CLINICALTHERAPEUTICSVVOL.19, NO.

1, 1997

Sedative Effects of Antihistamines: Safety, Performance,

Learning, and Quality of Life

ThomasM. Nolen, MD, FAAFP

Department of Family Medicine, College of Community Health Sciences, University of
Alabama, Birmingham, Alabama

allergic rhinitis. In contrast, the now-

preferred nonsedating agents do not read-
Antihistamines are frequently part of the ily cross the blood-brain barrier, do not
treatment regimen for seasonal and peren- produce CNS side effects, and, therefore,
nial allergic rhinitis occurring alone or in do not cause sedation or performance im-
conjunction with associated airway disor- pairment. The nonsedating agents provide
ders, such as asthma, sinusitis, and otitis a safer alternative for patients with allergic
media with effusion. These agents are also rhinitis. Their use can increase patient sat-
frequently prescribed for the treatment of isfaction with the health care received. Key
urticaria to eliminate the need for long- words: antihistamines, sedation, safety, per-
term corticosteroids. This paper reviews formance, learning, quality of life.
the side-effect profile of the sedating and
nonsedating agents (a classification given
INTRODUCTION
these drugs by the US Food and Drug Ad-
ministration) in terms of patient satisfac- The major adverse side effect of antihis-
tion and quality-of-life parameters. Be- tamines has traditionally been sedation.
cause the sedating antihistamines cross For patients with allergic rhinitis who may
the blood-brain barrier more quickly and already experience decreases in verbal
easily than the nonsedating antihista- learning, decision-making ability, and
mines, they produce more central nervous psychomotor speed during the allergy sea-
system (CNS) effects, further exacerbat- son,’ the effects of sedating antihistamines
ing the decreases in decision-making, may further exacerbate the impairment of
verbal learning, and psychomotor skills these central nervous system (CNS) func-
already experienced by the patient with tions and thus may have important per-

0149-2918/97/$3.50 39
 CLINICALTHERAPEUTICS@

formance implications in the workplace, lergic rhinitis with sedating antihistamines

the classroom, and the home. was recently estimated at $3.8 billion.6
Large numbers of allergy sufferers may Sedating and nonsedating antihista-
experience adverse CNS effects from se- mines are often used to treat both sea-
dating antihistamines. According to 1988 sonal and perennial allergic rhinitis alone
figures, approximately 22.4 million peo- or in conjunction with associated chronic
ple in the United States (9.3%) have al- airway diseases (eg, asthma, sinusitis, oti-
lergic rhinitis.2 An earlier report estimated tis media with effusion, nasal polyps). An-
the incidence of self-reported upper respi- tihistamines are also prescribed for the
ratory allergy at 41.5 million people treatment of chronic urticaria, to obviate
(17.7% of the population), based on pro- the need for long-term corticosteroids.7
jections from a national probability sam- This paper reviews the sedative effects of
ple of 3800 households comprising 10,300 antihistamines on patient safety, perfor-
people.3 mance, learning, and quality of life.
Data from the 1985 National Ambula-
tory Medical Care Survey“ reveal that 9.8
CLASSIFICATION OF
million physician visits were made for al-
ANTIHISTAMINES
lergic rhinitis in 1985 and that 92% of
these visits resulted in prescriptions for The US Food and Drug Administration
treatment. The direct and indirect costs of (FDA) classifies antihistamines as either
treating allergic rhinitis and associated sedating or nonsedating (Table Is-29) (J.
airway diseases are estimated to be as high Hankin, JD, FDA, Division of Drug Mar-
as $8.9 billion per year5 In fact, the an- keting, Advertising, and Communication,
nual cost of lost productivity to employ- personal communication, 1995). Sedating
ers and society as a result of treating al- antihistamines or their metabolites cross

Table I. Classification and effects of representative antihistamines for seasonal and peren-
nial allergic rhinitis.

US Food and Drug Effect on

Drug AdministrationClassification Performance and Cognition

Astemizole Nonsedating
Fexofenadine Nonsedating
Loratadine Nonsedating
Terfenadine Nonsedating
Cetirizine Sedating
Chlorpheniramine Sedating
Clemastine Sedating
Diphenhydramine Sedating
Hydroxyzine Sedating
Promethazine Sedating
Triprolidine Sedating

*Reported in FDC Reports, “The Pink Sheet” (July 31, 1996).

40
T.M. NOLEN

the blood-brain barrier and block hista- terfenadine.” In the same study, fatigue
mine-l (Hi) receptors in neural tissues in occurred in 4.3% of chlorpheniramine-
the CNS. As a result, these agents impede treated patients and in 1.5% of terfena-
physical and mental function. Although dine-treated patients. Placebo-controlled
the precise mechanism of action for seda- safety studies comparing the nonsedating
tion remains unknown, it is recognized loratadine with the sedating clemastine
that the molecules of the sedating antihis- and with placebo revealed that patients
tamines are smaller than the molecules of talking loratadine had an incidence of se-
the newer, nonsedating agents (ie, astemi- dation comparable with that of placebo.12-17
zole, fexofenadine, loratadine, and terfen- By contrast, a 21% incidence of sedation
adine), making it easier for the sedating was noted in patients taking clemastine.12
agents to cross the blood-brain barrier.’
Among sedating antihistamines, the
Sleep &dies
ethanolamines, phenothiazhies, and piper-
azines have the greatest sedative effects. Sleep latency testing has revealed that
Drowsiness has been reported in approxi- the sedating antihistamine diphenhydra-
mately 50% of patients taking ethanol- mine more readily induced sleep than did
amines.s Hydroxyzine, a piperazine anti- terfenadine or placebo.7 Several sedating
histamine, is prescribed specifically for antihistamines, such as promethazine and
its sedative properties.7 Cetirizine, a newer chlorpheniramine, adversely impact
sedating antihistamine derived from hy- awakening and cause reduced alertness,
droxyzine, produces somnolence greater as measured by the Leeds Sleep Evalua-
than placebo?,s tion Questionnaire,‘* a self-assessment
The nonsedating agents are now pre- tool that requires patients to respond to a
ferred for allergic rhinitis and urticaria9 series of 10 questions concerning sleep
and are being used with increasing fre- and awakening.
quency in atopic dermatitis as well. The In addition to their effect on alertness
nonsedating antihistamines do not readily after awakening, some sedating antihista-
penetrate the blood-brain barrier, which mines may also prolong sleep. This was
may partially account for their lack of demonstrated in a double-masked study
sedative effects. In addition, the nonsedat- of 12 poor sleepers given placebo,
ing agents have a greater affinity for pe- promethazine 20 mg, or promethazine 40
ripheral rather than central H, receptors.9 mg.19 Promethazine in either dose in-
creased total sleep time by 1 hour com-
pared with placebo and reduced the num-
SEDATING ANTIHISTAMINES
ber of awakenings during the first 4 hours
Sedation occurs in as many as 10% to of sleep.
50% of patients using sedating antihista- A variety of objective and subjective
mines.‘O In a double-masked, placebo- tests measure the degree of sedation and
controlled, multicenter study of allergic performance impairment in patients taking
rhinitis patients, drowsiness was reported antihistamines. 1o,2oObjective assessments
by 18.8% of patients taking the sedating include choice reaction time, critical flicker
antihistamine chlorpheniramine and by fusion, digit-symbol substitution, driving
7.6% of patients taking the nonsedating tests, and the multiple sleep-latency test.

41
 CLINKAL THERAPEUTICS’

Subjective assessments include the Profile evoked electroencephalogram (EEG) re-

of Mood States Questionnaire and the Stan- sponse.22 The same effects have also been
ford Sleepiness Scale. Objective tests have documented in pediatric patients.23 Wgi-
an important advantage over subjective lance tests have demonstrated slower re-
tests because patients whose perfotmance action times among hydroxyzine-treated
and alertness are affected by antihistamines patients versus placebo-treated patients.%
do not always perceive their impairment, Sedating antihistamines such as triproli-
as is common with alcohol use. dine impair visual acuity compared with
Among 12 volunteers participating in a nonsedating antihistamines.25 Phenothi-
double-masked, modified, multiple sleep- azine, clemastine, and chlorpheniramine
latency test, those given diphenhydramine produced impairment in adaptive tracking
were nearly 50% sleepier than those given tests involving visuomotor coordination.26
terfenadine.i7 In another study involving Chlorpheniramine and triprolidine nega-
16 healthy subjects, diphenhydramine also tively affected the ability to drive a car27928
decreased the mean latent period to stage The sedating effects of hydroxyzine and
1 sleep? cetirizine were noted in patients with
chronic urticaria. Sedation occurred in 36%
of the hydroxyzine-treated group and in
Performance Testing
22% of the cetirizine-treated group.7 In a
Sedating antihistamines impair perfor- separate study, a dose-response relation-
mance by affecting sustained attention, ship was seen between the incidence of
cerebral processing, visual function, and somnolence and the amount of cetirizine
reaction time. Chlorpheniramine produced taken. Patients receiving cetirizine 10 mg
greater sedation and a slowed cerebral pro- or 20 mg exhibited a significantly greater
cessing rate compared with placebo in a incidence of sedation than those receiving
study evaluating cognitive effects through cetirizine 5 mg (Figure 1).28These dose-

Placebo Cetirizine Cetirizine Cetirizine

(n = 103) 5 mg/d 10 mg/d 20 mg/d
(n = 102) (n = 106) (n = 104)
Figure 1 Somnolence among patients with seasonal rhinitis taking cetirizine versus
placebo. Adapted with permission from Falliers et al.29

42
T.M. NOLEN

related sedation rates arc important factors ers exhibited weaving behavior typically
considering that more than 80% of patients, observed in subjects with blood alcohol
when given the option, titrated their dose levels of 0.05%, lasting up to 4 hours. Al-
of cetirizine higher than 5 mg to achieve though the drivers treated with triprolidine
symptom relief.3o were aware of their hampered performance
The sedating antihistamine triprolidine 1 to 2 hours after taking the agent, they no
hindered visuomotor coordination and in- longer felt sedative effects 3 to 4 hours af-
creased radial error at 1.5 to 7.5 hours af- ter drug ingestion, even though their per-
ter drug administration compared with formance remained impaired.
placebo.31 Triprolidine also reduced digit- A separate study involving 27 subjects
symbol test scores, symbol copying capa- also found that triprolidine impaired the
bilities, the flicker fusion threshold, and ability of drivers to maintain a steady lat-
dynamic visual acuity at various times af- eral position in highway traffic.34 The
ter drug ingestion.31 standard deviation of lateral position
(SDLP) assessed over a lo-km course was
Driving higher in drivers given triprolidine (5 mg
Numerous studies report on driving per- twice daily) than those given placebo. The
formance impairment in patients taking drivers who took triprolidine in this study
sedating antihistamines. In an investiga- experienced a lessening of self-perceived
tion examining the incidence of drug use sedation by day 4 of treatment. Cetirizine
among individuals killed in driving acci- 10 mg also increased the SDLP in this
dents in Ontario, Canada, during a l-year study, although the difference was not sta-
period, sedating antihistamines were de- tistically significant.
tected in 12 of 401 fatally injured driv- Ramaekers and colleagues35 studied 16
ers.32 The adjusted culpability rate for an- healthy volunteers treated with cetirizine
tihistamines in this study was 72% and found that the drug was associated
compared with 87% for alcohol, 90% for with increased sedation and impaired driv-
cannabinoids, and 97% for tranquilizers/ ing performance. The SDLP was in-
antidepressants. creased in drivers given cetirizine (10
A Japanese study found chlorphenir- mg) and alcohol (0.72 mg/kg lean body
amine to be associated with an increased mass) versus placebo and alcohol. In ad-
risk of inducing sleepiness during driv- dition, cetirizine alone produced eleva-
ing.33 Of 10 patients given the drug, 6 tions in the SDLP scores compared with
could not finish a 150minute continuous placebo. Early termination of three driv-
driving test. ing tests was necessary because of
The sedating antihistamine triprolidine drowsiness-two in drivers who ingested
impairs driving performance similarly to placebo plus alcohol and one after the in-
alcohol, according to road testing con- gestion of cetirizine and alcohol. Drivers
ducted in the Netherlands.28 Three tests reported feeling most drowsy after taking
were used to assess a driver’s ability to the cetirizine and alcohol combination.
maintain a steady position in the slow-traf- EEG activity measured during driving
fic lane of a roadway while driving at ap- was altered significantly by cetirizine.
proximately 60 miles per hour. Following The investigators concluded that ceti-
administration of 10 mg of triprolidine, driv- rizine produced acute sedation. They cau-

43
 CLINICAL THERAPEUTICS’

tioned that even drugs that cause a low Currently, 35 states and the District of
level of sedation may prove dangerous Columbia recognize sedating drugs as im-
for driving when combined with other se- pairing driving performance and have en-
dating drugs or alcohol. acted laws prohibiting the operation of a
C~o~he~ne in conjunction with motor vehicle while under the influence
alcohol also negatively affected driving of such agents (Figure 2).36 Punishment
performance compared with placebo in for breaking these laws includes fines
18 women selected for study participation ranging from $100 to $SOOO,suspension
because of their propensity to experience or revocation of driving license for 1
sedation when taking antihistamines.27 month to 2 years, and imprisonment for 1
This randomized, double-masked, cross- day to 2 years, depending on the state.
over study tested the effects of chlor-
pheniramine 12 mg, the nonsedating anti- .&fmning
histamine astemizole 30 mg, and placebo, Performance in the classroom is also
followed 2.5 hours later by 0.5 mg/kg adversely affected by sedating antihista-
body weight of ethanol in a simulated car- mines. A study conducted in the Nether-
tracking test with a joystick mechanism. lands involving 52 primary-school chil-
Chlorpheniramine plus alcohol produced dren with allergy and 21 healthy students
significantly greater performance impair- demonstrated that learning was impaired
ment than astemizole or placebo. In con- in atopic patients compared with healthy
trast, performance while taking astemi- controls.37 Purthermore, treatment with
zole did not differ significantly from the sedating antihistamine diphenhy-
performance while taking placebo, dramine impaired learning to an even

Figure 2. States (shaded) that have enacted laws prohibiting driving while taking sedat-
ing drugs. Adapted from the US repaint of TFanspo~ation Digest of Stare
Alcohol-Highway Safety Related Legislation, 14th ed.s6

44
T.M. NOLEN

greater degree than the atopy itself. mance impairment in real-life situations.
Learning was assessed using computer- He also points out that many of these stud-
simulated role-playing activities that re- ies are conducted in healthy young sub-
quired children to manage farmland in jects and that performance may be af-
North Africa while dealing with variables fected differently in older individuals and
such as weather. Results of this study con- when other agents are used concomitantly.
firm that learning performance is nega-
tively impacted by the onset of allergic
Tolerance
rhinitis and further compromised by treat-
ment with sedating antihistamines. In a randomized, double-masked study
of 12 patients, 42 those treated with di-
Awareness phenhydramine three times per day for 3
It is significant that the sedative effects days exhibited increased sleepiness and
of certain antihistamines and their impair- assembly-line work performance impair-
ment of driving and learning performance ment compared with placebo on the first
often go unrecognized by patients. This is day of treatment. However, by the third
demonstrated by the discrepancy between day, sedation and work performance were
subjective reporting of sedation and ob- not significantly different between diphen-
jective measurements of drowsiness and hydramine and placebo treatment, indi-
performance noted in several stud- cating the development of tolerance. The
ies.28*3g””For example, the sedating anti- authors note that despite the rapid onset
histamine ketotifen (2 mg/d for 21 days) of tolerance to diphenhydramine observed
produced EEG changes consistent with in this study, the possibility that the drug
sedation in eight healthy subjects, al- will affect performance cannot be ruled
though these subjects did not report expe- out. Such tolerance is not universal, con-
riencing sedative effects.3g The EEG sistent, or predictable, and if patients take
changes were greatest at 3 days after the the drug intermittently as needed, they
beginning of treatment with ketotifen, af- will experience sedation each time ther-
ter which they progressively diminished. apy is initiated.
A study by Goetz et al‘tc revealed a lack
of significant effects on psychomotor per-
Other Central Nervous System Effects
formance following a single nighttime
dose of hydroxyzine in contrast to sub- Some sedating antihistamines have been
jective reports of drowsiness on the fol- reported to cause CNS stimulatory effects.
lowing day. The authors speculate that the Anecdotal case reports of blepharospasm
relationship between subjective and ob- (spasm of the oculi muscle, producing clo-
jective effects is unpredictable at present sure of the eyelid) and other manifestations
and most likely depends on the drug be- of facial dyskinesia due to antihistamine
ing tested and the nature of the testing. use have appeared in the literatun~.~~One
As Nicholson41 observed, one must involved the occurrence of blepharospasm;
carefully weigh the results of studies mea- involuntary facial, tongue, and hand move-
suring the performance effects of drugs ments; nasal regurgitation; and verbal im-
and consider the appropriateness of the pairment in a %-year-old woman who had
testing methods for predicting perfor- been taking bromphenimmine and phenin-

45
 CLINICAL THEXAF’EUTICS@

damine for 10 years.43Another case report Peripheral Effects

recounted the onset of blepharospasm after
3 years of chlorpheniramine treatment in a Peripheral effects associated with se-
65-year-old woman, followed 2 years later dating antihistamines have been noted.
by impaired speech, choking, nasal regur- The patient mentioned previously who
gitation, and facial spasms. took brompheniramine and phenindamine
Among the other, less common CNS for 10 years and experienced blepharo-
stimulatory side effects associated with spasm and muscle spasms involving the
antihistamines are insomnia, nervousness, face also exhibited involuntary constant
vagal stimulation, tachycardia and hyper- semipurposive movements of the hands.43
tension, hyperreflexia, and convulsions.““ Other peripheral effects that have been re-
In an early study, Wyngaarden and Seev- ported with acute antihistamine toxicity
er8“ discussed five cases of fatal antihis- include toxic neuritis, paresthesias, paral-
tamine ingestion in pediatric patients in- ysis, and areflexia.44
volving convulsions, and they reported
two new cases of convulsions and subse-
NONSEDATING ANTIHISTAMINES
quent death in children who had ingested
diphenhydramine and dimenhydrinate. In contrast to the sedating antihistamines,
Although adults have also manifested con- numerous clinical studies have shown a
vulsions, antihistamine overdosage tends lack of sedation and performance impair-
to produce depressive effects with in- ment with the nonsedating agents astemi-
creasing age. 44 Pyribenzamine has also zole, loratadine, and terfenadine. For ex-
been shown to produce stimulatoty side ample, terfenadine 60 mg and 120 mg did
effects, including tachycardia and parox- not decrease performance in tests assess-
ysmal activity. 45 The agent produced ing visuomotor coordination, dynamic vis-
seizure activity in patients susceptible to ual acuity, and critical flicker fusion com-
convulsions during EEG.45 other possible pared with placebo. 31Another study found
side effects include postural hypotension, no difference between treatment with ter-
urinary retention, and glaucoma. Paradox- fenadine and placebo in psychomotor per-
ical effects that could occur in children as formance or sedation as measured by the
well as the elderly are insomnia, nervous- multiple sleep-latency test in 12 healthy
ness, and excitability. volunteers.47 Subjects were given re-
Neuropsychiatric side effects associ- peated administrations of terfenadine 120
ated with acute antihistamine toxicity in- mgld for 3 days.
clude nightmares, impaired judgment, Two studies evaluating the effects of
delusions, hallucinations, mental depres- terfenadine versus those of the sedating
sion, reduced mental efficiency, confu- antihistamine chlorpheniramine or pla-
sion, and toxic psychosis.U Impaired cebo have shown a lack of sedative ef-
consciousness was the most common fects and performance impairment associ-
symptom encountered in 29 patients who ated with terfenadine. In the first study,
attempted suicide by diphenhydramine 22 healthy subjects demonstrated less se-
overdose.46 Somnolence was experi- dation with terfenadine than with chlor-
enced by approximately one third of pheniramine, as assessed by EEG mea-
these patients. surement of cerebral processing speed.22

46
T.M. NOLEN

The second study, involving 15 pediatric double-masked study, 144 patients re-
patients with allergic rhinitis, found a ceived terfenadine 120 mg/d and 141 were
lower incidence of subjectively reported given cetirizine 10 mg/d for 1 week.
sedation and cognitive impairment with Symptom relief was considered complete
terfenadine than with chlorpheniramine, or marked in 46% of terfenadine- and 45%
after a single dose of either agent.23 of cetirizine-treated patients. A statisti-
Use of the nonsedating antihistamines cally significant difference in drowsiness
astemizole and terfenadine did not impair was observed, with 10 cetirizine- and only
dynamic visual acuity or critical flicker 2 terfenadine-treated patients experienc-
fusion capability versus placebo in six ing this side effect.
healthy subjects, although the sedating The nonsedating antihistamines have
antihistamine triprolidine did.25 In this been shown to produce little or no effect
study, there was also a trend toward on driving performance in several studies
greater sedation, decreased concentration, comparing these agents with sedating an-
and lower effectiveness with triprolidine tihistamines and placebo. In the case of
that was not seen with either astemizole terfenadine, the extent of sleepiness dur-
or terfenadine. ing driving did not differ from placebo,
Loratadine, another of the nonsedating leading the investigators to conclude that
antihistamines, did not increase daytime this nonsedating agent does not cause
sleepiness or decrease performance mea- CNS depressive effects that impact the
sures compared with placebo in a double- operation of a motor vehicle.33 O’Han-
masked study of 16 healthy volunteers.21 lon28 showed that neither terfenadine
Daytime sleepiness was assessed by the 60 mg nor loratadine 10 mg affected driv-
multiple sleep-latency test, and perfor- ers’ ability to maintain a steady position
mance testing included evaluation of re- within a designated lane of traffic or to
action time, copying, digit-symbol substi- keep a constant speed of 60 mph.
tution, and vigilance tasks. In contrast, In another study assessing driving per-
diphenhydramine increased the circadian formance, neither terfenadine nor ceti-
sleepiness that occurs at midday and de- rizine compared with placebo impaired
creased performance on the digit-symbol highway driving among 27 healthy sub-
substitution test. jects.34 However, Ramaekers et a135
A multicenter comparison of loratadine demonstrated driving impairment in 16
and cetirizine in 108 patients with sea- volunteers receiving cetirizine with or
sonal allergic rhinitis demonstrated equal without alcohol versus placebo, although
efficacy between the two agents.48 How- loratadine with or without alcohol did not
ever, somnolence occurred in 20% of ce- impair driving compared with placebo.
tirizine-treated patients and only 13% of One person taking cetirizine and alcohol
loratadine-treated patients. Severe som- had to terminate a driving test early be-
nolence was observed in 7% of patients in cause of drowsiness.
the cetirizine group but in no patients in The use of nonsedating antihistamines
the loratadine group. The nonsedating does not pose problems for aircraft pi-
agent terfenadine also demonstrated less lots. The nonsedating agent terfenadine
sedating effects than cetirizine, as shown (120 mg/d) did not produce drowsiness
by Backhouse et al.49 In this multicenter, or affect the performance of 10 healthy

47
 CLINICAL THF%APEUTICS”

Table II. Federal Aviation Administration (FAA) guidelines for antihistamine use by pilots.

Agents Guidelines

Astemizole Permitted with physician’s report indicating

Loratadine absence of side effects
Lcratadine
and pseudcephedrine
sulfate
Terfenacline

Terfenadine Prohibited ~24 hours before flight in anyone taking

and pseudoephedrine concomitant cardiovascular drug
hydrochloride

Chlorpheniramine Prohibited Q4 hours before flight or if required regularly

Clemastine
Diphenhydramine

Fexofenadine prohibited for 12 months following introduction

Cetirizine Not appropriate until additional data suggest otherwise

Source: M. Moody,FAAAir Medical Certification Division (personal communication,April 1996).

licensed pilots on a simulated flight path gest that loratadine may be used safely
test measuring the steadiness of course, by pilots without impeding their flight
altitude, height, speed, and the operation performance.
of navigational tools.50 Loratadine did According to US Federal Aviation Ad-
not cause sedation or negatively affect ministration guidelines, pilots are permit-
the flight performance of 40 commercial ted to use the nonsedating antihistamines
and military pilots during flight-simula- astemizole, loratadine, and terfenadine as
tion testing. 51 The subjects were rated ob- long as they have a physician’s report doc-
jectively based on their performance in umenting the absence of side effects
the simulator and also reported their sub- (Table II).52 Other antihistamines are pro-
jective symptoms of drowsiness, lack of hibited within 24 hours of flight time, de-
attention, and diminished reflexes. Nei- pending on the specific agent. To date, no
ther objective nor subjective measures published studies exist demonstrating the
were altered by loratadine compared with lack of sedation or impairment associated
placebo. Often, individuals with nasal al- with fexofenadine, a metabolite of terfen-
lergies are screened out as candidates for adine and the most recently introduced
pilots, as nasal obstruction leading to nonsedating antihistamine, and its use by
barotitis or barosinusitis is the major rea- pilots is currently prohibited.
son for grounding pilots. The authors sug- Even for those who do not operate mo-

48
T.M. NOUN

tor vehicles, airplanes, or heavy machin- effects do exist. The use of terfenadine
ery, nonsedating antihistamines provide a and astemizole has been associated with
definite advantage over the sedating the occurrence of the ventricular arrhyth-
agents. For example, although diphenhy- mia torsades de pointes. A review of the
dramine reduced learning ability in 25 cases of torsades de pointes subsequent
schoolchildren with seasonal allergic to terfenadine treatment reported to the
rhinitis, loratadine improved the impaired FDA from May 1985 to April 1992 re-
learning ability that occurs with untreated vealed that 3 of the patients took high
allergy symptoms.37 The authors empha- doses of the agent with suicidal intent and
size the importance of prescribing nonse- 4 patients were taking more than the sug-
dating antihistamines for schoolchildren gested dose of 120 mgid.54 Another 6 pa-
who experience seasonal allergic rhinitis. tients had cirrhosis or were alcohol
Left untreated, the condition has a nega- abusers, and 11 were taking other med-
tive effect on learning ability during al- ications that inhibit the hepatic metabo-
lergy season, which often falls during the lism of terfenadine.
final examination period. Treatment with Certain predisposing factors that may
a sedating antihistamine may worsen the increase the risk of torsades de pointes in
learning impairment. patients taking terfenadine include hy-
The effect of alcohol was not potenti- pothyroidism, hypokalemia, hypomagne-
ated by either loratadine or terfenadine, as semia, and coronary artery disease. The
O’Hanlon28 reported in a study of driving authorr?“ caution against prescribing ter-
performance under actual road conditions. fenadine with other agents known to block
The 16 healthy volunteers who partici- potassium channels, lengthen the cardiac
pated in this study showed no significant output (QT) interval, and increase the risk
difference in lateral positioning during of torsades de pointes. These include
driving in a designated lane whether they disopyramide, haloperidol, quinidine,
received placebo, terfenadine, or lorata- pentamidine, probucol, procainamide, so-
dine. When alcohol was given in addition talol, and thioridazine. In addition, the
to these agents, no significant difference flavonoids in grapefruit juice may also in-
was noted in performance among these crease terfenadine concentration, leading
three regimens. An earlier study involving to prolongation of the QT interval. In
20 healthy volunteers also revealed that 1992, the FDA issued an official warning
terfenadine 120 mg did not worsen per- regarding the possibility of rare cardio-
formance on psychomotor testing or sub- vascular occurrences such as torsades de
jective feeling of drowsiness or drunken- pointes in patients taking terfenadine or
ness when given in conjunction with astemizole.55 The manufacturers were re-
alcohol 0.75 g/kg body weight versus al- quired to add boxed warnings to the prod-
cohol alone.53 uct labeling. The warnings caution against
the concomitant administration of terfen-
adine and ketoconazole or erythromycin
Cardiovascular Effects
and the importance of not exceeding the
Although there are no significant CNS recommended dosage of either terfena-
side effects with the nonsedating antihis- dine or astemizole. In a study of 18 healthy
tamines, differences in cardiovascular side volunteers, Honig et a156 showed that

49
 CLINICAL THERAPEUTICS@

erythromycin and clarithromycin given in pretreated with the chlorpheniramine/

conjunction with terfenadine led to the phenylpropanolamine combination versus
accumulation of unmetabolized terfena- placebo. 58 Eustachian tube function also
dine that affected cardiac repolarization. was better with combination therapy than
Recently, the FDA has decided to seek the with placebo. However, chlorpheniramine
withdrawal of terfenadine due to the po- is a sedating agent.
tential for cardiac side effects, as reported In a more recent study, 193 patients
in FDC Reports, “The Pink Sheet” (Janu- with seasonal allergic rhinitis and asthma
ary 20, 1997). were treated with the nonsedating antihis-
Unlike terfenadine and astemizole, lor- tamine loratadine in combination with the
atadine has not been associated with decongestant pseudoephedrine. Com-
changes in cardiovascular measurements pared with placebo therapy, this combina-
such as the (QT) interval. In a study of tion significantly improved rhinitis, as-
loratadine 10 mg/d plus erythromycin 500 thma, and pulmonary function measures
mg/d for a lo-day period, the plasma lev- in this patient population, thereby provid-
els of loratadine and its major metabolite ing the widest range of symptom relief.
increased, but prolongation of the QT in- This combination recently became avail-
terval did not occur.57 able in a once-daily formulation.
Prolongation of the QT, interval (ie,
QT interval corrected for heart rate) has
PATIENT SATISFACTION
not been detected clinically with fexofen-
AND QUALITY-OF-LIFE
adine, a terfenadine metabolite. How-
CONSIDERATIONS
ever, labeling for fexofenadine does in-
clude a precaution citing an increase in In 1995, Consumer RepodO conducted a
plasma levels when coadministered with survey of 70,000 Americans to gauge their
ketoconazole or erythromycin, as re- level of satisfaction with their physicians
ported in FDC Reports, “The Pink Sheet” and the medical care received. Approxi-
(July 31, 1996). mately 12% of the respondents reported
dissatisfaction with a physician they had
consulted during the previous year be-
ANTIHISTAMJNE/DECONGESTANT
cause of allergies. The highest negative
COMBINATION THERAPY
rating was given for chronic headache,
Studies of antihistamine/decongestant with about 23% of respondents reporting
combination therapy have shown the ef- they were dissatisfied. Because these
fectiveness of this approach in patients types of chronic ailments may be difficult
with allergic rhinitis whose symptoms in- to diagnose and manage, they may be as-
clude congestion. Congestion is a frequent sociated with less favorable outcomes.
complaint associated with allergic rhini- The symptoms associated with allergic
tis, occurring in 40% to 70% of patients. rhinitis and some of the agents used to
A double-masked, crossover study of 10 treat it can have a significant adverse im-
adults with allergic rhinitis caused by ex- pact on quality of life and thus can nega-
posure to ragweed pollen revealed an im- tively affect the patient’s impressions of
provement in nasal airway resistance af- the health care received. In addition to the
ter exposure to the pollen in patients learning, driving, and work performance

50
T.M. NOLEN

impairments discussed previously, the se- spray or loratadine. Patients taking lorat-
dating effects produced by some antihis- adine had better quality-of-life scores for
tamines may have other negative conse- eye and nasal symptoms and for emotional
quences. In the process of developing a factors compared with fluticasone-treated
quality-of-life assessment tool for use in patients after 2 and 4 weeks of therapy.
patients with rhinoconiunctivitis, Jumper
and Guyat6’ conducted a survey of-85
CONCLUSIONS
adults to identifv the variables to include
in the questionnaire. The respondents Many studies have shown that sedating an-
rated sleep problems, nonnasal/psychoso- tihistamines, including cetirizine, produce
cial symptoms (eg, fatigue and decreased effects such as sedation and cognitive im-
productivity and concentration), practical pairment that fmquently aggravate the CNS
problems, nasal and eye symptoms, and symptoms already present in patients with
emotional factors as important items to allergic rhinitis. The range of consequences
include. When the questionnaire was that affect both children and adults includes
tested in 60 adult patients with hay fever the inability to safely perform many daily
being treated with beclomethasone dipro- functions (eg, operating motor vehicles,
pionate, the results revealed the important aircraft, or machinery), decreased learning
impact the illness has on the lives of pa- capability, and memory and concentration
tients, producing sleep disturbances, lim- impairment. Moreover, there is an in-
iting activities, and creating emotional creased risk of occupational injury.63All of
distress. The authors emphasized the im- these adverse effects of treatment with se-
portance of measuring these types of vari- dating antihistamines worsen the patient’s
ables because of the negative impact condition and create dissatisfaction with
seemingly minor illnesses may have on the health care provided. The availability
quality of life. of nonsedating antihistamines that do not
If the treatment for the condition exac- produce these side effects offers a safer al-
erbates some of the symptoms, as with ternative for patients with allergic rhinitis.
sedating antihistamines, this can lead to Use of these agents can improve quality of
noncompliance with therapy and, subse- life and increase satisfaction with the health
quently, to poor control of allergic rhini- care received.
tis. Ultimately, patients will be dissatis-
fied with their treatment, the health care
ACKNOWLEDGMENT
provider, and, if applicable, the managed
care organization, as the Consumer Re- Support for this paper was provided
ports survey implies.60 through an unrestricted educational
The use of nonsedating antihistamines grant from Schering\Key, Kenilworth,
has the potential to improve the quality of New Jersey.
life of patients with allergic rhinitis. A
separate quality-of-life survey developed
by Juniper and Guyatt? for use in ado- Address correspondence to: Dr. Thomas
lescent patients with allergic rhinocon- M. Nolen, Columbiana Associates, 22266
junctivitis compared results achieved in Highway 25 Bypass, Columbiana, AL
245 patients treated with fluticasone nasal 35051.

51
 CLINICAL THERAPEUTICS’

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