Triazolam

Triazolam
Names
Trade namesHalcion, others
IUPAC name
  • 8-Chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Clinical data
Drug classBenzodiazepine (BZD)[1]
Main usesTrouble sleeping[1]
Side effectsInsufficient breathing, suicide, anaphylaxis, addiction, agitation, inability to form new memories[1]
InteractionsOpiates[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: C[2]
  • US: X (Contraindicated)[2]
    Routes of
    use    		By mouth
    Onset of action30 min[3]
    Duration of actionUp to 4 hrs[3]
    Typical dose0.25 mg[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa684004
    Legal
    License data
    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)
    Pharmacokinetics
    Bioavailability44% (oral route), 53% (sublingual), 98% (intranasal) [[4]]
    MetabolismLiver
    Elimination half-life1.5–5.5 hours
    ExcretionKidney
    Chemical and physical data
    FormulaC17H12Cl2N4
    Molar mass343.21 g·mol−1
    3D model (JSmol)
    SMILES
    • ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=CC=C(Cl)C=C42
    InChI
    • 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

    Triazolam, sold under the brand name Halcion among others, is a benzodiazepine (BZD) used short term to treat trouble sleeping.[1] Use is not recommended beyond 10 days.[1] It is taken by mouth.[1] Effects begin in about 30 minutes and last for up to 4 hours.[3]

    Common side effects include sleepiness, poor coordination, and nausea.[1] Serious side effect may include insufficient breathing, suicide, anaphylaxis, addiction, agitation, and inability to form new memories.[1] Use during pregnancy may harm the baby.[1] It appears to work by enhancing the effects of the GABA neurotransmitter.[1]

    Triazolam was initially patented in 1970 and approved for medical use in the Netherlands in 1977 but was withdrawn from the market there in 1980.[5][6] It went on sale in the United States in 1982.[6] In 2017, it was the 280th most commonly prescribed medication in the United States, with more than one million prescriptions.[7][8] In the United States it costs about 1 USD per dose.[9] Its sale has been banned in the United Kingdom since 1993.[10]

    Medical uses

    Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. 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[11] 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.[12]

    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.[13]

    Dosage

    The typical dose is 0.25 mg; though doses of 0.125 to 0.5 mg may be used.[1]

    Side effects

    Associated side effects may 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.[15] Confusion and amnesia have been reported.[16]

    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.[17]

    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.[18] A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.[19]

    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.[14]

    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.[20] Triazolam belongs to the Pregnancy Category X of the FDA.[21][2] 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.[22] Daytime withdrawal effects can occur.[23]

    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.[23] One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.[23]

    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.[24]

    Interactions

    Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects.[25] 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.[26] Caffeine reduces the effectiveness of triazolam.[27] Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin.[28][29] Triazolam should not be administered to patients on Atripla.

    Overdose

    See also: Benzodiazepine overdose

    Symptoms of an overdose include:[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.[30]

    Pharmacology

    The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites.[11] 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.[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]

    In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced, as well.[34]

    History

    Its use at low doses has been deemed acceptable by the U.S. Food and Drug Administration (FDA) and several other countries.[11]

    Society and culture

    Cost

    This medication has a cost in the U.S. of $12 (USD) for 2 tablets (0.25 mg)[35]

    • Triazolam costs (US)
      Triazolam costs (US)
    • Triazolam prescriptions (US)
      Triazolam prescriptions (US)

    Recreational use

    See also: Benzodiazepine drug misuse

    Triazolam issued nonmedically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.[36]

    Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances[37] 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 (designer) names include 2'-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Triazolam Monograph for Professionals". Drugs.com. Archived from the original on 30 September 2020. Retrieved 17 September 2021.
    2. 1 2 3 "Triazolam (Halcion) Use During Pregnancy". Drugs.com. 18 September 2020. Archived from the original on 26 October 2020. Retrieved 24 October 2020.
    3. 1 2 3 Newman, Michael G.; Takei, Henry; Klokkevold, Perry R.; Carranza, Fermin A. (29 May 2018). Newman and Carranza's Clinical Periodontology E-Book. Elsevier Health Sciences. p. 871. ISBN 978-0-323-53323-2. Archived from the original on 23 September 2021. Retrieved 19 September 2021.
    4. ↑ Lui, CY; Amidon, GL; Goldberg, A (1991). "Intranasal absorption of flurazepam, midazolam, and triazolam in dogs". J Pharm Sci. 80 (12): 1125–9. doi:10.1002/jps.2600801207. PMID 1815070.
    5. ↑ Halcion : an independent assessment of safety and efficacy data. Washington, D.C.: National Academy Press. 1997. p. Chp 3. ISBN 9780309059763. Archived from the original on 22 September 2020. Retrieved 19 September 2021.
    6. 1 2 Shorter, Edward (2005). "B". A Historical Dictionary of Psychiatry. Oxford University Press. ISBN 9780190292010. Archived from the original on 2021-08-28. Retrieved 2020-09-20.
    7. ↑ "The Top 300 of 2020". ClinCalc. Archived from the original on 18 March 2020. Retrieved 11 April 2020.
    8. ↑ "Triazolam - Drug Usage Statistics". ClinCalc. Archived from the original on 12 April 2020. Retrieved 11 April 2020.
    9. ↑ "Triazolam Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 9 November 2016. Retrieved 19 September 2021.
    10. ↑ Dyer, C (13 February 1999). "Edinburgh university fined forlack of safety checks". BMJ (Clinical research ed.). 318 (7181): 418B. doi:10.1136/bmj.318.7181.418b. PMID 9974447.
    11. 1 2 3 4 Wishart, David (2006). "Triazolam". DrugBank. Archived from the original on 2019-12-30. Retrieved 2006-03-23.
    12. ↑ Mauri MC, Gianetti S, Pugnetti L, Altamura AC (1993). "Quazepam versus triazolam in patients with sleep disorders: a double-blind study". Int J Clin Pharmacol Res. 13 (3): 173–7. PMID 7901174.
    13. ↑ "Comparison of Triazolam and Zaleplon for Sedation of Dental Patients | Dentistry Today". Archived from the original on 2019-01-01. Retrieved 2019-01-06.
    14. 1 2 3 "Halcion- triazolam tablet". DailyMed. 10 December 2019. Archived from the original on 26 October 2020. Retrieved 23 October 2020.
    15. ↑ 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.
    16. ↑ Lieberherr, S; Scollo-Lavizzari, G; Battegay, R (1991). "Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)". Schweizerische Rundschau für Medizin Praxis. 80 (24): 673–5. PMID 2068441.
    17. ↑ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Archived from the original on 24 September 2020. Retrieved 23 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    18. ↑ Kirkwood CK (1999). "Management of insomnia". J Am Pharm Assoc (Wash). 39 (5): 688–96, quiz 713–4. doi:10.1016/S1086-5802(15)30354-5. PMID 10533351.
    19. ↑ Kales A; Scharf MB; Kales JD; Soldatos CR. (1979-04-20). "Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines". JAMA: The Journal of the American Medical Association. 241 (16): 1692–5. doi:10.1001/jama.241.16.1692. PMID 430730.
    20. ↑ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (Nov 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
    21. ↑
    22. ↑ Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (Feb 2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Med Rev. 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127.
    23. 1 2 3 Bayer, A.J.; Bayer EM; Pathy MSJ; Stoker MJ. (1986). "A Double-Blind Controlled Study of Chlormethiazole and Triazolam in the Elderly". Acta Psychiatrica Scandinavica. 329 (suppl 329): 104–111. doi:10.1111/j.1600-0447.1986.tb10544.x. PMID 3529832. S2CID 24226217.
    24. ↑ Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother. 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
    25. ↑ Varhe A, Olkkola KT, Neuvonen PJ (December 1994). "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole". Clin. Pharmacol. Ther. 56 (6 Pt 1): 601–7. doi:10.1038/clpt.1994.184. PMID 7995001. S2CID 39127216.
    26. ↑ 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): 337–9. doi:10.1111/j.1440-1819.1996.tb00577.x. PMID 9014234. S2CID 22742117.
    27. ↑ 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): 286–9. doi:10.1111/j.1600-0773.1992.tb00473.x. ISSN 0901-9928. PMID 1351673.
    28. ↑ Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacol Bull. 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946. S2CID 1543185. Archived from the original (PDF) on 2007-07-09.
    29. ↑ Arayne, MS.; Sultana, N.; Bibi, Z. (Oct 2005). "Grape fruit juice-drug interactions". Pak J Pharm Sci. 18 (4): 45–57. PMID 16380358.
    30. ↑ 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 Sci. Int. 86 (1–2): 35–41. doi:10.1016/S0379-0738(97)02110-5. PMID 9153780.
    31. ↑ Oelschläger H. (1989-07-04). "Chemical and pharmacologic aspects of benzodiazepines". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451.
    32. ↑ Professor heather Ashton (April 2007). "Benzodiazepine equivalency table". Archived from the original on September 28, 2007. Retrieved September 23, 2007.
    33. ↑ Chweh AY; Swinyard EA; Wolf HH; Kupferberg HJ (February 25, 1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sci. 36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID 2983169.
    34. ↑ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. Archived from the original on 2019-12-11. Retrieved 2020-10-24.
    35. ↑ "Triazolam Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 23 August 2020. Retrieved 9 April 2021.
    36. ↑ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
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