RISK-BENEFIT ASSESSMENT Drug Safety 13 (4): 257-270.1995 0114-5916/95/OO10-0257/S07.OO/0

© Adls lnterna1lonal Lmited. All nghts reserved.

An Assessment of Short-Acting Hypnotics Wallace B. Mendelson and Bharat Jain Sleep Disorders Center, Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Contents Summary ............. . 1. Insomnia ............. . 2. Indications for Pharmacotherapy 3. Pharmacological Agents Available for Treatment of Insomnia

3.1 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . 3.2 Nonbenzodlazepine, Nonbarbiturate Hypnosedatlves

4. Pharmacology . . . . . . . . 4. 1 Neuroreceptor Binding. . . . . 4.2 Sleep Architecture . . . . . . . 4.3 Cognitive and Motor Function

5. Pharmacokinetics 6. Clinical Efficacy

6.1 Triazolam. 6.2 Zolpldem. . 6.3 Zopiclone .

7. Adverse Reactions . 7.1 Daytime Sedation 7.2 Drug Withdrawal/Rebound Insomnia 7.3 Short Term Anterograde Amnesia 7.4 Delirium ........ . 7.5 Respiratory Depression .. . 7.6 Tolerance ......... . 7.7 Physiological Dependence 7.8 Lethality in Overdose. 7.9 Abuse and Misuse

8. Cost 9. Conclusion ...... .

· 257 · 258 · 259 · 259 · 260 · 261 · 262 · 262 · 262 · 262 · 262 · 263 · 263 · 263 · 263 · 263 .264 · 264 · 265 · 265 · 265 · 266 · 266 · 266 · 266 · 267 · 267

Summary Insomnia, the experience of poor quality or quantity of sleep, is a very common complaint. Approximately 65 million adults (36% of the American population) complain of poor sleep, and of this group, 25% have insomnia on a chronic basis. These chronic insomniacs not only report higher rates of difficulty with concen­tration, memory and the ability to cope with minor irritations but also have 2.5 times more fatigue-related automobile accidents than do good sleepers. Despite its ubiquity, insomnia is often either untreated or inadequately treated. Short-

258

1. Insomnia

Mendelson & Jain

acting hypnotics are advocated for transient insomnia, which lasts less than 3 weeks, and in patients with chronic insomnia as an adjunctive treatment where nonpharmacological treatment is not sufficient to alleviate insomnia and the related daytime detrimental effects. The putative adverse effects of hypnotics must be weighed against the severe health effects caused by continued sleep impairment. If hypnotic agents are used, they should be taken nightly only for brief use, or intermittently in longer term use.

Benzodiazepines, zolpidem and zopiclone (in countries where the latter is available) remain the recommended hypnotic agents, although in the past few years there has been much criticism in lay magazines and on television about the use ofbenzodiazepines. However, this review of the efficacy and tolerability data of the short-acting hypnotics suggests that triazolam is comparable with other short-acting hypnotics at equipotent doses while taking into consideration that for every hypnotic, different study populations display different degrees of efficacy. In addition, contrary to previous suggestions that such adverse effects as rebound insomnia and anterograde amnesia are unique to triazolam, hypnoti­cally equivalent doses of triazolam have not been shown to produce these effects more frequently than other short-acting hypnotics. The newer nonbenzodiazepine hypnotics seem to be equally efficacious as the short-acting benzodiazepines; whether they will truly have a better adverse effect profile will be determined as more clinical experience accumulates. Despite the availability, relative safety and efficacy of these newer hypnotic agents, they should not be perceived as the sole treatment for insomnia and should be used in conjunction with nonpharmacologi­cal techniques (such as adherence to good sleep hygiene, sleep restriction, stim­ulus control and biofeedback therapy).

Insomnia, the experience of poor quality or quantity of sleep, is a very common complaint. The Gallup organisation in 1991 conducted a national telephone survey in the US and observed that approx­imately 65 million adults (36% of the population) complain of poor sleep, of whom 25% have insom­nia on a chronic basis.[l] These chronic insomniacs also reported higher rates of difficulty with concen­tration, memory and the ability to cope with minor irritations compared with good sleepers. In addition, these chronic insomniacs reported 2.5 times more fatigue-related automobile accidents than did good sleepers. The problem of insomnia is even more pronounced in the elderly. It is estimated that half of those over 65 years of age who reside at home and two-thirds of those who are institutionalised have disturbed sleepP] Despite its ubiquity, insomnia

is often either untreated or inadequately treated. The Gallup organisation also noted that only 5% of insomniacs specifically visited a physician to dis­cuss their sleeping problem and prescription medica­tions had only been used at any time in the past by 20%.

Insomnia is often divided into transient and chronic forms. Transient insomnia, which lasts less than 3 weeks and is characteristically associated with an identifiable stressor, is the most common sleep disorder, even though a majority of affected individ-

Table I. Some causes of drug-induced insomnia

Nonprescription Decongestants, caffeine, nicotine, alcohol (ethanol)

Prescription J3-Agonists, aminophylline, J3-blockers, corticosteroids, calcium channel blockers, sedatives (withdrawal), diuretics, eNS stimulants, lovastatin

© Adis International Limited. All rights reserved. Drug Safety 13 (4) 1995

Assessment of Short-Acting Hypnotics

Table II. Sleep hygiene measures

Maintain a regular bedtime and time of arising

Avoid routine daytime naps

Exercise regularly, but avoid exercise just prior to bedtime

Do not take heavy meals within 2 hours of bedtime; a light snack at bedtime may, however, help sleep

Avoid stimulants such as coffee, tea, cola drinks, etc. for at least 8 hours prior to bedtime

Do not drink alcohol to help sleep, and avoid smoking

Use sleep medications sparingly

Control bedroom environment and avoid annoying noise, light or temperature extremes

Reserve the bedroom for only sleep or sexual activity and eliminate such stimulating activities as watching television, reading and making phone calls

Go to bed only when ready for sleep and leave if unable to fall sleep within 30 minutes. Do not try harder and harder to fall asleep

For troubling recurrent thoughts affecting sleep, write them down with a possible plan of action

Avoid the bedroom clock, as clock·watching kills sleep

uals do not seek medical help. Recovery frequently occurs when either the stressor subsides or follow­ing adaptation to the stressor. Short term use of hypnotic medication is often useful in these pa­tients.

Chronic insomnia, which lasts several months, may have many aetiologies. A frequent cause is an underlying psychiatric illness, and screening ques­tions to evaluate for depression and anxiety should be asked. 13] Chronic insomnia can also result from medical disorders that manifest as pain, dyspnoea or frequency of micturition; in such situations, emphasis should be placed on treating the underlying disorder. Several medications, including a variety of prescription and nonprescription drugs may cause insomnia (table I). Poor sleep habits such as sleep­ing at various times throughout the 24-hour cycle, or exercising or consuming heavy meals just prior to bedtime can also result in an inability to fall asleep 'on schedule'.

The most effective therapy for chronic insomnia is to treat the underlying cause. For example, sedating tricyclic antidepressants such as amitriptyline may be used when insomnia is associated with depres-

© Adis Intematlonal Limited. All righls reserved.

259

sion. In addition, an attempt should be made to improve sleep hygiene (table II). Behavioural pro­grammes such as stress management, stimulus control and sleep restriction must be considered especially in patients with conditioned insomnia, wherein they become conditioned to being awak­ened rather than relaxed by the bedroom environ­ment.

2. Indications for Pharmacotherapy

Currently, pharmacological treatment of insom­nia is advocated for transient insomnia and may, in addition, be used as an adjunctive treatment in patients with chronic insomnia in whom nonpharma­cological treatment is not sufficient to alleviate insomnia and the related daytime detrimental ef­fects.l4,5] If hypnotic agents are used, they should be taken nightly for brief use or intermittently in longer term use. Although there is some evidence that hypnotics, especially those with a long half-life, may be used at night twice a week on a long term basis without significant adverse effects in patients with chronic insomnia, 16] the various drawbacks that may occur when hypnotics are used on a long term basis must be considered (table III). Prior to initiation of pharmacotherapy, it is imperative to rule out the possibility of such underlying illnesses as respiratory disorders, substance abuse and ob­structive sleep apnoea syndrome, which are contra­indications to hypnosedative use.

3. Pharmacological Agents Available for Treatment of Insomnia

The pharmacological and therapeutic profile of an 'ideal' hypnotic drug is shown in table IV. For the drug to reliably allow a rapid onset of sleep

Table III. Adverse effects of hypnotiCS

Residual sedative effects

Rebound insomnia Physical dependence

Tolerance

Drug interactions (especially CNS depressants) Effects on memory

Respiratory suppression

Drug Sofely 13 (4) 1995

260

Table IV. Pharmacological and therapeutic profile of an 'ideal' hypnotic

Therapeutic profile Rapid sleep induction

No residual effects

No effect on memory

Pharmacokinetic profile

Rapid absorption

Specific receptor binding

Optimal half-life

No active metabolites

Pharmacodynamic profile

No tolerance

No physical dependence

No respiratory/CNS depression

within the physiological need, the pharmacokinetic characteristics of the drug must be such that, by rapid absorption, therapeutic concentrations are reached in the brain within 15 to 30 minutes of ingestion and that the concentration is maintained for no more than 5 to 7 hours. Intuitively, it would make sense that the ideal hypnotic should restore the sleep to its natural pattern, although the function of the various sleep stages is not clearly understood. In addition, the hypnotic should sustain therapeutic effectiveness during short, intermediate and long term use, as needed by the patient. It should also be free from such adverse effects as respiratory depres­sion, effects on short term memory and rebound insomnia, and should not interact with other medications such as eNS depressants. A wide mar­gin of safety in overdose and no potential for abuse following long term administration would also be expected from the ideal hypnotic.

The available hypnotics can be classified on phar­macokinetic grounds into short -acting (plasma elim-

Table V. Characteristics of short-acting barbiturates

Drug

Methohexital

Hexobarbital

Heptabarb (heptabarbital)

Abbreviation: IV = intravenous.

Mean elimination half-life (hours)

1.6

4.4

7.7

© Adis International Limited. All rights reserved.

Mendelson & Jain

ination half-life of less than 6 hours), intermediate­acting (6 to 24 hours) and long-acting (over 24 hours) drugs and this article is limited to reviewing the use of short-acting hypnotics. There are currently many short-acting hypnosedative medications available for the treatment of insomnia. These in­clude barbiturates (table V), benzodiazepines (table VI) and the nonbarbiturate, nonbenzodiazepine hypnotics (table VII). Of these available classes, the medications that are currently the least often pre­scribed are the barbiturates and the older nonbarbitur­ate, nonbenzodiazepine hypnotics because of seri­ous adverse effects, which include death from overdose. These 2 groups of sedative hypnotics have been superseded by the relatively well tolerated benzodiazepines and the newer nonbarbiturate, nonbenzodiazepine hypnotics that include the im­idazopyridines (e.g. zolpidem) and cyclopyrrolone derivatives (e.g. zopiclone).

3.1 Benzodiazepines

The benzodiazepines, which are primarily used for their sedative hypnotic qualities, meet many of the above mentioned characteristics of an 'ideal' hypnotic and have been the primary pharmacolog­ical agents in the treatment of insomnia. They have been in use for over 30 years and have largely re­placed barbiturates, which have a small therapeutic index and a marked liability for abuse. Among the various short-acting benzodiazepines that have been used clinically, triazolam has been the most extensively prescribed short-acting hypnotic in the US and this drug is the prototype that is used to represent this class of hypnotics in this review. The doses of the other commonly used short-acting hypnotics that are equipotent to triazolam 0.25mg are shown in table VIII.

HypnotiC dose Route Reference (mg/kg)

3 IV 7

8 IV 8

6.6 Oral 9

Drug Safety 13 (4) 1995

Assessment of Short-Acting Hypnotics

Table VI. Characteristics of short-acting benzodiazepines

Drug Elimination half-life (hours)

Estazolam 8-24

Loprazolam 4.6-11.4

Lormetazepam 7.9-11.4

Temazepam 8-20

Triazolam <5

Despite their relative safety, benzodiazepines have been associated with adverse effects, most

commonly residual daytime sedation (especially long-acting benzodiazepines), anterograde amne­sia and rebound insomnia. In general, the rate of occurrence of these adverse effects varies from

drug to drug and is dose-dependent, with higher

doses being typically associated with an increase in the occurrence and severity of adverse effects. [I 9]

Anecdotal reports of unusual adverse reactions to triazolam,[20] such as hallucinations and bizarre

behaviour, together with extensive negative pub­

licity in the lay media, have reduced the extent of triazolam use. Although controlled clinical or epi­demiological studies have not established that tri­azolam causes such effects with a frequency greater than other benzodiazepines when used in appropri­ate doses, outpatient prescriptions for triazolam in the US fell from 11 million in 1981 to 8.7 million in 1989.[21] In response to this controversy, the US

Food and Drug Administration reviewed the use of this medication in 1990 and 1992, and declared

triazolam to be a safe and effective medication

261

Hypnotic dose (mg) Route Reference

1-2 Oral 10

1-2 Oral 11

1-2 Oral 12

10-30 Oral 10

0.125-0.25 Oral 10

provided it is used in appropriate doses (0.125 to 0.25mg).

3.2 Nonbenzodiozepine, Nonbarbiturote Hypnosedotives

3.2.1 Zolpidem The characteristics of zolpidem include a rapid

onset of action (approximately 2.2 hours) and a short half-life (1.5 to 2.4 hours). It is generally well tolerated and has been shown to be effective in the

treatment of insomnia. The usual adult dosage is 10 to 20mg in patients under 65 years of age, and 5 to 10mg in geriatric patients.

3.2.2 Zopiclone Zopiclone belongs to the new class of sedative

hypnotics, the cyclopyrrolones. It is not available for use in the US, although it is marketed in a number of other countries. It has a short half-life of approx­imately 5 to 6 hours. The usual adult dosage of zopiclone is 7.5mg orally at bedtime, and 3.75mg at bedtime for the elderly.

Table VII. Characteristics of short-acting nonbarbiturate, nonbenzodiazepine hypnotics

Drug Elimination half-life Hypnotic dose (mg) (hours)

Older agents

Chloral hydrate 5-9.5 500-1000

Methaqualone 4-5 150-300

Glutethimide 3.8-22 250-500

Newer agents

Zolpidem 1.5-2.4 5-10 (age> 65 years) 10·20 (age < 65 years)

Zopiclone 5-6 3.75 (age> 65 years) 7.5 (age < 65 years)

© Adis International Limited. All rights reserved.

Route

Oral

Oral

Oral

Oral

Oral

Reference

13

14

15

16

17

Drug Safety 13 (4) 1995

262

Table VIII. Doses of comparator hypnotics that are equipotent to triazolam 0.25mg[18)

Comparator hypnotic Dose (mg)

Brotizolam 0.25

Loprazolam

Lormetazepam

Midazolam 7.5

Temazepam 30

Zopiclone 0.75

Zolpidem 10

4. Pharmacology

4.1 Neuroreceptor Binding

Zopiclone binds to a site related to the benzodia­zepine binding site on the y-aminobutyric acid (GABA) receptor complex.122] Zolpidem interacts with the same GABA receptor and chloride ion channel complex as benzodiazepines, although it exhibits high affinity binding at the central benzo­diazepine 1 receptor sUbtype. This has been postu­lated by some to explain its selective hypnotic effect, and weak myorelaxant, anxiolytic and disinhibitory properties. This difference in binding may also explain the different dose response curves for zolpi­dem compared with zopiclone and brotizolam, a benzodiazepine.l23] The anticonvulsant and myo­relaxant effects of zolpidem appear at much higher doses than its sedative action, with the opposite effect being observed with either zopiclone or brotizolam.

4.2 Sleep Architecture

In a study comparing the effects of brotizolam (0.2Smg) and zopiclone (7.Smg) on the sleep archi­tecture of 7 healthy young women (aged 20 to 21 years), no statistically significant difference was observed between the effects of these 2 drugs.l24] There are, however, conflicting reports of the effect of zopiclone on slow-wave sleep. One study re­ported an increase of 40%,[25] another no effect,126] while a third study reported a decrease in slow­wave sleep}27]

In a double-blind, placebo-controlled crossover study, zolpidem in doses of S, 10, IS and 20mg

© Adis Interna~onal Umlted. All rights reserved.

Mendelson & Jain

were compared with placebo in 30 elderly non­insomniac volunteers.128] Zolpidem decreased sleep latency, increased subjective total sleep time and sleep efficiency (at all doses). In contrast to the usual finding with benzodiazepines, there were no changes in delta sleep at any dose of zolpidem; a small but significant decrease in rapid eye move­ment (REM) sleep was observed at doses of 10 and 20mg. Similar results were observed by Blois and his coworkersl29] and, in contrast to benzodiaze­pines or zopiclone, no increase in spindle density was observed following the administration of zolpidem.

4.3 Cognitive and Motor Function

In a randomised, double-blind crossover study involving 8 healthy volunteers, significant impair­ment of standing steadiness was observed 1 to 2 hours following administration of triazolam (0.2Smg) compared with zopiclone (7.5mg).130] While admin­istration of zopiclone at doses lower than 7.Smg had a minimal effect on psychomotor function in healthy volunteers or patients with insomnia,I17] higher doses resulted in impaired psychomotor function that was observed for 6 hours.

With regards to cognitive or psychomotor per­formance the morning following the drug adminis­tration, zolpidem (S or lOmg) at bedtime for 7 con­secutive nights did not produce an impairment in 24 healthy elderly volunteerspl] There are, how­ever, conflicting reports of the effects of night-time zopiclone on next -day performance. While zopiclone 7.Smg did not impair psychomotor function the morning after the night-time administration in elderly insomniacs,132] an impairment in next­day performance was observed in healthy volun­teersP3]

5. Pharmacokinetics

Triazolam is rapidly absorbed and has no active metabolite. Zolpidem is also rapidly absorbed, but exhibits first-pass metabolism, resulting in an ab­solute availability of 67% after oral doses of S to 20mg.l16) None of the metabolites of zolpidem are pharmacologically activeP4) The bioavailability

Drug Safely 13 (4) 1995

Assessment of Short-Acting Hypnotics

of zopiclone is 80%, indicating an absence of sig­nificant hepatic first-pass extraction,[35] with only the N-oxide metabolite (which accounts for 11 % of the dose) demonstrating hypnotic activity.

6. Clinical Efficacy

6.1 Triazolam

A number of studies have compared the efficacy of triazolam with placebo)36] Triazolam 0.125mg seemed to have its greatest effect on total sleep time and improving sleep quality, with a less strik­ing effect on reducing the sleep latency and number of awakenings. More potent effects are seen with 0.25mg, with little or no further efficacy with 0.5mg.

6.2 Zolpidem

Zolpidem has been shown to have hypnotic ef­fects in healthy volunteers, and both young and elderly insomniacs.[37] The most useful informa­tion derived from placebo-controlled trials of zolpidem is that 1 to 2 weeks of use of 10mg at bedtime results in a decrease in sleep latency, no REM suppression, no REM rebound on withdrawal and no effect on nocturnal awakenings)38,39] Re­sults of the noncomparative and comparative trials indicate that zolpidem 10mg is as effective as 20mg, with 10mg appearing to increase the total sleep time by approximately 1 hour and decrease the sleep latency by approximately 30 to 40 min­utes in insomniacs.

When compared with the benzodiazepines, zolpidem has equal efficacy in inducing and main-

263

taining sleep (table IX), with a similar adverse ef­fect profile and incidence.

6.3 Zopiclone

In a study of 68 elderly patients with chronic insomnia, 2 weeks of treatment with zopiclone 3.75, 5, 7.5 or 10mg established 7.5mg as the op­timum dose for elderly patients in improving the sleep quality and duration,[32] although other groups have recommended 3.75mg. In several other stud­ies which included patients aged between 18 and 65 years with insomnia, zopiclone 3.5 to 15mg significantly improved sleep latency, sleep dura­tion, sleep quality and number of awakenings compared with baseline or placebo)44-46] There have been at least 6 studies comparing the hypnotic effects of zopiclone with those of triazolam, with zopiclone 7.5mg appearing to be at least as effi­cacious as triazolam 0.125 to 0.25mg (table X).

7. Adverse Reactions

Among 3507 patients who reported medical events in phase 111111 studies, the most common events that were reported with the use ofbenzodia­zepines included: sedation (14.3%), headache (7.3%), dizziness (7.3%), impaired coordination (3.5%) and nervousness (3.5%).[50] Memory im­pairment, which has received extensive media at­tention with the use of triazolam, was relatively rare (0.5%).

In a series of 1067 insomniac patients, zolpidem had to be discontinued in 6%)51] No dose-depend­ent relationship was observed in those patients taking 10mg compared with 20mg of zolpidem.

Table IX. Summary of clinical studies of zolpidem vs triazolam for the treatment of insomnia

Drug (dosage mg/day) Number of patients Duration (days)

Z (SIlO); T (0.2S)

Z (10); T (0.2S)

Z (SIlO); T (0.2S)

Z (10); T (0.2S)

218

3S7 24

139

21

14

Change in sleep pattern"

Z=T>P

Z=T>P

Z=T>P

Z=T

Reference

40 41 42 43

a 'Change in sleep pattern' consisted of decreased sleep latency, increased total sleep time, decreased nocturnal awakenings and improved quality of sleep.

Abbreviations and symbols: P = placebo; T = triazolam; Z = zolpidem; (» = significantly more effective; (=) = no significant difference.

© Adis International Limited. All rights reserved. Drug Safety 13 (4) 1995

264 Mendelson & Jain

Table X. Summary of clinical studies of zopiclone vs triazolam in patients with chronic insomnia

Drug Mean age Number of patients Duration Change in Reference (dosage mg/day) (years) (days) sleep patterna

Z (517.5); T (0.125/0.25) 76 44 21 Z=T>P 44

Z (7.5); T (0.25) 67 10 15 Z=T 45

Z (517.5); T (0.125/0.25) 41 41 17 Z=T 47

Z (7.5); T (0.25) 51 38 7 Z=T 48

Z (7.5); T (0.25) 47 127 7 Z=T 49

a 'Change in sleep pattern' consisted of decreased sleep latency, increased total sleep time, decreased nocturnal awakenings and improved quality of sleep.

Abbreviations and symbols: P = placebo; T = triazolam; Z = zopiclone; (» = significantly more effective; (=) = no significant difference.

The adverse effects that were observed following the use of IOmg zolpidem were: somnolence (3.4%), amnesia (2.6%), headache (2.4%), nausea (2.4%), vertigo (2.1 %) and falls (1 %).

In a postmarketing surveillance study of 20 513 patients, the overall frequency of adverse events during 21 days of treatment with zopiclone 3.75 (10.5%) or 7.5mg (87.5%) did not differ with age (9 to 10% )J52] Confusion, memory complaints and difficulty rising in the morning - which are common with benzodiazepines - were less frequently reported with zopiclone. The most frequently reported ad­verse effects were: bitter taste (3.6%), dry mouth (1.6%), difficulty with morning rising (1.3%) and somnolence (0.5%). Falls were reported in 8 pa­tients aged 72 to 84 years.

7.1 Daytime Sedation

Daytime sedation is frequently observed with the use of longer-acting as compared with short­acting hypnotics. In the elderly, who are most susceptible to daytime sedation, the use of triazo­lam 0.125mg did not impair daytime wakefulness acutely[53] or following 12 weeks of administra­tion.[54]

Zolpidem 10 to 20mg administered at night has been reported to have no signficant effects on day­time motor activity in healthy volunteers.[55] Lilie et aU56] reported no effects of zolpidem 10 to 15mg on mood or various psychomotor tests in insomni­acs. Zopiclone 3.75 to 7.5mg has been reported to have no effects on the multiple sleep latency test in healthy volunteers, but the higher dose impaired coordination in the morning.[57]

© Adis International Limited. All rights reserved.

7.2 Drug Withdrawal/Rebound Insomnia

One problem with the use of hypnotics, especially short-acting hypnotics, is rebound insomnia: upon discontinuation, sleep may transiently worsen compared with pretreatment levels. There is no clear agreement on the definition of rebound insomnia. Kales and his coworkers[58] have defined rebound insomnia as a 'statistically significant increase or an increase of 40% or greater in the mean group value for total wake time for a single withdrawal night or the entire withdrawal condition as compared to baseline'. This phenomena may occur after intake of some medications for even 1 night[59] and some­times lasts for 1 to 3 weeks following discontinua­tion. The importance of rebound insomnia is unclear, although the resultant distress could potentially result in patients restarting their hypnotic drugs.

Among the factors that are known to effect re­bound insomnia are the type of patient and the dose of hypnotic. Merlotti and his coworkers[60] have shown that patients with poorer sleep efficiencies and longer sleep latencies had more severe rebound following discontinuation of hypnotics. Studies on triazolam[54,59] show clear dose-effect relation­ships with regards to the development of rebound insomnia. For example, Mamelak et aU59] demon­strated withdrawal effects following the discontin­uation of a 0.5mg dose of triazolam compared with no change in sleep electroencephalogram parame­ters following withdrawal of 0.25mg triazolam. This relationship between the dose and rebound may not be linear, however. Specifically, it has been demonstrated that rebound occurs at doses beyond

Drug Safety 13 (4) 1995

Assessment of Short-Acting Hypnotics

which there is no further increase in hypnotic effi­cacy.£61) The intensity of rebound is, however, in­dependent of the duration of administration.£60) A tapering schedule of hypnotic withdrawal has been shown to reduce the risk of rebound insomnia.£62)

In healthy volunteers, the usual dose of 7.5mg of zopiclone is associated with rebound in some patients.[61,63,64) However, there has been no evi­dence to suggest that the degree of rebound dif­fers significantly between zopiclone and triazo­lam. [44,45,65)

In a related issue, there have been allegations by some authors regarding early morning awakening (so called 'mini-withdrawal') following the use of triazolamJ66) However, the same authors and oth­ers have also published data demonstrating the ab­sence of these awakenings in the latter part of the night.£67,6S)

7.3 Short Term Anterograde Amnesia

Several studies have identified short term ant­erograde amnesia, i.e. acute memory loss following the administration of the drug, as a significant ad­verse effect of hypnotics.£69,70) This memory loss may be related to the general sedative nature of these compounds, with sleep onset interfering with memory consolidationPl) Although these hypnot­ics have an anterograde amnesic effect, the overall issue is also complicated by the fact that insomnia by itself may be associated with anterograde am­nesia[l) and that sleep has a retrograde amnesic effect. [72)

Anterograde amnesia does occur with benzodia­zepines, although without a change in a person's normal activities or behaviours. The cognitive im­pairments appear to be limited to the consolidation and storage phase of memory acquisition and to those aspects of memory that require active con­scious recallp3) Anterograde amnesia has been shown to be dose-dependent, with triazolam 0.5mg, for example, producing greater amnesic effects than triazolam 0.25mg and with both these levels producing greater amnesia than placebo.£74) These amnesic effects persist longer following the ad­ministration of triazolam 0.5mg, compared with

© Adls International limited. All rights reserved.

265

either triazolam 0.25mg or zopiclone 7.5mgP5) Anterograde amnesia is also observed following the use of at least 15mg of zolpidem[2S) and 7.5mg of zopicloneP6)

7.4 Delirium

Although there is minimal systematic prospec­tive data of the frequency of delirium with the use of triazolam, case reports suggest that they have occurred with the use of higher dosages and in the elderlyP7-79) Similarly, psychotic reactions with the use of zolpidem are rare and, except for a report wherein 2 young women developed psychotic re­actions following the use of zolpidem lOmg, there have been no other reports of this adverse effect. [SO)

7.5 Respiratory Depression

The benzodiazepines have a significantly re­duced respiratory depressant effect compared with the barbiturates, but do have it to some degree. In contrast to the long-acting benzodiazepines, the limited data that are available suggest that triazo­lam 0.25mg may not be detrimental when given to patients with sleep apnoea.£SI,S2) Indeed, 1 study has suggested that triazolam may actually improve central sleep apnoeaJS3)

Zolpidem appears to be well tolerated, with no respiratory suppression up to doses of 10mg and minimal suppression of mean inspiratory drive at doses of 20mg.£S4) In a double-blind, crossover, placebo-controlled trial involving 10 healthy non­obese heavy snorers, zolpidem lOmg did not sig­nificantly alter the mean oxygen saturation. The apnoea/hypopnoea index was modestly increased by zolpidem, although in all but 1 participant it remained <5 with both zolpidem and placebo.£s5) Similar results were reported by McCann and his coworkers.£s6) However, there is at least 1 study that suggests that zolpidem should be used with caution in patients with obstructive sleep apnoea syndromeJs7) In patients with mild to moderate chronic obstructive pulmonary diseases (COPD), arterial oxygen saturation for the entire night, by hour and stage, and the apnoea-hypopnoea index for the entire night was not significantly different

Drug Safety 13 (4) 1995

266

between patients who received placebo, zolpidem (S or 1Omg) or triazolam (0.2Smg)J43] Zolpidem 10mg did not change the partial pressures of arte­rial oxygen and carbon dioxide for at least 60 days in 12 hypercapnic patients with severe COPD who were experiencing insomnia.[88]

Zopiclone 7.Smg does not cause respiratory de­pression in healthy human volunteersJ89] However, it causes mild respiratory depression in patients with COPD[90] and increases the severity of sleep apnoea in patients with an apnoea index greater than 20PI]

7.6 Tolerance

While 1 group of investigators[92] have reported that the tolerance to the initial effectiveness of tri­azolam develops rapidly, other studies have failed to confirm this result.[93-95] There are conflicting reports regarding the development of tolerance with the continued use of zolpidem 10 or 20mg. While in I study, the drug was effective for 1 year,l9?] the long term efficacy of zolpidem began to dissipate following 21 to 28 days of continued use in another studyJ98] With regards to zopiclone, there has been evidence for lack of tolerance de­velopment following 8 to 17 weeks of treat­mentP9,JOO]

7.7 Physiological Dependence

Triazolam, like any other benzodiazepine hyp­notic, can produce physiological dependence. The abrupt discontinuation of short-acting benzodia­zepines such as triazolam, results in withdrawal symptoms that occur more rapidly than those ob­served with longer-acting benzodiazepinesJ77,101] The withdrawal symptoms include the worsening of pre-existing insomnia for which the agent was prescribed or the development of such new symp­toms as photophobia, auditory and visual hyper­sensitivity, tinnitus and even seizures. The fre­quency and severity of these withdrawal symptoms are probably related to the dose and duration of drug administration.

© Adis International Limited. All rights reserved.

Mendelson & Jain

Preliminary data suggest that abrupt discontin­uation of zolpidem is not associated with rebound insomnia or withdrawal effects.

7.8 Lethality in Overdose

The benzodiazepines have a remarkably favour­able safety profile compared with the barbiturates. The absence of mortality in clinical case reports of substantial overdose (Sg) with triazolam[77] attests to the remarkable safety of these compounds.

The safety of zolpidem taken alone in overdos­age is not as clear as the safety of oral benzo­diazepines, but no fatalities have been reported with overdoses of up to 1400mgJ102] A review of 239 reports of voluntary zopiclone overdosage showed that CNS depression was the most fre­quently reported event,[103] although there has been a report of atrioventricular block following inges­tion of 127.Smg of zopiclone.[104] The benzodiaze­pine receptor antagonist flumazenil appears to be an effective antidote for zolpidem[105] and zopicloneP06] Although these 2 hypnotics have a reasonably good safety profile, they should be considered poten­tially lethal when mixed with other sedatives or alcohol.

7.9 Abuse and Misuse

Triazolam has less abuse liability than the inter­mediate duration barbiturates. Although there are no credible data, there is, however, substantial specu­lation that the abuse liability of triazolam may be greater than other benzodiazepine hypnotics.[lO?]

In a double-blind, crossover study involving IS healthy men with a history of drug abuse, the abuse liability of zolpidem (1S, 30 and 4Smg) and triaz­olam (0.2S, O.S and 0.7Smg) was studiedJlO8] Both drugs scored higher than placebo on a variety of subjective measures that would be desirable to sed­ative abusers (e.g. drug liking and drug effect). However, unlike triazolam, zolpidem also produced the following negative-addiction-risk responses: blurred vision, unsteadiness, mental slowing, light­headedness, dysphoria and anxiousness, making it less likely to be abused than triazolam. Some sleep experts also believe that zolpidem has little poten-

Drug Safety 13 (4) 1995

Assessment of Short-Acting Hypnotics

tial for abuse because higher doses are associated with increased incidence of nausea and vomiting.

There has been no evidence for the development of physical dependence for at least 4 weeks follow­ing the use of zopiclone 30 mg/day)109]

8. Cost

The costs of various short-acting hypnotics are summarised in table XI. The average wholesale price of I zolpidem tartrate lOmg tablet is $US1.48[11O] and this is comparatively more expensive than tri­azolam 0.2Smg ($USO.67) or chloral hydrate SOOmg ($USO.08).

9. Conclusion

Insomnia is a symptom of an underlying condi­tion, and proper treatment is contingent upon ac­curate evaluation and diagnosis. Pharmacological and nonpharmacological treatments for insom­nia are available. Benzodiazepines, zolpidem and zopiclone (in countries where the latter is avail­able) remain the recommended hypnotic agents, al­though in the past few years there has been much criticism in lay magazines and on television about the use of benzodiazepines. However, this review of the efficacy and tolerability data of the short­acting hypnotics suggests that triazolam is compa­rable with other short-acting hypnotics at equi­potent doses while taking into consideration that for every hypnotic, different study populations display different degrees of efficacy. In addition, contrary to previous suggestions that such adverse effects as rebound insomnia and anterograde amnesia are unique to triazolam, hypnotically equivalent doses of triazolam have not been shown to produce these effects more frequently than other short­acting hypnotics. The newer nonbenzodiazepine hypnotics seem to be equally efficacious as the short-acting benzodiazepines; whether they will truly have a better adverse effect profile will be determined as more clinical experience accumu­lates.

The putative adverse effects of all hypnotic medications must be weighed against the severe health effects caused by continued sleep impair-

© Adis International Limited. All rights reserved.

267

Table XI. Aquisition cost of various short-acting hypnotics[1101

Drug (dose) Average wholesale price for 100 tablets/capsules ($US)

Barbiturates Pentobarbital 100mg

Secobarbital 100mg

Benzodiazepines Triazolam 0.25mg

Estazolam 1 mg

Temazepam 15mg

6.50

6.20

67.26

82.02

61.38

Nonbarbiturate, nonbenzodiazepine hypnotics (older) Chloral hydrate 500mg 8.25

Glutethimide 500mg

Ethchlorvynol 750mg

11.93

159.13

Nonbarbiturate, nonbenzodiazepine hypnotics (newer) Zolpidem 10mg 147.60

ment) 11 I] Despite the availability, relative safety and efficacy of the newer hypnotic agents, they should not be perceived as the sole treatment for insomnia and should be used in conjunction with nonpharmacological techniques (such as adher­ence to good sleep hygiene, sleep restriction, stim­ulus control and biofeedback therapy).

Acknowledgements

This work was partially supported by NIMH grant lK05MHOl139.

References I. Sleep in America. National Sleep Foundation. Los Angeles:

Gallup Organization, Inc. 1991 2. National Institutes of Health Consensus Development Confer­

ence Statement: the treatment of sleep disorders of older peo­ple, March 26-28,1990. Sleep 1991; 14 (2): 169-77

3. Ford DE, Kamerow DB. Epidemiologic study of sleep distur­bances and psychiatric disorders. An opportunity for preven­tion? JAMA 1989; 262: 1479

4. Consensus conference. Drugs and insomnia: the use of medica­tions to promote sleep. JAMA 1984; 251: 2410-4

5. Hishikawa Y. Appropriate use of benzodiazepines in insomnia; clinical update. J Clin Psychiatry 1991; 52: 10-3

6. Scharf MB. Feasibility of an every-other-night regimen in in­somniac patients: subjective hypnotic effectiveness of quazepam, triazolam, and placebo. J Clin Psychiatry 1993; 54 (1): 33-8

7. Breimer DD. Pharmacokinetics of methohexitone following in­travenous infusion in humans. Br J Anaesth 1976; 48: 643-9

Drug Sofety 13 (4) 1995

268

8. Breimer DD. Honhoff C. Zilly W. et al. Pharmacokinetics of hexobarbitol in man after intravenous infusion. J Phar­macokinet Biopharm 1977; 3: I-II

9. Breimer DD. DeBoer AG. Pharmacokinetics and relative bio­availability of heptabarbitol and heptabarbitol sodium in man after oral administration. Eur J Clin Pharmacol 1975; 9: 169-78

to. Greenblatt DJ. Benzodiazepine hypnotics: sorting the pharma­cological facts. J Clin Psychiatry 1991; 52 Suppl.: 4- to

It. Mcinnes GT. Bunting EA. Ings RMJ. et al. Pharmacokinetics and pharmacodynamics following single and repeated nightly administration of loprazolam. a new benzodiazepine hyp­notic. Br J Clin Pharmacol 1985; 19: 649-56

12. Pierce DM. Franklin RA. Harry TVA. et al. Pharmacodynamic correlates of modified absorption: studies with lormetazepam. Br J Clin Pharmacol1984; 18: 31-5

13. Breimer DD. Ketelaars HCJ. Van Rossum JM. The determina­tion of chloral hydrate. trichloroethanol. and trichloroacetic acid in blood and urine. employing dead-space analysis. J Chromatogr 1974; 88: 55-63

14. Alvan G. Lindgren JE. Bogentoft C. et al. Plasma kinetics of methaqualone in man after single oral doses. Eur J Clin Phar­macol 1973; 6: 187-90

15. Curry SH. Riddall D. Gordon JS. et al. Disposition of glutethi­mide in man. Clin Pharmacol Ther 1971; 12: 849-57

16. Langtry HD. Benfield P. Zolpidem: a review of its pharmaco­dynamic and pharmacokinetic properties and therapeutic po­tential. Drugs 1990; 40: 291-313

17. Goa K. Heel R. Zopiclone: a review of pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986; 32: 48-65

18. Reynolds JEF. editor. Martindale: the extra pharmacopoeia. 29th ed. London: The Pharmaceutical Press; 1989: 717. 747-49.775

19. Roth T. Roehrs TA. Issues in the use ofbenzodiazepine therapy. J Clin Psychopharmacol 1992; 53 Supp!.: 14-8

20. Bixler EO. Kales A. Brubaker BH. et al. Adverse reactions to benzodiazepine hypnotics: spontaneous reporting system. Pharmacology 1987; 35: 286-300

2t. Wysowski DK. Baum C. Outpatient use of prescription seda­tive-hypnotic drugs in the United States. 1970 through 1989. Arch Intern Med 1992; 152: 1779-83

22. Blanchard JC. Boireau A. Garrett C. et al. In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. Life Sci 1979; 24: 2417-20

23. Perrault G. Morel E. Sanger DJ. et al. Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem. J Pharmacol Exp Ther 1992; 263 (I): 298-303

24. Kim YD. Zhuang HY. Tsutsumi M. et al. Comparison of the effect of zopiclone and brotizolam on sleep EEG by quantita­tive evaluation in healthy young women. Sleep 1993; 16 (7): 655-61

25. Jovanovic UJ. Dreyfus JE Polygraphical sleep recordings in insomniac patients under zopiclone or nitrazepam. Int Phar­macopsychiatry 1982; 17 Suppl. 2: 136-45

26. Wright NA. Belyavin A. Borland RG. et al. Modulation of delta activity by hypnotics in middle-aged subjects: studies with a benzodiazepine (flurazepam) and a cyclopyrrolone (zopiclone). Sleep 1986; 9: 348-52

27. Mamelak M. Scina A. Price V. Effects of zopiclone on the sleep of chronic insomniacs. Int Pharmacopsychiatry 1982; 17 Suppl. 2: 156-64

© Adis International Limited. All rights reserved.

Mendelson & Jain

28. Scharf MB. Mayleben DW. Kaffeman M. et al. Dose response effects of zolpidem in normal geriatric subjects. J Clin Psy­chiatry 1991; 52 (2): 77-83

29. Blois R. Gaillard JM. Attali p. et al. Effect of zolpidem on sleep in healthy subjects: a placebo-controlled trial with poly­somnographic recordings. Clin Ther 1993; 15 (5): 797-809

30. Tada K. Sato Y. Sakai T. et al. Effects of zopiclone. triazolam. and nitrazepam on standing steadiness. Neuropsychobiology 1994; 29 (I): 17-22

31. Fairweather DB. Kerr JS. Hindmarch I. The effects of acute and repeated doses of zolpidem on subjective sleep. psychomotor performance and cognitive function in elderly volunteers. Eur J Clin PharmacoI1992; 43 (6): 597-601

32. Dehlin O. Rundgren A. Borjesson L. et al. Zopiclone to geriatric patients. A parallel double-blind dose-response clinical trial of zopiclone as a hypnotic to geriatric patients: a study in a geriatric hospital. Pharmacology 1983; 27 Suppl.: 173-8

33. Mizuki Y. Hirano H. Miyoshi A. et al. Residual effects of zopiclone on subsequent daytime functions in normal hu­mans. Hum Psychopharmacol1987; 2: 1l9-26

34. Thenot JP. Hermann p. Durand A. et al. Pharmacokinetics and metabolism of zolpidem in various animal species and in hu­mans. In: Sauvanet JP. Langer SZ. Morselli PL. editors. Im­idazopyridines in sleep disorders. New York: Raven Press. 1988: 139-53

35. Gaillot J. Heusse D. Houghton GW. et al. Pharmacokinetics and metabolism of zopiclone. Pharmacology 1983; 27 Suppl. 2: 76-91

36. Mendelson WB. Human sleep: research and clinical care. New York: Plenum Press. 1987: 1-436

37. Zolpidem for insomnia. Med Lett Drugs Ther 1993; 35: 35-6 38. Monti JM. Effect of zolpidem on sleep in insomniac patients.

Eur J Clin Pharmacol 1989; 36: 461-6 39. Kryger MH. Steljes D. Pouliot Z. et al. Subjective versus objec­

tive evaluation of hypnotic efficacy: experience with zolpidem. Sleep 1991; 14: 399-407

40. Roger M. Attali p. Coquelin JP. Multicenter. double-blind. con­trolled comparison of zolpidem and triazolam in elderly pa­tients with insomnia. Clin Ther 1993; 15: 127-36

41. Morgan PJ. Chapados R. Chung Fr. et al. Efficacy of zolpidem in patients with transient insomnia on the night before elective surgery [abstract]. Founding Congress of World Federation of Sleep Research Societies. 1991; Cannes. 21-5

42. Steens RD. Pouliot Z. Millar TW. et al. Effects of zolpidem and triazolam on sleep and respiration in mild to moderate chronic obstructive pulmonary diseases. Sleep 1993; 16 (4): 318-26

43. Rosenberg J. Ahlstrom F. Randomized. double blind trial of zolpidem tomg versus triazolam 0.25mg for treatment of in­somnia in general practice. Scand J Prim Health Care 1994; 12 (2): 88-92

44. Elie R. Prenay M. Le Morvan p. et al. Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomni­acs. Int Clin Psychopharmacol 1990; 5 Suppl. 2: 39-46

45. Mouret J. Ruel D. Maillard P, et al. Zopiclone versus triazolam in insomniac geriatric patients: a specific increase in delta sleep with zopiclone. Int Clin Psychopharmacol 1990; 5 Suppl. 2: 47-55

46. Lamphere JK. Roehrs TA. Zorick FJ. et al. The dose effects of zopiclone. Hum Psychopharmacol 1989; 4: 41-6

47. Venter CP, Joubert PH. Stahmer SD. et al. Zopiclone compared to triazolam in insomnia in geriatric patients. Curr Ther Res 1986 40: to62-8

Drug Safety 13 (4) 1995

Assessment of Short-Acting Hypnotics

48. Chaudoir PJ, Jarvie NC, Wilcox OJ. The acceptability of a non­benzodiazepine hypnotic (zopicJone) in general practice. J Int Med Res 1983 11: 333-7

49. Hayoun G, Bagot C. Comparative efficacy and safety of triaz­olam and zopicJone in insomniacs seen in general practice. Curr Ther Res 1989; 46: 1236-44

50. Klett JC. Review of triazolam data. J Clin Psychiatry 1992; 53 (12):61-7

51. Palminteri R, Narbonne G. Safety profile of zolpidem. In: Sauvanet JP, Langer SZ, Morselli PL, editors. Im­idazopyridines in sleep disorders. New York: Raven Press, 1988: 351-61

52. Allain H, Delahaye C, Le Coz F, et aI. Postrnarketing surveil­lance of zopicJone in insomnia: analysis of 20,513 cases. Sleep 1991; 14: 408-13

53. Roehrs T, Kribbs N, Zorick F, et aJ. Hypnotic residual effects ofbenzodiazepines with repeated administration. Sleep 1986; 9: 309-16

54. Roehrs T, Zorick F, Wittig R, et aJ. Efficacy of a reduced triaz­olam dose in elderly insomniacs. Neurobiol Aging 1985; 6: 293-6

55. Borbely AA, Youmbi-Balderer G, Jaggi-Schwartz K. Zolpidem (IOmg and 20mg): hypnotic action and residual effects af­ter a single bedtime dose. In Sauvanet JP, Langer SZ, Morselli PL, editors. Imidazopyridines in sleep disorders. New York: Raven Press, 1988

56. Lilie JK, Lahmeyer HW, Belzer U. Effect of zolpidem in cog­nitive functioning and mood in insomniacs. Sleep Res 1989; 18: 12

57. Billiard M, Besset A, de Lustrac C, et aJ. Dose-response effects of zopicJone on night sleep and on nighttime and daytime functioning. Sleep 1987; 10 SuppJ. I: 27-34

58. Kales A, Soldatos CR, Bixler EO, et aJ. Rebound insomnia and rebound anxiety: a review. Pharmacology 1983; 24: 121-37

59. Mame1ak M, Csima A, Price V. The effects of a night's dosing with triazolam on sleep the following night. J Clin Pharmacol 1990; 30: 549-55

60. Merlotti L, Roehrs T, Zorick F, et al. Rebound insomnia: dura­tion of use and individual differences. J Clin Psycho­pharmacol 1991; 11: 368-73

61. Lader M, Frcka G. Subjective effects during administration and on discontinuation of zopicJone and temazepam in normal subjects. Pharmacopsychiatry 1987; 20: 67-71

62. Greenblatt OJ, Harmatz JS, Zinny MA, et al. Effect of gradual withdrawal on the rebound sleep disorder after discontinua­tion oftriazolam. N Engl J Med 1987; 317: 722-8

63. Godtlibsen OB, Dreyfus JE Effect of7 .5mg zopicJone on sleep pattern in normal subjects. Waking Sleeping 1980; 4: 319-25

64. Dorian P, Sellers EM, Kaplan H, et aJ. Evaluation of zopicIone physical dependence liability in normal volunteers. Int Clin Psychopharmacol 1982; 17 Suppl. 2: 228-34

65. Fleming JA, McClure DJ, Mayes C, et al. A comparison of the efficacy, safety and withdrawal effects of zopicJone and tri­azolam in the treatment of insomnia. Int Clin Psy­chopharmacol1990; 5 Suppl. 2: 29-38

66. Tan TL, Bixler EO, Kales A, et al. Early morning insomnia, daytime anxiety and organic mental disorder associated with triazolam. J Fam Pract 1985; 20: 592-4

67. Kales A, Bixler EO, Vela-Bueno A, et al. Comparison of short and long half-life hypnotics: triazolom and quazepam. Clin Pharmacol Ther 1986; 40 (4): 378-86

68. Roehrs T, Zovick F, Witting R, et aJ. Efficacy of a reduced triazolam dose in the elderly. Neurobiol Aging 1985; 6: 293-6

© Adis Intematlonal Umlted. All rights reserved.

269

69. Roth T, Hartse KM, Saab PG, et al. The effects of flurazepam, lorazepam and triazolam on sleep and memory. Psychophar­macology 1980; 70: 231-7

70. Subhan Z, Hindmarch I. Effects of zopicIone and benzodiazep­ine hypnotics on search in short-term memory. Neu­ropsychobiology 1984; 12: 244-8

71. Curran HV. Tranquillizing memories: a review of the effects of benzodiazepines on human memory. Bioi Psychol 1986; 23: 179-213

72. Greenblatt DJ, Harmatz JS, Engelhardt N, et al. Pharmaco­kinetic determinants of dynamic differences among three benzodiazepine hypnotics: flurazepam, temazepam and triaz­olam. Arch Gen Psychiatry 1989; 46: 326-32

73. Weingartner HJ, Eckardt MJ, Hommer DW, et aJ. Specificity of memory impairment with triazolam use. Lancet 1991; 338: 883-4

74. Roehrs T, Zorick F, Sicklesteel J, et aJ. Effects of hypnotics on memory. J Clin Psychopharmacol1983; 3: 310-3

75. Hindmarch I, Sherwood N, Kerr JS. Amnesic effects oftriazo­lam and other hypnotics. Prog Neuropsychopharmacol Bioi Psychiatry 1993; 17: 407-13

76. Warot D, Bensimon G, Danjou PH, et aI. Comparative effects of zopicJone, triazolam and placebo on memory and psycho­motor performance in healthy volunteers. Fundam Clin Phar­maco11987; 1: 145-52

77. Trappler B, Bezeredi T. Triazolam intoxication [letter]. Can Med Assoc J 1982; 126: 893-4

78. Einarson TR, Yoder ES. Triazolam psychosis: a syndrome? Drug Intell Clin Pharm 1982; 16: 330

79. Patterson JE Triazolam syndrome in the elderly. South Med J 1987; 80: 1425-6

80. Ansseau M, Pitchot W, Hansenne M, et aJ. Psychotic reactions to zolpidem [letter]. Lancet 1992; 339: 809

81. Berry RB, Kouchi K, Bower J, et al. Triazolam in patients with obstructive sleep apnea. Am J Respir Crit Care Med 1995; 151: 450-4

82. Mendelson WB. Safety of short-acting benzodiazepine hypnot­ics in patients with impaired respiration [letter]. Am J Psychi­atry 1991; 148 (10): 1401

83. Bonnet MH, Dexter JR, Arand DL. The effect of triazolam on arousal and respiration in central sleep apnea patients. Sleep 1990; 13 (1): 31-41

84. Cohn MA. Effects of zolpidem, codeine phosphate and placebo on respiration. A double-blind, crossover study in volunteers. Drug Saf 1993; 9 (4): 312-9

85. Quera-Salva MA, McCann C, Boudet J, et al. Effects of zolpidem on sleep architecture, night time ventilation, day­time vigilance and performance in heavy snorers. Br J Clin Pharmacol1994; 37 (6): 539-43

86. McCann CC, Quera-Salva MA, Boudet J, et al. Effect of zolpidem during sleep on ventilation and cardiovascular vari­ables in normal subjects. Fundam Clin Pharmacol1993; 7 (6): 305-10

87. Cirignotta F, Mondini S, Zucconi M, et al. Controlled poly­somnographic study of the effects ofbenzodiazepine and non­benzodiazepine hypnotics (zolpidem) in obstructive sleep apnea patients: preliminary results. In: Sauvanet JP, Langer SZ, MorseJli PL, editors. Imidazopyridines in sleep disorders. New York: Raven Press, 1988: 165-73

88. Murciano D, Aubier M, Palacios S, et al. Comparison of zolpidem, triazolam and flunitrazepam effects on arterial blood gases and control of breathing in patients with severe chronic obstructive pulmonary disease. Chest 1990; 97 Suppl.: 51S-2S

Drug Safely 13 (4) 1995

270

89. Ranlov PJ, Nielsen SP. Effect of zopiclone and diazepam on ventilatory response in normal human subjects. Sleep 1987; 10 Supp!. I: 40-7

90. Muir JF, DeFouilloy P, Broussier R, et a!. Comparative study of the effects of zopiclone and placebo on respiratory function in patients with chronic obstructive respiratory insufficiency. Int Clin Psychopharmacol 1990; 5 Supp!.: 85-94

91. Inoue Y, Takata K, Veda K, et a!. Comparison of zopiclone and flurazepam on sleep apnea in the elderly. Jpn J Psychiatry Neurol 1991; 45: 924-5

92. Kales A, Kales J, Bixler EO, et a!. Hypnotic efficacy of triazo­lam: sleep laboratory evaluation of intermediate-term effec­tiveness. J Clin Pharmacol 1976; 18: 302-9

93. Miller MM, Seidel WF, Van Den Hoed J, et a!. Comparative hypnotic effects offlurazepam, triazolam and placebo: a long­term simultaneous nighttime and daytime study. J Clin Psy­chopharrnacol 1984;4: 2-16

94. Pegram V, Hyde P, Linton P. Chronic use of triazolam: the ef­fects on the sleep patterns of insomniacs. J Int Med Res 1980; 8: 224-31

95. Leibowitz M, Sunshine H. Long term efficacy and safety of triazolam and flurazepam. J Clin Pharmacol 1978; 18: 302-9

96. Schlich D, L'Heritier C, Coquelin JP, et a!. Long term treatment of insomnia with zolpidem: a multicenter general practitioner study of 107 patients. J Int Med Res 1991; 19: 271-9

97. Hertich AJ, Capwell R, Roy-Byrne PP. A case of psychosis and delirium following withdrawal from triazolam. J Clin Psychi­atry 1987; 48: 168-9

98. Shaw SH, Curson H, Coquelin JP. A double blind, comparative study of zolpidem and placebo in the treatment of insomnia in elderly psychiatric in-patients. J Int Med Res 1992; 20: 150-61

99. Fleming J AE, Bourgouin J, Hamilton P. A sleep laboratory eval­uation of the long term efficacy of zopiclone. Can J Psychiatry 1988; 33: 103-7

© Adis International Limited. All rights reserved.

Mendelson & Jain

100. Pecknold J, Wilson R, Le Morvan P. Long term efficacy and withdrawal of zopiclone: a sleep laboratory study. Int Clin Psychopharmacol1990; 5 Supp!. 2: 57-67

101. Fleming JAE. Triazolam abuse. Can Med Assoc J 1983; 129: 324-5

102. Garnier R, Guerault E, Muzard D, et a!. Acute zolpidem poison­ing - analysis of 344 cases. J Toxicol Clin Toxicol 1994; 32 (4): 391-404

103. Guerault E, Garnier R, Efthymiou ML. Intoxication aigue voluntaire par la zopiclone: 239 cas [ abstract]. Therapie 1992; 47: 223

104. Regouby Y, Delomez G, Tisserant A. PR prolongation during voluntary zopiclone intoxication. Therapie 1989; 44: 375-80

105. Lheureux P, Debailleul G, De Witte 0, et a!. Zolpidem intoxi­cation mimicking narcotic overdose: response to flumazeni!. Hum Exp Toxicol1990; 9: 105-7

106. Ahmad Z, Herepath M, Ebden P. Diagnostic utility of flumazenil in coma with suspected poisoning. BMJ 1991; 302:92

107. Griffiths RR, Lamb JL, Ator NA, et a!. Relative abuse liability of triazolam: experimental assessment in animals and hu­mans. Neurosci Behav Rev 1985; 9: 133-51

108. Evans SM, Funderburk FR, Griffiths RR. Zolpidem and triazo­lam in humans: behavioral and subjective effects and abuse liability. J Pharmacol Exp Ther 1990; 255: 1246-55

109. Boissl K, Dreyfus JF, Delmotte M. Studies on the dependence­inducing potential of zopiclone and triazolam. Pharmacology 1987; 27 Supp!. 2: 242-7

110. Snesil NR, editor. Redbook update (1994). Montvale, NJ: Med­ical Economics Data; 1993

Ill. Oswald I, Adam K. Sleep helps healing. BMJ 1984; 289: 1400-1

Correspondence and reprints: Dr Wallace Mendelson, Depart­ment of Neurology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk 5-83, Cleveland, Ohio 44195, USA

Drug Safety 13 (4) 1995