@;ý 1w*EL
Technical Report Documentation Pae.

1. Report lMo. 2. Government Accession No. 3. Recipient's Catalog No.

FAA-AM-81 ".16

4. Title and Subtitle 45 Re.prt Data

A COMPARISON OF SOME EFFECTS OF THREE ANTIMOTION August 181l

SICKNESS DRUGS ON NYSTAGMIC RESPONSES TO ANGULAR 6. Performing Organization Code

ACCELERATIONS AND TO OPTOKINETIC STIMULIg

•-:"-•,' _ 8.Performinin Organization Report No,

7. Authorls) William E. Collins, David J. Schroeder, and 7, Gary W. Elam

i- 9. Performing Organization Name and Address 10. Work Unit No, (TRAIS)

FAA Civil Aeromedical Institute 1.Cntracto, Grant No.

•1. . P.O. Box 25082

"Oklahoma City, Oklahoma 73125 13. Type of Report and Period Covered

- 12. Sponsoring Agency Name and Address

Office of Aviation Medicine

Federal Aviation Administration

800 Independence Avenue, S.W. 14. Sponsoring Agency Code

Washington, D.C. 20591

15. Supplementary Notes

Work was performed under tasks AM-D-77/7 SY-6a M-A-80/8-PSY-86

16'.A tro t . .

01.rfn'aviation, some pilot trainees experience motion sickness early in their training and drug remedies are not prohibited when prescribed for dual flights. Moreover,

some motion sickness preventives do not require prescriptions. In addition, spouses

or business associates often accompany private pilots on flying trips; some of these

passengers, who may be required to pilot the aircraft in an emergency, use antimotion

sickness drugs. While the basic efficacy of such drugs is rcoted in the reduction of

motion sickness symptoms, adverse side effects are important practical considerations

of their usage in aviation. This study examined the influence of three established

antimotion sickness drugs on nystagmic eye movement responses to angular acceleration

(whole-body movement) with vision either permitted or denied, and to optokinetic

stimulation (visual field movement). Dimenhydrinate and promethazine hydrochloride,

particularly at higher dose levels, reduced optokinetic nystagmus, thereby making less

accurate the following aLility of the eye. During whole-body motion in darkness,

there was little placebo-drug difference in the vestibular response under alert conditions; under relaxed conditions, dimenhydrinate and promethazine hydrochloride produced significant declines in the vestibular eye movements. These same drugs also

interfered with the ibility of the individual to fixate adequately on a visual task

during motion. Subjects who received a combination of promethazine plus d-amphetamine

were able to suppress vestibular eye movements under the task condition and maintain

good visual fixation. Thus, the effect of a drug on nystagmus may be a poor indicator

of its value in preve t g motion stckness. Moreover, assessments of antimotion sickness drugs for many pract al situations should include as a possible adverse side

effect the inabilty tN m *frn 4n uv.ou" fit y •- i Aii ,n on

17. Key Words x 18. Distribution St.'tem nt -I

Motion Sickness Document is available to the public

Drugs through the National Technical

Nystagmus Information Service, Springfield,

Visual-Vestibular Interactions Virginia 22161

19. Security Classif. (of this report) 20. Security Clossif. (of thls page) 21. No. of Pages 22,. Price

Unclassified Unclassified. 25

Form DOT F 1700.7 (8-72) Reproduction of completed page authorized

_=A'c +r / . - . S-" _-..

,.-+- • -+• • m-
iI

A COMPARISON OF SOME EFFECTS OF THREE ANTIMOTION SICKNESS DRUGS ON

NYSTAGMIC RESPONSES TO ANGULAR ACCELERATIONS AND TO OPTOKINETIC STIMULI

Introduction.

In aviation, some pilot trainees experience varying degrees of motion

sickness early in their training and the use of drug remedies is not prohibited when prescribed for dual flights. Moreover, some motion sickness

preventives do not require prescriptions. In addition, spouses or business

executives often accompany private pilots on flying trips; some of these

passengers, who may be required to pilot the aircraft in an emergency, use

antimotion sickness drugs.

The majority of antimotion sickness drugs are depressants (2,11,12,17).

While their efficacy in this regard is based on the reduction of motion

sickness symptoms, there is the possibility that the use of such drugs might

have other (undesirable) consequences on functions associated with motion,

particularly with regard to the integrity of the visual and vestibular sys- L tems. Interferences with visual acuity, visual following ability, or the

ability to maintain visual fixation during the nystagmic eye movement responses to angular accelerations all have potentially adverse consequences

for spatial orientation and flight safety.

Among the factors which have a marked influence on vestibular nystagmus

are the presence or absence of oppoitunities for visual fixation (6,8,10,14) o•and the state of mental alertness of the individual (1,4,5). Ordinarily,

i() the slow-phase components of vestibularly induced eye movements in darkness are reduced during states of mental relaxation (reverie) as compared

with states of mental alertness, and (ii) nystagmic excursions are inhibited

by visual fixation (6). Assessments of drug effects on vestibular responses--or on responses related to vestibular function--need to consider both

of these factors. Several studies (1,9,10,14,15) have indicated that druginduced alterations in the alertness of subjects might lead to inexact

interpretations of the site of drug effects or to an incorrect apnraisal of

how a sensory system might perform under modified arousal conditions. For

example, in one study (10), vestibular nystagmus in darkness was not differentially affected by ordinary doses of d-amphetamine sulphate (10 mg),

secobarbital sodium (100 mg), or placebo if laboratory subjects were kept

mentally alert during stimulation. If the subjects were allowed to relax

and daydream, response variability increased markedly and the depressant,

secobarbital sodium, produced a notable deterioration of the ocular response

(10). Similar results were obtained with alcohol (14,15) and 1-hyoscine

hydrobromide (1). With vision permitted during vestibular stimulation, an

opposite effect has been reported, viz, ocular nystagmus was increased by

alcohol (14,15), amylobarbitotie sodium (13), and secobarbital sodium (10).

The present study was designed to investigate the effects of three antimotion sickness drugs on the ocular nystagmus response to angular stimulation. )des

•l or 1 Di~t j .•pucia2

Ivt
These tests were conducted under conditions in which (i) the subjects were

made alert or were encouraged to relax and (ii) visual fixation was permitted or denied, Additional information was obtained by exposing the subjects

to optokinetic stimulation. The drugs selected were (i) a readily available,

nonprescription remedy, (dimenhydrinate), (ii) an antihistaminic (promethazine

hydrochloride) which produces drowsiness (.16), (iii) a combination of the

mine), antihistaminic (promethazine hydrochloride) with an analeptic (dextroampheta- the combination representing an excepi:ionally effective remedy for

motion sickness (18).

Method.

Subjects. Male college students, with no history of any neuro-otological

difficulties, served as paid subjects. None had any previous laboratory

experiences involving vestibular stimulation. All ate a light breakfast at

about 7:00 a.m. and were not allowed to smoke or drink beverages containing

caffeine, except during a 2-h lunch period which preceded the final test

session. In the first of two studies, 40 subjects were divided into four

equal groups: a placebo (lactose), a 50 mg dimenhydrinate, a 25 mg promethazine hydrochloride, and a mixture (25 mg promethazine hydrochloride plus

10 mg d-amphetamine sulfate) group. The latter combination of drugs was

included because it has been cited as one of the most effective antimotion

sickness drugs in laboratory studies (17). In the second study (conducted to

clarify some findings from Study I), 30 new subjects were divided into three

equal groups: a placebo (lactose), a 100 mg dimenhydrinate and a 50 mg promethazine hydrochloride group. The drugs and placebo were placed in identical capsules; subjects were unaware of what their capsules contained.

Apparatus. A drum, painted with alternating black and white stripes (5

an and 6.25 cm in width, respectively) was located 0.6 m in front of the subject to provide the optokinetic stimulation. The drum, 40 cm high and 50 cm

in diameter, was mounted behind a gray screen which had a center opening

the full size of the drum. Stimuli comprised 30-s periods of drum rotation

at 10 rpm.

Vestibular stimulation was provided by oscillation of a modified StilleWerner RS-3 rotation device. This enclosed device was programed to provide'

a triangular waveform stimulus with a 4 8-s period and reach a peak velocity

of 1200/s in both counter-clockwise (CCW) and clockwise (CW) directions. Thus,

each 48-s period produced a 24-s cycle of CW stimulation and a 24-s cycle

of CCW stimulation, yielding cycles of both right-beating and left-beating

nystagmus, respectively. Subjects were seated directly over the center of

rotation with their heads fixed upright so that the lateral semicircular

canals were approximately in the plane of rotation.

The nystagmic eye movements resulting from optokinetic and vestibular

stimulation were recorded by using conventional electronystagmographic

techniques. A Beckman Type T electroencephalograph, with a 3-s time constant,

served as the recorder. Calibrations were obtained by having the subjects

sweep their eyes between two flashing pinlights on the front of the rotator

and between two markers near the optokinetic drum.

2

_4

_ __' -' - • .- 'i ." " . - ' . • - :
V. -

Procedure. During a single day, each subject was tested on five separate

occasions: a familiarization seesion, a Oredrug (baseline) session, and

three postdrup sessions. Inmediately following the predrug session

(between 10 a.m. and 11 a.m.), each subject ingested a capsule containing

either one of the drugs or a lactose-placebo. The capsules were administered in a double-blind procedure. The postdrug sessions occurred 1, 2,

and 4 hours following the ingestion of the capsule.

Each experimental session began with optokinetic stimulation; the stimulus period was 30 a and eye movements were recorded for-an additional 30 s

after the drum had stopped. The subject was periodically admonished to

"stay alert" and to continue focusing on the surface of the drum. Pulse

rates were recorded shortly after the end of the optokinetic trials.

The subject was taken next to a nearby room where the rotation device

was located. Each rotation session involved (i) three periods of whole-body

oscillation with the subject fixating visually and performing on a onedegree-of-freedom compensatory tracking task (alert with vision) and (ii) two

periods of whole-body oscillation in total darkness under two alertness

conditions. During the latter, the subjects were instructed either (i) to

solve mental arithmetic problems assigned by the experimenter or (ii) to

relax and daydream; i.e., assume a reverie (REV) state (4). The order ofI

presentation of these latter two conditions was counterbalanced and, in both

cases, the subject was instructed to keep his eyes open ar.d look straight

ahead.

Scoring. The total amount (degrees) of slow-phase eye displacement during vestibular stimulation was measured and the number of nystagmic eye movements

(beats) was counted across the three periods of rotation in the light and

across the first period of rotation in the dark. For optokinetic stimulation,

like values were calculated on the 30-s stimulus period. Scoring was

accomplished without knowledge of the group (drugs or placebo) to which any

subject belonged, and these absolute values (or the differences between them)

were used in the statistical analysis; for the latter, the minimal acceptable level for statistical significance was set at p < .05.

For some graphic presentations, however, "change" scores were computed.

For each group and each measure, the mean score for the predrug session was

plotted as a zero base; the percentagesof increase or decrease in scores

during subsequent sessions, which followed administration of a drug or

placebo, were. plotted as "percent ircrease" or "percent decrease" from the

predrug level.

Results.

Pulse Rates.

STUDY I

For each group, analyses of varia',ce followed by Tukey's Honestly

Sianificant Difference (NRM temtR n nnltie rater AernmR ReRnionR vielded

3
7l

similar findings, !__&' pulse rates were higher during the final sessions

<• < .05 - ..001) than they were during each previous session irrespactive of drugs or placebo and, with one exception (the 2-h postdrug session

for the mixture group), preingestion pulse rates were next highest (see 4

Table 1). Analyses of difference scores shoved no overall siguificant 4

between -.roups, Sdifferences but there wos a significant sessions effect

(< .001) due to the uniformly high pulse rates during the final session.

Those high rates are probably attributable to the subjects' anticipation A

that the end of the experimental period was approaching. In any event, the H presence or absence of drugs could not be ascertained by an inspection of

pulse rates.

Table 1. Mean Pulse Rates Obtained During Each Predrug

and Postdrup Session in Two Studies

Study I Postdrug Sessions

Group Predru 1 h 2 h 4h

Dimenhydrinate (50 mg) 68.7 62.8 62.0 77.9

Mixture (*) 64.8 63.3 67.3 78.4

Placebo 64.2 60.9 61.4 71.1

Promethazine

Hydrochloride (25 mg) 68.6 67.8 67.4 79.2

Mean 66.6 63.7 64.5 76.7

SLucly II

Dimenhydrinate (100 mg) 71.3 64.0 63.0 76.4

Placebo 65.0 60.4 57.8 68.2

Promethazine

Hydrochloride (50 mg) 65.8 60.2 60.8 69.4

Mean 67.4 61.5 60.5 71.3

(*) 25 mg promethazine hydrochloride plus 10 mg d-amphetamine sulphate. I

STUDY II

Complementing the findings of Study I, pulse rates uniformly dropped for

all groups during the first two postingestion sessions and reached their

4

-1•
highest levels during the final sessions for each group. Owing at least

partly to the effects of the double dosages of drugs, the array of statistically significant findings differed between the two studies. Specifically,

in Study II (1) the final session for each group had significantly higher

(p <.05 - p <.001) pulse rates than the two preceding sessions but did not

differ from the predrug session, (Ii) placebo group scores during the 2-h

session were lower (Q < .01) than predrug pulse rates and (iii) pulse rates

for the dimenhydrinate group were lower than baseline during both the 1-h

and 2-h sessions (p <.05 in both cases). The overall analysis of difference

scores yielded findings almost identical with those of Study I; there were no significant group differences but there was a session effect (P- < .001) due

to the elevated scores during the final sessions. Even with the increased

drug dosages used in this study, pulse rates did not distinguish the presence

or absence of the two depressant drugs.

Effects of Instructions.

STUDY I

Analyses of variance were applied separately to the slow-phase output

and the number of eye movements (beats) elicited in darkness. The two

different sets of instructions regarding mental activity yielded significant

F-ratios for each ocular measure. For slow-phase displacement, instructions

Ml( <.01), sessons (p < .01), and the instructions by sessions by groups

interaction (2 < .05) were significant; for the total number of eye movements,

the same variables were significant (p < .01, p < .05, p < .01 respectively)

plus the two-way interactions of sessions by groups and sessions by instructions (both at 2 < .05). For every session and every group, slow-phase

measures for the mental arithmetic (MA) instructions were greater than those

for the REV instructions (see Figure 1). The effect of instructions on the

number of eye movements (Figure 2) showed different patterns, viz, (i) during

the preingestion (baseline) sessions for all groups, the number of beats was

greater for REV than for MA instructions, (ii) this pattern was maintained

for both the placebo and mixture groups during subsequent sessions, and (iii)

the REV output dropped below that of MA during two postirgestion sessions

each for the groups given dimenhydrinate (1-h arid 2-h postdrug) and promethazine (2-h and 4-h postdrug).

Response trends across sessions were examined within each group via oneway analysis of variance and Tukey's HSD test. For the MA task, no significant effects were obtained for dimenhydrinate or promethazine. For the

placebo group the number of eye movements was lower during the 1-h postingestion session than it was during all other sessions (p < .05 - .01).

Somewhat similarly, the mixture group had less nystagmus output (Q <.05)

during the 1-h postingestion session than during the predrug session for both

nystagmus measures; in addition, slow-phase scores during the 2-h session

for the mixture group were lower (Q < .05) than the predrug Rrores. REV

sessions produced a different pattern of results.

5
F

1200 MIXTURE 120o PROMETHAZINE HYDROCHLORIDE

1000O 1000 - o ..-. -

B00 - 00

D 600 600

, 400 o--a Mental Arithmetic 400

i- (I)>. 200 • Reverie 200 p , I .. • I

Z Pre I 2 4 P. W 2 4

LIJ

0. 1200 O DIMENHYDRINATE i200 PLACEBO

,Ono S~-a.. oo-F

Soo

600 600 F

400 400

Pro I 2 4 Pr* I 2 4

HOURS AFTER INGESTION

,Figure 1. The total amount of slow-phase vestibular nystagmus obtained

during rotation in total darkness under mental arithmetic and

reverie instructions before (pre) and after ingestion of a drug

or placebo. Drugs were dimenhydrinate (50 mg), promethazine hydro- chloride (25 mg) and a mixture (25 mg promethazine hydrochloride

plus 10 mg dextroamphetamine).

For this instructional condition, no significant effects were obtained for

either the placebo or the mixture group. However significant declines for

both REV nystagmus measures (2. <.05 in all case.;, %. re present between the

predrug and the 1-h postingestion session for the dimenhydrinate group and

between the 1-h and 4-h postingestion sessions for the promethazine group.

Anaiyses of variance of difference scnres (each postingestion score subtracted from the prodrug score) and subsequent simple effects tests permitted

assessment of difference between the groups. For the MA instructions, only

one significant difference emerged, viz, for slow-phase activity during the

first postin~estion session between the mixture and promethazine groups

(2. < .05). The difference is attributable to the sharp increase in this

6

J 777...
ISO- MIXTURE 13Or PROMETHAZINP. HYOOCHLORIOC

:•-~it -0 Ito0 ,.... ...

00- 100L -- ----

90 - soU) 0*--" Mental Arithmetic

707a~- Reverie

4 Pa, po I 4

-W

130 OIM.NHYDRINATE 13U PLACEBO

M II I Ito IRO.

z

so. 90s

•.!so- so

•-i70 70 S~?' ,, ,....'

Pro a Pro 2 4

HOURS AFTER INGESTION

Figure 2. The total number of fast-phase beats of nystagmus obtained during

rotation in total darkness befure (pre) and after ingestion of a

drug or placebo. Drugs and tasks were as in Figure 1.

measure of nystagmus for the promethazine group (see Figure 3). (This latter

finding helped prompt the conduct of Study II.) REV instructions resulted

in a greater number of significant effects (p <.05 in all cases), each of

which involed depressed scores during the 1-h postingestion session for the

dimenhydrinate group; specifically between the dimenhydrinate and mixture

groups for both ocular measurements (Figures 3 and 4) and between the dimenhydrinate and placebo groups for the number of eye movements (Figure 4).

STUDY II

Analyses of variance applied to the two measures of nystagmus yielded

almost identical patterns of significant F-ratios. For both measures,

instructions (p <-.01), session (p <.01) and the groups by sessions

(p <.01), instructions by sessions (P < .01), and three-way interactions

(p < .01.) were all significant. The groups by instructions interaction was

significant (R < .05) only for the number of ocular beats. Slow-phase

output for every session and every group was greater for MA than for REV

7
A

1 o MENTAL ARITHMETIC

to

- go /•

10

0 - -

•. -a Miature

z••30 REVERIE o-o 2 ,:a

kto

-10-

01

I A

V./) 6-& ixur

S3-20 R R-

-40

0- 10

-22

-So

i A I

Pro 2 4

HOURS AFTER INGESTION

Figure 3. Changes in the output of slow-phase vestibular nystagmus following ingestion of a drug or placebo. Drugs and tasks were as in

Figure 1. The 0 scores represent the base levels of ocular output for the four groups under mental arithmetic and reverie instruc- tions; output scores for the postingestion sessions were converted

to percentages of increase or decrease from the base levels.

-- D
MENTAL ARITHMETIC

tot o0. AW--------

7 -*-o-

-0

• e-10

')Pro I 2 4

co S so REVERIE '" -- "Mixture Dimenfhydriflbto

LL0 Placebo

20 - a--a Prometharlne

2.r a,-o

W o0

-20

-40

- 5 0 i A

Pro 1 2 4

HOURS AFTER INGESTION

Figure 4. Changes in the total number of fast-phase beats of vestibular

nystagmus following ingestion of a drug or placebo. Drugs,

tasks, and plotting procedures were as in Figure 3.

9

i -• 
..... . .. .. .. , 

CuOw4 0

CO. 4 4-i

N 4-i1 10 0 -

Cu~44-W

Z 04 .,r 44

Z i 0 r41~ 11 ~44Jz r- toCD0

C6 4.1 0 wO1 0 1 44

I I I 0 4J.C 0

ZI a

M 4-4 r.~

P 0 ~4-4

W4 0r u 60. 

0 to

10 41 m-. p_ b
1

instructions; also the differences in output between the instructions grew

clearly greater during postingestion sessions for dimenhydrinate and

promethazine (see Figure 5). For the number of eye movements, all preingestion sessions showed higher scores during REV than during MA. This difference declined during postingestion sessions for the placebo group, but Ihe

scores stayed within +10 percent of each other. For both promethazine and dimenhydrinate, sharp declines in ocular beats occurred during postingestion

sessions, with REV scores markedly below MA scores during all three postingestion sessions for dimenhydrinate and during the last two sessions for

promethazine.

In examining response trends across sessions for each group, the MA

condition yielded significant F-ratios only for slow-phase measures

(Figure 6), only for the 2-h postingestion session, and only for the placebo

and promethazine groups, viz, for the former group, that session differed

(scores were lower) from the predrug and the 4-h postingestion sessions

(p < .05 in both cases), while for promethazine subjects the 2-h session

(with a lower score) differed only from the predrug trial (p < .05).

Although these differences were significant, the sessional range of scores

was quite narrow (see Figure 6). Intersession comparisons for the REV

instruction condition resulted in no significant F-ratios for the placebo

group. However, dimenhydrinate produced marked postingestion declines in both

measures of nystagmus (Figures 6 and 7), with all postingestion scores lower

than the predrug levels (p < .01 - .001). Promethazine also produced sharp

declines in each of the two measures of ocular activity, viz, all postingestion sessions were depressed from the predrug level for slow-phase scores,

and all except the 1-h session were significantly depressed for the number

of eye movements (2 < .001 in all cases). In addition, the 1-h promethazine

postingestion session differed significantly from the last two sessions (they

were lower) for both nystaginus measures (2 < .05 and .01 respectively for

slow-phase; 2 < .001 in both cases for number of eye movements).

Analyses of variance of difference scores and subsequent simple effects

tests to assess between-groups differences yielded none for the MA instructions (see Figures 6 and 7). REV instructions resulted in the following

significant findings: (i) for all three postingestion sessions, slow-phase

scores (Figure 6) for both drug groups showed a significantly greater drop

(P < .01 - .001) from predrug levels than did the placebo group, (ii) for

the number of ocular beats (Figure 7), promethazine scores dropped significantly more than placebo scores for the 2-h (2 < .05) and the 4-h

(2 <.01) postingestion 3essions.

II
20 MENTAL ARITHMETIC

-0 Ao

1 0-

0

-30

Pro I 2 4

20- REVERIE

Z W lo-

~ 10

a. _10 A.

n~ -9O0 ,, .,,

- 20 -

0j o--o 0-\-* Dim enhydrlnate Placebo

W -30 A--A Promethazine

w - Hydrochloride w -4 0 -

~-0

-50

49

Pro 1 2 4 1

HOURS AFTER INGESTION

-Figure 6. Changes in the output of slow-phase vestibular nystagmus following ingestion of a drug or placebo. Dosages and tasks were as in

Figure 5. The 0 scores represent the base levels of ocular output for the four groups; output scores for the postingestion

sessions were converted to percentages of increase or decrease

from the base levels.

12

... ....-- ...
S20 MENTAL ARITHMETIC

10o0 . .. .........

...... ...... 

< Pre I2 4

II

U. 20 REVERIE 0OW4

W 0---* Dimenhydrinate

10 o--o Placebo A--A Promethazine co Hydrochloride 0-

z -10

-20 \ "'-

S-30

e -40

-50

S; I A I I I

Pre I 2 4

4I HOURS AFTER INGESTION

Figure 7. Changes in the total number of fast-phase beats of vestibular

nystagmus following ingestion of a drug or placebo. Dosages,

tasks, and plotting procedures were as in Figure 6.

13
Effects of Visual Fixation on Vestibular Nystagmus.

STUDY I

Within Groups Comparisons. One-way analyses of variance and Tukey's

HSD tests yielded significant F-ratios for both the slow-phase and the

number of beats measures for the placebo (P- < .05) and mixture ( < .01)

groups. Dimenhydrinate had no statistically significant effect across the

four sassions but all postdrug scores exceeded the baseline levels. Proiethazine produced a significant overall F(2 < .05) only for slow-phase scores

(due to the elevated output 2-h after taking the drug), but all. the paired- session comparisons fell short of statistical reliability.

The placebo group showed a general decline-in nystagmus across sessions

with both slow-phase displacement measures and the number of eye movements

during the final session falling significantly below (21 < .01) baseline

levels. The mixture group declined more sharply than did the placebo subjects, but showed some recovery during the final session. For ocular beats,

only the 2-h postingestion session for mixture subjects was significantly below the predrug level (p < .01), but for slow-phase measures all three

postingestion sessions were lower than the baseline (p < .01, p < .001,

and p < .01, respectively).

Thus both the placebo and mixture groups showed improved control of eye

movements (lower scores) across sessions, while the subjects given dimenhydrinate and promethazine had elevated scores (reduced ocular control) after

drug-taking.

Between Groups Comparisons. The overall analyses of variance and subsequent simple effects tests yielded significant findings for groups

(2 < .01 - .001) for each of the two ocular measures, and a significant groups-by-sessions interattion for the number of eye movements (2 < .05).

For the latter measure, the only group difference occurred during the 2-h

postingestion session between the promethazine (high score) and mixture (low score) groups (p < .001). For slow-phase measures, the mixture group had

less displacement than both the dimenhydrinate and promethazine groups during the 2-h (R < .01 and p < .001, respectively) and the 4-h sessions (p < .01

and p < .05, respectively). In addition, the promethazine group scores

were h4her (p < .05) than the placebo group scores during the second post- ingestion session.

14
to NUMBER OF BEATS

310 s.

0 0

-10-

-20 -

I -30

x hI • I I

PrI 2 4

w

..J

-30 SLOW PHASE NYSTAGMUS

JA 0 .- ..

! - I0 ••-~~/-0-S......

-20

-30 .• Demenhydlrinate •.-

&-aMiature 40 A--- Placebo

o--o Prometho3l0- Hydrochlorlde

, I I I

Pre I 2 4

HOURS AFTER INGESTION

Figure 8. Changes in slow-phase and fast-phase (number of beats) vestibular

nystagmus during visual fixation on a tracking task. Drugs were

dimenhydrinate (50 mg), promethazine hydrochloride (25 mg) and a

mixture (25 mg promethazine hydrochloride plus 10 mg dextroamphetamine). The 0 scores represent the base levels of ocular output

for the four groups; output scores for the postingestion sessions

were converted to percentages of increase or decrease from the

base levels.

15

4. m. - -
NUMBER OF BEATS

to-=

20

- 10-

LaL

-0 1

Z -20-

X -30-

x . I Pre I I 2 4

SLOW PHASE NYSTAGMUS

50-

() 40 /

30:

20

.Dimenhydrinate

A.'.• &--a. Plaocebo

o--e Promethaulnt

Hydrochlorlide

- = - -.- =

~ 20 = 0--V °at

-30; I A/ I i I

Pre I 2 4

HOURS AFTER INGESTION

Figure 9. Changes in slow-phase and fast-phase (number of beats) vestibular nystagmus during visual fixation on a tracking task. Dosages

were 100 mg of dimenhydrinate or 50 mg of promethazine hydrochloride. Plotting procedureswere as in Figure 8.

16
STUDY II

Within Groups Comparisons. One-way analyses of variance yielded significant effects across sessions for both measures of nystagmus for the placebo

(P_ <.01.) and promethazine Qp < .05) groups; for dimenhydrinate subjects,

only the number of eye movements varied significantly (P -<.05). Tukey's

HSD tests yielded no sessional differences for dimenhydrinate although scores

were elevated during the first two postingestion hours and several comparisons

involving the second postingestion hour were very near statistical significance. For both measures of nystagmus, promethazine produced significantly

higher scores (.2 < .05) during the second postingestion hour than prior to

drug-taking and two other comparisons involving the 2-h postingestion session were close to significance. The last session for the placebo group

was significantly lower (2 <.01) in output than the first session for both

measures of nystagmus, culminating a regular decline in eye movement

(improved control) across sessions.

Between Groups Comparisons. Analyses oi variance yielded significant F- ratios for groups (p <.01), sessions (p <.05), and for the groups by

sessions interactions (p. <.05 for slow phase and p < .01 for number of

movements). For both measures dimenhydrinate (P.. <.05) and promethazine

(p <.001) scores were significantly higher (less control) than placebo

scores during the 2-h postingestion session. Promethazine scores remained

significantly elevated during the last session in comparison with placebo

(2- <.03. for slow-phase and p < .001 for ocular beats) and were higher than

dimenhydrinate scores (P < .05) during that session only for the number of

eye movements.

Optokinetic Nystagmus.

STUDY I

Within Groups Comparisons. One-way analyses of variance across sessions

for each group yielded no significant F-ratios for either slow-phase measures

or the number of beats. While slow-phase scores generally declined across

sessions, all scores were within +10 percent of the preingestion levels.

Beats of eye movement were somewhat more stable across sessions and showed

a narrower range of variability from predrug scores (Figure 10).

Between Groups Comparisons. Overall analyses of variance for the total

number of optokinetic eye movements yielded no significant F-ratios; total

slow-phase output yielded only a significant sessions effect (P_ <.05) which

is accounted for primarily by the somewhat lower scores which occurred

during the last two sessions. Individual comparisons between the groups at

each session yielded no significant effects although, for number of beats,

the promethazine-dimenhydrinate groups differences at the 1-h and 2-h postingestion sessions, and the promethazine-mixture group differences at the

last session, all approached significance.

17

.. ~"--
-~~~ ..~,,.~ ..

NUMBER OF BEATS

e---o 01meoihydrlnote 20 &-0& Mixture

u <o--o IMocebo

at

10 Promethazine Hydrochloride

Z Pro I 2 4

W 20 SLOW PHASE NYSTAGMUS

0 g 10S0 .S

CL 0

------------ 0 A

Cie -10 _

Pro I 2 4

HOURS AFTER INGESTION

j Figure 10. Changes in the output of optokinetic nystagmus obtained before

(pre) and after ingestion of a drug or placebo. Drugs were

dimenhydrinate (50 mg), promethazine hydrochloride (25 mg), and

a mixture (25 mg promethazine hydrochloride plus 10 mg dextroamphetamine). The 0 scores represent the base levels of ocular

output for the four groups; output scores for the postingestion

sessions were converted to percentages of increase or decrease

from the base levels.

18

-A
10 NUMBER OF BEATS

U 10.

0 --------------------------------------------------- o

0-4 Dlrimnhydrinate U)c -20- a0o Placebo

&-'Promethzine Hydrochloride

S-30

Pre I2 4

z SLOW PHASE NYSTAGMUS

o U20-

W loz

g I 0________

Pre 2 4

figure 11. Changes in Lhe output of uiptokinetic nystaginus obtained before

(pre) and after ingestion of a drug or placebo. Dosages were

100 mg of dimenhvdrinate or 50 mg of promethazine hydrochloride.

Ploitting procedures were as in Figure 10.

19

MAI
STUDY I1

Within Groups Comparisons. One-way analyses of variance across sessions

yielded significant effects only for the promethanine group. Comparisons

between trials indicated that the last promethazine session had significantly

less output for both measures of nystagmus than either the predrug (p <(.01

in both caces) or the 1-h postingestion session (p < .05 - .01); in addition, for slow-phase activity, the 2-h session was significantly below (P -<.01) the predrug level. Slow-phase displacement scores for the 2-h session also IA

approached significance for the dimenhydrinate group; the slow-phase decline

during this session fell short of the a <.05 level in comparisons with

both the predrug and the 1-h postinpestion sessions. A

Between Groups Comparisons. Overall analyses of variance for total slowphase output and for total number of eye movements yielded identical patterns

of significance, viz, for sessions (p < .01) and for the groups by sessions

interaction (I < .01). Both effects are due primarily to the variable (and

depressed) scores of the promethazine and dimenhydrinate groups during the

last two sessions as compared with the relatively stable scores of the placebo group (Figure 11).

Discussion.

The MA instructions tended to produce relatively stable session-tosession scores for slow-phase nystagmus regardless of the drug or dosage used

in these two studies. For every session, the slow-phase output for MA trials

exceeded the levels for REV instructions. REV resulted in more variability

of slow-phase responses across sessions, particularly for promethazine and

dimenhydrinate, and more variability for the double dosages than for the

single ones.

Counts of the number of eye movements yielded mixed results, Again MA

instructions produced relatively stable scores across sessions and the REV

condition yielded greater trial-to-trial variability. However, the number

of eye movements during each predrug session was consistently greater for

the REV condition than for MA instructions. This difference in output favoring REV persisted across all sessions for the placebo and mixture groups in

Study I, but was not maintained during the last two sessions for the placebo

group in Study II. The most marked changes occurred in the dimenhydrinate

and promethazine groups. The former evidenced a sharp decline in output 1-h

postdrug; that decline (to levels below those of the MA condition) showed

recovery during the final two sessions in Study I, but deepened during the

2-h session of Study II (under the double dosage) before some recovery was

evident. For promethazine the sharp drop did not occur until the 2-h session

in both studies and no recovery was apparent during the final sessions.

These differences are, of course, related to the different time courses of

peak action and duration of the drugs and their dosages.

20
Thus, 'he MA task effectively cancelled drug effects and stabilised the

nystagmic response across trials irrespective of the drug administered. REV

instructions permitted the depressant drugs (particularly at the higher dose A

levels) to affect nystagmus by means of an accelerated reduction in the

response output across sessions. The mixture, which combined an analeptic

(d-Waiphetamiue) with one of the depressants (promethauine), had effects on

nystagmuo that were more like the effects of a placebo.

The present findings regarding mental set are similar to those of a

previous study which assessed effects of secobarbital and of d-amphetamine

on the same nystagmus parameters (10). In that study the MA and REV

instructions produced about the same effects as were obtained in the present

report on both slow-phase and fast-phase measures of nystagmus. The effects

of secobarbital were more like the double dosages of dimenhydrinate and

promethazine in terms of the magnitude of the decline during REV, while the

effects of d-ampheltamine resembled those of the mixture group in the present

study.

Vestibular nystagmus during visual fixation yielded clear and consistent

effects of drugs. In both Study I and Study II, nystagmus increased (i.e.,

visual control of vestibular eye movements decreased) during the first 2

hours after ingestion of dimenhydrinate or promethazine and, at best, during

the final session, nystagmus output was back to the predrug level. Moreover,

the increase in nystagmus wns clearly greater for proups piven the double

dosages. The placebo group and the mixture group showed a different pattern

uf nystagmus activity, with general decline in output evident ar.ross all

sessions. The declines saggest improved control of vestibular eye movements

by means of visual fixation. Similar but less marked results were evident

for the involuntary ocular l'ollowing movements generated by optokinetic

stimulation. Optokinetic effects were clearer for the double dosages which

reduced both the speed of the following movements (reflected in less slowphase displacement) and the frequency of fast-phases (smaller number of

beats) thereby increasing the discrepaa&cy between the speed of the moving

object and the speed of the eye. It is of more than passing interest that

the mixture group showed none of these negative effects.

These results and others (1,8,10,13,14,15) suggest that moderate

dosages of depressant drugs have effects on vestibular nystagmus that are

different depending upon the presence or absence of vision and the mental

set of the subject. With respect to the latter, the instructional set

assumed by the subject during vestibular testing appears to be one of the

most important variables in determining overall slow-phase nystagmic outp"'.

SIn the present study, the alert set (mental arithmetic) prevented the

response declines that were evident under the nonalert set (reverie) for the

promethazine and dimenhydrinate groups. If alertness is not controlled, what

may appear to be a drug-induced alteration in the responses might be simply

a drug-induced alteration in the alertness of the subjects; such a difference

may have considerable practical as well as theoretical significance. In the

absence of instructions regarding arousal it is likely that subjects under

21

L• • • • -- • •,-.• J /•.. ••i,...•-- -- • .i" ,,- • , • - • • .. . . . • .. . .. . . . . . .. . ... . .
the influence of such drugs would drift into reverie-like states and thereby

show reduced vestibular nystagmus. It is of interest that in the present

study and in a previous one (10), the initial effect of REV instructions was

to decrease the slow-phase activity but increase the number of fa*L-phase

beats of nystagmus in darkness. With repetition of the REV condition (which,

one might assume, would increase the ability to relax and daydream), the

fast-phase activity also begins to fall off and such declines are accelerated

by depressant drugs. It woulS appear that both the eye-centering reflex and

the vestibularly induced slow-phase displacement mechanism are generally

suppressed during a fairly complete state of mental relaxation. However, the

two componento do not seem to be equally responsive to the introduction of

the REV szate since at least the frequency of the fast-phase activity is not

only initially reduced, but may show temporarily increased activity.

With respect to the influence of vision on nystagmus, both depressant

drugs reduced the involuntary (rptokinetic) following ability of the eye

(with the higher dosage) as well as the ability of an individual to suppress

vestibularly induced eye movements through visual fixation (with both dose

levels). These may be important modifications in practical situation involving visual judgments about moving objects in the one case; and, in the

other, in preventing blurred vision during motion. Of significance in this

regard is that the combination of d-amphetamine sulphate and promethazine

produced none of these undesirable consequences. In fact, the nptagmic

responses obtained from the mixture group in the prepert 'su.-y *.ppear very

much like those obtained in earlier studies (9,10) from subjec~d who were

given d-amphetamine sulphate alone. Thus, although the central action of

drugs that are effective in reducing malaise due to motion are still not

clearly defined (3,11,12), the mixture combination has distinct advantages

as a motion sickness preventive, viz, it has a high degree of efficacy in

reducing or preventing undesirable motion sickness symptoms without ocular

disadvantages that seem to be manifested by depressants alone. Other similar

combinations (e.g., scopolomine plus amphetamine (11,18), scopolomine plus

ephedrin (11,17), and promethazfne plus ephedrin (11,18)), which also have

proven highly effective as antimotion sickness preparations, are likely to

have this same advantage.

The available data also suggest that the effects of a drug on vestibular

nystagmus may be a poor indicator of its value in preventing motion sickness.

Alc.hol (14,15) and secobarbital (10), neither of which has any documented

usefulness as a motion sickness preventive, produce effects on vestibular

responses that are not unlike those of the 100-mg dose of dimenhydrinate or

the 50-mg dose of promethazine, both of which provide a reasonable degree of

protection against motion sickness (16). Moveover, assessments of the

capacity of drugs to combat motion sickness in many practical situations

should include as a possible adverse side effect the inability to maintain

visual fixation during motion.

22

____________________________

• • _ • .. ,• • . . • , ._ . • .. •,• . • •.,• .: ; • .•.,•• . . ,.. :.• .•: .... . ,..,_ .• • - • ..- , .-- .. , ;..,.. ....... . .:. *- . |
While the basic efficacy of sn antimotion sickness drug is rooted in the

reduction cf motion sickness symptoms, sites of drug action and adverse side

effects are among the theoretical and practical considerations of drug usage

in transportation systems. This study examined the influence of three

establichid antimotion sicknesm drugs on nystagmic ey. movement responses

(i) to angular acceleration (whole-body movement).under conditions of mental

alertness or relaxation and with vision either permitted or denied, and (ii)

to optokinetic stimulation (,visual field movement). Dimenhydrinate and

'nrcmethazine, particularly at higher dose levels, reduced optokinetic

aystagmus, thereby making less accurate the following ability of the eye.

During whole-body motion in darkness, there was little evidence of any

placebo-drug differences in the vestibular response under alert conditions;

however, under relaxed conditions, dimenhydrinate and promvthauiue produced

significant declines in the vestibular eye movement measures. With visiou

permitted during angular acceleration, these same drugs also interfered

with the ability of the individual to fixate adequately on a visual task.

Subjects who received a combination drug promethazine plus d-amphetamine)

responded much like placebo subjects under the visual task condition,

demonstrating an ability to suppress vestibular eye movements and thereby

maintain good visual fixation on a task. Thus, the effect of a drug on

vestibular or optokinetic nystagmus may be a poor indicator of its value in

preventing motion sickness. Moreover, assessment of the efficacy of drugs

to combat motion sickness in many practical situations should include as a

possible adverse side effect the inability to maintain visual fixation

during motion.

23
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3. B.IandtTh., J. Dichgans, and W. Wagner. 1974. Drug effectiveness on

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24

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9.Clis .EadR .Pe 92 mhtmnaosl n ua
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h •. , " . ..,• !. • I:'• •i!." ....... , "-• •,

• . ,,, : :.

{•'."

.. . . . ", .,•

• ,. v " .

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•angular accelerations. .,.Aerosp. Med. 42: 959-970.. Sto . --. ..... . . . •i.. '•

• 15. SchrOeder, 'D, J. , 1972. someeffects of.alcohdl.on nystagmus and r ":i'i" . " ':'i\'•''•''!:•i" S.... vertigO during ca•orlc and:,op.tokinetlc stimulation. -Ann. Otd•:i-"": ,... )

Rhino-• Laryngol. 81: 218-229. " ; ' " " .... :;:•

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Sl

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18. Wood, ¢° D. and A. Graybiel. 1970• Evaluation of anttmotion sickness .iii

drugs: A new effective remedy revealed Aerosp, Med, 41: 932-933, ' ; •-•!

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