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Triazolam
Triazolam
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Triazolam
Clinical data
Trade namesHalcion, others
AHFS/Drugs.comMonograph
MedlinePlusa684004
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability44% (oral route), 53% (sublingual)
MetabolismLiver
Onset of action15–30 minutes[3]
Elimination half-life1.5–5.5 hours
ExcretionKidney
Identifiers
  • 8-Chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.044.811 Edit this at Wikidata
Chemical and physical data
FormulaC17H12Cl2N4
Molar mass343.21 g·mol−1
3D model (JSmol)
  • Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
  • InChI=1S/C17H12Cl2N4/c1-10-21-22-16-9-20-17(12-4-2-3-5-14(12)19)13-8-11(18)6-7-15(13)23(10)16/h2-8H,9H2,1H3 checkY
  • Key:JOFWLTCLBGQGBO-UHFFFAOYSA-N checkY
  (verify)

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives.[4] It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia.[5][unreliable medical source?] In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.[6]

Triazolam was initially patented in 1970 and went on sale in the United States in 1982.[7] In 2017, it was the 289th most commonly prescribed medication in the United States, with more than one million prescriptions.[8]

Medical uses

[edit]

Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. It is an ideal benzodiazepine for this use because of its fast onset of action and short half-life. It puts a person to sleep for about 1.5 hours, allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anesthesia[5][unreliable medical source?] or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep due to its short half-life, with quazepam showing superiority.[9]

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short- to medium-duration flights. If this use is contemplated, the user avoiding the consumption of alcohol is especially important, as is trying a ground-based "rehearsal" 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).[citation needed] Triazolam causes anterograde amnesia, which is why so many dentists administer it to patients undergoing even minor dental procedures. This practice is known as sedation dentistry.[10]

Side effects

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Adverse drug reactions associated with the use of triazolam include:

Triazolam, although a short-acting benzodiazepine, may 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, psychomotor impairment, and diminished 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.[12] Confusion and amnesia have been reported.[13] Triazolam use can shift the circadian cycle.[14]

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[15]

Tolerance, dependence, and withdrawal

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Main article: Benzodiazepine withdrawal syndrome

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. Benzodiazepine hypnotics should be used at their lowest possible dose and for a short period of time. Nonpharmacological treatment options were found to yield sustained improvements in sleep quality.[16] A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.[17]

Other withdrawal symptoms can range from mild unpleasant feelings to a major withdrawal syndrome, including stomach cramps, vomiting, muscle cramps, sweating, tremor, and in rare cases, convulsions.[11]

Contraindications

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Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, in alcoholics, or in other drug-dependent individuals and individuals with comorbid psychiatric disorders.[18] Triazolam belongs to the Pregnancy Category X of the FDA.[19][1] It is known to have the potential to cause birth defects.

Elderly

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Triazolam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness. Falls and hip fractures are frequently reported, especially by elderly persons. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.[20] Daytime withdrawal effects can occur.[21]

An extensive review of the medical literature regarding the management of insomnia and the elderly found considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages and that these interventions are underused. 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. 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.[21] One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.[21]

In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[22]

Interactions

[edit]

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects.[23] 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 kidney failure.[citation needed] Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications.[24] Caffeine reduces the effectiveness of triazolam.[25] Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin.[26][27] Triazolam should not be administered to patients on efavirenz/emtricitabine/tenofovir (Atripla).[28]

Overdose

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See also: Benzodiazepine overdose

Symptoms of an overdose[5][unreliable medical source?] include:

Death can occur from triazolam overdose, but is more likely to occur in combination with other depressant drugs such as opioids, alcohol, or tricyclic antidepressants.[29]

Pharmacology

[edit]

Like other benzodiazepines, triazolam enhances the inhibitory effects of the neurotransmitter GABA by binding to the allosteric benzodiazepine receptor on GABAA receptor complexes.[30]

Triazolam is short-acting, is lipophilic, and is metabolized hepatically via oxidative pathways. Triazolam produces one short-acting active metabolite, alpha-hydroxytriazolam, which is suspected to be of minor clinical significance.[31] The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.[32] It has anticonvulsant effects on brain function.[33]

Society and culture

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Recreational use

[edit]
See also: Benzodiazepine use disorder

Triazolam, like other benzodiazepines, is susceptible to misuse and abuse. Its rapid onset of action and short half-life contribute to its abuse potential, but its relative obscurity compared to other fast-acting benzodiazepines (such as alprazolam or lorazepam) prevent its abuse from becoming particularly commonplace. Likewise, because it is not prescribed as often or as readily as alprazolam or lorazepam, there is less triazolam available to be diverted for recreational use.[34]

[edit]

Its use at low doses has been deemed acceptable by the US FDA and in several other countries.[5][unreliable medical source?]

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances[35] and the US Controlled Substances Act.[citation needed]

Brand names

[edit]

The drug is marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other names include 2'-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.[citation needed]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Triazolam

View on Grokipedia
from Grokipedia

Triazolam is a compound that acts as a short-acting agent, primarily indicated for the short-term treatment of involving difficulty in sleep onset.
Developed by the Upjohn Company and marketed as Halcion, it received approval from the U.S. in 1982, rapidly gaining prominence as a leading prescription sleep aid due to its in reducing sleep latency.
Triazolam features a rapid oral and a plasma ranging from 1.5 to 5.5 hours, which minimizes effects while enhancing sleep induction through enhancement of gamma-aminobutyric acid-mediated inhibition in the .
Despite its therapeutic utility, triazolam is associated with significant risks including potential for , abuse, , and paradoxical adverse reactions such as or hallucinations, prompting post-marketing surveillance by regulatory bodies and dosage restrictions or bans in certain countries.

History and Development

Discovery and Initial Approval


Triazolam was first synthesized in 1969 by researchers at the Upjohn Company as part of efforts to develop triazolobenzodiazepines with potent hypnotic properties, initially assigned the code name U-33,030. This synthesis occurred amid broader pharmaceutical research into benzodiazepine derivatives aimed at improving sleep induction without prolonged residual effects. Preclinical testing and subsequent clinical trials evaluated triazolam's efficacy in reducing sleep latency and nocturnal awakenings in insomniac patients, confirming its rapid . Pharmacokinetic studies during development revealed a short plasma elimination of 1.5 to 5.5 hours, supporting its suitability for short-term use in transient . The U.S. granted approval for triazolam, marketed as Halcion, on November 15, 1982, for the short-term treatment of based on controlled clinical studies demonstrating at doses of 0.125 to 0.25 mg. This positioned Halcion as a novel short-acting option compared to established longer-acting benzodiazepines like , emphasizing minimal accumulation with repeated dosing.

Early Controversies and Market Withdrawals

In 1979, Dutch psychiatrist C. van der Kroef published reports detailing a of adverse reactions to triazolam (marketed as Halcion), including , hallucinations, confusion, agitation, , and depersonalization, based on observations in approximately 20 patients; he attributed several suicides to the drug and called for its withdrawal. These claims prompted temporary suspension of triazolam in the in 1979, though a lower 0.25 mg dose was reauthorized in 1980 after review, leading to exit the market there voluntarily. In the United States, where triazolam was approved by the FDA in 1982, van der Kroef's reports spurred ; FDA data from the late documented disproportionate reports of , hallucinations, bizarre , and agitation compared to other hypnotics like , with over 100 cases of severe psychiatric reactions noted by 1990. FDA investigations in the 1980s and early 1990s, including analysis of spontaneous reports, confirmed elevated risks of and paradoxical reactions such as hallucinations at therapeutic doses (0.125–0.5 mg), leading to label updates emphasizing short-term use (7–10 days) and warnings against higher doses or prolonged therapy. Studies by Kales et al. in the early 1990s reinforced these concerns, reviewing FDA data showing triazolam's association with severe behavioral toxicity—including in up to 1 in 100 users and hallucinations—far exceeding comparator benzodiazepines, though incidence was linked to dose (e.g., 0.5 mg) and often resolved upon discontinuation. Despite defenses from citing controlled trials with low rates (e.g., <5% for in short-term use) and arguing that reports reflected misuse rather than inherent risk, regulators retained approval in the based on evidence of efficacy for acute outweighing rare severe events when prescribed appropriately. In contrast, the suspended triazolam's license in October 1991 following media reports, lawsuits alleging amnesia-linked accidents, and Committee on Safety of Medicines review of over 1,000 adverse reaction reports emphasizing psychiatric events like depression, hallucinations, and aggression; the decision cited unfavorable risk-benefit profile amid high sales (over 1 million prescriptions annually). contested the ban legally, asserting no causal link beyond and comparable safety to other benzodiazepines, but the suspension held, with subsequent European Court affirmation in 1999; studies post-withdrawal reported no significant harm from abrupt cessation but highlighted substitution challenges with increased adverse events on alternatives. This divergence reflected differing regulatory thresholds: retention prioritized empirical trial data showing rarity (<1% severe events in meta-analyses) for short-term use, while action amplified spontaneous reports amid public scrutiny.

Medical Uses

Indications and Efficacy Evidence

Triazolam is indicated for the short-term treatment (generally 7 to 10 days) of in adults, with a primary focus on difficulties initiating due to its rapid . Clinical evidence from sleep laboratory studies demonstrates that triazolam significantly reduces sleep latency, increases total duration, and decreases nocturnal awakenings compared to . A of randomized controlled trials (RCTs) on benzodiazepines, including triazolam, found modest improvements in objective measures, such as a reduction in sleep latency by approximately 4 to 10 minutes and an increase in total time by 20 to 30 minutes, though effect sizes vary by agent and patient population. The (AASM) guidelines conditionally recommend triazolam for sleep-onset based on meta-analytic data from multiple RCTs showing clinically meaningful reductions in latency, emphasizing its utility over no treatment for acute cases. Efficacy is most pronounced in transient or situational insomnia rather than chronic forms, where non-pharmacological interventions like (CBT-I) are prioritized in guidelines due to sustained benefits without dependency risks. RCTs comparing triazolam to behavioral therapies indicate immediate reductions in sleep latency with the drug, but maintenance of gains is less reliable post-treatment compared to therapy. Meta-analyses highlight that while triazolam outperforms in short-term RCTs for primary , the overall magnitude of benefit is modest, prompting calls for individualized assessment to weigh empirical gains against potential overreliance on benzodiazepines in protocols that undervalue pharmacological evidence for acute disruptions. Triazolam has also been investigated for circadian rhythm disruptions, such as , where small-scale RCTs show it facilitates adaptation to phase shifts by reducing sleep latency and improving sleep-wake homeostasis in simulated westward travel models. However, such use remains off-label, with evidence limited to specific protocols demonstrating enhanced circadian realignment over , though not endorsed as first-line in major guidelines due to insufficient large-scale trials. Long-term efficacy data are absent, aligning with consensus against extended use beyond 2-3 weeks without reevaluation.

Dosage Recommendations

The recommended dosage for adults is 0.25 mg administered orally once daily immediately before bedtime, with a maximum of 0.5 mg reserved for exceptional cases where lower doses prove insufficient; however, 0.125 mg may be adequate for many patients, particularly those with low body weight. In elderly or debilitated patients, initiate treatment at the lowest effective dose of 0.125 mg orally once daily before bedtime to reduce the risk of next-day impairment, with careful based on response and tolerability. For patients with hepatic impairment, administer a reduced dose due to prolonged elimination and increased risk of accumulation; use is not recommended in severe hepatic impairment, and caution is advised in moderate cases with individualized adjustment starting at the lowest dose. Prescribing should emphasize the lowest effective dose and shortest duration of therapy, typically not exceeding 7-10 days, to mitigate risks of tolerance and dependence as highlighted in class warnings.

Pharmacology

Mechanism of Action

Triazolam functions as a positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, binding to a specific allosteric site at the extracellular interface between the α and γ subunits, distinct from the orthosteric -binding site. This interaction potentiates the receptor's response to , the chief inhibitory neurotransmitter in the , by increasing affinity and thereby facilitating greater chloride ion conductance upon channel opening. The resulting neuronal hyperpolarization suppresses excitatory activity, primarily manifesting as and effects rather than or muscle-relaxant actions. Triazolam demonstrates particularly high potency at GABAA receptors incorporating the α1 subunit, which are abundant in brain regions associated with arousal and memory processing, such as the and . This subtype selectivity contributes to its pronounced amnestic and properties, with evidence from discriminative stimulus studies indicating α1 involvement in triazolam's subjective effects, while affinity for α5-containing receptors appears less critical. In contrast to non-selective benzodiazepines like , triazolam's enhanced efficacy at α1 receptors yields a narrower therapeutic profile focused on , minimizing broader peripheral effects mediated by α2 or α3 subtypes. Electrophysiological assays confirm triazolam's superior modulation of GABA currents in α1β2γ2 receptor configurations compared to other benzodiazepines.

Pharmacokinetics and Metabolism

Triazolam is rapidly absorbed after , with peak plasma concentrations typically reached within 1 to 2 hours. The drug demonstrates high , unaffected by short-term multiple dosing at up to four times the recommended amount. Its elimination averages 1.5 to 5.5 hours in healthy adults, contributing to minimal accumulation with once-nightly use and supporting its suitability for transient without prolonged sedative carryover. Triazolam is extensively metabolized in the liver via the 3A (CYP3A) enzyme subfamily through , yielding primary inactive metabolites α-hydroxytriazolam and 4-hydroxytriazolam. These hydroxylated products undergo glucuronide conjugation prior to . Clearance occurs predominantly renally, with about 80% of the administered dose recovered in as conjugated metabolites and only negligible unchanged parent drug. Pharmacokinetic parameters can vary with factors such as age and hepatic function; for instance, half-life prolongation has been observed in due to altered CYP3A activity. This profile underscores triazolam's design for acute hypnotic effects, with rapid offset facilitating next-day alertness in otherwise healthy individuals.

Adverse Effects

Common and Short-Term Effects

The most common short-term adverse effects of triazolam, observed in placebo-controlled clinical trials involving 1,003 patients treated for 1 to 42 days, include drowsiness at an incidence of 14%, at 9.7%, and at 7.8%. Other frequently reported effects encompass light-headedness (4.9%), coordination disorders or (4.6%), and or (4.6%), with these generally being dose-related and transient during acute use. In some trial cohorts, sedation or drowsiness rates reached up to 23.5%, reflecting central nervous system depression consistent with . Next-day impairment, including residual drowsiness and reduced psychomotor performance, occurs due to triazolam's short elimination of approximately 1.5 to 5.5 hours, which can lead to incomplete clearance by morning in certain individuals. , a class effect of benzodiazepines exacerbated by triazolam's rapid onset and brief duration, has been documented in clinical settings, with reports of memory impairment episodes in up to 83% of subjects in small controlled studies following dosing. Patients are advised to avoid activities requiring alertness, such as , until fully recovered from these effects. Rebound insomnia, characterized by worsened sleep latency and increased wake time compared to baseline, emerges upon discontinuation even after brief or intermittent administration, as evidenced by in controlled withdrawal studies. This transient exacerbation typically follows short-term use and resolves within days, but underscores the need for limited-duration therapy.

Serious Psychiatric and Behavioral Risks

Triazolam, a high-potency , has been associated with rare but severe psychiatric effects including hallucinations, depersonalization, and agitation, often emerging shortly after administration due to its rapid enhancement of GABA_A receptor activity, which can disrupt normal inhibitory signaling and lead to paradoxical or incomplete . Case reports document instances of visual and auditory hallucinations following therapeutic doses, such as 0.25 mg, particularly in dental or preoperative settings, where patients experienced delirium-like states without full loss of consciousness. These effects stem from triazolam's potent agonism at GABA_A receptors containing α1 subunits, which underlies its hypnotic action but can impair encoding and heighten vulnerability to cognitive fragmentation when dosage exceeds individual tolerance thresholds. Complex sleep-related behaviors, including sleep-driving and automatisms like preparing food or engaging in conversations without subsequent recall, have been reported in post-marketing , often linked to higher doses (e.g., 0.5 mg) or concurrent factors such as alcohol, where partial arousal combines with to enable actions without volitional awareness. FDA adverse event data indicate psychiatric reactions, including confusional states and depersonalization, occur at rates up to 56 times higher for triazolam compared to , based on spontaneous reports adjusted for exposure, highlighting its elevated risk profile among hypnotics. Early clinical trials underreported these events, with dropout rates tied to behavioral abnormalities suggesting underestimation of severity, as retrospective analyses revealed disproportionate and agitation signals not fully captured in controlled settings. These risks are not uniform across users but are causally influenced by dosage escalation, genetic variations in sensitivity, and predisposing conditions like latent psychiatric vulnerabilities, rather than being an inevitable outcome of short-term use at recommended levels (0.125-0.25 mg). Guidelines minimizing these dangers, such as those downplaying short-acting specificity, overlook comparative data favoring longer-acting alternatives with lower incidence of such disruptions, underscoring the need for individualized over generalized reassurance.

Tolerance, Dependence, and Withdrawal

Tolerance to triazolam develops rapidly, often within days of repeated dosing, primarily through neuroadaptive changes including downregulation and uncoupling of GABA_A receptors, leading to reduced . have shown tolerance to triazolam-induced EEG alterations after chronic administration spanning 5 to 21 months, with diminished effects observed. In humans, similar acute tolerance patterns occur with short-acting benzodiazepines, where initial enhancements in and reductions in latency diminish over consecutive nights, as evidenced by EEG monitoring in controlled trials. This receptor-level underscores the need for short-term use to preserve , as prolonged exposure exacerbates the loss of therapeutic benefit without proportional gains in architecture. Dependence on triazolam arises from both physical and psychological mechanisms, heightened by its short plasma of 1.5 to 5.5 hours, which fosters and incentivizes dose escalation for sustained effects. Longitudinal data on benzodiazepines indicate that 15-44% of chronic users experience moderate to severe withdrawal upon discontinuation, with risks emerging even in short-term therapeutic regimens due to the drug's potent and amnestic properties. While specific incidence for triazolam in brief use remains understudied, its pharmacokinetic profile—rapid onset and offset—amplifies dependence potential compared to longer-acting agents, as users report escalating needs to counteract interdose withdrawal. Withdrawal from triazolam manifests as rebound , heightened anxiety, , tremors, and autonomic instability, with severe cases involving or , particularly after abrupt cessation following high-dose or extended use. Symptoms typically onset within 6-12 hours due to the drug's brevity, peaking in intensity over 1-4 days and potentially persisting for weeks in protracted forms driven by persistent receptor hypersensitivity. Management prioritizes gradual tapering, often substituting longer-acting benzodiazepines like for smoother withdrawal, with protocols reducing doses by 10-25% weekly while monitoring for symptom exacerbation; case series of triazolam-dependent patients demonstrate successful detoxification via such inpatient or supervised outpatient regimens, avoiding approaches that elevate risk.

Contraindications and Special Populations

Absolute Contraindications

Triazolam is contraindicated in individuals with known to the drug, its components, or other benzodiazepines, as this can precipitate severe allergic reactions including and . The drug is also contraindicated in patients with acute narrow-angle , where benzodiazepines may elevate and worsen the condition, based on pharmacological effects observed across the class. Severe respiratory depression represents an absolute , particularly in untreated cases, due to triazolam's potential to further suppress respiratory drive, as evidenced by case reports of ventilatory failure requiring intervention even at therapeutic doses. Concurrent administration with strong CYP3A4 inhibitors (e.g., , , , ) is contraindicated, as these agents markedly inhibit triazolam's hepatic , resulting in 3- to 4-fold increases in peak plasma concentrations and area under the curve, thereby heightening risks of excessive and respiratory , per dedicated pharmacokinetic interaction studies. Use with opioids is contraindicated owing to synergistic , which elevates the risk of profound sedation, , and ; FDA analyses of adverse event databases and clinical trials document rates up to 10-fold higher in such combinations compared to monotherapy. Triazolam carries an FDA X designation and is absolutely contraindicated in , supported by animal studies showing embryofetal toxicity and skeletal malformations at doses approximating human equivalents, alongside human case reports linking first-trimester exposure to increased risks of congenital anomalies.

Use in Elderly and Vulnerable Groups

Elderly patients exhibit increased sensitivity to triazolam due to age-related reductions in drug clearance and heightened pharmacodynamic effects, resulting in higher plasma concentrations and prolonged sedation compared to younger adults. Pharmacokinetic studies demonstrate approximately 50% lower clearance in older individuals, necessitating an initial dose reduction to 0.125 mg from the standard 0.25 mg adult dose to mitigate excessive impairment. This sensitivity correlates with elevated risks of adverse outcomes, including 2-3 times higher incidence of falls and fractures, as well as cognitive disruptions such as and psychomotor deficits, based on modeling from real-world geriatric data and controlled trials showing greater at equivalent doses. Guidelines from regulatory bodies emphasize short-term use (7-10 days) with close monitoring to balance relief against these amplified hazards, as prolonged exposure exacerbates geriatric syndromes like . In patients with hepatic or renal impairment, triazolam requires cautious dosing due to its primary metabolism via in the liver, leading to delayed elimination and intensified effects; renal dysfunction has lesser direct impact but compounds overall vulnerability when combined with age-related changes. Individuals with a history of face heightened dependence risk, as evidenced by case series of high-dose triazolam escalation (up to 15 mg daily) in dependent users, underscoring the need for avoidance or stringent oversight to prevent rapid tolerance and withdrawal amplification. Empirical data from short-term trials affirm triazolam's for onset in monitored elderly cohorts at reduced doses, countering overly restrictive institutional recommendations that may undervalue benefits in cases where non-pharmacologic alternatives fail, provided risks are individualized via pharmacokinetic-pharmacodynamic assessments.

Drug Interactions

Pharmacokinetic Interactions

Triazolam is predominantly metabolized by the hepatic and intestinal 3A4 () enzyme, predisposing it to pharmacokinetic interactions with modulators that alter its clearance, plasma concentrations, area under the curve (AUC), and . Strong inhibitors substantially increase triazolam exposure by impeding its metabolism, elevating the risk of excessive and adverse effects. For instance, coadministration with , a prototypical strong inhibitor, markedly elevates triazolam AUC and prolongs its through of , as demonstrated in models and clinical extrapolations mirroring human drug-drug interactions. Such potent interactions with and other strong inhibitors like or render concomitant use contraindicated, per product labeling, due to the potential for 2- to 4-fold increases in triazolam systemic exposure. Moderate inhibitors, including , also impair triazolam , though to a lesser degree. Ingestion of with triazolam increases its AUC by up to 96% and prolongs the elimination via irreversible inhibition of intestinal , with repeated dosing exacerbating the effect through sustained enzyme suppression. Clinical guidelines advise avoidance of grapefruit products during triazolam therapy to prevent amplified effects and heightened toxicity risk. In contrast, inducers accelerate triazolam metabolism, reducing its bioavailability and therapeutic efficacy. Rifampin, a potent inducer, induces in the gut and liver, rendering triazolam ineffective for in clinical settings by hastening clearance and diminishing plasma concentrations. Coadministration with rifampin or similar inducers necessitates caution, often with dose escalation or alternative therapies, as the interaction can abolish triazolam's pharmacodynamic response without compensatory adjustments. Alcohol exhibits negligible pharmacokinetic interaction with triazolam, minimally affecting its CYP3A4-mediated clearance, though any subtle additive effects on absorption are overshadowed by predominant pharmacodynamic potentiation.

Pharmacodynamic Interactions

Triazolam, a short-acting that enhances GABA_A receptor activity, produces pharmacodynamic interactions primarily through additive (CNS) depression when coadministered with other agents that potentiate inhibitory . These interactions amplify , psychomotor impairment, and respiratory suppression without relying on alterations in triazolam's absorption, distribution, or elimination. Clinical evidence from class warnings indicates that such synergies arise from convergent effects on pathways, increasing the risk of profound drowsiness and reduced arousal even at therapeutic doses. Concomitant use with opioids exemplifies severe pharmacodynamic potentiation, where triazolam and opioids synergistically depress respiration and brainstem function, elevating the likelihood of apnea, hypoxia, , and fatal overdose. FDA analyses of post-marketing data and controlled studies on benzodiazepine-opioid combinations report heightened respiratory events, with recommendations to limit co-prescription to cases where alternatives are inadequate, employing the lowest effective doses and close monitoring for signs of over-sedation. Similarly, alcohol augments triazolam's CNS effects via shared enhancement of chloride influx at GABA receptors, resulting in greater impairment of coordination and cognition than either agent alone; pharmacokinetic studies confirm this pharmacodynamic dominance, as minimally affects triazolam's plasma levels. Interactions with other benzodiazepines or non-benzodiazepine sedatives, such as certain antipsychotics, further intensify sedation and through cumulative GABA modulation, independent of metabolic changes. Antidepressants like have demonstrated increased maximum psychomotor and effects in human trials, with peak impairments rising significantly after chronic dosing, underscoring the need for dose adjustments to mitigate excessive CNS inhibition. Guidelines emphasize gradual and vigilance in scenarios to counteract these amplified responses, prioritizing risk-benefit assessments over prohibitive bans given triazolam's established efficacy in isolated use.

Overdose

Symptoms and Management

Overdose with triazolam primarily results in , manifesting as extreme , , slurred speech, , and diminished reflexes; in severe cases, respiratory depression, , , and apnea may occur. Seizures have been reported occasionally following high doses. Management focuses on supportive care, including securing the airway, providing if ensues, and monitoring and cardiac function; gastrointestinal decontamination with activated charcoal may be considered if ingestion was recent, though its efficacy diminishes rapidly due to triazolam's short of 1.5 to 5.5 hours. is ineffective given the drug's high protein binding and . Flumazenil, a , can reverse and respiratory depression but is not routinely administered due to risks of precipitating , particularly in patients with chronic use, mixed overdoses, or underlying seizure disorders; case series indicate adverse events in up to 50% of treated patients in certain contexts. Triazolam monotherapy overdoses carry low lethality, with death uncommon without co-ingestants like opioids or alcohol, though fatalities have occurred in isolated cases involving massive ingestion. Poison control data for benzodiazepines broadly show fatalities predominantly in scenarios.

Abuse Potential

Patterns of Misuse

Triazolam misuse primarily occurs through diversion of prescription tablets, where individuals obtain the without a medical need to self-medicate , anxiety, or to enhance recreational effects from other substances. Users often exceed recommended doses of 0.125–0.25 mg, motivated by the 's rapid onset of sedation and , which can produce a brief euphoric "high" sought for its intensity despite the short duration. Non-oral routes, including intranasal of crushed tablets, have been documented among misusers to accelerate absorption and intensify , though triazolam-specific prevalence remains lower than for longer-acting congeners due to its limited availability. The short elimination of triazolam (1.5–5.5 hours) contributes to patterns of repeated dosing throughout the night or day, as users attempt to sustain effects and mitigate , often leading to dose escalation and unintentional accumulation. This pharmacokinetic profile, while advantageous for minimizing next-day impairment in therapeutic short-term use (typically 7–10 days), drives misuse cycles in non-compliant individuals, distinguishing diversionary from controlled medical applications where adherence limits such risks. National surveys indicate that compliant prescribers rarely contribute to misuse epidemics, with diversion from patient stockpiles or "" accounting for the majority of non-medical supply. Epidemiological data from U.S. (ED) surveillance reveal rising misuse since , with triazolam implicated in polydrug scenarios, particularly combinations with opioids that elevate overdose risks through synergistic respiratory depression. SAMHSA reports document over 200,000 annual ED visits involving benzodiazepines and opioids by , a trend persisting into the , where co-ingestion triples the likelihood of adverse outcomes compared to either alone; triazolam, listed among involved agents, features in such cases due to its potency despite comprising a smaller share of total prescriptions. Misuse prevalence among young adults (18–25 years) peaks, often tied to obtaining tablets via illicit networks rather than diversion.

Comparative Liability with Other Benzodiazepines

Triazolam's abuse liability, assessed through self-administration paradigms and subjective effect ratings in controlled studies, is generally lower than that of intermediate-acting barbiturates such as , with reduced reinforcing properties observed in both models and volunteers with histories of . Among benzodiazepines, quantitative indices rank triazolam's potential as moderate, with a 42% likelihood score based on self-administration (++), liking/ (++), and documented (+), placing it below longer-acting agents like (67%) and (67%) but above (25%) or (13%). This profile aligns with clinical observations identifying triazolam's abuse potential as particularly low relative to other benzodiazepines, despite its short of approximately 2-3 hours promoting rapid onset and offset. The pharmacokinetic characteristics of short-acting benzodiazepines like triazolam—rapid absorption and quick elimination—can enhance preference in acute self-administration compared to longer-acting counterparts like (half-life 20-50 hours), as the abrupt withdrawal prompts redosing to mitigate rebound effects, a pattern evidenced in pharmacokinetic models of dependence risk. Nonetheless, empirical data from therapeutic contexts indicate low progression to dependence with triazolam's recommended short-term use (7-10 days), where rates remain minimal absent predisposing factors like prior substance use disorders. In comparisons with non-benzodiazepine hypnotics such as , triazolam elicits comparable subjective effects and behavioral profiles in abusers, suggesting equivalent abuse liability under experimental conditions. Triazolam, however, is linked to greater in performance tasks relative to , potentially influencing its distinct risk indices in assessments incorporating cognitive disruption.

Scheduling and Availability

Triazolam is classified as a Schedule IV under the U.S. , indicating a low potential for abuse relative to Schedule III substances, alongside accepted medical use and limited risk of physical or when used as prescribed. This classification was established by the (DEA) upon the drug's FDA approval in December 1982, reflecting clinical data on its efficacy for short-term treatment balanced against evidence of misuse potential in higher-risk populations. As a Schedule IV , triazolam requires a valid prescription from a licensed healthcare provider, with federal regulations mandating secure storage, record-keeping for dispensers, and no refills without new authorization to mitigate diversion risks. In 2016, the FDA updated labeling for all benzodiazepines, including triazolam, with a highlighting risks of abuse, addiction, respiratory depression, and interactions leading to profound or death, particularly when combined with opioids or alcohol; this emphasizes short-term use (typically 7-10 days) and patient monitoring without imposing a formal and Mitigation Strategy (REMS) program. The scheduling rationale prioritizes evidence-based access for acute unresponsive to non-pharmacologic interventions, countering advocacy for reclassification to Schedule III or higher based on isolated abuse reports, as population-level data show triazolam's short (1.5-5.5 hours) limits cumulative dependence compared to longer-acting benzodiazepines while preserving therapeutic utility. Globally, triazolam is regulated similarly in jurisdictions adhering to UN conventions, often as a prescription-only with controls akin to U.S. Schedule IV, though enforcement varies by national drug agencies.

International Variations and Bans

Triazolam has been banned in several countries, including the since October 1991, when the Medicines Control Agency suspended its marketing authorization due to post-marketing reports indicating a higher incidence of psychiatric adverse reactions such as , hallucinations, , agitation, and bizarre behavior compared to other benzodiazepines like . Similar prohibitions were enacted in , , , and around the same period, attributed to clusters of severe behavioral side effects documented in the and early 1990s, including and psychotic-like reactions linked to its short and potent hypnotic effects. These decisions stemmed from data revealing disproportionate reporting rates—up to 56-fold higher for with triazolam versus comparators—prompting causal attributions to the drug's , though critics noted potential from higher doses or vulnerable patient populations. In contrast, triazolam remains available in the United States and much of the under strict controls, such as limited short-term prescribing (typically 7-10 days) and black-box warnings for dependency and cognitive risks, reflecting divergent regulatory interpretations of the same data where efficacy for severe onset is deemed to outweigh risks in stratified, low-dose applications. permits its use via prescription as a Schedule IV controlled substance, emphasizing short-term administration to mitigate rebound and withdrawal, aligned with broader guidelines restricting duration to avoid tolerance. In , availability has been curtailed, with Halcion tablets recalled in for quality issues and subsequently delisted from the Australian Register of Therapeutic Goods, though imports may occur under special access with rigorous short-term limits. Recent regulatory reviews in retaining jurisdictions, such as those by the in the 2010s and FDA reassessments into the 2020s, have upheld triazolam's niche role for transient unresponsive to non-pharmacologic interventions, based on meta-analyses confirming superior onset efficacy over longer-acting alternatives while advocating dose minimization to address historical psychiatric event clusters empirically tied to supratherapeutic use rather than inherent molecular flaws. This persistence highlights variations in risk-benefit calculus, where bans in select nations prioritized precautionary responses to anecdotal report surges—potentially amplified by media scrutiny—over longitudinal data emphasizing patient selection and monitoring to avert causal pathways like accumulation in the elderly or interactions.

Society and Culture

Brand Names and Marketing

Halcion, developed and originally marketed by the Company, serves as the primary brand name for triazolam in the United States and several other countries. Following Upjohn's merger with in 1995 and Pfizer's acquisition of the combined entity in 2003, continued to promote Halcion as a short-acting . The drug received U.S. approval in 1982 and was positioned for short-term use in treating , highlighting its rapid onset within 15-30 minutes and elimination half-life of about 2-5 hours to minimize next-day residual effects. Early promotional materials from in the 1980s emphasized its efficacy for initiation over longer-acting alternatives, contributing to peak U.S. prescription volumes exceeding 30 million annually by the late 1980s. Generic triazolam tablets became widely available after Halcion's protections expired, with multiple manufacturers entering the market by the mid-2000s, reducing reliance on the branded product. strategies evolved in response to post-marketing surveillance data; by 1991, Upjohn updated Halcion's labeling to include warnings about potential , hallucinations, and behavioral disturbances, amid increased scrutiny and litigation over unreported adverse events in clinical trials. These changes tempered promotional claims, shifting focus to stricter short-term prescribing guidelines (7-10 days maximum) and contraindications with certain patient populations. Internationally, triazolam is sold under varying brand names, such as Apo-Triazo in and Trilam in some markets, reflecting local regulatory approvals and distribution. Prescription trends show an initial surge post-launch, with global volumes stabilizing or declining since the due to competition from non-benzodiazepine alternatives like , whose prescriptions rose to over 27 per 1,000 population in U.S. cohorts by the , compared to triazolam's lower utilization. Market analyses indicate triazolam's share remains niche, with projected global revenue under $0.25 billion annually through 2034 and near-zero growth, underscoring a pivot away from benzodiazepines in favor of agents with reduced dependency risks.

Recreational and Non-Medical Use

Triazolam, marketed as Halcion, has seen non-medical use primarily for its rapid-onset sedative-hypnotic effects and pronounced , often sought in party or social settings to facilitate disinhibited without retention, a users describe as "blackouts." Doses exceeding therapeutic levels (typically 0.125–0.25 mg) amplify these effects, with reports indicating onset within 15–30 minutes and duration of 6–7 hours, making it appealing for short-term but contributing to erratic actions during impairment. Such recreational patterns mirror broader misuse among young adults, where 5–10% of U.S. high school seniors report lifetime non-medical use, though triazolam ranks lower in popularity compared to longer-acting agents like due to its brevity. Illicit combinations with or alcohol exploit triazolam's synergistic CNS depression to intensify or blunt comedowns, per pharmacological reviews of polydrug interactions, though this elevates overdose hazards via compounded respiratory suppression. observations note its occasional role in opioid maintenance scenes for sleep induction amid withdrawal, distinct from standalone euphoria-seeking. Public perception shifted amid 1990s media scrutiny of Halcion's amnestic risks, including high-profile cases linking it to hallucinations and behavioral aberrations, which fueled bans in countries like the and by 1991–1992 and amplified stigma through reports of dependency after brief exposure. Underground persistence endures via diversion from prescriptions or illicit markets, undeterred by these narratives, as evidenced by ongoing forum discussions of dose escalation for intensified blackouts. Standalone triazolam overdoses remain rare, with benzodiazepine-involved fatalities—totaling 12,290 in the U.S. in 2020—predominantly polysubstance, involving opioids in over 80% of cases per CDC surveillance, underscoring causal interplay over isolated agency.

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