Triazolam

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.[3] It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia.[4] In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.[5]

Triazolam
Clinical data
Trade namesHalcion
AHFS/Drugs.comMonograph
MedlinePlusa684004
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: Schedule IV
  • DE: Prescription only (Anlage III for higher doses)
  • UK: Class C
  • US: Schedule IV
  • UN: N IV
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability44% (oral route), 53% (sublingual), 98% (intranasal) [[2]]
MetabolismLiver
Elimination half-life1.5–5.5 hours
ExcretionKidney
Identifiers
IUPAC name
  • 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
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 Y
  • Key:JOFWLTCLBGQGBO-UHFFFAOYSA-N Y
  (verify)

Triazolam was initially patented in 1970 and went on sale in the United States in 1982.[6] In 2017, it was the 288th most commonly prescribed medication in the United States, with more than one million prescriptions.[7][8]

Medical uses

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[4] or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep, however, 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 alcoholic beverages 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). 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

Adverse drug reactions associated with the use of triazolam include:

  • Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems
  • Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances
  • Rare (<0.5% of patients): constipation, taste alteration, diarrhea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, parasthesia, tinnitus, dysesthesia, weakness, congestion[11]

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]

In September 2020, the U.S. 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.[14]

Tolerance, dependence, and withdrawal
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.[15] A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.[16]

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

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.[17] Triazolam belongs to the Pregnancy Category X of the FDA.[18][1] 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.[19] Daytime withdrawal effects can occur.[20]

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.[20] One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.[20]

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.[21]

Interactions

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects.[22] 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. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications.[23] Caffeine reduces the effectiveness of triazolam.[24] Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin.[25][26] Triazolam should not be administered to patients on Atripla.

Overdose

Symptoms of an overdose[4] include:

  • Coma
  • Hypoventilation (respiratory depression)
  • Somnolence (drowsiness)
  • Slurred speech
  • Seizures[11]

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.[27]

Pharmacology

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites.[4] 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.[28] The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.[29] It has anticonvulsant effects on brain function.[30]

History

Its use at low doses has been deemed acceptable by the U.S. Food and Drug Administration (FDA) and several other countries.[4]

Society and culture

Recreational use

Triazolam issued nonmedically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.[31]

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances[32] and the U.S. Controlled Substances Act.

Brandnames

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.

References
  1. "Triazolam (Halcion) Use During Pregnancy". Drugs.com. 18 September 2020. Retrieved 24 October 2020.
  2. Lui CY, Amidon GL, Goldberg A (December 1991). "Intranasal absorption of flurazepam, midazolam, and triazolam in dogs". Journal of Pharmaceutical Sciences. 80 (12): 1125–1129. doi:10.1002/jps.2600801207. PMID 1815070.
  3. "Benzodiazepine Names". non-benzodiazepines. Archived from the original on 2008-12-08. Retrieved 2008-12-29.
  4. Wishart, David (2006). "Triazolam". DrugBank. Retrieved 2006-03-23.
  5. Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. PMID 18855614.
  6. Shorter E (2005). "B". A Historical Dictionary of Psychiatry. Oxford University Press. ISBN 9780190292010.
  7. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
  8. "Triazolam - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
  9. Mauri MC, Gianetti S, Pugnetti L, Altamura AC (1993). "Quazepam versus triazolam in patients with sleep disorders: a double-blind study". International Journal of Clinical Pharmacology Research. 13 (3): 173–177. PMID 7901174.
  10. "Comparison of Triazolam and Zaleplon for Sedation of Dental Patient". Dentistry Today. September 2005.
  11. "Halcion- triazolam tablet". DailyMed. 10 December 2019. Retrieved 23 October 2020.
  12. Vermeeren A (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115. S2CID 25592318.
  13. Lieberherr S, Scollo-Lavizzari G, Battegay R (June 1991). "[Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)]". Schweizerische Rundschau für Medizin Praxis. 80 (24): 673–675. PMID 2068441.
  14. "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Retrieved 23 September 2020. This article incorporates text from this source, which is in the public domain.
  15. Kirkwood CK (1999). "Management of insomnia". Journal of the American Pharmaceutical Association. 39 (5): 688–96, quiz 713–4. doi:10.1016/S1086-5802(15)30354-5. PMID 10533351.
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  20. Bayer AJ, Bayer EM, Pathy MS, Stoker MJ (1986). "A double-blind controlled study of chlormethiazole and triazolam as hypnotics in the elderly". Acta Psychiatrica Scandinavica. Supplementum. 329 (suppl 329): 104–111. doi:10.1111/j.1600-0447.1986.tb10544.x. PMID 3529832. S2CID 24226217.
  21. Bain KT (June 2006). "Management of chronic insomnia in elderly persons". The American Journal of Geriatric Pharmacotherapy. 4 (2): 168–192. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
  22. Varhe A, Olkkola KT, Neuvonen PJ (December 1994). "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole". Clinical Pharmacology and Therapeutics. 56 (6 Pt 1): 601–607. doi:10.1038/clpt.1994.184. PMID 7995001. S2CID 39127216.
  23. Tokinaga N, Kondo T, Kaneko S, Otani K, Mihara K, Morita S (December 1996). "Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin". Psychiatry and Clinical Neurosciences. 50 (6): 337–339. doi:10.1111/j.1440-1819.1996.tb00577.x. PMID 9014234. S2CID 22742117.
  24. Mattila ME, Mattila MJ, Nuotto E (April 1992). "Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects". Pharmacology & Toxicology. 70 (4): 286–289. doi:10.1111/j.1600-0773.1992.tb00473.x. PMID 1351673.
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  26. Arayne MS, Sultana N, Bibi Z (October 2005). "Grape fruit juice-drug interactions". Pakistan Journal of Pharmaceutical Sciences. 18 (4): 45–57. PMID 16380358.
  27. Kudo K, Imamura T, Jitsufuchi N, Zhang XX, Tokunaga H, Nagata T (April 1997). "Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs". Forensic Science International. 86 (1–2): 35–41. doi:10.1016/S0379-0738(97)02110-5. PMID 9153780.
  28. Oelschläger H (July 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweizerische Rundschau für Medizin Praxis. 78 (27–28): 766–772. PMID 2570451.
  29. Professor heather Ashton (April 2007). "Benzodiazepine equivalency table". Retrieved September 23, 2007.
  30. Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ (February 1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sciences. 36 (8): 737–744. doi:10.1016/0024-3205(85)90193-6. PMID 2983169.
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  • "Triazolam". Drug Information Portal. U.S. National Library of Medicine.
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