Triazolam: a review of its pharmacological properties and therapeutic efficacy in patients with insomnia

Triazolam is a triazolobenzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia, situational insomnia in hospitalised patients, and insomnia associated with other disease states. As triazolam has a relatively short half-life of about 2 to 3 hours in healthy subjects and has only 1 short acting active metabolite, alpha-hydroxytriazolam, it would seem more suitable as an hypnotic than longer acting drugs such as flurazepam, nitrazepam or flunitrazepam, particularly when residual sedative effects on the day after ingestion are undesirable. Thus, with usual hypnotic doses of triazolam (0.25 or 0.5 mg) impairment of psychomotor and cognitive function is generally not carried over into the day after ingestion, although at doses of 1 mg or greater, residual effects may appear. In short term comparative studies triazolam was clearly superior to a placebo, and was at lest as effective as flurazepam, or other benzodiazepines such as nitrazepam or diazepam, in hastening sleep onset, reducing nocturnal awakenings, and increasing sleep duration. In other studies it was often superior to chloral hydrate, methyprylone or quinalbarbitone (secobarbital). In a small number of patients with chronic insomnia receiving extended treatment with triazolam in a clinical setting or in some sleep laboratory studies, no evidence of tolerance occurred; however, some evidence of reduced effect with repeated administration has been reported in one sleep laboratory study. Thus, a definitive statement about the likelihood of tolerance occurring on repeated administration is difficult to make at this time.     

Pharmacology and hypnotic efficacy of triazolam

Triazolam is a new triazolobenzodiazepine drug that is indicated for the treatment of insomnia. The usual adult dosage is 0.25 to 0.5 mg; for geriatric patients a dose of 0.125 to 0.25 mg is recommended. Triazolam is readily absorbed and quickly eliminated with a half-life of 2-5 hours, making it the shortest acting benzodiazepine available in the United States. Sleep laboratory and non-laboratory clinical trials found triazolam 0.25 and 0.5 mg effective in inducing and maintaining sleep. It remained effective in laboratory studies of up to one month duration and non-laboratory studies of up to six months duration when the drug was administered nightly. On discontinuation disturbed sleep for one or two nights was observed in some studies. Triazolam impairs performance for several hours after administration. However, unlike benzodiazepines with long-acting metabolites, triazolam is relatively free of daytime residual effects, which is attributable to its short half-life. Overall, triazolam is an effective and safe compound for the symptomatic treatment of insomnia complaints.     

Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study

We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.     

Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia

Loprazolam is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1 mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies. Thus, with its 'intermediate' elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.     

Triazolam diminishes daytime sleepiness and sleep fragmentation in patients with periodic leg movements in sleep.

Fifteen subjects (9 men and 6 women) exhibiting objective evidence of excessive daytime somnolence and periodic leg movements in sleep underwent 4-7 days of treatment with triazolam (0.25 or 0.50 mg) and placebo in a double-blind crossover design. One night of polysomnography followed by daytime multiple sleep latency testing were conducted on the first and last days of each treatment block. By the last day of treatment, the mean multiple sleep latency test score after triazolam (9.0 minutes) was significantly greater than that after placebo (5.7 minutes). Thus, triazolam treatment led to a decrease in daytime somnolence. Triazolam also improved sleep architecture and continuity; it increased total sleep time, decreased the number of awakenings and arousals, and decreased stage 1 and increased stage 2 percentages. Although the frequency of periodic electromyographic bursts remained unchanged, the frequency of associated arousals decreased after treatment. Short-term treatment with triazolam is thus effective in diminishing daytime sleepiness and in improving sleep architecture, continuity and duration in patients with periodic leg movements in sleep. These effects do not seem to be mediated through a decrease in periodic leg movement activity.     

Rebound insomnia: duration of use and individual differences.

This study assessed consistency, duration of use, and individual difference in rebound insomnia. Eleven healthy men, 20-30 years old, with normal sleep by both subjective and polysomnographic criteria, received each of four treatments in a double-blind Latin Square design (triazolam 0.50 mg for 1, 6, and 12 nights and placebo for 12 nights), followed by two placebo discontinuation nights. Triazolam increased sleep compared with placebo without differences in effects between the first and last nights of treatment. On discontinuation following active drug, sleep efficiency was reduced compared with placebo, but duration of administration did not alter the likelihood or intensity of rebound insomnia. Those subjects (5) showing poorer sleep on discontinuation from the 12-night treatment also had poorer sleep in the 1- and 6-night treatment. Subjects with rebound insomnia had poorer baseline sleep and a greater drug effect than did subjects without.     

Rebound insomnia: a critical review

Rebound insomnia, a worsening of sleep compared with pretreatment levels, has been reported upon discontinuation of short half-life benzodiazepine hypnotics. This paper reviews the existing sleep laboratory studies for the presence or absence of rebound insomnia following treatment with triazolam, temazepam, and flurazepam in insomniac patients or poor sleepers and, when possible, in normals. The results indicate that rebound insomnia is a distinct possibility after discontinuation of triazolam in both insomniacs and normal controls. Compared with baseline, disturbed sleep was reported in insomniacs or poor sleepers for the first 1 or 2 nights of withdrawal in seven of nine polygraphically recorded sleep studies following triazolam 0.5 mg and in one of two studies following triazolam 0.25 mg. In one study conducted in normal volunteers, rebound insomnia was observed following triazolam 0.5 mg but not triazolam 0.25 mg. In another study, which used subjective reports of sleep rather than polygraphic recordings, rebound insomnia was significantly attenuated after triazolam 0.5 mg by tapering the dose over 4 nights. The risk of rebound insomnia after temazepam 15 or 30 mg was low. In keeping with its long elimination half-life, flurazepam (30 mg) continued to exert beneficial effects for the first 2-3 withdrawal nights, but the possibility of a mild rebound insomnia cannot be dismissed during the intermediate withdrawal period (nights 4-10) following prolonged, consecutive, nightly administration (more than 30 nights). The benzodiazepine hypnotics are generally preferred over other types (barbiturates or nonbenzodiazepine, nonbarbiturate), but there are advantages and disadvantages related to half-life of the benzodiazepines. The risk of rebound insomnia is greater with the short half-life as compared with the long half-life benzodiazepines.     

Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia

The effects of two nights of treatment with the short-acting benzodiazepine receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary insomniacs using two concurrent, multi-center, randomized, double-blind, Latin Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60 mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically recorded sleep parameters and patient reports of sleep quality were collected during baseline and two consecutive nights during the four treatment phases in each study. All doses of zaleplon produced significant decreases in latency to persistent sleep. Although no minimally effective dose could be determined, dose-response effects were apparent. Triazolam 0.25 mg produced a decrease in latency to persistent sleep that was comparable to that of zaleplon 10 mg. Only the triazolam dose and the 60 mg dose of zaleplon produced significant increases in total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced decreases in the percentage of REM sleep compared to placebo. Patient reports of efficacy were consistent with objective findings. In addition, all doses of zaleplon tended to increase while triazolam decreased the percentage of stage 3/4 sleep. There was no evidence of residual daytime impairment for any of the zaleplon doses, however, triazolam administration produced significant impairment in performance on a digit copying test. A higher number of adverse events were seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and placebo. At higher doses, zaleplon is more effective than triazolam at reducing latency to persistent sleep in chronic insomnia and is not associated with the decrease in slow-wave sleep or residual impairment observed with triazolam. However, increases in total sleep time were apparent only at doses which produced concomitant increases in the number of adverse events. In contrast, triazolam (0.25 mg) produced increases in total sleep time (;25 min) and decreases in latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley & Sons, Ltd.     

The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs.

Insomnia, a common complaint among the elderly, is generally treated with benzodiazepines. Long-acting benzodiazepines (e.g., flurazepam) often produce daytime somnolence and performance deficits, whereas short-acting drugs (e.g., triazolam) have been associated with marked rebound insomnia and anterograde memory loss. The authors designed a pilot study to evaluate the efficacy of an intermediate-acting benzodiazepine, estazolam (e.g., ProSom), as well as its side effects. The parameters studied were sleep, daytime performance, and memory. Ten geriatric patients (greater than 60 years of age) with insomnia participated in the study. They received placebo nightly for 2 weeks (baseline), estazolam 1 mg nightly for the next 4 weeks (treatment phase), and placebo again for 2 weeks (withdrawal period). Sleep was monitored by polysomnography the first two nights of each week in a sleep laboratory. Estazolam significantly decreased sleep latency, nocturnal awakenings, and wake time after sleep onset. Total sleep time increased an average of 63 minutes the first night of treatment. Significant improvements in wake time after sleep onset and total sleep time also were observed in the fourth week of estazolam treatment. Rebound insomnia occurred on the first withdrawal night only for wake time and total sleep time. By the next night, these sleep parameters returned to baseline. Neither day-time performance nor anterograde memory was adversely affected by estazolam treatment or its withdrawal. A 1-mg dose of estazolam appears to be a safe and effective hypnotic for elderly patients with insomnia.     

Zaleplon: a review of its use in the treatment of insomnia

Zaleplon is a pyrazolopyrimidine hypnotic agent which is indicated for the short term (2 to 4 weeks) management of insomnia. Zaleplon 5 and 10 mg at bedtime (usual recommended doses) significantly reduced sleep latency compared with placebo in clinical trials in nonelderly and elderly patients with insomnia. In general, sleep maintenance (sleep duration and number of awakenings) and sleep quality were not significantly different from placebo with zaleplon 5 and 10 mg/night. Zaleplon 20 mg/night significantly improved sleep latency and duration in nonelderly patients, but effects on number of awakenings were inconsistent and sleep quality generally did not improve. The relative hypnotic efficacy of zaleplon compared with that of triazolam and zolpidem is not yet clearly established. Tolerance to the hypnotic effects of zaleplon generally did not occur during 5 weeks' treatment, or during long term treatment (6 or 12 months) according to a small number of studies presented as abstracts. Zaleplon was well tolerated in clinical trials. The most common event was headache but the incidence was similar to that observed with placebo. Zaleplon 5 and 10 mg did not impair psychomotor function or memory even immediately after the dose in studies in volunteers or patients with insomnia. Zaleplon 20 mg, however, impaired psychomotor function and memory immediately after the dose but next-day effects were not observed. The psychomotor profile of zaleplon appears to be better than that of comparator agents. Rebound insomnia was not observed after sudden discontinuation of up to 12 months' treatment with zaleplon 5 and 10 mg/night and up to 4 weeks' treatment with zaleplon 20 mg/night. In addition, the potential for withdrawal syndrome with zaleplon appears to be low according to limited data. In conclusion, zaleplon 5, 10 and 20 mg administered at bedtime, or later if patients have difficulty sleeping, is an effective and well tolerated hypnotic agent. There was no evidence of next-day residual effects with the 5 and 10 mg dosages, and the incidence of withdrawal effects with zaleplon 5, 10 and 20 mg did not differ significantly to that observed with placebo. In addition, tolerance to the effects of zaleplon is unlikely to develop when administered for the recommended treatment period. The comparative efficacy and tolerability of zaleplon with other short acting nonbenzodiazepine hypnotics is difficult to establish. However, on the basis of current efficacy evidence and the lower incidence of residual effects with zaleplon 5 and 10 mg relative to comparator agents, this drug represents a useful option in the management of patients with insomnia who have difficulties initiating sleep.     

Activity of the hypnotics, flunitrazepam and triazolam, in man

1 Effects of flunitrazepam and triazolam (0.25 and 0.5 mg) on sleep and on performance were studied in six healthy adult males. Sleep was assessed by electroencephalography and analogue scales, and performance by a visuo-motor coordination task.

2 Over the same dose range triazolam had a more pronounced effect than flunitrazepam. Total sleep time was increased by 0.25 and 0.5 mg triazolam, and by 0.5 mg flunitrazepam. Both drugs decreased awake activity and drowsy sleep, though the effect of flunitrazepam was limited to the 0.5 mg dose and restricted to the first 6 h after sleep onset. There were no changes in slow wave sleep.

3 Latency to the first period of rapid eye movement (REM) sleep was increased with 0.5 mg triazolam, and when doses were combined (0.25-0.5 mg) the latencies with both drugs were increased. Both doses of triazolam reduced the duration and percentage of REM sleep during the early part of the night, though the whole night duration of REM sleep was not changed.

4 After the morning ingestion of 0.25 mg flunitrazepam performance was impaired for 2.0 h, but there were no residual effects when 0.25 or 0.5 mg were taken at night. With the morning ingestion of 0.25 mg triazolam performance was impaired from 0.5 to at least 5.0 h after ingestion. There were no residual effects with 0.25 mg overnight, but with 0.5 mg triazolam there was an effect on performance 10 h after ingestion with recovery within 1.5 h (11.5 h of ingestion).

5 Triazolam (0.25 mg) and 0.5 mg flunitrazepam provide useful hypnotic activity when impaired performance the next day is to be avoided. The activity of 0.5 mg triazolam is accompanied by only limited residual sequelae compared with some other benzodiazepines of comparable efficacy, and so may prove to be useful when a more powerful effect is required.

     

Comparison of the short-acting benzodiazepines midazolam and triazolam with placebo

The hypnotic effect of midazolam (Dormicum, 15 mg) and triazolam (0.5 mg) were compared with each other and with a placebo. Their effects on the quality of dreams and of morning awaking were also evaluated. 30 out-patients were included in a double-blind cross-over study for a period of 11 consecutive nights in which the order of the drugs was randomized according to the Latin squares method. The active substances and the placebo were each administered in 3-night blocks separated from each other by an intercalary placebo night. On waking each morning the patients answered a questionnaire concerning the previous night. Some of the responses were recorded on a visual analogue scale. Midazolam and triazolam significantly decreased the latency of onset of sleep and the number of nocturnal and premature morning awakenings. The patients' overall impression of their night was better under the active drugs than under placebo. However, there were no differences between placebo and the benzodiazepines as far as side effects or the quality of dreams and of morning awakening were concerned. The two drugs had an identical effect on sleep latency, but under midazolam the patients woke more frequently during the night and slightly earlier in the morning, suggesting that the duration of action is shorter. The intercalary placebo nights were better after 3 nights of placebo than after 3 nights of benzodiazepine. This rebound effect was more marked after triazolam than after midazolam. In conclusion the two benzodiazepines were both effective and well tolerated but midazolam is slightly shorter acting and has slightly less rebound effect than triazolam.     

Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety

In a double-blind placebo-controlled study, following a 1 week washout, 75 outpatients suffering from generalized anxiety disorder with severe insomnia as the target symptom were randomly assigned to 4 weeks of treatment with zopiclone 7.5 mg, triazolam 0.5 mg or placebo at bedtime. Zopiclone was significantly better than placebo on most sleep parameters. Triazolam tended to be superior to placebo, but its superiority was significant only on the sleep induction factor. Triazolam-treated patients presented significantly more day-time-interdose anxiety than zopiclone as assessed by the weekly HARS and Clinical Global Assessment of Anxiety. Although daytime-interdose anxiety was observed with both drugs, this treatment emergent symptom was more frequent and severe with triazolam. Side-effects were of a mild to moderate intensity for both zopiclone and triazolam; however, taste perversion frequently appeared with zopiclone. Although both drugs share similar pharmacological properties and bind to benzodiazepine receptors, they differ significantly with respect to side-effects and daytime anxiety.     

Central nervous system toxicity associated with concurrent use of triazolam and cimetidine

A 49-year-old woman treated with cimetidine 300 mg tid for more than 18 months for Zollinger-Ellison syndrome experienced lethargy, dizziness, ataxia, and auditory and visual hallucinations after receiving triazolam 0.375 mg hs for sleep. Triazolam plasma concentrations were measured, and a triazolam elimination half-life was calculated to be approximately 8 hours (reported range 1.7-3 h). Cimetidine has been reported to decrease the apparent oral clearance of triazolam, resulting in increased triazolam plasma concentrations with the potential for exaggerated triazolam pharmacologic effects. Cimetidine may have been responsible for the unusually large elimination half-life in this patient. Until the mechanisms and clinical significance of this potential drug interaction are determined, clinicians should use the combination of triazolam and cimetidine with caution.     

Use of zolpidem 10 mg as a benzodiazepine substitute in 84 patients with insomnia

The antagonistic effects of zolpidem 10 mg on withdrawal symptoms caused by abrupt or gradual discontinuation (half-dose over 4 nights) of triazolam 0·25 mg in patients with chronic insomnia, who had been receiving regular treatment for over one month, were assessed in a randomized, double-blind, placebo-controlled clinical trial in general practice. Eighty-four patients were enrolled, mostly women (67·9%), with a mean age of 54·3±11·0 years. Twenty-one different general practitioners were solicitated for the recruitment. The subjects were randomized into four groups, and all received triazolam 0·25 mg during the run-in phase from day 1 (D1) to day 3 (D3). The following treatments were given from D4 to D7: triazolam 0·125 mg+zolpidem 10 mg (Group 1); zolpidem 10 mg (Group 2); placebo (Group 3); or triazolam 0·125 mg+placebo (Group 4). Groups 1 and 2 received zolpidem 10 mg from D7 to D24, while Groups 3 and 4 received placebo. Finally, all four groups received placebo (blind withdrawal phase) from D25 to D28. The following assessment criteria were used: clinical global impression (CGI) scale completed by the practitioner; patient questionnaire based on routine sleep criteria, wakefulness and daytime alertness. Secondary criteria were sleep diaries and visual analogue scales. Study drop-outs were reported and explained. The effectiveness/tolerance ratio was found to be statistically significant using the CGI (p<0·007) in favour of zolpidem 10 mg. There was no significant difference in patients subjective assessment between the groups except for nightmares (p<0·04) less frequent in patients receiving zolpidem. Zolpidem was found to be more effective than placebo at D21 (CGI) according to sleep diaries; the zolpidem group showed a statistically significant difference as compared to the three other concerning four sleep parameters: number of awakenings, anxiety, sleep duration, energy. Drop-out rates were significantly lower in the zolpidem group than in other ones (p<0·01). Abrupt and gradual triazolam withdrawal over 4 nights induced withdrawal symptoms. Equally no specific phenomena were observed at the end of the trial during the blind withdrawal phase. This study shows that zolpidem 10 mg improves sleep quality and reduces withdrawal symptoms after abrupt or gradual discontinuation of triazolam 0·25 mg in chronic patients with chronic insomnia. Copyright © 1998 John Wiley & Sons, Ltd.     

Comparison of the effects of full and partial allosteric modulators of GABA(A) receptors on complex behavioral processes in monkeys

Two baselines involving a repeated acquisition task were used to assess the effects of bretazenil, imidazenil, and triazolam. The first baseline was a multiple schedule of repeated acquisition and performance of conditional discriminations. In the first component, the subject acquired a four-response chain by responding sequentially on three keys in the presence of different combinations of colors and geometric forms displayed on a center key. Acquisition of the discrimination was defined by a decrease in errors as the session progressed. In the performance component, the four-response chain was the same each session. Incorrect responses in either component produced a 5s time out during which responding had no programmed consequence. The second procedure, which has been used to evaluate the effects of drugs on memory, involved the acquisition of a discrimination, followed by a 1h delay and a retest of the same discrimination to assess retention. Triazolam (0.32 and 0.56mg/kg) administered alone, produced dose-related decreases in response rate in each component. In addition, triazolam also produced a dose-related increase in percentage errors in acquisition with no effect in performance. Triazolam (0.32mg/kg) eliminated retention (0 percent savings) in the memory task. Bretazenil (0.1-5.6mg/kg) or imidazenil (0.1-1.8mg/kg) administered alone had little or no effect on either rate of responding or accuracy in either component. Furthermore, bretazenil but not imidazenil disrupted retention at the higher doses tested. The combination of imidazenil or bretazenil with triazolam produced dose-related attenuation of the disruptive effects of triazolam on both behavioral baselines. These data suggest that the disruptive effects of benzodiazepines on learning and memory may be a function of the intrinsic efficacy of these compounds at different GABA(A) receptor subtypes.     

Zopiclone in elderly patients: Efficacy and safety

Zopiclone is an hypnotic medication belonging to the cyclopyrrolone family of drugs. It is chemically unrelated to the benzodiazepines and binds to a specific site of the GABA_A receptor complex. Zopiclone has been found to be effective as an hypnotic for the elderly: single doses of 7.5 mg have been found to decrease sleep onset Latency and the number of nocturnal awakenings: to improve sleep duration and sleep quality, and to cause minimal impairment of psychomotor performance and mental alertness the morning after a normal bed-time dose. Importantly, the drug has been shown to have little or no effect on short-term memory, a function that is often impaired by earlier hypnotic drugs particularly in elderly patients. Furthermore, there is little evidence of dependency or rebound insomnia on withdrawal of the medication after continued use. The drug is well tolerated by patients of all ages, and adverse effects are infrequently reported, the majority of side-effects being taste disturbance (3.6 per cent in the largest trial to date) and dry mouth (1.6 per cent). Zopiclone is now a well-established alternative to the benzodiazepine hypnotics.     

Hypnotic self administration and dose escalation

The dependence liability of benzodiazepines in the context of their use as hypnotics (i.e. by insomnia patients as pre-sleep medications) is unresolved. A recent study found that insomniacs self administer capsules at bedtime at a high rate, with triazolam (0.25 mg) taken as often as placebo. This study sought to determine if differential self administration would develop when multiple capsules are available nightly. Eighteen men and women, age 21–45 years, with insomnia complaints (nine with objective sleep disturbance and nine without) were studied, I week with placebo and I week with triazolam (0.25 mg). The two conditions were administered double-blind and presented in a counter-balanced order with a week between conditions. In each condition, after 3 consecutive sampling nights of the available single capsule for that condition, subjects could self administer 0–3 capsules before bed on the 4 subsequent nights. Triazolam was self administered as many nights as placebo, but the number of placebo capsules self administered was twice that of triazolam capsules. The objective insomniacs self administered more capsules than the subjective insomniacs and neither group differentially choose triazolam over placebo. The number of triazolam capsules taken nightly was stable and the number of placebo capsules variable. It is concluded that insomniacs show no shortterm escalation of triazolam dose, but do choose an increased and variable number of placebos, a pattern which is interpreted as being insomnia relief-seeking behavior.     

Triazolam attenuates amphetamine but not morphine conditioned place preferences

In a series of four experiments the benzodiazepine triazolam was tested for reinforcing effects and for effects on reinforcement induced by amphetamine and morphine. Reinforcement was assessed in a conditioned place preference paradigm. Triazolam did not produce reinforcing or aversive effects when administered in doses ranging from 0.0625 to 0.5 mg/kg. Triazolam did attenuate reinforcing effects produced by 0.75 and 1.25 mg/kg amphetamine. No effect of triazolam was observed on morphine-induced reinforcement. These results indicate that the administration of triazolam can affect the brain mechanisms that mediate the reinforcing effects of amphetamine but not morphine.     

Hypnotic self administration: forced-choice versus single-choice

Twenty-four men and women with insomnia, age 21–50?years, self administered hypnotics under a single-choice with placebo, single-choice with triazolam (0.25?mg), or forced-choice of placebo versus triazolam (0.25?mg) paradigm. Subjects received 4-sampling nights of placebo or triazolam in the single-choice conditions or 2 nights of each in the forced-choice condition. Then on 7 choice nights they could self administer a capsule, or not, in the single-choice conditions, or were required to choose one of two color-coded capsules in the forced-choice condition. In the single-choice conditions, subjects chose placebo 80% of nights and triazolam 77% of nights, while in the forced-choice condition triazolam was chosen on 86% of nights. Thus, the self administration of triazolam did not vary significantly between single or forced choice conditions, but that of placebo did. Placebo rate was high when it was the only alternative, but low when competing with triazolam. On sampling nights, compared to placebo, triazolam produced a significant increase in total sleep time, a reduction in latency to sleep, wake after sleep onset, and percentage stage 1 sleep. Triazolam, relative to placebo, also improved mood in the morning on some sampling nights. For subjects choosing capsules <?100% of opportunities (n?=?14), on nights a capsule was chosen versus nights none was chosen (regardless of whether placebo or triazolam was the choice), self-ratings 30?min before bedtime on the Profile of Mood States vigor scale were significantly higher.