Benzodiazepine Dependence

Pétursson, Hannes; Lader, Malcolm

doi:10.1111/j.1360-0443.1981.tb00218.x

Cited by 160 publications

(40 citation statements)

References 78 publications

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“…A discontinuation syndrome associated with benzodiazepine use has been described in man and in several animal models (Petursson & Lader, 1981;File, 1982;Owen & Tyrer, 1983;Roy-Byrne & Hommer, 1988;Woods et al, 1987;1988;Miller et al, 1988c). In animals, this syndrome is characterized by increased motor activity (Miller et al, 1988c), and increased sensitivity to the effects of inverse agonist compounds (Little et al, 1987a,b).…”

Section: Discussionmentioning

confidence: 99%

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Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

Schatzki

Lopez

Greenblatt

et al. 1989

British J Pharmacology

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The effects of lorazepam discontinuation on responses to benzodiazepine agonists and antagonists were studied in mice. The convulsant dose of pentylenetetrazol was decreased after an acute dose of lorazepam (0.5 mg kg−1) at 4 days after drug discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. The percentage of mice undergoing convulsions after an acute dose of FG 7142 (40 mg kg−1) was increased at 4 days after lorazapam discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. After an acute dose (0.5 mg kg−1), lorazepam concentrations in cortex tended to be greater in lorazepam‐treated compared to vehicle‐treated mice at 4 days after discontinuation compared to 1 and 7 days. These data indicate a shift toward reduced agonist sensitivity and increased inverse agonist sensitivity in mice 4 days after lorazepam discontinuation.

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Section: Discussionmentioning

confidence: 99%

“…Discontinuation syndromes associated with benzodiazepine administration have been reported widely in man and may limit clinical use of benzodiazepines (Petursson & Lader, 1981;Owen & Tyrer, 1983;Woods et al, 1987;1988;Roy-Byrne & Hommer, 1988). However, the mechanism of benzodiazepine discontinuation syndromes remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

Schatzki

Lopez

Greenblatt

et al. 1989

British J Pharmacology

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“…The main problem with long-term BDZ usage lies in the development of tolerance and dependence (Petursson and Lader, 1981;Greenblatt and Shader, 1978;Schweizer and Rickels, 1998). In fact, numerous clinical and experimental reports have shown that the abrupt discontinuation from repeated BDZ administration leads to a well-recognized withdrawal syndrome (File, 1990;Schweizer and Rickels, 1998;Bateson, 2002).…”

Section: Introductionmentioning

confidence: 99%

Increased Fear Learning Coincides with Neuronal Dysinhibition and Facilitated LTP in the Basolateral Amygdala following Benzodiazepine Withdrawal in Rats

Isoardi

Martijena

Carrer

et al. 2004

Neuropsychopharmacol

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Animals chronically administered with diazepam (DZM -2 mg/kg/day i.p.) or vehicle (VEH) for 21 days were tested in a fear-conditioning paradigm 4 days after the last administration. Increased freezing was observed in DZM withdrawn rats as compared to VEH injected control rats in both associative and nonassociative context and this increase was greatest for the DZM withdrawal group in the paired context. In animals anesthetized with urethane, single pulses in the medial prefrontal cortex evoked a field potential including a population spike (PS) in the basolateral complex of the amygdala (BLA) of control animals, whereas in DZM withdrawn animals multiple PSs were evoked. In brain slices from control rats, stimulation of the external capsule evoked a field potential including a PS in the BLA, whereas in DZM withdrawn rats multiple PSs were evoked. The amplitude of the PS was smaller in slices obtained from DZM withdrawn rats than from control rats, and paired pulse inhibition was significantly less in the former. Perfusion with DZM 2 mM of slices obtained from DZM withdrawn rats eliminated repetitive spiking. GABAergic blockade with 50 mM picrotoxin in control rats resulted in the appearance of multiple secondary PSs. In slices from DZM withdrawn rats high-frequency stimulation induced a highly significant potentiation that lasted at least 2 h (LTP), whereas in control rats the same stimulation did not induce LTP. Neuronal hyperexcitability leading to facilitated LTP observed in BLA of DZM withdrawn rats could be due to depressed GABAergic activity (dysinhibition). The increased synaptic plasticity may be at the root of the increased fear learning observed in withdrawn animals.

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“…56,66 Older people may also become dependent on benzodiazepines, it has been estimated that 35% of patients taking benzodiazepines for more than four weeks develop dependency, and with four months of regular use most users develop dependence. 67,68 It is unclear whether dependency is more likely with long-acting as opposed to short-acting drugs.…”

Section: Benzodiazepinesmentioning

confidence: 99%

Managing Insomnia in Older People

Woodward

2007

Pharmacy Practice and Res

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Although insomnia is a common problem in older people, there have been few therapeutic advances in the last decade. Benzodiazepines continue to be overused and the newer benzodiazepine-like drugs (e.g. zopiclone) are proving to be no more effective and have their own risk of adverse effects. Nonpharmacological management remains the preferred option, but is poorly taught and infrequently adhered to, especially in hospital and residential care settings. Older people themselves often request drugs. Progress towards improved management of insomnia will require a significant shift in knowledge and attitudes in both health professionals and the community. INTRODUCTIONSleep is vital for health and quality of life and older people frequently find sleep elusive. Poor sleep interacts with many medical and psychiatric conditions which are more common in older age, thus exacerbating their morbidity. It would therefore be expected that there have been ongoing and major developments in the understanding and management of insomnia in older people. While some progress has been made there is still a long way to travel before older people with insomnia have a good understanding of sleep disorders, are well assessed, are correctly managed, and participate as informed partners in an effective management program.Changes in the amount and pattern of sleep in older people include spending more time in bed, but less time asleep and easy arousal from sleep, when compared with younger people. 1-5 Average total sleep time actually increases slightly after 65 years of age. 6 Time from retiring to bed and sleep onset increases with age, and there are changes in the quality of sleep. Slow wave (deeper, restorative) sleep reduces with age, there is increased fragmentation of sleep and rapid eye movement (REM) sleep is reduced. 7,8 These changes in sleep and wakefulness with age are in the direction of impaired sleep maintenance and depth. This increased night-time wakefulness is mirrored by increases in daytime fatigue, daytime napping and the likelihood of falling asleep during the day. Advancing age is associated with a tendency to fall asleep by day and to sleep less well at night. These age-related changes in sleep appear to be partly dependent on medical and psychiatric disorders, rather than universal features of normal ageing. 9,10

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Benzodiazepine Dependence

Cited by 160 publications

References 78 publications

Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

Increased Fear Learning Coincides with Neuronal Dysinhibition and Facilitated LTP in the Basolateral Amygdala following Benzodiazepine Withdrawal in Rats

Managing Insomnia in Older People

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