Triazolam drug administration

Wysowski DK, Barash D. Adverse behavioral reactions attributed to triazolam in the Food and Drug Administration s Spontaneous Reporting System. Arch Intern Med 1991 151 2003-2008. 

Roache, J.D. and Griffiths, R.R., Diazepam and triazolam self-administration in sedative abusers concordance of subject ratings, performance and drug self-administration, Psychopharmacology, 99, 309, 1989. 

Finally, in November 1991, the FDA approved new labeling for Halcion (Food and Drug Administration, 1992). The new label emphasizes that triazolam is indicated for short-term use and specifies 7-10 days. Treatment lasting longer than 2-3 weeks requires a complete reevaluation of the patient. In addition, the label emphasizes the use of the lowest possible dose. 

Division of Epidemiology and Surveillance, Office of Epidemiology and Biostatistics. (1990, March 20). Memorandum Increased frequency report Triazolam deaths, interaction with alcohol, and CNS depression. Rockville, MD Center for Drug Evaluation and Research, Food and Drug Administration. 

Even after relatively short periods of administration, discontinuation of short and intermediate half-life BZDs, such as triazolam and temazepam, may result in marked worsening of sleep, even worse than baseline levels (i.e., rebound insomnia), although this does not seem to occur with zolpidem (95, 102, 103, 109, 110, 113, 285, 297, 316, 325, 326, 327, 328, 329, 330, 331,332, 333, 334, 335, 336 and 337). Gradual dose reduction may attenuate the incidence of rebound, and with flurazepam and quazepam, little sleep disturbance occurs, even after abrupt drug withdrawal ( 99, 100, 101, 102, 103,104, 105 and 106, 280, 338, 339, 340 and 341). 

Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse effects of many 3A4-dependent drugs. For example, triazolam levels are increased by concurrent administration of nefazodone such that a reduction in triazolam dosage by 75% is recommended. Likewise, administration of nefazodone with simvastatin has been associated with 20-fold increase in plasma levels of simvastatin. 

Consistent with their depressant and sedative effects, benzodiazepines administered acutely typically decrease CFF threshold.119 120 Specifically, significant decreases have been reported for 1 mg alprazolam, 10 mg diazepam, and 15 mg quazepam 121 4 to 11 mg midazolam 122 7.5 to 50 mg oxazepam 123 1 and 2 mg lorazepam 124 and 0.5 mg triazolam and 1 mg flunitrazepam.120 As is evident, this effect on CFF threshold was observed at therapeutic doses of each drug, and when multiple doses were tested, the effect was dose-related. However, there are reports of acute, therapeutic doses of diazepam (5 mg)125 and lorazepam (1 and 2 mg)125,126 having no effect on CFF threshold. One study investigating numerous benzodiazepines120 reported next-day impairment after acute doses of triazolam (0.5 mg) and lormetazepam (1 to 2 mg). No studies were found that examined the effect of chronic benzodiazepine administration on CFF threshold. 

Compared with focused attention, fewer studies have examined the effects of benzodiazepines on selective attention. Two studies have shown that performance on the Stroop test was impaired by lorazepam.119 131 Acute administration of triazolam and lorazepam produced dose-dependent decrements in response rate and accuracy in a simultaneous matching-to-sample task, which required subjects to determine which of two comparison visual stimuli was identical to the sample stimulus.148 161 The drug effects differed as a function of task difficulty, such that the benzodiazepine-induced impairment was reduced when discriminability of the non-matching stimulus was increased. 

S toops, W.W. and Rush, C.R., Differential effects in humans after repeated administrations of zolpidem and triazolam, Am. J. Drug Alcohol Abuse, 29, 281, 2003. 

Soldatos et al. (1986) reported on serious adverse drug reactions in all five psychiatric inpatients during a clinical trial of 0.5 mg triazolam and placebo. The patients and nurses were blind in the study, but not the physician with medical responsibility for the patients. The study consisted of 1 week of placebo baseline, 2 weeks of triazolam administration, and 1 week of withdrawal on placebo. All five patients developed severe reactions to triazolam. Case 1 developed anxiety and hallucinations on the last two days of triazolam administration and the first withdrawal day. Case 2 had a sudden increase in anxiety and became irritable, uncooperative, and depressed. She became withdrawn and cried, and showed considerable impairment of memory and orientation. On withdrawal of triazolam, she became more incoherent, expressing paranoid ideas of persecution that persisted about a week. She required Haldol to control her delusions. Case 3 developed severe insomnia during withdrawal and reported considerable anxiety and irritability along with an uncontrollable fear of death, which persisted to the next day when she additionally manifested a marked degree of memory impairment. Case 4, by... 

Kales et al. (1991), in a placebo-controlled sleep lab study, showed that even under brief, intermittent administration and withdrawal of triazolam (and, to a lesser extent, temazepam), patients experienced rebound insomnia, thereby predisposing to drug-taking behavior and increasing the potential for drug dependence. ... 

Midazolam, Triazolam, and Flurazepam The feasibility of intranasal administration of midazolam, flurazepam, and triazolam has been studied and compared with oral absorption in dogs. There was a 3.4-fold increase in the Cmax after nasal administration, from 5.5-8.7ng/mL to 17.4-30.0 ng/mL. The mean tm showed comparable values for both routes. The Tnmx obtained after nasal administration of midazolam was found to be 15 min, as compared with the 15-45 min observed for oral dosing, while the Cmax after nasal administration was 6.5-20.3 ng/mL, as compared with 3.0-8.6ng/mL observed for the oral route. Like midazolam and triazolam, flurazepam also showed a shorter half-life, 15 min, as compared with 15 15 min with oral administration. The Cmax for oral administration was 0.14-0.59 ng/mL after nasal administration it was in the range of 2.6-11.1 ng/mL, a 16.4-fold increase. Since the gastrointestinal tract at bedtime is likely to be in the fed state, causing a twofold decrease in the absorption of midazolam and triazolam, the nasal route may be a better option for the treatment of amnesia, since these drugs cross the nasal mucosa effectively without the use of an absorption enhancer, as shown in these studies [108],... 

Nefazodone is a weak inhibitor of CYP2D6, but a potent inhibitor of CYP3A4, and increases plasma concentrations of drugs that are substrates of CYP3A4, such as triazolam, alprazolam, ciclosporin, astemizole, cisapride, terfenadine, and carbamazepine (26). Co-administration with terfenadine, astemizole, or cisapride should be avoided, because of the risk of cardiac dysrhythmias (SEDA-20, 9). 

Following GI absorption or IV administration, benzodk azepines are rapidly distributed to the CNS. Subsequently, benzodiazepines are more slowly redistributed from the CNS to more poorly perfused tissue, such as adipose tissue and muscle. The rate of this redistribution is an important determinant of the duration of action of benzodiazepines and, like that for GI absorption, is largely determined by drug lipophihcity, with the more lipophilic drugs, such as midazolam and triazolam, having the shortest duration of action. Additional factors that influence the duration of benzodiazepine action are hepatic metaboHsm and acute tolerance, resulting in decreased response to benzodiazepines with continued drug exposure. 

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