|Systematic (IUPAC) name|
|Pregnancy cat.||X (US)|
|Legal status||Schedule IV(US)|
|Bioavailability||44% (oral), 53% (sublingual)|
|Mol. mass||343.2 g/mol|
|(what is this?)|
|This article relies on references to primary sources. (February 2013)|
Triazolam (marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam) is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties triazolam possesses, amnesic, anxiolytic, sedative, anticonvulsant and muscle relaxant properties are also present. Due to its short half-life, triazolam is not effective for patients that suffer from frequent awakenings or early wakening.
According to one psychiatrist in the USA who has published numerous papers on hypnotic medications, the risk/benefit ratio of triazolam, even at low dosage, is so high that he questioned if triazolam should be the market in the USA.
Triazolam is usually used for short-term treatment of acute insomnia including jet lag. It is an ideal benzodiazepine for this use, because its fast onset of action and short half-life, it puts one asleep for not more then 1.5 hours (approximately 1 – 2 hours) allows its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anesthesia or to reduce anxiety during brief events like MRI scans. Triazolam is ineffective in maintaining sleep however, due to its short half-life with quazepam showing superiority.
Triazolam is frequently prescribed as a sleep aid for passengers travelling on short to medium duration flights. If this use is contemplated, it is especially important to avoid the consumption of alcoholic beverages, and to do a ground based 'trial' of the medication to ensure that the side effects and potency of this medication are understood by the user prior to using it in a relatively more public environment (as disinhibition can be a common side effect, with potentially severe consequences).
Adverse drug reactions associated with the use of triazolam include:
- Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems.
- Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
- Rare (<0.5% of patients): constipation, taste alteration, diarrhea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, parasthesia, tinnitus, dysesthesia, weakness, congestion.
Triazolam, although a short-acting benzodiazepine, may still cause residual impairment into the next day, especially the next morning. A meta-analysis demonstrated that residual 'hangover' effects after nighttime administration of triazolam such as sleepiness, impaired psychomotor, and cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures. Confusion and amnesia has been reported.
Tolerance, dependence and withdrawal
A review of the literature found that long term use of benzodiazepines including triazolam is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. It recommended that benzodiazepine hypnotics are used at their lowest possible dose and for a short period of time. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. The risk of withdrawal reactions and drug dependence is much higher with triazolam than with other benzodiazepines. Triazolam has a very high risk of dependency with chronic users often taking exceedingly high daily doses. Regular use of triazolam may cause a hypnotic drug dependence. Withdrawal symptoms typically appear when triazolam dosage is reduced or stopped altogether. Withdrawal symptoms including a worsening of insomnia (rebound insomnia) compared to baseline typically occurs after discontinuation of triazolam even after short term single nightly dose therapy.
Daytime withdrawal symptoms are commonly associated with triazolam. This is due to its very short half-life. After only 10 nights of triazolam use, patients report anxiety, become distressed, display weight loss, experience panics, and experience depression, feel unreal, and develop paranoia. These reactions occurred more commonly with triazolam than lormetazepam, which has an intermediate half-life. Thus the more short-acting a benzodiazepine hypnotic the more severe the daytime withdrawal symptoms. This phenomenon of day time withdrawal anxiety from nightly hypnotic use does not seem to be exclusive to triazolam but occurs with other hypnotic drugs although reactions are not as severe as those seen with triazolam.
Contraindications and special cautions
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. Triazolam belongs to the Pregnancy Category X of the FDA. This means that it is known to have the potential to cause birth defects.
Triazolam, similar to other benzodiazepines and nonbenzodiazepines causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. There can be daytime withdrawal effects.
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including triazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls.  One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.
In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
The pharmacological effects of triazolam are similar to those of most other benzodiazepines. Triazolam does not generate active metabolites. Triazolam is a short acting benzodiazepine, is lipophilic, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter GABA at the GABAA receptor. The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug. Triazolam has anticonvulsant effects on brain function.
In EEG studies in rats triazolam significantly increased the energy of the beta frequency band and significantly increased the relative EEG power density in the delta frequency band and decreased the energy of the theta frequency band. Triazolam caused EEG changes characterised by high-voltage slow waves and desynchronization of hippocampal theta waves and an increase in the energy of the delta frequency band on the spectral analysis of the electroencephalogram in rats. Benzodiazepines induce a light sleep, and, as a result, suppress deep-sleep stages, making benzodiazepines, in general, poor treatments for insomnia. This is especially true in elderly patients that already have naturally less deep sleep. Triazolam produced a decrease in delta activity in rats. The effect of benzodiazepine drugs on delta activity may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep. Delta activity is thought to reflect sleep quality with lower levels of delta sleep reflecting poorer quality of sleep.
Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects. Anxiety, tremor and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia and renal failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications. Caffeine reduces the effectiveness of triazolam. Other important interactions include cimetidine, diltiazem, erythromycin, fluconazole, grapefruit juice, isoniazid, itraconazole, ketoconazole, nefazodone, rifampicin, ritonavir, troleandomycin.
Symptoms of an overdose include
- Anterograde amnesia in overdoses higher than 1–3 mg.
- Cardiac arrest
- Hypoventilation (respiratory depression)
- Somnolence (drowsiness)
- Slurred speech
- Seizures have been reported.
Triazolam is a drug with high potential for misuse: recreational use wherein the drug is taken to achieve or continued long-term dosing against medical advice. A study in baboons showed that triazolam was the most preferred benzodiazepine in drug liking self injection tests.
In the Media
In 1992, television host Larry King told President George H.W. Bush that he had used Halcion for an extended period following diagnosis of a heart condition, and Bush replied that he didn't know if the drug was "so bad" and felt it had "gotten a bad rap"; the exchange was broadcast live to satellite dish owners tracking and recording backhaul channels.
Manufacturing triazolam involves the reaction of o-aminobenzophenones with α-amino acid derivatives. The reaction of 2-amino-2′,5-dichlorobenzophenone with glycine ethyl ester gives 7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-H-1,4-benzodiazepin-2-one. By interacting this with phosphorus pentasulfide, the carbonyl group is transformed into a thiocarbonyl group, giving 7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-H-1,4-benzodiazepin-2-thione. The resulting cyclic thioamide on interaction with acetylhydrazine, gives the corresponding acetylhydrazone, which upon heating cyclizes into triazolam.
- Long term effects of benzodiazepines
- Benzodiazepine withdrawal syndrome
- Benzodiazepine dependence
- Rebound insomnia
- Halcyon, a term that originates from the Greek myth of Alcyone, is used most often to mean golden or marked by peace and prosperity.
- Halcyon (Orbital song), a famous techno song by the British duo Orbital, was dedicated to their mother, who was addicted to Triazolam under its Halcion brand name.
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