Triazolam

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.^[1] 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.^[2]

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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Triazolam was temporarily withdrawn from the market in several countries because of concerns about serious side effects (mostly psychological) associated with high dosages of the drug.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.^[1]

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.^[1] 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.^[3] The half life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.^[4]

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.^[5] 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.^[6]

Dependence

Triazolam has a very high risk of dependency with chronic users often taking exceedingly high daily doses.^[7] 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.^[8]

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.^[9] See (benzodiazepine withdrawal syndrome).

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^[1] or to reduce anxiety during brief events like MRI scans.

Dosage

  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.^[10] 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.^[11]

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.^[12]

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

Contraindications

Pregnancy

Triazolam 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^[1] 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.^[13]

See also

• Benzodiazepines
• Estazolam
• Midazolam
• Brotizolam