Sensitivity to triazolam in the elderly
Open accessAbstract
BACKGROUND: Elderly persons frequently appear to be sensitive to the effects of many drugs that depress the central nervous system. We studied the effect of age on the pharmacokinetics and pharmacodynamics of the benzodiazepine hypnotic agent triazolam, now the most frequently prescribed hypnotic drug in the United States. METHODS: Twenty-six healthy young subjects (mean age, 30 years) and 21 healthy elderly subjects (mean age, 69 years) participated in a four-way crossover study. After a single-blind adaptation trial with placebo, each subject received, in random order and in double-blind fashion, single doses of placebo, 0.125 mg of triazolam, and 0.25 mg of triazolam. For 24 hours after the administration of each of the three study medications, plasma triazolam levels were determined and psychomotor performance, memory, and degree of sedation were assessed. RESULTS: Plasma triazolam concentrations increased in proportion to the dose, but the elderly subjects had higher plasma concentrations due to reduced clearance of the drug. The degree of sedation as rated by an observer and the reduction in the subjects' performance on the digit-symbol substitution test were both greater in the elderly than in the young subjects after they were given the same doses. The relation of the plasma triazolam concentration to the degree of impairment was similar for the two groups. As part of the study, information was presented 1 1/2 hours after the administration of the drugs; the subjects' ability to recall the information 24 hours later was impaired by both doses of triazolam, and the percent decrease was similar in the young and elderly groups. CONCLUSIONS: Triazolam caused a greater degree of sedation and greater impairment of psychomotor performance in healthy elderly persons than in young persons who received the same dose. These effects resulted from reduced clearance and higher plasma concentrations of triazolam rather than from an increased intrinsic sensitivity to the drug. On the basis of these results, the dosage of triazolam for elderly persons should be reduced on average by 50 percent.
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Cites
(2017) · Arzneimittelforschung · doi:10.1055/s-00000175 · Cited by 1,134 · see citing works
Psychotropic Drug Use and the Risk of Hip Fracture
Ray, W. A., Griffin, M. R., Schaffner, W., Baugh, D. K., & Melton, L. J. (1987) · New England Journal of Medicine · doi:10.1056/nejm198702123160702 · Cited by 1,006 · see citing works
Current Status of Benzodiazepines
Koch‐Weser, J., Greenblatt, D. J., Shader, R. I., & Abernethy, D. R. (1983) · New England Journal of Medicine · doi:10.1056/nejm198308183090705 · Cited by 451 · see citing works
Self-citationThe amnesic action of benzodiazepines in man
Lister, R. G. (1985) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(85)90034-x · Cited by 448 · see citing works
Clearance approaches in pharmacology.
Wilkinson, G. R. (1987) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06653-0 · Cited by 356 · see citing works
Increased sensitivity to nitrazepam in old age
Castleden, C. M., George, C. F., Marcer, D., & Hallett, C. (1977) · BMJ · doi:10.1136/bmj.1.6052.10 · Cited by 320 · see citing works
Desforges, J. F., Prinz, P. N., Vitiello, M. V., Raskind, M. A., & Thorpy, M. J. (1990) · New England Journal of Medicine · doi:10.1056/nejm199008233230805 · Cited by 318 · see citing works
Benzodiazepines and Human Memory: A Review
Ghoneim, M. M., & Mewaldt, S. P. (1990) · Anesthesiology · doi:10.1097/00000542-199005000-00024 · Cited by 305 · see citing works
Current Status of Benzodiazepines
Koch‐Weser, J., Greenblatt, D. J., Shader, R. I., & Abernethy, D. R. (1983) · New England Journal of Medicine · doi:10.1056/nejm198308113090607 · Cited by 248 · see citing works
Self-citationToxicity of high‐dose flurazepam in the elderly
Greenblatt, D. J., ALLEN, M. D., & Shader, R. I. (1977) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt1977213355 · Cited by 244 · see citing works
Self-citationRelationship between diazepam dose, plasma level, age, and central nervous system depression
Reidenberg, M. M., Levy, M., Warner, H., Coutinho, C. B., Schwartz, M. A., Yü, G., & Cheripko, J. A. (1978) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt1978234371 · Cited by 208 · see citing works
Rebound Insomnia and Rebound Anxiety: A Review
Kales, A., Soldatos, C. R., Bixler, E. O., & Kales, J. D. (2008) · Pharmacology · doi:10.1159/000137794 · Cited by 198 · see citing works
Relationship between Diazepam Dose, Plasma Level, Age, and Central Nervous System Depression
Reidenberg, M. M., LEVY, M., Warner, H. F., COUTINHO, C. N., Schwartz, M. A., Yu, G., & Cheripko, J. A. (1979) · Survey of Anesthesiology · doi:10.1097/00132586-197904000-00012 · Cited by 170 · see citing works
Sleeping Pills, Insomnia and Medical Practice
Solomon, F., White, C. C., Parron, D. L., & Mendelson, W. B. (1979) · New England Journal of Medicine · doi:10.1056/nejm197904053001423 · Cited by 165 · see citing works
Pakes, G. E., Brogden, R. N., Heel, R. C., Speight, T. M., & Avery, G. S. (1981) · Drugs · doi:10.2165/00003495-198122020-00001 · Cited by 153 · see citing works
Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs
Greenblatt, D. J., Divoll, M., Harmatz, J. S., MacLaughlin, D. S., & Shader, R. I. (1981) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1981.191 · Cited by 150 · see citing works
Self-citationAnxiety caused by a short-life hypnotic.
Morgan, K., & Oswald, I. (1982) · BMJ · doi:10.1136/bmj.284.6320.942 · Cited by 137 · see citing works
Daytime Carryover of Triazolam and Flurazepam in Elderly Insomniacs
Carskadon, M. A., Seidel, W. F., Greenblatt, D. J., & Dement, W. C. (1982) · SLEEP · doi:10.1093/sleep/5.4.361 · Cited by 128 · see citing works
Self-citationAdjusting for differential base rates: Lord's Paradox again.
Wainer, H. (1991) · Psychological Bulletin · doi:10.1037/0033-2909.109.1.147 · Cited by 127 · see citing works
Concentration-independent plasma protein binding of benzodiazepines
Moschitto, L. J., & Greenblatt, D. J. (1983) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1983.tb04302.x · Cited by 114 · see citing works
Self-citationTraveler's amnesia. Transient global amnesia secondary to triazolam
Morris, H. H. (1987) · JAMA · doi:10.1001/jama.258.7.945 · Cited by 104 · see citing works
Implications of Altered Drug Disposition in the Elderly: Studies of Benzodiazepines
Greenblatt, D. J., Shader, R. I., & Harmatz, J. S. (1989) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1989.tb03246.x · Cited by 102 · see citing works
Self-citationRebound Insomnia: A Critical Review
GILLIN, J. C., SPINWEBER, C. L., & JOHNSON, L. C. (1989) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-198906000-00002 · Cited by 99 · see citing works
Greenblatt, D. J., Divoll, M., Moschitto, L. J., & Shader, R. I. (1981) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)80261-3 · Cited by 98 · see citing works
Self-citationEffect of Gradual Withdrawal on the Rebound Sleep Disorder after Discontinuation of Triazolam
Greenblatt, D. J., Harmatz, J. S., Zinny, M. A., & Shader, R. I. (1987) · New England Journal of Medicine · doi:10.1056/nejm198709173171202 · Cited by 96 · see citing works
Self-citationReduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.
Greenblatt, D. J., Divoll, M., Abernethy, D., Moschitto, L. J., Smith, R. B., & Shader, R. I. (1983) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1983.tb01503.x · Cited by 92 · see citing works
Self-citationIncreased sensitivity of the elderly to the central depressant effects of diazepam.
Pomara, N., Stanley, B., Block, R. I., Berchou, R. C., Stanley, M., Greenblatt, D. J., Newton, R. E., & Gershon, S. (1985) · PubMed · Cited by 87 · see citing works
Self-citationPharmacokinetic Determinants of Dynamic Differences Among Three Benzodiazepine Hypnotics
Greenblatt, D. J. (1989) · Archives of General Psychiatry · doi:10.1001/archpsyc.1989.01810040032006 · Cited by 79 · see citing works
Self-citationBenzodiazepines of long and short elimination half-life and the risk of hip fracture
Ray, W. A. (1989) · JAMA · doi:10.1001/jama.262.23.3303 · Cited by 78 · see citing works
Can a Rapidly-eliminated Hypnotic Cause Daytime Anxiety?
Adam, K., & Oswald, I. P. (1989) · Pharmacopsychiatry · doi:10.1055/s-2007-1014592 · Cited by 77 · see citing works
Adverse Reactions to Benzodiazepine Hypnotics: Spontaneous Reporting System
Bixler, E. O., Kales, A., Brubaker, B. H., et al. (2008) · Pharmacology · doi:10.1159/000138322 · Cited by 75 · see citing works
Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo
Greenblatt, D. J., Harmatz, J. S., Dorsey, C. M., & Shader, R. I. (1988) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1988.158 · Cited by 74 · see citing works
Self-citationEffect of Subject Age and Gender on the Pharmacokinetics of Oral Triazolam and Temazepam
Smith, R. B., Divoll, M., Gillespie, W. R., & Greenblatt, D. J. (1983) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-198306000-00005 · Cited by 71 · see citing works
Self-citationMorgan, K. (1990) · Drugs · doi:10.2165/00003495-199040050-00004 · Cited by 70 · see citing works
Relative abuse liability of triazolam: Experimental assessment in animals and humans
Griffiths, R. R., Lamb, R. J., Ator, N. A., Roache, J. D., & Brady, J. V. (1985) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(85)90039-9 · Cited by 70 · see citing works
Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam
Abernethy, D. R., Greenblatt, D. J., Divoll, D., et al. (1983) · Psychopharmacology · doi:10.1007/bf00436169 · Cited by 68 · see citing works
Self-citationComparison of short and long half-life benzodiazepine hypnotics: Triazolam and quazepam
Kales, A., Bixler, E. O., Vela-Bueno, A., Soldatos, C. R., Nikiaus, D. E., & Manfredi, R. L. (1986) · Clinical Pharmacology and Therapeutics · doi:10.1038/clpt.1986.194 · Cited by 66 · see citing works
Swift, C. G., Ewen, J., Clarke, P. B. S., & Stevenson, I. (1985) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1985.tb05040.x · Cited by 64 · see citing works
Influence of age and previous use of diazepam dosage required for endoscopy.
Giles, H. G., MacLeod, S. M., Wright, J. R., & Sellers, E. M. (1978) · PubMed Central · Cited by 63 · see citing works
Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty
Nikaido, A. M., Ellinwood, E. H., Heatherly, D. G., & Gupta, S. K. (1990) · Psychopharmacology · doi:10.1007/bf02245796 · Cited by 61 · see citing works
Sleep Laboratory Studies of Hypnotic Drugs: Efficacy and Withdrawal Effects
KALES, A., & KALES, J. D. (1983) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-198304000-00038 · Cited by 61 · see citing works
Shorr, R. I., Bauwens, S. F., & Landefeld, C. S. (1990) · The American Journal of Medicine · doi:10.1016/0002-9343(90)90213-w · Cited by 59 · see citing works
Kinetic and dynamic components of increased benzodiazepine sensitivity in aging animals.
BARNHILL, J. G., Greenblatt, D. J., Miller, L. G., Gaver, A., Harmatz, J. S., & Shader, R. I. (1990) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)13216-3 · Cited by 54 · see citing works
Self-citationSedative effects and impaired learning and recall after single oral doses of lorazepam
Shader, R. I., Dreyfuss, D. A., Gerrein, J. R., Harmatz, J. S., Allison, S. J., & Greenblatt, D. J. (1986) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1986.90 · Cited by 51 · see citing works
Self-citationResidual effects of hypnotics: Triazolam, flurazepam, and nitrazepam
Ogura, C., Nakazawa, K., Majima, K., Nakamura, K., Ueda, H., Umezawa, Y., & Wardell, W. M. (1980) · Psychopharmacology · doi:10.1007/bf00426651 · Cited by 50 · see citing works
Efficacy of a reduced triazolam dose in elderly insomniacs
Roehrs, T., Zorick, F. J., Wittig, R. M., et al. (1985) · Neurobiology of Aging · doi:10.1016/0197-4580(85)90006-5 · Cited by 50 · see citing works
Bliwise, D. L., Seidel, W. F., Ismet, K., Mitler, M. M., Roth, T. G., Zorick, F. J., & Dement, W. C. (1983) · SLEEP · doi:10.1093/sleep/6.2.156 · Cited by 50 · see citing works
Pharmacology and Hypnotic Efficacy of Triazolam
Roth, T. G., Roehrs, T., & Zorick, F. J. (1983) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/j.1875-9114.1983.tb03237.x · Cited by 48 · see citing works
Effects of diazepam on recall memory: relationship to aging, dose, and duration of treatment.
Pomara, N., Deptula, D., Medel, M., Block, R. I., & Greenblatt, D. J. (1989) · PubMed · Cited by 47 · see citing works
Self-citationEnhanced Bioavailability of Triazolam Following Sublingual Versus Oral Administration
Scavone, J. M., Greenblatt, D. J., Friedman, H. L., & Shader, R. I. (1986) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1986.tb02935.x · Cited by 46 · see citing works
Self-citationMiller, L. G., Greenblatt, D. J., BARNHILL, J. G., Deutsch, S. I., Shader, R. I., & Paul, S. M. (1987) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1987.tb01032.x · Cited by 37 · see citing works
Self-citationTriazolam Syndrome in the Elderly
Patterson, J. F. (1987) · Southern Medical Journal · doi:10.1097/00007611-198711000-00020 · Cited by 34 · see citing works
The Neuropsychiatric Effects of Aspartame in Normal Volunteers
Lapierre, K. A., Greenblatt, D. J., Goddard, J. E., Harmatz, J. S., & Shader, R. I. (1990) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1990.tb03485.x · Cited by 34 · see citing works
Self-citationEffect of age, body composition, and lipid solubility on benzodiazepine tissue distribution in rats.
Scavone, J. M., Friedman, H. L., Greenblatt, D. J., et al. (1987) · PubMed · Cited by 33 · see citing works
Self-citationDiazepam, behavior, and aging: increased sensitivity or lower baseline performance?
Hinrichs, J. V., & Ghoneim, M. M. (1987) · Psychopharmacology · doi:10.1007/bf00215487 · Cited by 28 · see citing works
A brief review of the effects of diazepam on memory.
Romney, D. M., & Angus, W. R. (1984) · PubMed · Cited by 25 · see citing works
Lack of influence of cigarette smoking on triazolam pharmacokinetics.
Ochs, H., Greenblatt, D. J., & Burstein, E. (1987) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1987.tb03112.x · Cited by 24 · see citing works
Self-citationBenzodiazepine Hypnotics and Insomnia
Kales, A. (1990) · Hospital Practice · doi:10.1080/21548331.1990.11704103 · Cited by 22 · see citing works
Triazolam Kinetics: Interaction with Cimetidine, Propranolol, and the Combination
Friedman, H. L., Greenblatt, D. J., Burstein, E. S., et al. (1988) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1988.tb03137.x · Cited by 21 · see citing works
Self-citationPharmacodynamics and Pharmacokinetics of Ethanol, Diazepam and Pentobarbital in Young and Aged Rats
Guthrie, S. K., Cooper, R. L., Thurman, R. G., & Linnoila, M. (1987) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1987.tb01825.x · Cited by 19 · see citing works
Profile of mood states changes during and after 5 weeks of nightly triazolam administration.
Dl, B., Seidel, W. F., Sa, C., et al. (1988) · PubMed · Cited by 18 · see citing works
Woo, E., Proulx, S. M., & Greenblatt, D. J. (1991) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1991.tb03702.x · Cited by 14 · see citing works
Self-citationDouble-blind crossover comparison of triazolam and lorazepam in the posthypnotic state.
Jb, C. (1984) · PubMed · Cited by 13 · see citing works
Aging: Changes in a passive-avoidance response with brain levels of temazepam
Komiskey, H. L., Rahman, A., & Mundinger, K. L. (1988) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(88)90238-9 · Cited by 7 · see citing works
(1989) · Archives of General Psychiatry · doi:10.1001/archpsyc.1989.01810090035006 · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [9]9. Pakes GE, Brogden RN, Heel RC, Speight TM, Avery GS. Triazolam: a review of its pharmacological properties and therapeutic efficacy in patients with insomnia. Drugs 1981; 22:81-110.
- [40]40. Greenblatt DJ. Analysis of benzodiazepines by electron-capture gas-liquid chromatography. In: Sunshine I, Jatlow PI, eds. Methodology in analytical toxicology. Vol. 2. Boca Raton, Fla.: CRC Press, 1982:19-24.
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Glass, J., Lanctôt, K. L., Herrmann, N., Sproule, B. A., & Busto, U. E. (2005) · BMJ · doi:10.1136/bmj.38623.768588.47 · Cited by 1,161 · see citing works
Jaeger, J. (2018) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000941 · Cited by 836 · see citing works
Use of benzodiazepines in anxiety disorders
Wood, A. J. J., Shader, R. I., & Greenblatt, D. J. (1993) · New England Journal of Medicine · doi:10.1056/nejm199305133281907 · Cited by 341 · see citing works
Self-citationSex-specific differences in CYP450 isoforms in humans
Scandlyn, M. J., Stuart, E. C., & Rosengren, R. J. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.4.413 · Cited by 199 · see citing works
CURRAN, H. V., COLLINS, R., FLETCHER, S., KEE, S. C. Y., WOODS, B., & ILIFFE, S. (2003) · Psychological Medicine · doi:10.1017/s0033291703008213 · Cited by 190 · see citing works
Greenblatt, D. J., Gan, L., Harmatz, J. S., & Shader, R. I. (2005) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2005.02409.x · Cited by 33 · see citing works
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Greenblatt, D. J., & Zammit, G. K. (2012) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2012.741588 · Cited by 28 · see citing works
Self-citationJung, M. E., Metzger, D. B., & Hall, J. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172873 · Cited by 8 · see citing works
- Authors
- Greenblatt, D. J., Harmatz, J. S., Shapiro, L., Engelhardt, N., Gouthro, T. A., & Shader, R. I.
- Affiliations
- Tufts University (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1991-06-13
- Volume
- 324
- Issue
- 24
- Pages
- 1691-1698
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2062847583
- Cited by
- 258
- References
- 65
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 7 · 2014: 1 · 2013: 10 · 2012: 10
- FWCI
- 25.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 34223)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- triazolam, older adults, age-related drug sensitivity, benzodiazepines, hypnotics, pharmacokinetics, pharmacodynamics, plasma drug concentration, drug clearance, sedation, psychomotor performance, memory impairment, dose adjustment
- MeSH terms
- Adult, Age Factors, Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Male, Memory, Middle Aged, Psychomotor Performance, Triazolam
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