Triazolam

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{{Unreliable medical source|date=March 2024}} 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.{{cite journal | vauthors = Mauri MC, Gianetti S, Pugnetti L, Altamura AC | title = Quazepam versus triazolam in patients with sleep disorders: a double-blind study | journal = International Journal of Clinical Pharmacology Research | volume = 13 | issue = 3 | pages = 173–177 | year = 1993 | pmid = 7901174 }}

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|date=October 2014}} 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.{{cite web | url=http://www.dentistrytoday.com/ce-articles/286-comparison-of-triazolam-and-zaleplon-for-sedation-of-dental-patients | title=Comparison of Triazolam and Zaleplon for Sedation of Dental Patient | website=Dentistry Today | date=September 2005 | access-date=6 January 2019 | archive-date=1 January 2019 | archive-url=https://web.archive.org/web/20190101105716/http://www.dentistrytoday.com/ce-articles/286-comparison-of-triazolam-and-zaleplon-for-sedation-of-dental-patients | url-status=dead }}

Adverse drug reactions associated with the use of triazolam include:

• Relatively common (>1% of patients): somnolence, dizziness, lightheadedness, coordination problems
• Less common (0.9% to 0.5% of patients): euphoria, tachycardia, fatigue, delirium, memory impairment, cramps/pain, depression, visual disturbances
• Rare (<0.5% of patients): constipation, taste alteration, diarrhea, dry mouth, dermatitis/allergy, abnormal dreams or nightmares, insomnia (paradoxical), paresthesia, tinnitus, dysesthesia, weakness, nasal/sinus congestion{{cite web | title=Halcion- triazolam tablet | website=DailyMed | date=10 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0da0dba-a56d-486b-a45b-e8a7cdfbeac6 | access-date=23 October 2020}}

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.{{cite journal | vauthors = Vermeeren A | title = Residual effects of hypnotics: epidemiology and clinical implications | journal = CNS Drugs | volume = 18 | issue = 5 | pages = 297–328 | year = 2004 | pmid = 15089115 | doi = 10.2165/00023210-200418050-00003 | s2cid = 25592318 }} Confusion and amnesia have been reported.{{cite journal | vauthors = Lieberherr S, Scollo-Lavizzari G, Battegay R | title = [Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)] | journal = Schweizerische Rundschau für Medizin Praxis | volume = 80 | issue = 24 | pages = 673–675 | date = June 1991 | pmid = 2068441 }} Triazolam use can shift the circadian cycle.{{Cite book |title=Williams Textbook of Endocrinology |publisher=Elsevier |year=2024 |isbn=9780323933476 |edition=15th |pages=108}}

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.{{cite web | title=FDA expands Boxed Warning to improve safe use of benzodiazepine drug | website=U.S. Food and Drug Administration (FDA) | date=23 September 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | archive-url=https://web.archive.org/web/20200924002523/https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | url-status=dead | archive-date=24 September 2020 | access-date=23 September 2020}} {{PD-notice}}

{{Main|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.{{cite journal | vauthors = Kirkwood CK | title = Management of insomnia | journal = Journal of the American Pharmaceutical Association | volume = 39 | issue = 5 | pages = 688–96; quiz 713–4 | year = 1999 | pmid = 10533351 | doi = 10.1016/S1086-5802(15)30354-5 }} A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.{{cite journal | vauthors = Kales A, Scharf MB, Kales JD, Soldatos CR | title = Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines | journal = JAMA | volume = 241 | issue = 16 | pages = 1692–1695 | date = April 1979 | pmid = 430730 | doi = 10.1001/jama.241.16.1692 }}

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.

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.{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–413 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001 }} Triazolam belongs to the Pregnancy Category X of the FDA.{{cite web |url=http://www.fda.gov/Medwatch/SAFETY/2003/03Jun_PI/Halcion_PI.pdf |title= Halcion triazolam tablets |website=www.fda.gov |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20031106143612/http://www.fda.gov/Medwatch/SAFETY/2003/03Jun_PI/Halcion_PI.pdf |archive-date=6 November 2003 |url-status=dead}} It is known to have the potential to cause birth defects.

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.{{cite journal | vauthors = Mets MA, Volkerts ER, Olivier B, Verster JC | title = Effect of hypnotic drugs on body balance and standing steadiness | journal = Sleep Medicine Reviews | volume = 14 | issue = 4 | pages = 259–267 | date = August 2010 | pmid = 20171127 | doi = 10.1016/j.smrv.2009.10.008 }} Daytime withdrawal effects can occur.{{cite journal | vauthors = Bayer AJ, Bayer EM, Pathy MS, Stoker MJ | title = A double-blind controlled study of chlormethiazole and triazolam as hypnotics in the elderly | journal = Acta Psychiatrica Scandinavica. Supplementum | volume = 329 | issue = suppl 329 | pages = 104–111 | year = 1986 | pmid = 3529832 | doi = 10.1111/j.1600-0447.1986.tb10544.x | s2cid = 24226217 }}

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

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.{{cite journal | vauthors = Bain KT | title = Management of chronic insomnia in elderly persons | journal = The American Journal of Geriatric Pharmacotherapy | volume = 4 | issue = 2 | pages = 168–192 | date = June 2006 | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006 }}

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects.{{cite journal | vauthors = Varhe A, Olkkola KT, Neuvonen PJ | title = Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole | journal = Clinical Pharmacology and Therapeutics | volume = 56 | issue = 6 Pt 1 | pages = 601–607 | date = December 1994 | pmid = 7995001 | doi = 10.1038/clpt.1994.184 | s2cid = 39127216 }} Anxiety, tremor, and depression have been documented in a case report following administration of nitrazepam and triazolam. {{cn span|Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia, and kidney failure.|date=April 2023}} Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications.{{cite journal | vauthors = Tokinaga N, Kondo T, Kaneko S, Otani K, Mihara K, Morita S | title = Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin | journal = Psychiatry and Clinical Neurosciences | volume = 50 | issue = 6 | pages = 337–339 | date = December 1996 | pmid = 9014234 | doi = 10.1111/j.1440-1819.1996.tb00577.x | s2cid = 22742117 }} Caffeine reduces the effectiveness of triazolam.{{cite journal | vauthors = Mattila ME, Mattila MJ, Nuotto E | title = Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects | journal = Pharmacology & Toxicology | volume = 70 | issue = 4 | pages = 286–289 | date = April 1992 | pmid = 1351673 | doi = 10.1111/j.1600-0773.1992.tb00473.x }} Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin.{{cite journal | vauthors = Wang JS, DeVane CL | title = Pharmacokinetics and drug interactions of the sedative hypnotics | journal = Psychopharmacology Bulletin | volume = 37 | issue = 1 | pages = 10–29 | year = 2003 | pmid = 14561946 | doi = 10.1007/BF01990373 | url = http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf | url-status = dead | s2cid = 1543185 | archive-url = https://web.archive.org/web/20070709230745/http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf | archive-date = 9 July 2007 }}{{cite journal | vauthors = Arayne MS, Sultana N, Bibi Z | title = Grape fruit juice-drug interactions | journal = Pakistan Journal of Pharmaceutical Sciences | volume = 18 | issue = 4 | pages = 45–57 | date = October 2005 | pmid = 16380358 }} Triazolam should not be administered to patients on efavirenz/emtricitabine/tenofovir (Atripla).{{cite web | title=Medicines You Should Not Take with Atripla | url=http://www.atripla.com/Content.aspx?bmscontentpg=hiv-medications | publisher=Bristol-Myers Squibb & Gilead Sciences, LLC | year=2008 | access-date=3 January 2010 | archive-url=https://web.archive.org/web/20100425050127/http://www.atripla.com/Content.aspx?bmscontentpg=hiv-medications | archive-date=25 April 2010 | url-status=dead }}

{{See also|Benzodiazepine overdose}}

Symptoms of an overdose{{Unreliable medical source|date=March 2024}} include:

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

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.{{cite journal | vauthors = Kudo K, Imamura T, Jitsufuchi N, Zhang XX, Tokunaga H, Nagata T | title = Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs | journal = Forensic Science International | volume = 86 | issue = 1–2 | pages = 35–41 | date = April 1997 | pmid = 9153780 | doi = 10.1016/S0379-0738(97)02110-5 }}

Like other benzodiazepines, triazolam enhances the inhibitory effects of the neurotransmitter GABA by binding to the allosteric benzodiazepine receptor on GABA_A receptor complexes.{{cite journal |vauthors=Oelschläger H |date=July 1989 |title=[Chemical and pharmacologic aspects of benzodiazepines] |journal=Schweizerische Rundschau für Medizin Praxis |volume=78 |issue=27–28 |pages=766–772 |pmid=2570451}}

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.{{cite journal | vauthors = Pakes GE, Brogden RN, Heel RC, Speight TM, Avery GS | title = Triazolam: a review of its pharmacological properties and therapeutic efficacy in patients with insomnia | journal = Drugs | volume = 22 | issue = 2 | pages = 81–110 | date = August 1981 | pmid = 6114852 | doi = 10.2165/00003495-198122020-00001 }} The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.{{cite web | url = http://www.bcnc.org.uk/equivalence.html | title = Benzodiazepine equivalency table | access-date = 23 September 2007 | author = Professor heather Ashton | date = April 2007 | archive-date = 28 September 2007 | archive-url = https://web.archive.org/web/20070928121055/http://www.bcnc.org.uk/equivalence.html | url-status = dead }} It has anticonvulsant effects on brain function.{{cite journal | vauthors = Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ | title = Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines | journal = Life Sciences | volume = 36 | issue = 8 | pages = 737–744 | date = February 1985 | pmid = 2983169 | doi = 10.1016/0024-3205(85)90193-6 }}

{{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.{{cite journal | vauthors = Griffiths RR, Johnson MW | title = Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 9 | pages = 31–41 | year = 2005 | pmid = 16336040 }}

Its use at low doses has been deemed acceptable by the US FDA and in several other countries.{{Unreliable medical source|date=March 2024}}

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances{{cite web

| url= http://www.incb.org/pdf/e/list/green.pdf

| title= List of psychotropic substances under international control

| work= Green list

| publisher= International Narcotics Control Board

| access-date= 23 March 2006

| archive-date= 31 August 2012

| archive-url= https://web.archive.org/web/20120831222336/http://www.incb.org/pdf/e/list/green.pdf

| url-status= dead

}} and the US Controlled Substances Act.{{cn|date=March 2024}}

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.{{cn|date=April 2023}}

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