Clin[ Otolaryn`ol[ 0888\ 24, 3640

The effects of oral pseudoephedrine on nasal patency in the

common cold: a double-blind single-dose placebocontrolled trial
D[ TAVERNER\ C[ DANZ + D[ ECONOMOS
Department of Clinical and Experimental Pharmacolo`y\ University of Adelaide and Royal Adelaide Hospital\ South Australia\
Australia
Accepted for publication 16 August 0887

TAVERNER D[\ DANZ C[ + ECONOMOS D[

"0888# Clin[ Otolaryn`ol[ 13\ 3640

The effects of oral pseudoephedrine on nasal patency in the common cold: a

double-blind single-dose placebo-controlled trial
A placebo!controlled double!blind randomized trial was carried out to assess the e.cacy of
pseudoephedrine in relieving nasal congestion in the common cold[ Fifty!four previously healthy persons
who had a common cold for at least 4 days or less at the start of the study with moderate to severe nasal
congestion were recruited\ 41 completed the trial[ Following a single dose of oral pseudoephedrine "59 mg
capsule# or placebo\ symptoms of congestion improved signi_cantly compared with placebo at times 59\
89\ 019\ and 049 min after the dose[ Total nasal minimum cross!sectional area and nasal volume measured
by acoustic rhinometry increased signi_cantly compared to placebo "P  9[907 and P  9[992\
respectively# after the dose[ There was no signi_cant change in nasal area as measured by active posterior
rhinomanometry after pseudoephedrine compared to placebo[ We conclude that in the acute common
cold\ a single 59 mg dose of pseudoephedrine produces signi_cant increases in the dimensions of the nasal
cavity compared to placebo and this is associated with a reduction in the symptom of congestion[
Keywords pseudoephedrine common cold rhinomanometry acoustic rhinometry nasal con`estion

Acute viral upper respiratory infections in the nose lead to the

release of in~ammatory mediators[ These cause hyperaemia
of the erectile tissue which contain extensive venous sinusoids\
which in turn reduces the nasal lumen at the region of the
nasal valve at the anterior end of the inferior turbinate causing
increased nasal airways resistance[ As a consequence\ the most
signi_cant symptom of the common cold is nasal congestion\
and this can be treated pharmacologically[
Topical administration of ipratroprium reduces rhinor!
rhoea and sneezing but not congestion in the common cold[0
Topical vasoconstrictors such as oxymetazoline are e}ective
in relieving congestion\ by constricting both precapillary
arterioles and venous sinusoids[1
Pseudoephedrine is an orally active a!adrenoceptor agonist
with vasoconstrictor and decongestant e}ects on the nose in
normal subjects\ acting by constricting venous sinusoids[ It is
rapidly absorbed and has high bioavailability[2
Correspondence] David Taverner\ MD\ FRACP\ Senior Lecturer\
Department of Clinical and Experimental Pharmacology\ University
of Adelaide\ South Australia\ 4994\ Australia[
0888 Blackwell Science Ltd

In dose!response studies of histamine!enhanced nasal air!

ways resistance in normal subjects the minimum e}ective sin!
gle dose of pseudoephedrine was 59 mg\ with no greater thera!
peutic e}ect seen at 019 or 079 mg[ At the 59 mg dose changes
in blood pressure did not occur\ while higher doses sig!
ni_cantly increased heart rate and blood pressure[ Other side!
e}ects at this dose are minimal[3
Nasal airways resistance showed a reduction after a single
dose of pseudoephedrine in subjects with both acute and
chronic nasal congestion\4 but this study did not include sub!
jects with the common cold[ A review of published controlled
trials of decongestants in the common cold5 found two pla!
cebo!controlled trials of oral pseudoephedrine6\7 both of
which detected a signi_cant improvement in symptoms of
congestion with treatment[ Objective measurements of nasal
congestion were not made in these studies[
In experimental rhinovirus infection\ combination treat!
ment with 59 mg pseudoephedrine and 9[2 mg atropine "5!
hourly for 4 days# reduced nasal airway resistance when com!
pared with placebo\ but did not alter nasal secretion or symp!

36

37 D[ Taverner et al[

toms of nasal congestion[8 Anticholinergic side!e}ects were

reported by the majority of subjects on active therapy[
Since the subjective symptom of congestion depends upon
the sensation of nasal air~ow\ agents that provide nasal sen!
sory stimulation such as inhaled menthol can induce a sub!
jective improvement in the symptom of congestion in the
absence of any improvement in nasal airway obstruction[09
Objective measures of the airway are necessary to establish
whether a change in symptoms is due to changes in airway
geometry[
There are no placebo!controlled trials of the objective
e}ects of pseudoephedrine in the common cold[ We report
a randomized\ double!blind\ placebo!controlled\ single!dose
study of pseudoephedrine in subjects presenting with symp!
toms of the severe common cold[ The primary aims of this
study were to evaluate changes in nasal congestion\ using
estimates of minimal cross!sectional area and nasal volume
determined by acoustic rhinometry\ and nasal airway resist!
ance as determined by posterior rhinomanometry[ Secondary
aims were to assess the severity of nasal congestion as reported
by the subject\ and adverse e}ects[

Patients and methods

The study was approved by the Research Ethics Committee
of the Royal Adelaide Hospital\ and written informed consent
was obtained prior to study enrolment[
Subjects with symptoms of nasal congestion due to common
cold infections of less than 4 days duration were recruited by
advertisement during September to November 0884[ Medical
and drug history were obtained\ resting blood pressure was
taken and the oropharynx and nasal cavity were directly exam!
ined by speculum[
Inclusion criteria were] symptoms of an acute common cold
"acute nasal congestion combined with rhinorrhoea and:or a
sore throat#\ evidence of acute viral upper respiratory tract
infection as de_ned by the presence of pharyngeal erythema\
and moderate or severe nasal obstruction on examination by
anterior rhinoscopy[ The presence of hay fever\ broncho!
pulmonary disease\ anatomical nasal obstruction\ hyper!
tension and the prior ingestion of vasoactive drugs\ ca}eine
and alcohol within a prede_ned time period were reasons for
exclusion[
Eligible subjects were allocated in a double!blind ran!
domization schedule which assigned subjects to one of the
two rhinomanometers:acoustic rhinometers used in this study
and to the pseudoephedrine or placebo group in equal
numbers[
Subjects were familiarised with the testing procedures prior
to study[ Subjects were seated for 09 min before data was
collected and remained seated for each measurement period
to minimize extraneous sources of variability[

ACOUSTIC
METHODS

RHINOMETRY

AND

RHINOMANOMETRY

Acoustic rhinometry "AR# is a non!invasive method of nasal

structural assessment which does not depend upon an
adequate airway in each nasal cavity\ and thus has the poten!
tial to be more reliable than ~ow measurements in the assess!
ment of severe nasal congestion[00 It provides the cross!sec!
tional area and volume of the cavity at distances from the
posterior margin of the anterior nares of up to 59 mm^ beyond
this point measurements may be unreliable due to sinus
echoes[ Two RM1099 acoustic rhinometers were used in this
study[ They were internally calibrated before each measure!
ment[ In addition\ a known _xed arti_cial cavity was measured
using AR at di}erent times during the study[ The accuracy
"observed:expected# of volume and cross!sectional area
measurement was 9[77\ with an inter!day coe.cient of vari!
ation of reproducibility of 9[01[
Three area:distance curves were collected when the subject
had closed their mouth\ mid!breath[ The median value was
selected for on!line analysis[ The minimum cross!sectional
area "MCSA# of each nasal cavity were recorded between
11 mm to 43 mm from the anterior nares "i[e[ the nasal valve#^
also the nasal volume between the MCSA depth and 43 mm
depth "NVol#[ Left and right values for MCSA were added to
provide total CSA "tCSA#^ left and right NVol were added to
calculate tNVol[
Active posterior rhinomanometry is an established tech!
nique for measuring nasal airway pressure!~ow relationships
from which total nasal airway resistance "tNAR# can be
derived[01\02 Two SR1999 rhinomanometers were used[ Re!
calibration against reference pressure and air ~ow meters was
performed at regular intervals throughout the study[ The pres!
sure and ~ow channels were linear in the range of 9299 Pa
and 9299 ml:s on repeated static testing "r 9[887#[ Cali!
bration errors were less than 09)[ Using the posterior rhi!
nomanometric method\ pressure!~ow data was acquired from
three consecutive breaths[

STUDY PROCEDURE
Symptoms of congestion were marked by the subject on a 4!
point categorical score "9no congestion^ 3very severe con!
gestion# prior to each measuring period[
NAR\ tCSA\ tNVol and congestion were measured at base!
line "T9#[ The test drug was administered within 09 min of T9[
Ingestion was con_rmed by inspection of the oral cavity[ At
29!min intervals after administration measurement of all vari!
ables was repeated until the _nal time "T5# 079 min after
ingestion[
Any adverse events were recorded at the end of the study
and all subjects were contacted 0 month later and asked to
report any subsequent symptoms[ The randomization code
0888 Blackwell Science Ltd\ Clinical Otolaryn`olo`y\ 13\ 3640

Ef_cacy of pseudoephedrine in the common cold 38

Table 0[ Minimum cross!sectional area of both nasal cavities "tCSA#

after 59 mg pseudoephedrine orally or placebo "cm1 2 SD#

Table 1[ Volume of the de_ned section of both nasal cavities "tNVol#

after 59 mg pseudoephedrine orally or placebo "cm2 2 SD#

Time after dosing

"min#

Placebo "n  15#

Pseudoephedrine "n  13#

Time after dosing

"min#

Placebo "n  15#

Pseudoephedrine "n  13#

Baseline
29
59
89
019
049
079

0[94 2 9[12
9[82 2 9[07
9[78 2 9[08
9[74 2 9[07
9[71 2 9[04
9[79 2 9[05
9[64 2 9[05

0[01 2 9[10
9[88 2 9[11
9[83 2 9[06
9[82 2 9[08
9[80 2 9[07
9[82 2 9[08
9[82 2 9[08

Baseline
29
59
89
019
049
079

6[12 2 0[49
5[19 2 0[35
5[23 2 0[43
5[25 2 0[49
5[21 2 0[41
5[49 2 0[53
5[02 2 0[22

6[38 2 0[04
6[00 2 0[49
6[15 2 0[32
6[17 2 0[55
6[21 2 0[28
6[19 2 0[55
6[24 2 0[42

was not broken until all data\ including delayed adverse

events\ had been collated[

8.0

STATISTICAL ANALYSIS
Statistical analysis methods were determined prior to the
study[ Nasal area "NAR# was calculated o}!line using Brom|s
method and the three values were averaged "tNAR#[ Missing
values and those more than 09 min o}!schedule were classed
as invalid and replaced by linear interpolation\ unless the _rst
"T9# or more than one data point was invalid\ in which case
that variable for the subject was excluded[ All data is presented
as mean 2 SD[ The AUC "linear trapezoidal method# for
each of the primary variables "tNAR\ tCSA and tNVol# was
calculated[ The AUCs were analysed by two!way ANOVA using
drug treatment and machine as covariates[ Log!trans!
formation was applied to NAR data before analysis[ The
symptoms of congestion data was analysed at each time point
by a two!sample t!test on the change from baseline value[
Statistical signi_cance was reported if P 9[94[

1.2

tMCA (cm2)

1.1
1
0.9
0.8
0.7

tNVol (cm3)

7.5
7.0
6.5
6.0
5.5
5.0
30

30
60
90
120
Time after dosing (min)

150

180

Figure 1[ TVOL at times after dosing of either 59 mg pseudoephedrine

or placebo "mean 2 SE#[ e\ TVNol placebo^ \ TVNol pseudo!
ephedrine[

Results
Ninety!nine subjects were screened\ 43 subjects satis_ed the
inclusion and exclusion criteria[ Most exclusions were due to
prior drug administration or to an inconsistent history of cold
symptoms[
Of the 43 subjects who were entered randomization\ two
failed to complete the study[ Fifty!two "age 15 2 8 years\
range 0744 years\ 29 men 11 women# subjects provided data
for analysis[ Twenty!_ve of these took pseudoephedrine and
16 took a placebo[ Forty!eight sets of tNAR data\ 49 sets of
tNVol and tCSA data\ and 49 sets of congestion data had
su.cient valid data and were analysed as an intention!to!treat
population[

0.6
0.5
30

TOTAL MINIMAL CROSS!SECTIONAL AREA

0

30
60
90
120
Time after dosing (min)

150

180

Figure 0[ MCA at times after dosing of either 59 mg pseudoephedrine

orally or placebo "mean 2 SE#[ e\ tMCA placebo^ \ tMCA pseudo!
ephedrine[
0888 Blackwell Science Ltd\ Clinical Otolaryn`olo`y\ 13\ 3640

The overall mean tCSA at the start of the study did not di}er
between pseudoephedrine and placebo groups "Table 0#\ but
tCSA fell with time in both groups[ ANOVA of AUC"tCSA#
showed a signi_cant e}ect of treatment "P  9[907# indicating

49 D[ Taverner et al[

an average 6) increase in AUC"tCSA# with pseudoephedrine

compared to placebo[ "Table 0^ Fig[ 0#[
TOTAL NASAL VOLUME
The mean tNVol[ at the start of the study did not di}er
between pseudoephedrine and placebo groups "Table 1#[
ANOVA of the AUC"tNVol# showed a signi_cant e}ect of treat!
ment "P  9[992# indicating a 00) increase in AUC"tNVol#
with pseudoephedrine compared to placebo[ "Table 1^ Fig[ 1#[

SYMPTOMS OF CONGESTION
Reported symptoms of congestion were similar in both groups
at time 9 and were reduced through the 2!h study "Table 3#[
The reduction in symptoms after pseudoephedrine adminis!
tration was signi_cantly greater than placebo at all timepoints
between 59 and 049 min after dosing[ "Table 3^ Fig[ 3#[
ADVERSE EVENTS
No adverse events occurred that were causally related to the
study or medication[

NASAL AIRWAY RESISTANCE

The tNAR at the start of the study for all valid subjects was
9[65 2 0[0 Pa[cm2 and did not di}er between the pseudo!
ephedrine and placebo groups[ The data had a skew distri!
bution\ and the average intra!individual coe.cient of vari!
ation "SD:mean# during placebo treatment was high "9[46#[
There was no di}erence between treatment groups at any time
"Table 2# and ANOVA of AUC "tNAR# showed no signi_cant
treatment e}ect "P 9[4#[ "Table 2^ Fig[ 2#[

Discussion
Subjects with symptoms of an acute upper respiratory tract
infection of less than 4 days duration were recruited for this
study[ The high mean tNAR at baseline "9[65\ normal range
in our unit is 9[39 Pa[s[cm2#\ and the signi_cant symptoms
of nasal congestion support the reliability of the selection
criteria[ The group selected was representative of subjects with

Table 3[ Reported symptoms of nasal congestion after 59 mg pseudo!

ephedrine orally or placebo "arbitrary units 2 SD#
Table 2[ Change in nasal airways resistance "tNAR# after 59 mg
pseudoephedrine orally or placebo "Pa[s[cm2 2 SD#
Time after dosing
"min#

Placebo "n  14#

Pseudoephedrine "n  12#

29
59
89
019
049
079

9[95 2 9[86
9[96 2 9[83
9[93 2 9[62
9[99 2 9[82
9[95 2 0[98
9[01 2 9[71

9[99 2 9[39
9[28 2 0[05
9[92 2 0[26
9[02 2 9[49
9[07 2 9[74
9[96 2 9[13

Time after dosing

"min#

Placebo "n  17#

Pseudoephedrine "n  13#

Baseline
29
59
89
019
049
079

2[99 2 9[44
2[04 2 9[61
2[93 2 9[65
1[78 2 9[53
1[69 2 9[56
1[63 2 9[60
1[43 2 9[54

1[77 2 9[63
1[68 2 9[72
1[49 2 9[61
1[31 2 9[61
1[18 2 9[75
1[18 2 9[64
1[16 29[72

NAR (Pa.s / cm3)

2.5
2.0
1.5
1.0
0.5
0.0
30

30
60
90
120
Time after dosing (min)

150

180

Figure 2[ NAR after dosing with either 59 mg pseudoephedrine orally

or placebo "mean 2 SE#[ e\ NAR placebo^ \ NAR pseudo!
ephedrine[

Change in congestion from baseline

(arbitrary units)

 Indicates di}erence from baseline compared to placebo "P 9[94#[

3.5

2.5

1.5
30

30
60
90
120
Time after dosing (min)

150

180

Figure 3[ Reported symptoms of congestion at times after dosing with

59 mg pseudoephedrine or placebo "mean 2 SE#[ e\ CON placebo^
\ CON pseudoephedrine[
0888 Blackwell Science Ltd\ Clinical Otolaryn`olo`y\ 13\ 3640

Ef_cacy of pseudoephedrine in the common cold 40

an acute common cold\ having a wide age range and equal

sex distribution[
There was no di}erence between the treatment and placebo
groups in any of the baseline variables[ After placebo\ tMCA
and tNVol was reduced over the subsequent 2 h\ while symp!
toms of congestion improved[ In this study\ the e}ect of
pseudoephedrine was distinguished from these spontaneous
changes[
The optimal dose of pseudoephedrine for relieving con!
gestiongestion is 59 mg[3 This study demonstrates that in sub!
jects with the common cold\ this dose of pseudoephedrine is
signi_cantly more e}ective than placebo in reducing the fall
in the cross!sectional area of the nasal valve over a 2!h period[
Nasal area is largely dependent on the nasal valve which is
the region assessed by CSA measurement[ The di}erence in
tCSA in this study may be expected to cause a corresponding
decrease in NAR on treatment[ Acoustic rhinometry has been
shown to correlate with changes in posterior NAR measure!
ments in normal subjects after drug administration[00\03 A
signi_cant change in NAR was not seen with pseudoephedrine
in this study[ Upper respiratory tract infection is associated
with an increase in the amplitude of variations in nasal airway
resistance[04 The rhinomanometry ~ow head of the SR!1999
which congestiontained the pressure and ~ow sensors\ was
found to be sensitive to changes in position\ as a result of this
less reproducible results were found in subjects compared to
static calibration[
The high spontaneous variability of the placebo NAR
values "CV 9[47# would preclude the detection of signi_cant
di}erences in this study design[ A larger number of subjects
would be required to overcome this[
In the present study\ no signi_cant correlations were found
between the baseline values of tCSA and tNAR or changes in
the di}erent variables analysed[ This may be due to the high
variability of NAR measurements in the common cold[
The increase in tCSA is likely to be physiologically sig!
ni_cant since it was accompanied by a signi_cant improve!
ment in reported symptoms of congestion with pseudo!
ephedrine compared with placebo[
Nasal volume in a prede_ned segment from the nasal valve
to a point 43 mm from the anterior nares also increased sig!
ni_cantly during the 2 h after pseudoephedrine compared with
placebo[ This indicates decongestion of vascular tissues in this
area and supports the e.cacy of pseudoephedrine[ This nasal
volume increase as well as the increase in tCSA\ may have
contributed to the symptom improvement after pseudo!
ephedrine[
This study is the _rst to show that pseudoephedrine when
used as a single agent in the common cold produces a sig!
ni_cant di}erence in nasal congestion compared to a placebo[
Pseudoephedrine also signi_cantly relieves the symptoms of
congestiongestion in the 59049!min period after adminis!
tration[ The study design excluded placebo e}ects\ subject
bias and observer bias[
0888 Blackwell Science Ltd\ Clinical Otolaryn`olo`y\ 13\ 3640

This study supports the use of single doses of oral pseudo!

ephedrine "59 mg# to relieve the symptoms of congestion in
acute colds\ with a low level of side!e}ects[

Acknowledgements
This study was supported by Procter + Gamble Technical
Centres Ltd[ We would like to acknowledge the assistance of
Sarah Moody\ Larissa Bickford and Professor Richard Jarrett
for the statistical analysis[

References
0 HAYDEN F[G[\ DIAMOND L[\ WOOD P[B[ et al[ "0885# E}ectiveness
and safety of intranasal ipratroprium bromide in common colds[
Ann[ Int[ Med[ 014\ 7885
1 GRAF P[ + JUTO J[E[ "0884# Sustained use of xylometazoline nasal
spray[ Rhinolo`y 22\ 0306
2 REYNOLDS J[\ ed[ "0885# Sympathomimetics[ In Martindale\ The
Extra Pharmacopoeia\ 20st edn\ p[ 0477[ Royal Pharmaceutical
Society\ London
3 EMPEY D[W[\ YOUNG G[A[\ LETLEY E[ et al[ "0879# Dose!response
study of the nasal decongestant and cardiovascular e}ects of
pseudoephedrine[ Br[ J[ Clin[ Pharmacol[ 8\ 240247
4 ROTH R[P[\ CANTEKIN E[I[\ BLUESTONE C[D[ et al[ "0866# Nasal
decongestant activity of pseudoephedrine[ Ann[ Otol[ Rhinol[
Laryn`ol[ 75\ 124131
5 SMITH M[B[ + FELDMAN W[ "0882# Over!the!counter cold medi!
cations] a critical review of clinical trials between 0849 and 0880[
JAMA 158\ 11471152
6 BYE C[E[\ COOPER J[\ EMPEY D[W[ et al[ "0879# E}ects of pseudo!
ephedrine and triprolidine\ alone and in combination\ on symp!
toms of the common cold[ BMJ 170\ 078089
7 SPERBER S[J[\ SORRENTINO J[V[\ RIKER D[K[ et al[ "0878# Evalu!
ation of an alpha!agonist alone and in combination with a non!
steroidal anti!in~ammatory agent in the treatment of experimental
rhinovirus colds[ Bull[ NY Acad[ Med[ 54\ 034059
8 DOYLE W[J[\ RIKER D[K[\ MCBRIDE T[P[ et al[ "0882# Therapeutic
e}ects of an anticholinergic!sympathomimetic combination in
induced rhinovirus colds[ Ann[ Otol[ Rhinol[ Laryn`ol[ 091\ 410416
09 ECCLES R[\ JAWAD M[S[ + MORRIS S[ "0889# The e}ects of oral
administration of menthol on nasal resistance to air~ow and nasal
sensation of air~ow in subjects su}ering from nasal congestion associ!
ated with the common cold[ J[ Pharm[ Pharmacol[ 31\ 541543
00 AUSTIN C[E[ + FOREMAN J[C[ "0883# Acoustic rhinometry com!
pared with posterior rhinomanometry in the measurement of his!
tamine! and bradykinin!induced changes in nasal airway patency[
Br[ J[ Clin[ Pharmacol[ 26\ 2226
01 SHELTON D[M[ + EISER N[M[ "0881# Evaluation of active anterior
and posterior rhinomanometry in normal subjects[ Clin[ Otol!
aryn`ol[ 06\ 067071
02 JONES A[S[\ LANCER J[M[\ STEVENS J[C[ et al[ "0876# Nasal resist!
ance to air~ow "its measurement\ reproducibility and normal par!
ameters#[ J[ Laryn`ol[ Otol[ 090\ 799797
03 SCADDING G[K[\ DARBY Y[C[ + AUSTIN C[E[ "0883# Acoustic
rhinometry compared with anterior rhinomanometry in the assess!
ment of the response to nasal allergen challenge[ Clin[ Otolaryn`ol[
08\ 340343
04 ECCLES R[\ REILLY M[ + ECCLES K[S[J[ "0885# Changes in the
amplitude of the nasal cycle associated with symptoms of acute
upper respiratory tract infection[ Acta Otolaryn`ol[ 005\ 6670