Triazolam

Triazolam

File:Triazolam.svg
File:Triazolam3d.png
Clinical data
Pregnancy category	X (US)
Routes of administration	Oral
ATC code	N05CD05 (WHO)
Legal status
Legal status	Schedule IV(US)
Pharmacokinetic data
Bioavailability	44% (oral) 53% (sublingual)
Metabolism	Hepatic
Elimination half-life	1.5-5.5 hours
Excretion	Renal
Identifiers
IUPAC name 8-chloro-6-(2-chlorophenyl)-1-methyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine
CAS Number	28911-01-5
PubChem CID	5556
DrugBank	APRD00313
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C17H12Cl2N4
Molar mass	343.2

Triazolam (marketed under brand names Halcion®, Novodorm®, Songar®) is a benzodiazepine derivative drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat insomnia. Insomnia can best be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Triazolam is a short acting benzodiazepine and is sometimes used in patients who have difficulty in falling asleep. Short half life hypnotics such as triazolam are not effective in patients who suffer from frequent awakenings or early wakening due to their very short half life. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.

History

Triazolam was temporarily withdrawn from the market in several countries because of concerns about serious side effects (mostly psychological) associated with high dosages of the drug. Its use at lower doses has been deemed safe by the American Food and Drug Administration (FDA) and most other countries.

However, Triazolam has remained banned in the UK since 1991, when the Committee on the Safety of Medicines (CSM) concluded that it caused a higher frequency of psychiatric side-effects than other hypnotics.

It has been alleged to cause strange behavior and in some instances violent reactions. However, these allegations are anecdotal in nature. While triazolam as the instigator of violence has been accepted in some trials (particularly criminal offenses of defendants without violent tendencies) the anecdotal evidence has not risen to the level that the FDA has determined it statistically verifiable.

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 GABA_A receptor. The half life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.

In EEG studies triazolam significantly increases the energy of the beta frequency band and significantly increases the relative EEG power density in the delta frequency band and a decrease in the energy of the theta frequency band. Triazolam causes 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. Benzodiazepines induce a light sleep and conversely, suppress deep sleep stages, making benzodiazepines generally poor treatments for insomnia. This is especially true in elderly patients who already have naturally less deep sleep. Triazolam produces a decrease in delta activity. The effect of benzodiazepine drugs on delta however 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. Thus triazolam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality based on EEG studies.

Dependence

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 compared to baseline typically occurs after discontinuation of triazolam even after short term single nightly dose therapy.

Abrupt withdrawal after long term use from therapeutic doses of triazolam may result in a severe withdrawal syndrome. Reports in the medical literature report of psychotic states developing after abrupt withdrawal from triazolam. 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. See (benzodiazepine withdrawal syndrome).

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 - 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 - 10 days after the cessation of a more short acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.

Indications

Triazolam is usually used for short term treatment of acute insomnia including jet lag. It is an ideal benzodiazepine for this use, due to the fact that its fast onset of action and short half-life (approximately 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.

Dosage

File:Triazolam DOJ.jpg

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

Side effects

Triazolam causes transient anterograde amnesia (failure to remember new things, especially during the time the medication is in the user's system) at dosages higher than 1-3mg. 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.

Fuzzy, clouded thoughts, as well as incomprehension of the passage of time, may occur in lower doses as well as higher ones. In some cases, violent and unpredictable mood swings can occur.

Interactions

Triazolam will have interactions similar to those seen with other benzodiazepine and other categories of anxiolytic/hypnotic.

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 erythrommycin may cause serious psychotic symptoms especially in those with other physical complications.

As with most prescription medications, caution is advised when combining other drugs with Triazolam.

Contraindications

Pregnancy

Halcion belongs to the Pregnancy Category X of the FDA [1]. This means that it is known to have the potential to cause birth defects.

Overdose

Symptoms of an overdose include

• Somnolence (drowsiness)
• Impaired motor function
• Slurred speech
• Coma
• Hypoventilation (respiratory depression)

Legal status

Internationally, triazolam is a Schedule IV drug under the Convention on Psychotropic Substances.

In Hong Kong, Triazolam is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purporses. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. More information can be found: [2]

External links

• Medlineplus.org - Triazolam
• Rx-List.com - Triazolam
• Inchem.org - Triazolam
• MentalHealth.com - Triazolam
• Halcion controversy - Newsweek August 19, 1991 - Sweet Dreams or Nightmare?