taverner (1999)

Clin[ Otolarynol[ 0888\ 24, 3640

The effects of oral pseudoephedrine on nasal patency in thecommon cold: a double-blind single-dose placebo-controlled trial

D[ TAVERNER\ C[ DANZ + D[ ECONOMOSDepartment of Clinical and Experimental Pharmacoloy\ University of Adelaide and Royal Adelaide Hospital\ South Australia\Australia

Accepted for publication 16 August 0887

TAVERNER D [ \ DANZ C [ + ECONOMOS D ["0888# Clin[ Otolarynol[ 13\ 3640

The effects of oral pseudoephedrine on nasal patency in the common cold: adouble-blind single-dose placebo-controlled trial

A placebo!controlled double!blind randomized trial was carried out to assess the e.cacy ofpseudoephedrine in relieving nasal congestion in the common cold[ Fifty!four previously healthy personswho had a common cold for at least 4 days or less at the start of the study with moderate to severe nasalcongestion were recruited\ 41 completed the trial[ Following a single dose of oral pseudoephedrine "59 mgcapsule# 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 measuredby 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 posteriorrhinomanometry after pseudoephedrine compared to placebo[ We conclude that in the acute commoncold\ a single 59 mg dose of pseudoephedrine produces signi_cant increases in the dimensions of the nasalcavity compared to placebo and this is associated with a reduction in the symptom of congestion[

Keywords pseudoephedrine common cold rhinomanometry acoustic rhinometry nasal conestion

Acute viral upper respiratory infections in the nose lead to therelease of in~ammatory mediators[ These cause hyperaemiaof the erectile tissue which contain extensive venous sinusoids\which in turn reduces the nasal lumen at the region of thenasal valve at the anterior end of the inferior turbinate causingincreased nasal airways resistance[ As a consequence\ the mostsigni_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}ectivein relieving congestion\ by constricting both precapillaryarterioles and venous sinusoids[1

Pseudoephedrine is an orally active a!adrenoceptor agonistwith vasoconstrictor and decongestant e}ects on the nose innormal subjects\ acting by constricting venous sinusoids[ It israpidly absorbed and has high bioavailability[2

Correspondence] David Taverner\ MD\ FRACP\ Senior Lecturer\Department of Clinical and Experimental Pharmacology\ Universityof Adelaide\ South Australia\ 4994\ Australia[

36 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 changesin 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 singledose of pseudoephedrine in subjects with both acute andchronic nasal congestion\4 but this study did not include sub!jects with the common cold[ A review of published controlledtrials of decongestants in the common cold5 found two pla!cebo!controlled trials of oral pseudoephedrine6\7 both ofwhich detected a signi_cant improvement in symptoms ofcongestion with treatment[ Objective measurements of nasalcongestion 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!

37 D[ Taverner et al[

toms of nasal congestion[8 Anticholinergic side!e}ects werereported by the majority of subjects on active therapy[

Since the subjective symptom of congestion depends uponthe 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 theabsence of any improvement in nasal airway obstruction[09

Objective measures of the airway are necessary to establishwhether a change in symptoms is due to changes in airwaygeometry[

There are no placebo!controlled trials of the objectivee}ects of pseudoephedrine in the common cold[ We reporta randomized\ double!blind\ placebo!controlled\ single!dosestudy of pseudoephedrine in subjects presenting with symp!toms of the severe common cold[ The primary aims of thisstudy were to evaluate changes in nasal congestion\ usingestimates of minimal cross!sectional area and nasal volumedetermined by acoustic rhinometry\ and nasal airway resist!ance as determined by posterior rhinomanometry[ Secondaryaims were to assess the severity of nasal congestion as reportedby the subject\ and adverse e}ects[

Patients and methods

The study was approved by the Research Ethics Committeeof the Royal Adelaide Hospital\ and written informed consentwas obtained prior to study enrolment[

Subjects with symptoms of nasal congestion due to commoncold infections of less than 4 days duration were recruited byadvertisement during September to November 0884[ Medicaland drug history were obtained\ resting blood pressure wastaken 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 asore throat#\ evidence of acute viral upper respiratory tractinfection as de_ned by the presence of pharyngeal erythema\and moderate or severe nasal obstruction on examination byanterior rhinoscopy[ The presence of hay fever\ broncho!pulmonary disease\ anatomical nasal obstruction\ hyper!tension and the prior ingestion of vasoactive drugs\ ca}eineand alcohol within a prede_ned time period were reasons forexclusion[

Eligible subjects were allocated in a double!blind ran!domization schedule which assigned subjects to one of thetwo rhinomanometers:acoustic rhinometers used in this studyand to the pseudoephedrine or placebo group in equalnumbers[

Subjects were familiarised with the testing procedures priorto study[ Subjects were seated for 09 min before data wascollected and remained seated for each measurement periodto minimize extraneous sources of variability[

0888 Blackwell Science Ltd\ Clinical Otolarynoloy\ 13\ 3640

ACOUSTIC RHINOMETRY AND RHINOMANOMETRY

METHODS

Acoustic rhinometry "AR# is a non!invasive method of nasalstructural assessment which does not depend upon anadequate 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 theposterior margin of the anterior nares of up to 59 mm^ beyondthis point measurements may be unreliable due to sinusechoes[ Two RM1099 acoustic rhinometers were used in thisstudy[ They were internally calibrated before each measure!ment[ In addition\ a known _xed arti_cial cavity was measuredusing AR at di}erent times during the study[ The accuracy"observed:expected# of volume and cross!sectional areameasurement 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 subjecthad closed their mouth\ mid!breath[ The median value wasselected for on!line analysis[ The minimum cross!sectionalarea "MCSA# of each nasal cavity were recorded between11 mm to 43 mm from the anterior nares "i[e[ the nasal valve#^also the nasal volume between the MCSA depth and 43 mmdepth "NVol#[ Left and right values for MCSA were added toprovide total CSA "tCSA#^ left and right NVol were added tocalculate tNVol[

Active posterior rhinomanometry is an established tech!nique for measuring nasal airway pressure!~ow relationshipsfrom which total nasal airway resistance "tNAR# can bederived[01\02 Two SR1999 rhinomanometers were used[ Re!calibration against reference pressure and air ~ow meters wasperformed at regular intervals throughout the study[ The pres!sure and ~ow channels were linear in the range of 9299 Paand 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 fromthree 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[ At29!min intervals after administration measurement of all vari!ables was repeated until the _nal time "T5# 079 min afteringestion[

Any adverse events were recorded at the end of the studyand all subjects were contacted 0 month later and asked toreport any subsequent symptoms[ The randomization code

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#

Time after dosing"min# Placebo "n 15# Pseudoephedrine "n 13#

Baseline 0[94 2 9[12 0[01 2 9[1029 9[82 2 9[07 9[88 2 9[1159 9[78 2 9[08 9[83 2 9[0689 9[74 2 9[07 9[82 2 9[08

019 9[71 2 9[04 9[80 2 9[07049 9[79 2 9[05 9[82 2 9[08079 9[64 2 9[05 9[82 2 9[08

was not broken until all data\ including delayed adverseevents\ had been collated[

STATISTICAL ANALYSIS

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

180

1.2

1.1

1

0.9

0.8

0.7

0.6

0.5

Time after dosing (min)

tMC

A (

cm2 )

150120906030030

Figure 0[ MCA at times after dosing of either 59 mg pseudoephedrineorally or placebo "mean 2 SE#[ e\ tMCA placebo^ \ tMCA pseudo!ephedrine[


Table 1[ Volume of the de_ned section of both nasal cavities "tNVol#after 59 mg pseudoephedrine orally or placebo "cm2 2 SD#


Baseline 6[12 2 0[49 6[38 2 0[0429 5[19 2 0[35 6[00 2 0[4959 5[23 2 0[43 6[15 2 0[3289 5[25 2 0[49 6[17 2 0[55

019 5[21 2 0[41 6[21 2 0[28049 5[49 2 0[53 6[19 2 0[55079 5[02 2 0[22 6[24 2 0[42

180

8.0

7.5

7.0

6.5

6.0

5.5

5.0


tNVo

l (cm

3 )

150120906030030

Figure 1[ TVOL at times after dosing of either 59 mg pseudoephedrineor placebo "mean 2 SE#[ e\ TVNol placebo^ \ TVNol pseudo!ephedrine[

Results

Ninety!nine subjects were screened\ 43 subjects satis_ed theinclusion and exclusion criteria[ Most exclusions were due toprior drug administration or to an inconsistent history of coldsymptoms[

Of the 43 subjects who were entered randomization\ twofailed to complete the study[ Fifty!two "age 15 2 8 years\range 0744 years\ 29 men 11 women# subjects provided datafor analysis[ Twenty!_ve of these took pseudoephedrine and16 took a placebo[ Forty!eight sets of tNAR data\ 49 sets oftNVol and tCSA data\ and 49 sets of congestion data hadsu.cient valid data and were analysed as an intention!to!treatpopulation[

TOTAL MINIMAL CROSS !SECTIONAL AREA

The overall mean tCSA at the start of the study did not di}erbetween pseudoephedrine and placebo groups "Table 0#\ buttCSA 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 pseudoephedrinecompared to placebo[ "Table 0^ Fig[ 0#[

TOTAL NASAL VOLUME

The mean tNVol[ at the start of the study did not di}erbetween 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#[

NASAL AIRWAY RESISTANCE

The tNAR at the start of the study for all valid subjects was9[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_canttreatment e}ect "P 9[4#[ "Table 2^ Fig[ 2#[

Table 2[ Change in nasal airways resistance "tNAR# after 59 mgpseudoephedrine orally or placebo "Pa[s[cm2 2 SD#


29 9[95 2 9[86 9[99 2 9[3959 9[96 2 9[83 9[28 2 0[0589 9[93 2 9[62 9[92 2 0[26

019 9[99 2 9[82 9[02 2 9[49049 9[95 2 0[98 9[07 2 9[74079 9[01 2 9[71 9[96 2 9[13

180

2.5

2.0

1.5

1.0

0.5

0.0


NA

R (

Pa.

s/c

m3 )

150120906030030

Figure 2[ NAR after dosing with either 59 mg pseudoephedrine orallyor placebo "mean 2 SE#[ e\ NAR placebo^ \ NAR pseudo!ephedrine[


SYMPTOMS OF CONGESTION

Reported symptoms of congestion were similar in both groupsat 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 timepointsbetween 59 and 049 min after dosing[ "Table 3^ Fig[ 3#[

ADVERSE EVENTS

No adverse events occurred that were causally related to thestudy or medication[

Discussion

Subjects with symptoms of an acute upper respiratory tractinfection of less than 4 days duration were recruited for thisstudy[ The high mean tNAR at baseline "9[65\ normal rangein our unit is 9[39 Pa[s[cm2#\ and the signi_cant symptomsof nasal congestion support the reliability of the selectioncriteria[ 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#


Baseline 2[99 2 9[44 1[77 2 9[6329 2[04 2 9[61 1[68 2 9[7259 2[93 2 9[65 1[49 2 9[6189 1[78 2 9[53 1[31 2 9[61

019 1[69 2 9[56 1[18 2 9[75049 1[63 2 9[60 1[18 2 9[64079 1[43 2 9[54 1[16 29[72

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

180

3.5

3

2.5

2

1.5


Ch

ang

e in

co

ng

estio

n fr

om

bas

elin

e(a

rbit

rary

un

its)

150120906030030

Figure 3[ Reported symptoms of congestion at times after dosing with59 mg pseudoephedrine or placebo "mean 2 SE#[ e\ CON placebo^\ CON pseudoephedrine[

Ef_cacy of pseudoephedrine in the common cold 40

an acute common cold\ having a wide age range and equalsex distribution[

There was no di}erence between the treatment and placebogroups in any of the baseline variables[ After placebo\ tMCAand tNVol was reduced over the subsequent 2 h\ while symp!toms of congestion improved[ In this study\ the e}ect ofpseudoephedrine was distinguished from these spontaneouschanges[

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 issigni_cantly more e}ective than placebo in reducing the fallin the cross!sectional area of the nasal valve over a 2!h period[

Nasal area is largely dependent on the nasal valve which isthe region assessed by CSA measurement[ The di}erence intCSA in this study may be expected to cause a correspondingdecrease in NAR on treatment[ Acoustic rhinometry has beenshown to correlate with changes in posterior NAR measure!ments in normal subjects after drug administration[00\03 Asigni_cant change in NAR was not seen with pseudoephedrinein this study[ Upper respiratory tract infection is associatedwith an increase in the amplitude of variations in nasal airwayresistance[04 The rhinomanometry ~ow head of the SR!1999which congestiontained the pressure and ~ow sensors\ wasfound to be sensitive to changes in position\ as a result of thisless reproducible results were found in subjects compared tostatic calibration[

The high spontaneous variability of the placebo NARvalues "CV 9[47# would preclude the detection of signi_cantdi}erences in this study design[ A larger number of subjectswould be required to overcome this[

In the present study\ no signi_cant correlations were foundbetween the baseline values of tCSA and tNAR or changes inthe di}erent variables analysed[ This may be due to the highvariability 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 valveto a point 43 mm from the anterior nares also increased sig!ni_cantly during the 2 h after pseudoephedrine compared withplacebo[ This indicates decongestion of vascular tissues in thisarea and supports the e.cacy of pseudoephedrine[ This nasalvolume increase as well as the increase in tCSA\ may havecontributed to the symptom improvement after pseudo!ephedrine[

This study is the _rst to show that pseudoephedrine whenused 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 ofcongestiongestion in the 59049!min period after adminis!tration[ The study design excluded placebo e}ects\ subjectbias and observer bias[


This study supports the use of single doses of oral pseudo!ephedrine "59 mg# to relieve the symptoms of congestion inacute colds\ with a low level of side!e}ects[

Acknowledgements

This study was supported by Procter + Gamble TechnicalCentres Ltd[ We would like to acknowledge the assistance ofSarah Moody\ Larissa Bickford and Professor Richard Jarrettfor the statistical analysis[

References

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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 experimentalrhinovirus colds[ Bull[ NY Acad[ Med[ 54\ 034059

8 DOYLE W[J[\ RIKER D[K[\ MCBRIDE T[P[ et al[ "0882# Therapeutice}ects of an anticholinergic!sympathomimetic combination ininduced rhinovirus colds[ Ann[ Otol[ Rhinol[ Larynol[ 091\ 410416

09 ECCLES R[\ JAWAD M[S[ + MORRIS S[ "0889# The e}ects of oraladministration of menthol on nasal resistance to air~ow and nasalsensationof air~ow in subjects su}ering fromnasal 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 anteriorand posterior rhinomanometry in normal subjects[ Clin[ Otol!arynol[ 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[ Larynol[ Otol[ 090\ 799797

03 SCADDING G[K[\ DARBY Y[C[ + AUSTIN C[E[ "0883# Acousticrhinometry compared with anterior rhinomanometry in the assess!ment of the response to nasal allergen challenge[ Clin[ Otolarynol[08\ 340343

04 ECCLES R[\ REILLY M[ + ECCLES K[S[J[ "0885# Changes in theamplitude of the nasal cycle associated with symptoms of acuteupper respiratory tract infection[ Acta Otolarynol[ 005\ 6670

taverner (1999)

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