Triazolam

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.

History
The pharmaceutical company Upjohn received FDA approval for Triazolam in 1982.

Triazolam was withdrawn from the market in several countries because of concerns about serious side-effects (mostly psychological) associated with the drug. Its use at low doses has been deemed acceptable by the American Food and Drug Administration (FDA) and several other countries. In Canada, manufacturers of triazolam have voluntarily made the medication only available in seven-day "blister packs", attached to patient information sheets. It is believed that blister packing reduces the probability of inadvertently taking extra doses when the drug's amnesiac properties take effect.

Studies have found a much higher incidence of psychiatric disturbances (sometimes severe) with triazolam, even when using the lower doses of 0.125 mg. Clinical trials which Upjohn had withheld from publishing showed a very unfavourable risk benefit ratio with 9.9% of patients dropping out of one triazolam study versus 1.9% of trial subjects taking a comparison benzodiazepine, flurazepam. Another study not published by Upjohn found 12.2% of triazolam patients dropped out, again due to psychiatric adverse effects compared against 4.1% for flurazepam. A further study found that after only 3 weeks use of triazolam patients typically became markedly anxious. As a result of these studies, both published and unpublished, coming to light showing frequent severe psychiatric disturbances the United Kingdom and Brazil decided to ban triazolam.

The medical literature has shown that triazolam is much more likely than other benzodiazepines to cause strange behavior and in some instances psychotic or violent reactions. The increased incidence of side-effects with triazolam is due to the pharmacological characteristics of triazolam, including its ultra-short elimination half-life, high affinity receptor-binding (high potency). The short half-life and very high potency of triazolam are the reasons why daytime rebound anxiety, amnesia, confusion, and psychiatric symptoms are much more common and severe than with other benzodiazepines. 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 poor that he questioned if triazolam should remain on the market in the USA.

Indications
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 (approximately 2 – 4 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).

Dosage
Dosages for triazolam are significantly lower than other benzodiazepines, and should be individualized depending on the needs of the patient. For insomnia, 0.125 mg to 0.25 mg are given at bedtime. Up to 0.5 mg or higher may be needed for resistant individuals.

Side-effects
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.

Severe side-effects both while using triazolam and after its discontinuation are more common with triazolam than with other hypnotic drugs. Triazolam causes a rapid development of tolerance and withdrawal symptoms including rebound insomnia and rebound anxiety. Other adverse effects include amnesia, confusion, and disinhibition, and occur much more commonly with triazolam than with other benzodiazepines such as quazepam. 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 phenomena of day time withdrawal anxiety from nightly hypnotic use does not seem to be exclusive to triazolam but occurs with other hypnotic drug although reactions are not as severe as those seen with triazolam.

Abrupt withdrawal after long-term use from therapeutic doses of triazolam may result in a severe benzodiazepine withdrawal syndrome. A psychotic state was reported in a patient, developing after abrupt withdrawal from triazolam and nitrazepam. The withdrawal symptoms included auditory hallucinations and visual cognitive disorder. Gradual and careful reduction of the dosage was recommended to prevent severe withdrawal syndromes from developing.

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.

Elderly
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.

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. 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.

Pharmacology
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. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality in rats, based on EEG studies in rats.

Interactions
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.

Overdose
Symptoms of an overdose include Death can occur from triazolam overdose but is more likely to occur in combination with other depressant drugs such as opiates, alcohol, or tricyclic antidepressants.
 * Somnolence (drowsiness)
 * Impaired motor function
 * Slurred speech
 * Coma
 * Hypoventilation (respiratory depression)
 * Seizures has been reported.
 * Anterograde amnesia in overdoses higher than 1–3 mg.

Drug misuse
Triazolam is a drug with the potential for misuse: recreational, wherein the drug is taken to achieve a high "euphoria", 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. Serial killer Jeffrey Dahmer used triazolam (Halcion) to sedate his victims, and in his biography Mötley Crüe member Nikki Sixx referenced using Halcion in combination with cocaine and heroin.

Legal status
Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances.

Chemistry
Triazolam is synthesized according to a method that contains a key stage of benzodiazepine synthesis—the reaction of o-aminobenzophenones with α-amino acid derivatives. In the given example, 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.
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