The effects of phenindamine sleepiness and psychomotor

tar&ate on performance

Theodore J. Wiiek, Jr., DrPH, David A. Canestrari, MS, R. David Miller, Joanna Y. Yang, PhD, and Donald K. Riker, PhD Shelton, Corm.

BS,

Phenindamine, an H,-receptor antagonist that was developed ulmost 50 years ago, has been associated with both drowsiness and insomnia. Since its central nervous system profile has not been well characterized, we used a series of psychomotor tests to conduct two studies. In the ,first, 12 subjects received single oral doses of phenindamine (25 mg), diphenhydramine (50 mg), terfenadine (60 mg), or placebo in a four-way crossover study. Psychomotor tests included choice reaction time (CRT), tracking, and hand steadiness (HS). In the second trial, 1.5 .sut@ts received single oral doses of phenindamine (2.5 mg), pseudoephedrine (60 mg), phenindamine und pseudoephedrine, diphenhydramine (50 mg), or placebo in ahve-way crossover study. Psychomotor tests included CRT, HS, and a task that divided attention between tracking and reaction time. Introspective drowsiness was measured in both trials with use of a visual anabg scale (VAS) and the Stanford Sleepiness Scale (SSS). All assessments were made before and I ( 3, and 5 hours after drug administration. In the Jirst trial, diphenhydramine produced .significant impairment relative to placebo (p < 0.05) in CRT- tracking, and HS tasks and higher SSS and VA/Asscores, with peak effect noted at 3 hours. Phenindamine did not significantlv differ from placebo or terfenadine. In the second trial, diphenhydramine produced signi$cant impairment relative to placebo (p < 0.05) in CRT, divided attention, HS, and VAS, and SSS. ulso peaking at 3 hours. Stanford Sleepiness Scale scores after phenindamine were greater than placebo at 3 hours (p < 0.05) but significantly less than diphenhydramine (p < 0.05). Psychomotor test scores after phenindamine and pseudoephedrine, either alone or in combination. were consistently and most often significantly better than diphenhydramine and not significantly different from placebo. Taken together, these data indicate that sleepiness after u single dose of phenindamine is rank ordered between placebo and diphenhydramine. We speculate that the relative lack of impairment reflected by the psychomotor tests .from phenindamine may be related to its paradoxic sedative and stimulaton~ yflecrs. (J AI.I.ERW C‘IJP: IMMUNOL

1992;90:953-61.)

Key words: Phenindamine, diphenhydramine, nntagonists. sleep, psychomotor performance

H,-receptor antagonists have been available for more than 50 years. A second generation of compounds that has recently entered the clinical area distinguish themselves from the older drugs by being relatively nonsedating and offering a potentially

From Regulatory and Clinical Development, Richardson-Vicks USA (A Procter & Gamble Company), Shelton, Conn. Presented, in part, at the Forty-eighth Annual Meeting of The American Academy of Allergy and Immunology. Orlando, Fla., March 1-6, 1992. Received for publication May 2R. 1992. Revised Aug. 14, 1992. Accepted for publication Aug. 24, 1992. Reprint requests: Donald K. Riker, PhD, Procter & Gamble Company, Regulatory and Clinical Development, 11370 Reed Hartman Highway, Cincinnati, OH 45241. l/1/41987

terfenadine,

pseudoephedrine,

Abbreviations

CRT: HS: VAS: SSS:

H.-receptor

used

Choice reaction time Hand steadiness Visual analog scale Stanford SleepinessScale

broader clinically useful profile. M These newer agents include terfenadine, astemizole, loratadine, cetiritine, azelastine, and others. ‘. ’ The favorable saporific profile of these drugs has been clinically documented by a low incidence of sedation in clinical trials,’ 7 no evidence of shortened latency to daytime sleep,‘-” and no significant impairment of psychomotor performance .‘. ‘“. ’ ’ Although no H,-receptor antagonist can 953

954 Witek et al. TABLE I. Psychomotor phenindamine tartrate

J ALLERGY CLIN IMMUNOL DECEMBER 1992

performance

Evaluation

Choice reaction time’, ’ Tracking’

Hand steadiness’,’ Divided attention*

Digit symbol substitution’

Arithmetic task’ Grammatical reasoning’ Stanford sleepinessscale’.Z Visual analogue scale’.*

tests and subjective

sleep

scales

used in two trials

Description

Primary

Subject respondsimmediately to the words “true” or “false” that appear randomly on the computer screenby pressing appropriately labeled button Using a joystick, subjectstrack a constantly moving cursor within the area defined by a sine wave

evaluating response

measure

Reaction time (msec)

Deviation from sinusoidal tracing (root mean square deviation) Subject is required to hold a small metal-tipped Percent contact’, Zand number probe within the lumen of a small metal jack of touches* Subject is required to divide attention while simulta- Deviation from circle (root neously performing compensatory tracking (keep a mean square deviation) and crosshairon a moving circle) and visual search reaction times (msec) activities (monitoring lights at the screen’sperimeter or in the moving circle) A paper and pencil task requiring subjects to insert Number of substitutions an appropriate symbol on a form indicated by a code at the top of the page A seriesof two digits appearing on the computer Correct responses screenhas to be added to another digit that ap pears at the beginning of the test A subject seesthree letters on the computer screen Correct responses for a short time and then has to answer questions on the order of the letters A widely used scale that describes,in words, seven Absolute score levels of sleepinessfrom least sleepy (1) to most sleepy (7) A computerized scale (50 characterswide) that is Scale in characters anchored by “not at all . . .” to “extremely . . .”

‘Study1. ‘Study2. be considered purely nonsedating, this label generally gets applied when soporific effects do not differ from placebo treatment. * The soporific profile of many of the first generation H,-receptor antagonists has not been well characterized. Pheninclamine tartrate is an Hi-receptor antagonist currently available by prescription (Nolabist) and approved for over-the-counter sale in the OTC Tentative Final Monograph. I2 It has been associated with both drowsiness and insomnia in older reports. 13-‘*In an attempt to better characterize this drug’s soporific profile, we conducted two studies of daytime sleepiness and psychomotor performance. Our observations form the basis of this report. METHODS Design Both studies were conducted in a randomized, doubleblind, placebo-controlled, crossover format. At least 72 hours were required between each leg of each study. Both studies were granted institutional review board approval, and all subjectsgave informed written consent.

Procedure Volunteers were recruited if they were between the ages of 18 and 45 years, in good health, and motivated to participate in the study. Subjects were disqualified from participation if they had a history, symptoms, or physical signs of asthma, hypertension, diabetes, thyroid disease, glaucoma, prostatic disease, ulcer, or bladder dysfunction. Within 30 days of starting the study, subjects were not allowed to be exposed to an investigational drug, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, phenothiazines, sedatives,or steroids. Those with a history of chronic antihistamine use, alcohol or drug abuse, abnormal sleep habits, and allergy or sensitivity to antihistamines or sympathomimetic decongestants were excluded. Also, those working evening or night shifts or excessive usersof caffeine were excluded. Good health was documented by a medical history and physical examination. At the time of entry screening, subjects received instructions on the psychomotor performance testing; 2 to 4 hours of intermittent practice in performing the psychomotor tests followed. Each time subjectsreported for treatment and testing they were qualified to participate on the basisof continued good

VOLUME SO NUMBER 6, PART 1

TABLE

_-

Soporific profile of phenldawlne

II. Anthropometric

and background

Age (yr) Study I (N = 12) Mean SD Study 2 (N = 15) Mean SD

TABLE (mean

Height (cm)

information

Weight kg)

on subject

Estimated sleep

weekend (hr)

Education level &r)

73.6 20.1

7.4 0.8

7.9 0.8

$4 i 1 :i

27.3 6.7

177.X 5.6

87.0 21.x

7.6 0.6

x.2 1.1

i5 6 it s “-_ - .._---

Mean

Jitteriness

I-.---.-

Estimated sleep

174.x X.4

Placebo

Alertness

weekday (hr)

31.2 x.7

III, A. Subjective assessments with use of visual r: SD) and change* at each time point listed

Sleepiness

volunteers

955

Baseline Change: Change: Change: Baseline Change: Change: Change: Baseline Change: Change: Change:

1 hr+ 3 hr+ 5 hr+ 1 hr+ 3 hr+ 5 hr+ 1 hr+ 3 hr+ 5 hr+

4.83 5.17 4.42 5.08 41.42 - 1.50 -3.50d -3.08 5.75 1.25 0.92 1 so

analog

scales

Terfenadine SD

4.45 4.88 6.84 7.39 9.03 6.97 7.60 8.61 8.10 2.34 3.75 3.71

Mean

health, including no upper respiratory allergy or infection, no use of medication during the preceding 72 hours, no consumption of alcohol within 24 hours, no caffeine consumption within 8 hours, and at least 7 hours of sleep the preceding night. An abbreviated version (approximately 10 minutes) of the performance battery was performed each morning for refamiliarization with the tests and environment. In both studies a complete assessment of subjective sleepiness and psychomotor performance was carried out before administration of drug and at 1, 3, and 5 hours after administration of drug. In the first crossover trial, subjects received single doses of phenindamine tartrate (25 mg), diphenhydramine HCl (50 mg), terfenadine (60 mg), or placebo. All drugs were supplied in capsules with the exception of terfenadine (Seldane tablets). Blinding was achieved by a double-dummy technique, with each subject receiving one capsule and one tablet at each dosing. In the second crossover study, subjects received a single capsule dose of phenindamine tartrate (25 mg), pseudoephedrine HCl(60 mg), phenindamine (25 mg) in combination with pseudoephedrine HCl (60 mg), diphenhydramine HCl (50 mg), or placebo.

1; actual

Phenindamine SD

X.50” 0.58 -1.08 0.92 39.25 - 0.42” 0.33” - 1.75 6.00 0.50 - 1.25 - 1.08

in study

8.68 6.68 1.40 10.75 X.94 7.15 3.52 7.77 5.64 6.17 4.90 4.70

Mean

7.25 5.25 4.50 0.75 40.25 -4.83 -4.50” - 1.25 3.50 3.25 3.42h 2.17

-

baseline

Diphenhydratine SD

5.82 7.53 7.56 3.28 9.85 6.31 6.10 4.33 3.42 4.65 3.87 5.44

-

&lean 5 X3

9 92” 16” [yd it x.92 42.5X -8.00 - 1 1.67 - 8.08 5.00 2.33 3 .X1” 1.67

-_-~ SD

6.38 11.29 13.76 17.24 7.20 Iif. 1s i 2.29 Ii.96 :i.o6 .4.6X 4.49 5.41)

Subjective ussessments and psychomotor tests. Subjective assessments focused on introspective sleepiness raings on the Stanford Sleepiness ScaleI” and a computerized visual analog scale in which the subjects marked the scale on the screen using the space bar and enter key of the computer. Alertness, jitteriness, and mouth dryness were also assessed with use of a visual analog scale. Al1 scales were anchored by the words “not at all“ to “extremely.” Subjective ratings always preceded the performance tasks. Psychomotor performance was evaluated with use of modified computerized tests taken from a vigilance test battery described by Rosa et al.‘” (Table I). Since the tirithmetic and grammatical tasks were not found to be sensitive to diphenhydramine (i.e., no significant impairment). they were not included in the second study. Divided attention and digit symbol substitution tasks were added to the second study. Only choice reaction time and hand steadiness were common to both trials. Test batteries in both studies required approximately 30 minutes to complete. Statistical design und analysis. Both studies were designed with use of a complete Latin square design assuring that every treatment followed every other treatment equally often. Data were analyzed by an anatysis of variance

956

Witek

TABLE (mean

J ALLERGY CLIN IMMUNOL DECEMBER 1992

et al.

III, B. Subjective assessments with use of visual +- SD) and change* at each time point listed

Alertness

Jitteriness

*From

baseline

Baseline Change: 1 hr+ Change: 3 hr+ Change: 5 hr+ Baseline Change: 1 hr+ Change: 3 hr+ Change: 5 hrf Baseline Change: 1 hr+ Change: 3 hr+ Change: 5 hr+ value.

A positive

in study

2; actual

baseline

Phenindaminelpseudoephedrine

Mean

SD

Mean

SD

Mean

SD

5.33 - 1.00 0.40

4.61 2.98 2.61

6.47 - 1.07

3.81 5.90

5.60 1.20

4.64 4.38

3.20 44.27 -0.40 -0.33d -3.20 6.47

8.24 5.34 1.84 1.91 7.75 8.05 5.70 6.99 6.89

-2.00 -1.07 43.87 -0.20

4.69 6.50 5.50 4.46

- 1.60 - 1.60 -0.73

change

scales

Pseudoedphedrine

Placebo

Sleepiness

analog

indicates

1.60’. d -0.27 5.40 0.07 1.87 2.27

an increase

in symptom,

i.e.,

0.07 0.47 44.20 -2.87

3.71 4.24 5.92 5.49

4.21

- 0.73d

4.42

6.41 6.17 3.37 6.21 5.28

-2.00 5.67 -0.13 1.67 1.00

5.69 5.65 3.40 4.67 4.69

more

sleepy,

more

alert,

or more jittery.

+ Hoursafter dose. Superscript a >placebo;

labels represent b Xerfenadine;

pairwise comparison differences at p < 0.05. ’ >phenindamine; d Miphenhydramine; ’ >pseudoephedrine;

TABLEIV. Primary variables change* at each time point

from listed

the divided

attention

Placebo Mean

Baseline Change: 1 hr+ Change: 3 hrf Change: 5 hr+ Perimeter responsetime Baseline Change: 1 hrf (msec) Change: 3 hrf Change: 5 hrf Baseline Central response time Change: 1 hr+ (msec) Change: 3 hr+ Change: 5 hr+ Tracking deviation

22.0 -0.05 0.58

1.70 513.39 20.25 40.56 52.69" 587.30

11.05 37.82 40.47

task(study

’ >phenindamine/pseudoephdrine.

2)actual

Pseudoephedrine

baseline

(mean

+ SD)

Phenindaminelpseudoephedrine

SD

Mean

SD

Mean

SD

4.4 4.22 2.04 5.15 121.54 63.62 46.47 59.77 102.71 41.62 50.84 58.86

22.6 -0.96 -0.83 -0.66 537.18 -9.14 14.74 36.09 607.28 -3.51 16.71 28.25

6.8 3.28 2.73 1.67 130.64 64.35 52.97 69.20

22.0 0.61 0.17 0.87 539.14 10.05 7.33 8.09 599.34 9.27 21.45 25.30

5.8 2.94 4.08 1.71 132.77 52.41 47.86 33.65 129.37 45.41 35.29 30.57

133.11 69.66 44.59 57.42

*From baseline value. A positive change indicates an increase in tracking deviation or in response + Hours after dose. Superscript labels represent significant pairwise comparison differences at p < 0.05. a >placebo; ’ >phenindamine; ’ >pseudoephedrine; f >phenindamine/pseudoephedrine.

(ANOVA) for a crossover design. All p values represent two-tailed tests. SAS (Statistical Analysis System; Gary, N.C.) computer software was used for all analysis. RESULTS Subjects Anthropometric and background information on the subject volunteers are summarized in Table II.

Subjective

and

time,

i.e.,

poorer

tracking

or slower

response

assessments

Introspective sleepiness data assessed by the Stanford Sleepiness Scale (SSS) is illustrated in Figs. 1, A and B for the first and second study, respectively. In the first study, diphenbydramine induced the highest degree of subjective sleepiness as reflected by SSS scores, with a peak observed at 3 hours after the single dose. At this time diphenhydramine-induced

Soporific profile of phenidarmp

VOLUME 90 NUMBER 6, PART 1

Phenindamine Mean

4.67 7 80” c ‘... 1.40 0.27 44.00 -2.27 -. 2.20” --0.67 4.67 0.93 2.20 0.67

Diphenhydramine SD

4.43 3.45 6.07 4.23 5.90 3.31 7.66 4.78 5.41 2.19 4.44 2.64

Phenindamine Mean

23.3 1.79 2.17 0.66 562.90 -2.63 6.67 5.01 617.49 12.41 27.0X 14.77

Mean

7.27 2.00 g,33a C.c 3.00 42.21 - 2.93 -9.41 - 4.07 7.20 0.67 3.47” 4.33”

SD

5.54 6.45 8.67 4.68 8.70 7.60 6.56 5.90 8.71 4.94 4.12 6.22

Diphenhydramine SD

8.0 4.31 5.43 3.74 151.97 58.98 75.44 68.64 149.52 53.76 59.95 37.05

Mean

22.4 3,958, e.! 7.91”. c.e. 1.86’ 542.17 23.37 50.71 27.40 601.37 59.50”‘.’ 79 60% c.C. 41.08

SD

8.2 4.19 14.04 3.31 153.10 32.01 87.63 60.09 137.45 51.97 55.20 73.78

sleepiness was significantly greater than the degree of sleepiness reported after either phenindamine, terfenadine, or placebo (p < O.OS), each of which were not significantly different from one another. Subjective responses from the visual analog scales (VAS) are summarized in Table III A. Diphenhydramine-treated subjects reported significantly higher levels of sleepiness at 3 hours than after taking phenindamine, terfenadine, or placebo (p < 0.05). No significant differences were noted among the responses after phenindamine, terfenadine, or placebo.

955

Other subjective ratings on the VAS indicated xmali but statistically significant higher levels :)t’ jittcrines\ after phenindamine and diphenhydramine cmq.xared with terfenadine, but not placebo. Also. subjects w ported significantly lower levels of alertness 3 hours after diphenhydramine compared with either plnccht, terfenadine, or phenindamine. In the second study diphenhydramme rz~i~d in significantly higher scores on the Stanford Sleepiness Scale than those reported after placebo or pseudoephedrine at 1 and 3 hours; its peak effect .~a\ c!bserved at 3 hours (Fig. I 1 B). Sleepiness scotes 1 and 3 hours after phenindamine tartrate were all c&l!‘icantly higher than after placebo. .;\t 3 hc?iIr\ at’tct dosing, however. phenindamine resulted in t,lgniffcantly less sleepiness than that reported after diphrnhydramine, indicating true rank ordering. The phenindamineipseudoephedrine combination resulted io higher sleepiness scores than placebo at 1 hour after dosing and significantly iower score\ than diphenhydramine at 3 hours. Sleepiness sc(Brc:,1 hur aht~r dosing were significantly higher fo!- phen~ndaminc than for pseudoephedrine alone. Diphenhydramine also produced its peak ::tf’ect on the sleepiness VAS at 3 hours after dosing ~Tahle III B). This mean change in sleepiness rating W’R> significantly greater than after placebo. The peak sedative effect after phenindamine occun-ed 1 hour after dosing; at this point. phenindamine was significantly more sedating than pseudoephedrine and placcbr~. The mean sleepiness: score 3 hours after phenirldaminc. either alone or in combination with pseudoephedrine. was significantly less than that reported after diphcnhydramine. Pseudoephedrine given alone VW slightly stimulating, with significantly less sleepiness than diphenhydramine reported at 3 and 5 hours after CioGng. At 5 hours, pseudoephedrine also producs:i Gpnificantly less sleepiness than placebo. Other subjective VAS ratings indicated tha: thi; peak mean decrease in subject’s reported alertne\ls was ohserved 3 hours after ingestion of diphenhqdraminc. For the H, receptor antagonists. increased sisepincss was associated with decreased alertness. 1.1~ mean alertness score after diphenhydramine at 3 hours ww significantly lower than that after placebo Signiticantly less alertness was observed 3 hours alter phenindamine when compared with pseudoephedrine At this time, however, the decrement in alertness after phenindamine, either alone or in combinarion with pseudoephedrine. was significantly less than that induced by diphenhydramine. The only increax in aicrtness scores was observed 3 hours after inycstion of pseudoephedrine alone.

958

Witek

J ALLERGY CLIN IMMUNOL DECEMBER 1992

et al.

t-

A

0

1 HOUR

+

E TIME

3 HOURS --j AFTER DOSE

E

m Phanindamine 60mg m

25mg Diphenhydramine

t-

3 HOURS

)-

TIME

AFTER

Placebo m

i-

1 HOUR

Tetfenadine

+

Phenindamine/Pseudo ocphedrine 60mg

+

5 HOURS

5 HOURS

+

50mg

+

DOSE

q

n

Diphanhydramine Phenindamine 25mg

50mg

FIG. 1. Mean change in Stanford Sleepiness Scores after A, placebo, terfenadine, phenindamine, and diphenhydramine (study 1); B, placebo, pseudoephedrine, phenindamine/pseudoephedrine, phenindamine, and diphenhydramine (study 2); p < 0.05; a, >placebo; b, xerfenadine; c, >phenindamine; d, >diphenhydramine; e, >pseudoephedrine, and t >phenindamine/pseudoephedrine. Positive change indicates more perceived sleepiness.

Jitteriness scores after diphenhydramine were significantly increased relative to placebo at 3 and 5 hours after drug. No statistically significant differences were noted among treatments for reports of mouth dryness; the largest increase was observed 1 hour after diphenhydramine dosing. Psychomotor

performance

In the first study choice reaction time significantly increased (i.e., slower response) 3 and 5 hours after diphenhydramine dosing compared with placebo treat-

ment. No statistically significant separations were noted for any of the other drugs (Fig. 2, A). The largest decrement in tracking ability ( 13%) was observed on the diphenhydramine-treatment day, with statistically significant impairment relative to placebo noted 3 hours after dosing. One hour after diphenhydramine dosing the hand steadiness of subjects was significantly worse compared with their own steadiness after taking placebo, terfenadine, or phenindamine. Three hours after dosing, subjects treated with diphenhydramine remained

VOLUME 90 NUMBER 6 PART 1

Soporific

I

$-,5.,

A

profile

of pherddmine

959

-L t---

1 HOUR

+

t-

3 HOURS

TIME

AFTER

m Terfenadine n P’acebo

l---

--i

5 HOURS

---j

DOSE

m Phenindamine m 60mg

25mg Diphenhydromine

3 HOURS

t-

50mg

z Ln 75.0 _ .I! x QJ SO.0 E I.2 FI

25.0 _

5 F

0.0 .

s ~-25.0 E Z yo.0

.

0

k

1 HOUR

-f

t-

TIME AFTER Phenindamine/Pseudo oephedrine 60mg FIG. 2. Mean diphenhydramine phenindamine, >phenindamine; doephedrine.

--I

5 HOURS

-j

DOSE m

m Diphenhydramine Phenindomine 25mg

50mg

in choice reaction time after A, placebo, terfenadine, phenindamine (study 1); B, placebo, pseudoephedrine, phenindamine/pseudoephedrine, and diphenhydramine (study 2); p < 0.05; a, >placebo; b, xerfenadine; d, >diphenhydramine; e, >pseudoephedrine, and t >phenindamine/pseuPositive change indicates increased reaction time (i.e., impaired response).

change

significantly impaired compared with placebo and phenindamine treatment. At 5 hours subjects treated with terfenadine had significantly less hand steadiness relative to placebo; however, the magnitude was small. Neither the grammatical reasoning nor the arithmetic tasks were impaired by any drug relative to placebo. In the second study diphenhydramine induced significant slowing of choice reaction time when compared with placebo at I and 3 hours. At all time points

and c,

the reaction time after diphenhydramine was significantly slower than phenindamine and pseudoephedrine, either alone or in combination. In addition, the improvement in reaction time 1 hour after pseudoephedrine ingestion was significantly different from the reaction time after phenindamine (Fig. 2. B). In the divided attention task. diphenhydramine induced statistically significant decrements in tracking ability relative to placebo at 1 and 3 hours after dosing (Table IV). The impairment after drphenhy-

960

Witek

et al.

dramine was also significantly different from phenindamine at 3 hours after dosing and different from phenindaminelpseudoephedrine 1 and 3 hours after drug. The improvements in tracking ability after pseudoephedrine alone were significantly different from the scores after diphenhydramine at all three time points. Diphenhydramine did not significantly impair perimeter response time. At 5 hours after drug, however, the slight impairment after phenindamine, either alone or in combination with pseudoephedrine, was significantly less than the impairment after placebo. By contrast, diphenhydramine caused significant increase in central response time (i.e., slower response) when compared with placebo and all other treatments at both 1 and 3 hours after drug (Table IV). The percent of contact of a handheld probe with the sides of a small jack did not differ significantly among treatment groups, with the exception of the greater percent contact after diphenhydramine relative to the phenindamine / pseudoephedrine combination. A significant difference was also noted in the change from baseline in number of touches (12.7 vs 55.6). The increase in the number of touches 1 hour after diphenhydramine was significantly different from that observed after placebo. At 5 hours after pseudoephedtine, there were approximately 20 fewer touches than the predrug observation, which was significantly different from the increased number of touches (26.5) after placebo. No differences occurred among treatments in the digit symbol substitution test. DISCUSSION Hi-receptor antagonists have been available for approximately 50 years. Until the relatively recent introduction of a second generation of “nonsedating” compounds, the clinical use of these widely used drugs was hampered by their propensity to cause drowsiness. The degree of drowsiness among these original compounds, however, has not been extensively studied. In the trials reported here we studied the effects of phenindamine tartrate on psychomotor performance in healthy subjects. Phenindamine, which was introduced in the late 1940s was chosen because previous reports indicated that its psychopharmacologic properties may differ from other first generation compounds. 13-18Diphenhydramine, one of the most sedating antihistamines, was chosen at 50 mg as a positive control, and terfenadine (60 mg), the first nonsedating drug introduced, was chosen as a negative control. The introspective drowsiness reported after phenindamine was generally ranked between placebo

J ALLERGY CLIN IMMUNOL DECEMBER 1992

and diphenhydramine. Although not significantly different from placebo or terfenadine in the first trial, phenindamine was significantly different from placebo in the second trial, possibly because of the larger sample size. In both trials, diphenhydramine-sensitive psychomotor performance tests were not altered by phenindamine. In addition, terfenadine and pseudoephedrine did not significantly alter performance tests. The impairment after diphenhydramine was similar to other trials of psychomotor performance,21 with peak effects observed 2 to 3 hours after dosing. The lack of impairment after terfenadine in our study was also consistent with previous reports of this agent.5 Finally, the lack of significant alteration in daytime performance after pseudoephedrine corroborates previous observations,** including the trend for slight improvement in daytime performance scores. Phenindamine, which was clearly less sedating than diphenhydramine, may be considered a mildly sedating compound. As a pyridindine, phenindamine is structurally unique among the first generation compounds, most of which fit into the ethanolamine (e.g., diphenhydramine), alkylamine (e.g., chlorpheniramine), or ethylenediamine (e.g., pyrilamine) structural classes. Its uniqueness is supported by recent observations that latency to daytime sleep, as measured by the Multiple Sleep Latency Test (MSLT), was not different between terfenadine or placebo.23 In a recent trial of phenindamine in patients with seasonal allergic rhinitis, however, the reported incidence of sedation after phenindamine (17%) was significantly greater than after placebo (3%).24 Nervousness and insomnia were also reported significantly more frequently in subjects treated with phenindamine.24 In addition, central nervous system stimulation has also been reported to be more frequent than after terfenadine or placebo during 1 week of use in a group of healthy volunteers. 25 It may be that the relative lack of impairment observed in our trial is related to its stimulating effects. Although phenindamine has been shown to increase the duration of the pressor response to 1-norepinephrine ,26the mechanism of its stimulatory properties remains unknown. In conclusion, phenindamine tarn-ate appears to be a unique first generation H,-receptor antagonist. It is clearly less sedating than diphenhydramine, does not shorten latency to daytime sleep,” and under the conditions of our study did not significantly alter performance on psychomotor performance tests. However, in actual use, phenindamine has recently been shown to cause sedation as well as nervousness and insomnia with extended dosing in patients with allergic rhinitis.24 A high incidence (51%) of insomnia has also been reported during 1 week of therapy in a group of

VOLUME 90 NUMBER 6. PART

Soporific

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of pheaide*~irie

961

1

healthy volunteers. 25 Therefore phenindamine does not exhibit a nonsedating profile and may have paradoxic stimulatory and sedative properties. The authors thank Shirley Ward, MD. for their assistance

Madden, RN, and Kenneth in the conduct of these trials.

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