3) an absence of alternative explanations for the increased frequency or number

of reports; (4) reports indicating a temporal relationship between the adverse

reactions and initial doses of the drug or increased doses of the drug;

(5) reports of dose-dependent reactions, that is, increased frequency or numbers

of adverse reactions with higher dosages;

(6) reports of positive dechallenge-- resolution of the reaction following drug

withdrawal; (7) reports of positive rechallenges--the reaction is provoked once

again by resuming the drug; (8) reports of adverse reactions in individuals; (9)

corroborating clinical experience (published and unpublished); (10) data from

clinical trials, including controlled trials;

(11) a rational medical and/or neurochemical explanation for a causal connection

between the drug and the adverse reaction, and the corresponding absence of a

better explanation.

The Federal Judicial Center (Bailey, Gordis, & Green, 1994) has proposed a

series of criteria that compact many of the points I have made. The difference

in approach is in part due to their epidemiological emphasis in contrast to my

clinical emphasis. Drawing on Koch's postulates, they state that " seven factors

should be considered when an epidemiologist determines whether the association

between an agent and a disease is causal. " Put in the form of questions, they

list the following factors:

1. How strong is the association between the exposure and the disease? 2. Is

there a temporal relationship?

3. Is the association consistent with other research?

4. Is the association biologically plausible? 5. Have alternative explanations

been ruled out?

6. Does the association exhibit specificity? 7. Is there a dose-response

relationship?

None of the above individual criteria is an absolute requirement for coming to a

scientific conclusion. One must weigh the best available evidence and come to as

sound a conclusion as possible. Commonly or even typically, decisions with a

high degree of probability will be made with an incomplete set of data.

While it would be helpful to have confirmation from controlled clinical trials,

it is typically impossible to obtain it, even in regard to known or proven

adverse drug reactions (Leber, 1992). Negative findings from controlled clinical

trials involving a drug cannot be used to rule out a causal connection between a

drug and an adverse reaction. In fact, the vast majority of changes made drug

labeling during the post-marketing phase is based on the kind of data that is

generated by the spontaneous reporting system and almost none of the changes

result from controlled clinical trials. Even when drugs are taken off the

market, they FDA often acts on the basis of spontaneous reports. In describing

the impact of the spontaneous reporting system, the FDA's director, David

Kessler (1993), said:

AIn response to voluntary reports from physicians to the FDA or the

manufacturer, the FDA has issued warnings, made label changes, required

manufacturers to conduct postmarketing studies, and ordered product withdrawals

that have ultimately prevented patient deaths and suffering.@

A recent FDA MEDWatch (FDA, 1995) publication makes clear that the spontaneous

reporting system is the most important source of postmarketing information on

adverse drug reactions. It frequently leads to scientific determinations for the

need to modify drug labels or to withdraw drugs from the market.

According to a 1990 Government Accounting Office (GAO) report, more than 50% of

all drugs approved by the FDA between 1976 and 1985 were found during

postmarketing to have previously undetected " serious " side effects, sometimes

requiring removal from the market. Fifteen psychopharmaceuticals were approved

during this period, nine of which turned up to have serious risks during

postmarketing, leading in one case to removal from the market (p. 25 & p.

74-78). Since then, yet another drug from that era has been withdrawn from the

market. The antidepressant nomifensine was found to cause massive intravascular

hemolytic anemia--but only after it had been on the market worldwide for eight

or nine years (Leber, 1992, p. 6).

I have reviewed the entire list of serious adverse reactions to psychiatric

drugs detected during the postmarketing period in the GAO study. It seems

probable that every one of them was discovered and confirmed through a

combination of the spontaneous reporting system and general clinical experience.

As far as I can ascertain, not one of these adverse reactions was primarily if

at all identified by means of a controlled clinical trial. Among the nine drugs,

alprazolam (Xanax) had rage added to the label as a paradoxical reaction and

amoxapine (Asendin) had neuroleptic malignant syndrome added.

 

 

 

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