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: 3.99). 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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    • "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 · 2.95 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 · 2.19 Impact Factor
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    • "The myriad behavioral effects of zolpidem are well documented in both laboratory animals (e.g., Sanger et al. 1987) and humans (see review by Rush 1998). In addition to its clinical usefulness for the treatment of insomnia, zolpidem's use also has been associated with a host of untoward effects such as abuse and dependence liability (Evans et al. 1990; Liappas et al. 2003; Rush et al. 1999; Victorri-Vigneau et al. 2007), somnambulism (Harazin and Berigan 1999; Sharma and Dewan 2005; Yang et al. 2005), nightmares (Ganzoni et al. 1995; Hajak and Bandelow 1998; Roger et al. 1993; Toner et al. 1999), hallucinations, delirium, and/or psychosis (Brodeur and Stirling 2001; Huang et al. 2003; Markowitz and Brewerton 1996; Toner et al. 1999; Tsai et al. 2003), and even compulsive behaviors such as sleep-eating (Morgenthaler and Silber 2002; Najjar 2007; Tsai et al. 2007). Effects such as these suggest that it is important to understand the basis of zolpidem's effects beyond its purported GABA A receptor pharmacology. "
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    ABSTRACT: Zolpidem is a nonbenzodiazepine sedative/hypnotic that acts at GABA(A) receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem's specific effects on neurochemistry in vivo. We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites. Proton magnetic resonance spectroscopy ((1)H MRS) at 4 T was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states. Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of "dizzy," "nauseous," "confused," and "bad effects" were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and "dizzy." Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and "dizzy" may be a function of zolpidem's interaction with alpha1GABA(A) receptors in the cerebellum, projecting through the vestibular system to the thalamus.
    Psychopharmacology 02/2009; 203(4):819-29. DOI:10.1007/s00213-008-1431-1 · 3.99 Impact Factor
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