Triazolam
Encyclopedia
Triazolam 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.
(FDA) and several other countries.
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 As a result of these studies, both published and unpublished, coming to light showing frequent severe psychiatric disturbances the United Kingdom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.
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.
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).
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.
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 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.
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.
, 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.
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
.
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.
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.
.
cyclizes into triazolam.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
to treat severe insomnia. In addition to the hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
properties triazolam possesses, amnesic, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
and muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
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
Its use at low doses has been deemed acceptable by the American Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) and several other countries.
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
Flurazepam
Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It produces a metabolite with a very long half-life , which may stay in the bloodstream for up to four days...
. 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
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
and Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
decided to ban triazolam.
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 insomniaInsomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
including jet lag
Jet lag
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...
. 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
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
in medical procedures requiring anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
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
Quazepam
Quazepam is a benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance...
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
Disinhibition
Disinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
can be a common side effect, with potentially severe consequences).
Side-effects
Adverse drug reactions associated with the use of triazolam include:- Relatively common (>1% of patients): somnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, feeling of lightness, coordination problems. - Less common (0.9% to 0.5% of patients): euphoriaEuphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
, tachycardiaTachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, tiredness, confusional states/memory impairment, cramps/pain, depressionDepression (mood)Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, visual disturbances. - Rare (<0.5% of patients): constipation, taste alteration, diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, dry mouth, dermatitisDermatitis-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...
/allergy, dreams/nightmares, insomnia, parasthesia, tinnitusTinnitusTinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
, dysesthesiaDysesthesiaDysesthesia comes from the Greek word "dys", meaning "not-normal" and "aesthesis", which means "sensation" . It is defined as an unpleasant, abnormal sense of touch, and it may be, or not be, considered as a kind of pain...
, weakness, congestion.
Severe side-effects both while using triazolam and after its discontinuation are more common with triazolam than with other hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
drugs. Triazolam causes a rapid development of tolerance and withdrawal symptoms including rebound insomnia and rebound anxiety. Other adverse effects include amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, and disinhibition
Disinhibition
Disinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
, and occur much more commonly with triazolam than with other benzodiazepines such as quazepam
Quazepam
Quazepam is a benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance...
. Triazolam, although a short-acting benzodiazepine, may still cause residual impairment into the next day, especially the next morning. A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
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
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
and amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause 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
Lormetazepam
Lormetazepam Lormetazepam Lormetazepam (INN, or methyl-lorazepam, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative. It possesses hypnotic, anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties....
, 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 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
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. 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
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
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
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
), 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 lipophilicLipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
at the GABAA receptor. The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug. Triazolam has anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
effects on brain function.
In EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
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
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
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
Cyproheptadine
Cyproheptadine , sold under the brand name Periactin, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.- Indications :...
may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality in rats, based on EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
studies in rats.
Interactions
KetoconazoleKetoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
and itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
have a profound effect on the pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
of triazolam, leading to greatly enhanced effects. Anxiety, tremor and depression have been documented in a case report following administration of nitrazepam
Nitrazepam
Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
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
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
reduces the effectiveness of triazolam. Other important interactions include cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
, diltiazem
Diltiazem
Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
, erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
, grapefruit juice
Grapefruit juice
Grapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
, isoniazid
Isoniazid
Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
, itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
, troleandomycin
Troleandomycin
Troleandomycin is a macrolide antibiotic. It is currently sold in Italy and Turkey.Side effects: It is a CYP3A4 inhibitor....
.
Overdose
Symptoms of an overdose include- SomnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(drowsiness) - Impaired motor function
- Slurred speech
- Coma
- HypoventilationHypoventilationIn medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...
(respiratory depression) - Seizures has been reported.
- Anterograde amnesiaAnterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
in overdoses higher than 1–3 mg.
Death can occur from triazolam overdose but is more likely to occur in combination with other depressant drugs such as opiates, alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, or tricyclic antidepressants.
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 killerSerial killer
A serial killer, as typically defined, is an individual who has murdered three or more people over a period of more than a month, with down time between the murders, and whose motivation for killing is usually based on psychological gratification...
Jeffrey Dahmer
Jeffrey Dahmer
Jeffrey Lionel Dahmer was an American serial killer and sex offender. Dahmer murdered 17 men and boys between 1978 and 1991, with the majority of the murders occurring between 1987 and 1991. His murders involved rape, dismemberment, necrophilia and cannibalism...
used triazolam (Halcion) to sedate his victims, and in his biography Mötley Crüe
Mötley Crüe
Mötley Crüe is an American heavy metal band formed in Los Angeles, California in 1981. The group was founded by bass guitarist Nikki Sixx and drummer Tommy Lee, who were later joined by lead guitarist Mick Mars and lead singer Vince Neil...
member Nikki Sixx
Nikki Sixx
Nikki Sixx is an American musician, songwriter, author, fashion designer, radio host, and photographer, best known as the co-founder and bassist of the band Mötley Crüe. Prior to forming Mötley Crüe, Sixx was a member of Sister before going on to form London with his Sister band mate Lizzie Grey...
referenced using Halcion in combination with cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and heroin.
Legal status
Triazolam is a Schedule IV drug under the Convention on Psychotropic SubstancesConvention on Psychotropic Substances
The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamines, barbiturates, benzodiazepines, and psychedelics signed at Vienna on February 21, 1971...
.
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 heatingcyclizes into triazolam.
- J.B. Hester, Jr., Ger. Pat. 2.012.190 (1970).
- J.B. Hester, Jr., U.S. Pat. 3.701.782 (1972).
- J.B. Hester, Jr., U.S. Pat. 3.987.052 (1976).
- G.A. Archer, L.H. Sternbach, U.S. Pat. 3.422.091 (1969).
- G.A. Archer, L.H. Sternbach, J. Org. Chem., 29, 231 (1964).
- J.B. Hester, A.D. Rudzik, B.V. Kamdar, J. Med. Chem., 14, 1078 (1971).
See also
- Long term effects of benzodiazepinesLong term effects of benzodiazepinesThe long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical health, and mental health. There are significant risks associated with the long-term use of benzodiazepines. However, not all people experience problems...
- Benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
- Benzodiazepine dependenceBenzodiazepine dependenceBenzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
- BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s - BrotizolamBrotizolamBrotizolam is a sedative-hypnotic thienodiazepine drug which is a benzodiazepine analog. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to short-acting benzodiazepines such as triazolam...
- AlprazolamAlprazolamAlprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
- EstazolamEstazolamEstazolam is a benzodiazepine derivative drug developed by Upjohn in the 1970s. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties...
- MidazolamMidazolamMidazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
- QuazepamQuazepamQuazepam is a benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance...
- 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.
External links
- PubPK - Triazolam Pharmacokinetics
- Medlineplus.org - Triazolam
- Rx-List.com - Triazolam
- Inchem.org - Triazolam
- MentalHealth.com - Triazolam
- Halcion controversy - Newsweek August 19, 1991 - Sweet Dreams or Nightmare?
- http://www.sussex.ac.uk/sociology/documents/ssm02.pdf