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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
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Definition of Sedation Depression of brain functioning by a medication, manifested by: sleepiness, drowsiness, fatigue slowed brain activity reduced wakefulness impaired performance
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Evaluating Sedation Self-report measures Physiologic measures Performance measures
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Evaluating Sedation Self-report measures Diary Cards Rating Scales, Mood Inventories Visual Analog Scales Personal Data Assistant (Palm Pilot) Prescription Event Monitoring
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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
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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
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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)
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MULTIPLE SLEEP LATENCY TEST AVERAGE NUMBER OF MINUTES TO FALL ASLEEP p=.003 p=.007
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SELF-REPORTED SLEEPINESS STANFORD SLEEPINESS SCALE (8:30 AM TEST) p=.04
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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
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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
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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
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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
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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
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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
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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.
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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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