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Etiology

Triazolam caused sedation and impairment of psychomotor performance in elderly persons

ACP J Club. 1991 Nov-Dec;115:94. doi:10.7326/ACPJC-1991-115-3-094


Source Citation

Greenblatt DJ, Harmatz JS, Shapiro L, et al. Sensitivity to triazolam in the elderly. N Engl J Med. 1991 Jun 13;324:1691-8.


Abstract

Objective

To evaluate the pharmacologic properties of triazolam and determine if the clinical response to this drug is enhanced in elderly persons.

Design

Randomized, double-blind, crossover study.

Setting

The New England Medical Center Hospital.

Participants

21 elderly persons (aged 62 to 83 y) and 26 younger persons (aged 21 to 41 y ); all were healthy and not taking any medications. Participant recruitment methods were not described.

Assessment of risk factors

Participants were given single doses of placebo and triazolam, 0.125 mg and 0.25 mg, double-blind, in random order, with ≥ 1 week between doses. The study drug was given at 0900 hours after overnight fasting and a liquid breakfast.

Main outcome measures

Plasma triazolam concentrations, percent change from baseline for degree of sedation rated by subjects and a blinded observer using a visual-analog scale, percent change from baseline on digit-symbol substitution scores, and percent change relative to scores after placebo on word-list free recall. Assessments were made before drug administration, every half hour for 3 hours, then 4, 6, 8, and 24 hours thereafter.

Main results

Peak plasma triazolam concentrations were higher (1.67 vs 1.08 ng/mL after 0.125 mg; 3.06 vs 2.02 ng/mL after 0.25 mg, P < 0.002 for both doses) and clearance was reduced (6.8 vs 11.4 mL/min per kg, P < 0.07 for 0.125 mg; 5.8 vs 10.5 mL/min per kg, P < 0.001 for 0.25 mg) in the older relative to the younger participants. Observer-rated degree of sedation for young and elderly participants paralleled plasma concentrations and was proportional to dose. Observer-rated degree of sedation was greater in the older than in the younger group at corresponding times with both triazolam doses; the interaction between age and study medication approached significance (P < 0.07). Although younger participants reported that the degree of sedation increased in proportion to dose, the older participants did not. Impairment on the digit-symbol substitution test was proportional to the dose for both groups, with an interaction between age and dose (P< 0.05). The subjects' ability to recall words presented 1.5 hours after drug administration 24 hours later was impaired by both doses; the percent decrease was similar in young and old participants.

Conclusions

Peak triazolam plasma concentrations were higher, and clearance was reduced in elderly compared with younger persons. Percent changes in the degree of sedation and psychomotor impairment were correspondingly greater.

Source of funding: Department of Health and Human Services.

Address for article reprint: Dr. D.J.Greenblatt, Division of Clinical Pharmacology, Box 1007, Tufts-New England Medical Center, 171 Harrison Avenue, Boston, MA 02111, USA.


Commentary

The use of long half-life benzodiazepine hypnotics (e.g., flurazepam) has been associated with an increased risk for adverse effects in elderly patients, ranging from excessive daytime somnolence to falls and hip fractures (1, 2). This has led to recommendations for the use of shorter half-life agents. The short half-life benzodiazepine, triazolam, is currently the most widely prescribed hypnotic agent in the United States. This study showed that the use of triazolam in both the 0.125-mg and 0.25-mg doses produced greater degrees of sedation and psychomotor performance impairment in healthy elderly persons. These effects were caused by age-related pharmacokinetic differences rather than by an increased intrinsic sensitivity to the drug. Despite the pharmacokinetic differences, acquisition and recall of information was impaired to a similar degree in the young and elderly groups.

These data suggest that the dose of triazolam should be reduced when it is prescribed for elderly patients. However, the elderly participants in this study were all healthy and were not taking any other medication. The effects of triazolam in terms of sedation and impairment of psychomotor performance may be more extreme in elderly patients who are taking other medications with psychoactive effects and in those with dementia. In considering whether to prescribe a benzodiazepine hypnotic to a patient complaining of sleeping difficulties, the first question to ask is not which drug to use or which dose but rather, is a drug needed at all. Nonpharmacologic approaches to the management of sleeping problems should always be emphasized.

Jerry H. Gurzwitz, MD
Harvard Medical SchoolBoston, Massachusetts, USA.


References

1. Greenblatt DJ, Allen MD, Shader RI. Toxicity of high-dose flurazepam in the elderly. Clin Pharmacol Ther. 1977;21:355-61.

2. Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA. 1989;262:3303-7.