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 Kay, et al. AAAAI. 1999..4.2 0 -2 -.4 -.6 -.8 Factor Divided attention/working memory Vigilance Speed Factor Score (mean change from baseline) DiphenhydramineLoratadinePlacebo

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 TEST AVERAGE NUMBER OF MINUTES TO FALL ASLEEP p=.003 p=.007

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

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

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. Kay, et al. Arch Intern Med. 1997. 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

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

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

15. 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. CRITICAL COGNITIVE DOMAINS FOR DEMONSTRATING SEDATION

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.