It was patented in 1968 and came into medical use in 1975.[5]
Medical uses
Estazolam is prescribed for the short-term treatment of certain sleep disorders. It is an effective hypnotic drug showing efficacy in increasing the time spent asleep as well as reducing awakenings during the night. Combination with non-pharmacological options for sleep management results in long-term improvements in sleep quality after discontinuation of short-term estazolam therapy.[6][7] Estazolam is also sometimes used as a preoperative sleep aid. It was found to be superior to
triazolam in side effect profile in preoperative patients in a trial.[8] Estazolam also has
anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with
anxiety.[9]
Side effects
A hang-over effect commonly occurs with next day impairments of mental and physical performance.[10] Other side effects of estazolam include
somnolence,
dizziness,
hypokinesia, and abnormal
coordination.[11]
In September 2020, the U.S.
Food and Drug Administration (FDA) required the
boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[12]
Tolerance and dependence
The main safety concern of benzodiazepines such as estazolam is a
benzodiazepine dependence and the subsequent
benzodiazepine withdrawal syndrome which can occur upon discontinuation of the estazolam. A review of the literature found that long-term use of benzodiazepines such as estazolam is associated with
drug tolerance,
drug dependence,
rebound insomnia and CNS related adverse effects. Estazolam should only be used short term and at the lowest effective dose to avoid complications related to long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.[13][14] The short-term benefits of benzodiazepines on sleep begin to reduce after a few days due to
tolerance to the hypnotic effects of benzodiazepines in the elderly.[15]
Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with
comorbidpsychiatric disorders.[16]
Pharmacology
Estazolam is classed as a "triazolo" benzodiazepine drug.[17] Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties.[18] Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.[19]
Pharmacokinetics
Peak plasma levels are achieved within 1–6 hours. Estazolam is an intermediate acting
benzodiazepine. The
elimination half life of estazolam is an average of 19 hours, with a range of 8–31 hours.[20][21] The major metabolite of estazolam is 4-hydroxyestazolam.[22] Other identified metabolites include 1-oxo-estazolam, 4'-hydroxy-estazolam, and
benzophenone.[3]
Interactions
Alcohol enhances the
sedativehypnotic properties of estazolam.[23] In package inserts, the manufacturer clearly warns about an interaction with
ritonavir, and although clinical interactions of ritonavir with estazolam have not yet been described, the lack of clinical descriptions of the interactions does not negate the seriousness of the interaction.[24]
EEG effects in rabbits
An animal study in rabbits demonstrated that estazolam induces a drowsy pattern of spontaneous
EEG including high voltage slow waves and spindle bursts increase in the
cortex and
amygdala, while the
hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the
cortical EEG. The EEG arousal response to
auditory stimulation and to electric stimulation of the mesencephalic reticular formation,
posteriorhypothalamus and centromedian
thalamus is significantly suppressed. The
photic driving response elicited by a flash light in the
visual cortex is significantly suppressed by estazolam.[25]
A primate study found that estazolam has abuse potential.[26] Two types of drug misuse can occur; recreational misuse, where the drug is taken to achieve a high or when the drug is continued long term against medical advice.[27] Estazolam became notorious in 1998 when a large amount of an 'herbal sleeping mix' called Sleeping Buddha was recalled from the shelves after the FDA discovered that it contained estazolam.[28] In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam.[29][30]
^Roehrs T, Zorick F, Lord N, Koshorek GL, Roth T (June 1983). "Dose-related effects of estazolam on sleep of patients with insomnia". Journal of Clinical Psychopharmacology. 3 (3): 152–156.
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^Mauro C, Sperlongano P (September 1987). "[Controlled clinical evaluation of 2 hypnotic triazole benzodiazepines, estazolam and triazolam, used the night before surgical interventions]". Minerva Medica (in Italian). 78 (18): 1381–1384.
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^Post GL, Patrick RO, Crowder JE, Houston J, Ferguson JM, Bielski RJ, et al. (August 1991). "Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study". Journal of Clinical Psychopharmacology. 11 (4): 249–253.
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^Müller KW, Müller-Limmroth W, Strasser H (1982). "[Alterations of sleep stage pattern in human beings and hang-over effects under the influence of estazolam/2nd Comm.: Studies on the hang-over effect in psycho-physiological performance (author's transl)]". Arzneimittel-Forschung (in German). 32 (4): 456–460.
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^Pierce MW, Shu VS, Groves LJ (March 1990). "Safety of estazolam. The United States clinical experience". The American Journal of Medicine. 88 (3A): 12S–17S.
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^Grad RM (November 1995). "Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk". The Journal of Family Practice. 41 (5): 473–481.
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^Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413.
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^Braestrup C, Squires RF (April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". European Journal of Pharmacology. 48 (3): 263–270.
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^Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A (March 2003). "Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists". Bioorganic & Medicinal Chemistry. 11 (5): 769–773.
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^Oishi R, Nishibori M, Itoh Y, Saeki K (May 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". European Journal of Pharmacology. 124 (3): 337–342.
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^Allen MD, Greenblatt DJ, Arnold JD (1979). "Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine". Psychopharmacology. 66 (3): 267–274.
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^Mancinelli A, Guiso G, Garattini S, Urso R, Caccia S (March 1985). "Kinetic and pharmacological studies on estazolam in mice and man". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 15 (3): 257–265.
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^Miura M, Otani K, Ohkubo T (May 2005). "Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 35 (5): 455–465.
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^Johanson CE (March 1987). "Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam". Pharmacology, Biochemistry, and Behavior. 26 (3): 521–526.
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^Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry. 66 (Suppl 9): 31–41.
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