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MEASURING IMPAIRMENT: VALIDATED TEST METHODS FOR ASSESSING SEDATING MEDICATIONS

MEASURING IMPAIRMENT: VALIDATED TEST METHODS FOR ASSESSING SEDATING MEDICATIONS. Gary G. Kay, Ph.D. Associate Clinical Professor of Neurology Director, Neuropsychology Division Georgetown University School of Medicine Washington, DC & President Washington Neuropsychological Institute

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MEASURING IMPAIRMENT: VALIDATED TEST METHODS FOR ASSESSING SEDATING MEDICATIONS

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  1. MEASURING IMPAIRMENT: VALIDATED TEST METHODS FOR ASSESSING SEDATING MEDICATIONS Gary G. Kay, Ph.D. Associate Clinical Professor of Neurology Director, Neuropsychology Division Georgetown University School of Medicine Washington, DC & President Washington Neuropsychological Institute Washington, DC FDA/NTSB PUBLIC HEARING: Transportation Safety and Potentially Sedating or Impairing Medications, November 14-15, 2001, Washington, DC

  2. Definition of Sedation • Depression of brain functioning by a medication, manifested by: • sleepiness, drowsiness, fatigue • slowed brain activity • reduced wakefulness • impaired performance

  3. Evaluating Sedation • Self-report measures • Physiologic measures • Performance measures

  4. Evaluating Sedation • Self-report measures • Diary Cards • Rating Scales, Mood Inventories • Visual Analog Scales • Personal Data Assistant (Palm Pilot) • Prescription Event Monitoring

  5. Evaluating Sedation:Self-Report Measures Problems with self-report • Subjectivity • Self-report bias • Validity – Self-report frequently is not consistent with physiological and performance evidence of sedation

  6. Cognitive Performance:Changes From Baseline in Non-Sleepy Patients Day 1 Treatment Effects Diphenhydramine Loratadine Placebo .4 .2 0 -2 Factor Score (mean change from baseline) -.4 • Factor • Divided attention/working memory • Vigilance • Speed -.6 -.8 -1.0 Kay, et al. AAAAI. 1999.

  7. Evaluating Sedation:Physiologic Measures • EEG (e.g., continuous EEG for microsleeps) • Evoked potentials (e.g., P300) • Functional brain imaging (e.g., PET and fMRI) • Multiple sleep latency test (MSLT) • Activity monitors (e.g., wrist actigraph)

  8. MULTIPLE SLEEP LATENCY TESTAVERAGE NUMBER OF MINUTES TO FALL ASLEEP p=.007 p=.003

  9. SELF-REPORTED SLEEPINESSSTANFORD SLEEPINESS SCALE (8:30 AM TEST) p=.04

  10. Functional MRI:Mental Arithmetic Test Change From Baseline to Day 3 of AM-PM Dosing: Frontoparietal Brain Activation 150 Placebo P = .002 CP 8 mg/TF 100 CP 12 mg/TF P = .009 50 Pixel activation 0 -50 -100 Starbuck, et al. AAAAI. 1998.

  11. Evaluating Sedation:Performance Measures • Simulation (e.g., driving, flying) • Cognitive testing* • Psychomotor testing* *Computer-based cognitive and psychomotor testing is employed by pharmaceutical industry and FDA to assess CNS effects

  12. Comparison of the Acute and Steady-State Effects of Loratadine, Diphenhydramine, and Placebo • Assess the cognitive, psychomotor, and subjective effects of these antihistamines. • Determine the relationship between self-reported sedation and cognitive performance. Subjects (N=98) were randomly assigned to one of the 3 treatment groups: • 10 mg loratadine • 50 mg diphenhydramine on Day 1, followed by 25mg 4x/day on Days 2-5 • placebo Kay, et al. Arch Intern Med. 1997.

  13. Better functioning Poorer functioning Day 1:Change in Factor Scores Mood & Working Divided sedation Speed memory attention 0.4 0.3 0.2 0.1 0 Factor scores, z-score units -0.1 -0.2 -0.3 Diphenhydramine -0.4 Loratadine -0.5 Placebo -0.6 Kay, et al. Arch Intern Med. 1997.

  14. Vigilance: Continuous Performance Test Accuracy Day 1 Results Diphenhydramine 100 Loratadine 98 Placebo 96 94 CPT accuracy, % 92 90 88 86 84 Kay, et al. Arch Intern Med. 1997.

  15. CRITICAL COGNITIVE DOMAINS FOR DEMONSTRATING SEDATION VIGILANCE: Capacity to sustain attention under conditions of minimal arousal (e.g., monotonous tasks). DIVIDED ATTENTION: Ability to perform simultaneous mental activities; also referred to as dual tasking. WORKING MEMORY: Ability to hold information temporarily in one’s head for purposes of using the information in a calculation, or other mental activity.

  16. Consistent Neuropsychological Findings with Sedating Medications • Tests of vigilance (i.e., lapses of attention) appear to be the most sensitive measures for detecting the sedation effects that may contribute to accidents. • Psychomotor effects (i.e., disruption of tracking) appear to persist (for weeks) after adaptation has occurred to cognitive effects.

  17. Summary • Sedating medications can cause impairment in the absence of sleepiness. • Sedating (OTC and Rx) medications don’t only cause sleepiness. They impair alertness, cognitive and psychomotor functioning. • Sedating effects may carry over to the following day even when medications are taken at night. • Vigilance, divided attention, and working memory are especially vulnerable to sedating medications • Assessment of sedation effects (and consumer/ prescriber information about sedation) should be based on more than self-report findings.

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