Rush CR, Baker RW, Wright K 1999. Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216, USA.
Psychopharmacology (Impact Factor: 3.88). 07/1999; 144(3):220-33. DOI: 10.1007/s002130050997
Source: PubMed

ABSTRACT The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of Like Drug, Happy, Good Effects, Friendly, Elated, Carefree and Bad Effects. Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam.

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    • "Clinical trials that explored the use of trazodone in insomnia were mostly short in duration. Reports in normal volunteers and subjects with a history of drug abuse comparing trazodone, triazolam and zolpidem seem to suggest that trazodone (dose range 100–300 mg) may have less potential for misuse among prior drug abusers [89]. Trazodone also had less performance-impairing effects, although it should be noted that these were acute studies of daytime administration [90]. "
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    ABSTRACT: Trazodone is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs). The drug is approved and marketed in several countries worldwide for the treatment of major depressive disorder (MDD) in adult patients. In clinical studies, trazodone has demonstrated comparable antidepressant activity to other drug classes, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). Moreover, the SARI action of trazodone may overcome the tolerability issues that are often associated with second-generation antidepressants such as SSRIs (i.e. insomnia, anxiety and sexual dysfunction). Recent focus has been placed on the development of a new prolonged-release once-a-day formulation of trazodone (TzCOAD), which may provide improved tolerability over the conventional immediate-release formulation of trazodone. Clinical studies have led to the recent approval in the USA of TzCOAD (as Oleptro™; Angelini Labopharm LLC, Princeton, NJ, USA), which may see resurgence of interest in the drug for the management of patients with MDD. Although trazodone is approved for the treatment of depression, evidence supports the use of low-dose trazodone as an off-label hypnotic for the treatment of sleep disorders in patients with MDD. The most common adverse effects reported with trazodone are drowsiness (somnolence/sedation), headache, dizziness and dry mouth. Other events reported, albeit with low incidence, include orthostatic hypotension (particularly in elderly patients or those with heart disease), minimal anticholinergic activity, corrected QT interval prolongation and torsade de pointes, cardiac arrhythmias, and rare occurrences of priapism and suicidal ideation. Overall, trazodone is an effective and well tolerated antidepressant (SARI) with an important role in the current treatment of MDD both as monotherapy and as part of a combination strategy. Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance.
    CNS Drugs 12/2012; 26(12):1033-49. DOI:10.1007/s40263-012-0010-5 · 5.11 Impact Factor
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    • "Higher doses or longer regimens could also augment the observed psychomotor effects of trazodone. Trazodone effects on behavior have been reported at doses up to 300 mg (Paterson et al., 2009a; Rush et al., 1997, 1999). Another limitation is the time course we chose for drug administration. "
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    ABSTRACT: Trazodone is prescribed widely as a sleep aid, although it is indicated for depression, not insomnia. Its daytime cognitive and psychomotor effects have not been investigated systematically in insomniacs. The primary goal of this study was to quantify, in primary insomniacs, the hypnotic efficacy of trazodone and subsequent daytime impairments. Sixteen primary insomniacs (mean age 44 years) participated, with insomnia confirmed by overnight polysomnography (sleep efficiency ≤ 85%). Trazodone 50 mg was administered to participants 30 min before bedtime for 7 days in a 3-week, within-subjects, randomized, double-blind, placebo-controlled design. Subjective effects, equilibrium (anterior/posterior body sway), short-term memory, verbal learning, simulated driving and muscle endurance were assessed the morning after days 1 and 7 of drug administration. Sleep was evaluated with overnight polysomnography and modified Multiple Sleep Latency Tests (MSLT) on days 1 and 7. Trazodone produced small but significant impairments of short-term memory, verbal learning, equilibrium and arm muscle endurance across time-points. Relative to placebo across test days, trazodone was associated with fewer night-time awakenings, minutes of Stage 1 sleep and self-reports of difficulty sleeping. On day 7 only, slow wave sleep was greater and objective measures of daytime sleepiness lower with trazodone than with placebo. Although trazodone is efficacious for sleep maintenance difficulties, its associated cognitive and motor impairments may provide a modest caveat to health-care providers.
    Journal of Sleep Research 05/2011; 20(4):552-8. DOI:10.1111/j.1365-2869.2011.00928.x · 3.35 Impact Factor
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    • "Zolpidem was approved for the short-term treatment of insomnia almost twenty years ago, and a number of studies were undertaken shortly thereafter to determine its potential for abuse. In agreement with findings documenting that drug history is a major determinant of the reinforcing effects of benzodiazepines (Woods et al., 1992; Griffiths and Weerts, 1997), laboratory studies demonstrated that human volunteers who had extensive drug histories reported more " drug liking " when zolpidem was compared to other hypnotics (Evans et al., 1990; Rush et al., 1999), while drug-naïve individuals did not experience abuse-related effects (Rush and Griffiths, 1996; Rush et al. 1998). A more recent study in healthy normal female participants reiterated those observations, and implied that a therapeutic dose of zolpidem may have aversive-like effects in the absence of drug experience (Licata et al., 2008). "
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    ABSTRACT: Recent case reports suggest that the short-acting benzodiazepine-like hypnotic, zolpidem, may have abuse potential among individuals who have no personal history of abusing drugs or alcohol, particularly at doses higher than those recommended for treating insomnia. This study recruited drug-naive volunteers to assess the subjective effects of multiple doses of zolpidem (0, 5, 10, or 20 mg) administered in a within-subject double-blind design. Participants (n=11) answered computerized questionnaires (Addiction Research Center Inventory, visual analog scales, and a hypothetical Drug versus Money Choice) to address the hypothesis that a supratherapeutic dose (20 mg) would increase ratings of abuse-related subjective effects, while lower therapeutic doses (5 and 10 mg) would not. Although participants rated some effects as negative at 10 and 20 mg, the highest dose engendered predominantly positive abuse-like effects such as 'High', 'Like', and 'Good Effects'. However, no dose of zolpidem was chosen over money ($0.35-$10) when participants made hypothetical choices between them. Results suggest that although individuals without a drug abuse history are not inclined to choose zolpidem when presented with an alternative reinforcer such as money, it may possess moderate abuse potential that limits its clinical utility.
    Behavioural pharmacology 02/2011; 22(2):160-6. DOI:10.1097/FBP.0b013e328343d78a · 2.15 Impact Factor
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