Triazolam

Triazolam (marketed in English speaking countries under the following brand names Apo-Triazo, Halcion, Hypam and Trilam) 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Triazolam was withdrawn from the market in several countries because of concerns about serious side effects (mostly psychological) associated with the drug.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 safe by the American Food and Drug Administration (FDA) and many 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. Triazolam was also stripped of its product license in Norway.

The medical literature has shown that triazolam is much more likely than other benzodiazepines to cause strange behavior and in some instances violent reactions. The reasons for increased incidence of side effects with triazolam are 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 day time rebound anxiety, amnesia, confusion and psychiatric symptoms are much more common and severe than with other benzodiazepines. The risk/benefit ratio of triazolam even at low dosage is so poor in the words of one psychiatrist in the USA who has published numerous papers on hypnotic medications that he questioned if triazolam should remain on the market in the USA. While triazolam as the instigator of violence has been accepted in some trials (particularly criminal offenses of defendants without violent tendencies).

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 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 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. 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 in rats, based on EEG studies in rats.

Dependence and withdrawal
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.

Day time 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, weight loss, panics and depression, felt 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 day time 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.

Singer Marc Almond was dependent on Halcion between 1985 and 1994.

Elderly
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.

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.

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
Severe side effects both while using triazolam and after its discontinuation is 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 are common. Other adverse effects include amnesia, confusion, and disinhibition 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.

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 erythrommycin may cause serious psychotic symptoms especially in those with other physical complications. Triazolam also interacts with caffeine. Other important interactions include cimetidine, diltiazem,erythromycin, fluconazole, grapefruit juice, isoniazid, itraconazole, ketoconazole, nefazodone,  rifampicin, ritonavir, troleandomycin.

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

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

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)
 * Anterograde amnesia in overdoses higher than 1-3mg.

Drug misuse
Triazolam is a drug with the potential for misuse. Two types of drug misuse can occur either recreational misuse is where the drug is taken to achieve a high or when the drug is continued long term against medical advice. A study in baboons showed that triazolam was the most preferred benzodiazepine in drug liking self injection tests.

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