MEASURING IMPAIRMENT: VALIDATED TEST METHODS FOR ASSESSING

SEDATING MEDICATIONS

Gary G. Kay, Ph.D.Associate Clinical Professor of Neurology

Director, Neuropsychology DivisionGeorgetown University School of Medicine

Washington, DC

&President

Washington Neuropsychological InstituteWashington, DC

FDA/NTSB PUBLIC HEARING: Transportation Safety and Potentially Sedating or Impairing Medications, November 14-15, 2001, Washington, DC

Definition of Sedation

Depression of brain functioning by a

medication, manifested by: sleepiness, drowsiness, fatigue

slowed brain activity

reduced wakefulness

impaired performance

Evaluating Sedation

Self-report measures

Physiologic measures

Performance measures

Evaluating Sedation

Self-report measures Diary Cards

Rating Scales, Mood Inventories

Visual Analog Scales

Personal Data Assistant (Palm Pilot)

Prescription Event Monitoring

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

Cognitive Performance:Changes From Baseline in Non-Sleepy Patients

Day 1 Treatment EffectsDay 1 Treatment Effects

Kay, et al. AAAAI. 1999.

.4

.2

0

-2

-.4

-.6

-.8

-1.0

Factor

Divided attention/working memory

Vigilance

SpeedFac

tor

Sco

re (

mea

n c

han

ge

fro

m b

asel

ine)

Diphenhydramine Loratadine Placebo

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)

MULTIPLE SLEEP LATENCY TESTAVERAGE NUMBER OF MINUTES TO FALL ASLEEP

0

2

4

6

8

10

12

DAY 2

Min

ute

s Placebo

CP 8mg

CP 12mg

p=.003p=.007

SELF-REPORTED SLEEPINESSSTANFORD SLEEPINESS SCALE (8:30 AM TEST)

1

2

3

4

5

6

7

DAY 2

Inc

rea

sin

g S

lee

pin

es

s

Placebo

CP 8mg

CP 12mg

p=.04

Functional MRI:Mental Arithmetic Test

Starbuck, et al. AAAAI. 1998.

Change From Baseline to Day 3 of Change From Baseline to Day 3 of AMAM--PMPM Dosing: Dosing:Frontoparietal Brain ActivationFrontoparietal Brain Activation

P = .009

P = .002

-100

-50

0

50

100

150

Pix

el a

ctiv

atio

n

Placebo

CP 8 mg/TF

CP 12 mg/TF

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

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

Day 1:Change in Factor Scores

Fac

tor

sco

res,

z-s

core

un

its

Betterfunctioning

Poorerfunctioning

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 &sedation Speed

Workingmemory

Dividedattention

DiphenhydramineLoratadinePlacebo

Vigilance: Continuous Performance Test Accuracy

Day 1 ResultsDay 1 Results

Kay, et al. Arch Intern Med. 1997.

84

86

88

90

92

94

96

98

100

CP

T a

ccu

racy

, %

DiphenhydramineLoratadinePlacebo

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

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.

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.