Thorax 1996;51:810-814

Effect of loratadine, an H1 antihistamine,on induced cough in non-asthmatic patientswith chronic cough

Shigehiro Tanaka, Kazuto Hirata, Naotsugu Kurihara, Junichi Yoshikawa, Tadanao Takeda

AbstractBackground - H1 antihistamines havebeen shown to have an antitussive effect inpatients with asthma, postnasal drip, andallergic rhinitis. No study has been per-formed to determine whether orally ad-ministered H1 antihistamines can reducethe number ofcoughs induced by stimula-tion of cough receptors in non-asthmaticpatients with chronic dry cough.Methods - The effect ofloratadine (10 mg)on the number of coughs induced byultrasonically nebulised distilled water(UNDW) was examined in 10 patients withnasal disease and in seven patients withunexplained chronic cough using a ran-domised, double blind crossover method.Eleven normal volunteers were also stud-ied. Each subject inhaled UNDW for oneminute, and the numbers of coughs dur-ing the one minute inhalation and the 30seconds following it were counted.Results - There was no difference in theresults of pulmonary function tests per-formed before and one minute afterUNDW inhalation for either patients ornormal subjects. There was also no sig-nificant difference between the results ofpulmonary function tests before or afteroral administration of loratadine. Lorata-dine significantly reduced the number ofcoughs in patients with nasal disease andin those with unexplained chronic cough,but not in normal subjects.Conclusions - The H1 antihistamine lorata-dine reduces cough induced by UNDW. Therelease of histamine may contribute to thechronic cough in patients with unexplainedchronic cough or nasal disease.(Thorax 1996;51:810-814)

Keywords: H, antihistamine, chronic cough, distilledwater challenge.

Chronic cough of unknown cause is a commonclinical problem. Specific treatments have beendevised for patients with chronic cough withpostnasal drip, asthma, and gastro-oesophagealreflux.' Pratter et al have reported an algorithmfor the treatment of chronic cough and suggestthat an H, antihistamine may be effective andthat bronchoprovocation challenge is useful ininvestigation.2 The newer non-sedating antihis-tamines such as loratadine and terfenadinemay be clinically useful for patients withchronic cough.3)5

Ultrasonically nebulised distilled water(UNDW) inhalation can induce bronchocon-striction in asthmatic subjects and this bron-choconstriction can be inhibited with H1 anti-histamines, inhaled anticholinergic agents, Dagonists, and disodium cromoglycate.5-10 Pro-tection against this bronchoconstriction maybe independent of bronchodilation since it hasbeen reported that oral terfenadine is a moreeffective inhibitor of distilled water-inducedbronchoconstriction than is inhaled ipratro-pium bromide.7 Bronchoconstriction associ-ated with UNDW inhalation in asthmatic sub-jects is thought to occur as a result of directosmotic changes in the mucosa or lining fluidthat may change wall thickness, together withosmotically stimulated local mediator re-lease." 12 However, in non-asthmatic subjectsinhalation of UNDW has no direct effect onthe size of the airway.'2 UNDW-induced coughis not caused by bronchoconstriction and isinhibited by inhaled lignocaine,5 inhaled anti-cholinergic bronchodilators, and c adrenergicagonists.l3 However, the effect of HI antihista-mine on UNDW-induced cough has not beensystematically studied in non-asthmatic pa-tients with chronic cough.The aim of this study was to determine

whether H1 antihistamines, which are widelyused antiallergic drugs, can reduce the numberof coughs induced by UNDW inhalation innon-asthmatic patients with chronic cough andin normal volunteers, and whether they havean acute effect on the results of pulmonaryfunction tests.

MethodsSUBJECTSThe three groups of subjects who took part inthe study comprised 10 non-asthmatic patientswith chronic cough and a history of nasaldisease, seven non-asthmatic patients withunexplained chronic cough and no nasaldisease, and 11 normal subjects. All patientsand subjects were non-smokers.The 10 patients (four men) with nasal

disease were aged 24-60 years and had chroniccough of more than eight weeks duration. Fourhad a history of allergic rhinitis only, four hadpostnasal drip only, and two had a history ofboth allergic rhinitis and postnasal drip (table1). The six patients with a history of allergicrhinitis had neither nasal discharge nor sneez-ing at the time of the study.The seven non-asthmatic patients (two men)

without nasal disease were aged 27-61 years

First Department ofInternal Medicine,Osaka City UniversityMedical School,1-5-7 Asahi-machi,Abenoku, Osaka 545,JapanS TanakaK HirataN KuriharaJ YoshikawaT Takeda

Correspondence to:Dr S Tanaka.

Received 28 February 1995Returned to authors28 April 1995Revised version received8 February 1996Accepted for publication28 February 1996

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Table 1 Characteristics ofpatients and normal subjects

FEV, (7) Cough durationAge Sex (%o predicted) (months) Atopy Diagnosis

Patients with nasal disease:1 49 F 1.85 (82) 6 PND2 27 F 1.82 (77) 6 + (AR)3 51 F 1.93 (78) 4 - PND4 60 F 1.92 (107) 10 + PND, (AR)5 29 F 2.44 (84) 2 PND6 44 F 2.54 (100) 2 + (AR)7 26 M 3.55 (88) 12 + (AR)8 29 M 4.10 (102) 3 PND9 24 M 4.48 (106) 2 + (AR)10 44 M 3.30 (102) 2 + PND, (AR)Mean (SD) 38 (13) 2.79 (1.0)

Patients with unexplained chronic cough:1 51 F 2.23 (104) 6 -

2 29 F 2.81 (96) 12 -

3 33 F 2.20 (81) 3 -4 61 F 1.98 (104) 6 -

5 54 F 2.84 (138) 3 -

6 27 M 4.24 (116) 36 -

7 58 M 2.92 (103) 12 -Mean (SD) 45 (15) 2.74 (0.8)

Normal subjects (n=1 1; 23-38 years; M:F, 6:5)Mean (SD) 28 (5.1) 3.55 (0.6)

FEV, = forced expiratory volume in one second; + = at least one positive reaction to skin tests with a battery of 12 commonairborne antigens or specific IgE antibodies to common aeroallergens or both; = negative; PND = postnasal drip; AR = allergicrhinitis.

and also had chronic cough of more than eightweeks duration (range 2-36 months) (table 1).Each patient made three visits to our labora-

tory. Patient examination included a respira-tory questionnaire, physical examination, pul-monary function tests, and methacholinechallenge tests. All patients had normal chestand sinus radiographs and none had anyhistory of oesophageal reflux. Six of thepatients with nasal disease were atopic asevidenced by at least one positive reaction toskin tests in a battery of 12 common airborneantigens or specific IgE antibodies to aeroaller-gens, or both. None of the patients had ahistory of postviral infection, shortness ofbreath, wheezing at rest, or use ofACE inhibi-tors.The 11 normal subjects (six men) were aged

23-38 years and made two visits to our labora-tory (table 1). None had a history of airwayinfection during the four week period preced-ing the study and none had taken anymedication, including H1 antihistamines, priorto the study.

Informed consent for participation in thestudy was obtained from each subject and thestudy was approved by the ethics committee ofOsaka City University Hospital.

UNDW INHALATION COUGH CHALLENGEUNDW inhalation tests based on the methodof Anderson et all4 were used with some minormodifications. One minute UNDW inhalationwas used because, in a previous study in whichthree minute UNDW inhalations were usedwith 30 minute intervals between inhalations,tachyphylaxis occurred in normal subjects."5The UNDW aerosol was inhaled from anultrasonic nebuliser (Devilbiss Ultra Neb 99,The Devilbiss Co, Somerset, Pennsylvania,USA) through a mouthpiece connected to atwo way valve (Igarashi's non-rebreathingvalve, Igarashi Medical Co, Japan) with tubing70 cm in length and 22 mm in internal

diameter. The UNDW inhalation challengewas performed during tidal breathing over oneminute with the subject wearing a noseclip.The mean output of the nebuliser without atwo way valve was 15 1/min and particle diam-eter ranged from 0.5 gm to 5 gm. The mean(SD) output of the nebuliser with a two wayvalve during tidal breathing was 10 (0.7) 1/minas measured with a Wright respirometer(Haloscale Compact, Ferraris Developmentand Engineering Co, UK) in seven normal vol-unteers after completion of their second day ofthe study. The mean (SD) amount of inhaleddistilled water for the seven normal volunteerswas 2.5 (0.3) ml. The number of coughsduring the one minute UNDW inhalation andthe 30 seconds immediately afterwards wascounted by an observer who had beeninstructed only to count and record into a taperecorder. No further coughs were counted afterthis time. Coughs were defined as plosiveevents which occurred in singles or in runs.Each plosive event was counted individuallyand episodes of throat clearing were notcounted. Pulmonary function tests (forcedvital capacity (FVC), forced expiratory volumein one second (FEV1), and maximum expira-tory flow at 25% vital capacity (V25)) were per-formed every two minutes before and afterUNDW inhalation with a Chestac-25 FSystem (Chest Co Ltd, Tokyo, Japan).

METHACHOLINE CHALLENGEThe methacholine provocation challenge testwas performed three or five days beforeUNDW inhalation using the method describedby Makino et al. 6 In brief, aerosols were gener-ated with a nebuliser at an air flow rate of 51/min. At five minute intervals each subjectinhaled the aerosol for two minutes duringquiet breathing through the mouth. An iso-tonic 0.9% saline solution was inhaled first,followed by methacholine in concentrationsranging from 20 to 10 000 ,ug/ml in doubling

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increments. The FEVy was measured beforeand after inhalation of the saline solution andafter each inhalation of methacholine. Whenthe change in FEV, from the baseline after theinhalation of saline was 10% or less in all sub-jects, inhalation of methacholine was started.The test was continued until the FEV, hadfallen by 20% or until the highest concentra-tion of methacholine had been administered.The threshold was defined as the lowestconcentration of methacholine that produced a20% fall in FEV, (PC20) which was calculatedby linear interpolation between the last twodata points on the dose-response curve or wasexpressed as 10 000 gg/ml if there had been noresponse.

STUDY DESIGNA randomised, double blind, crossover methodwas used. In the afternoon of the visit to thelaboratory on day 1 each subject inhaledUNDW for one minute and the number ofcoughs during the inhalation and the 30seconds following it were counted. One tabletof loratadine (10 mg, Schering-Plough, Osaka,Japan) or one tablet of an identical placebo(starch) were then administered in a ran-domised double blind fashion. One hour laterone minute UNDW inhalation was repeatedand the number of coughs was again counted.Intervals of one hour between UNDW inhala-tions were used because of the pharmacokinet-ics of loratadine.3 The second day of the studywas two days after day 1. Each subject inhaledUNDW for one minute and the number ofcoughs was counted. Placebo or loratadinewere then administered, whichever had notbeen given on day 1. One hour later oneminute UNDW inhalation was performed andthe numbers of coughs were counted again.

STATISTICAL ANALYSESThe results are expressed as mean (SD) but thenumbers of coughs, FEVI, and V25 values areexpressed as mean (SE). Comparison ofpretreatment UNDW challenges between days1 and 2 was performed using a two tailed Stu-dent's t test. The repeatability of the pretreat-ment UNDW cough challenges was assessedusing the method of Bland and Altman.'7 Themean number of coughs on days 1 and 2 wasplotted against the difference between themeans, both expressed on a logarithmic scale.Pretreatment differences in the number ofcoughs between groups were examined usingthe Mann-Whitney U test. Differences in thenumbers of coughs from baseline to treatmentwere analysed using the Wilcoxon's rank sumtest which compared intragroup differences.The Mann-Whitney U test was used tocompare differences in the numbers of coughsfrom control to treatment between the differ-ent groups. Changes in recorded FEV, and V25were analysed using analysis of variance(ANOVA). Values of p < 0.05 were taken toindicate statistical significance.

ResultsThere was no significant difference in thenumber of coughs before treatment on days 1

and 2. The calculated coefficient of repeatabil-ity for the UNDW challenge was 0.21 (fig 1).Tachyphylaxis did not occur during the oneminute UNDW inhalation in any of thepatients or the normal subjects. The twogroups ofpatients with chronic cough each hada significantly larger response to UNDW inha-lation testing than did the normal subjects (fig2). Neither placebo nor loratadine had anyeffect on the number of coughs in normal sub-jects and placebo had no effect in either of thepatient groups. However, compared with pla-cebo, loratadine significantly reduced thenumber of coughs in both patients with nasaldisease (p = 0.005) and those with unex-plained chronic cough (p < 0.05) (fig 3).There was no difference in the amount ofcough reduction between the two groups ofpatients. Since there was no significant differ-ence in FEV1 or V25 before and after UNDWinhalation or before and after oral administra-tion of placebo or loratadine in either patientsor normal subjects, loratadine had no acuteeffect on bronchodilation one hour after its oraladministration. Patients exhibited no hyperre-sponsiveness on methacholine challenge tests.

DiscussionThe findings of this study show that, fornon-asthmatic patients with chronic cough, theHI antihistamine loratadine, when given orallyin a dose of 10 mg, significantly reduces coughinduced by UNDW inhalation. This finding isimportant because it provides indirect evi-dence that, in at least some patients withchronic cough and a history of nasal diseasesand some with unexplained chronic cough andno nasal disease, histamine release in responseto a change in osmolarity of the airwayscontributes to the cough. Loratadine, whenorally administered an hour before pulmonaryfunction tests, had no acute bronchodilatingeffects in this study. It is clear that cough andbronchoconstrictor reflexes are mediatedthrough different afferent neuralpathways.7 18-20 However, it has been shownthat the bronchodilating effect may be one ofthe reasons for inhibition of cough induced byUNDW inhalation in normal volunteers, in

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Figure 1 Repeatability ofpretreatment number of coughsinduced by UNDW inhalation in all subjects (n = 28).

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patients with upper respiratory tract infections,and in those with asthma.'3 21 22 If coughing inthe patient groups receives a contribution fromheightened perception due to conductancechanges, HI antihistamines can decrease spe-cific airways conductance, thereby increasingFEV, or V25. A previous study reported thatboth distilled water and hypertonic saline pro-duced small increases in non-specific reactivityin non-asthmatic subjects and confirmed thatsubstantial osmotic challenge does not changeairway calibre.'2 Although the authors of thatstudy used a larger amount ofUNDW than inour study, in four subjects V25 was measuredand had a plateau similar to that of specific air-ways conductance.'2 In our study FEV, andV25 were not significantly changed in either thepatients or the normal subjects. Our findingssuggest that loratadine reduces the number ofcoughs induced by UNDW inhalation by anH, antihistamine effect rather than by an anti-cholinergic effect.The patient groups had a significantly larger

response to UNDW inhalation than didnormal subjects which indicated that bothpatients with nasal disease and those withunexplained chronic cough had a higher

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degree of cough sensitivity than normalsubjects. In a study in which three minuteUNDW inhalations with 30 minute intervalsbetween inhalations were used, tachyphylaxisoccurred in normal subjects.'5 No tachyphy-laxis occurred in either patients or normal sub-jects in our study using one minute UNDWinhalation and 60 minute intervals betweeninhalations. These findings suggest that pa-tients with chronic cough exhibit an abnor-mally excessive reaction to stimulation ofcough receptors by UNDW inhalation.H, antihistamines are known to be effective

in the treatment of cough in patients with nasaldisease.23 In our study six patients had a historyof allergic rhinitis but had no evidence of nasaldischarge at the time of examination. Based onprevious reports' 2 24 they should be diagnosedas having postnasal drip secondary to rhinitis.The cause of cough in patients with allergicrhinitis is unclear, but it is generally thought tobe due to postnasal drip secondary to rhinitis.In these patients histamine release may be oneof the reasons for chronic cough. Postnasaldrip may cause mechanostimulation ofpharyn-geal or laryngeal receptors with normal sensi-tivity. Prominent nasal obstruction with mouthbreathing and loss of nasal air conditioningmay lead to chronic irritation with enhancedsensitivity of afferent cough nerves.25 Furtherstudies are required to identify the mechanismof chronic cough in patients with postnasaldrip.The finding that treatment of patients with

unexplained chronic cough requires a longerperiod of time than treatment of those withnasal disease suggests that a difference existsbetween these two groups, but a large differ-ence was not found in this study. Patients withunexplained chronic cough should be followedup whether or not they have asthma.H, antihistamines inhibit the release of

histamine and leukotrienes produced by eosi-nophils and mast cells.2"28 Chronic cough innon-asthmatic patients has been shown to beassociated with airway inflammation by thepresence of eosinophils and metachromaticcells and epithelial damage.24 29 The findings ofthis study show that, in non-asthmatic patientswith chronic cough, H, antihistamines signifi-cantly reduce coughing induced by UNDWinhalation without affecting FEV, or V25. We

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Before After Before After Before After Before After Before After Before AfterPlacebo Loratadine Placebo Loratadine Placebo Loratadine

Figure 3 Effect of oral administration of loratadine on the number of coughs induced by UNDWinhalation in (A)normal subjects, (B) patients with nasal disease, and (C) patients with unexplained chronic cough.

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conclude that the H1 antihistamine loratadinereduces cough induced by UNDW, and that inpatients with unexplained chronic cough ornasal disease the release of histamine may con-tribute to the chronic cough.

The authors thank Dr L Bao, Dr T Otsuka and Dr T Fujii forassisting in the performance of this study, and Yuriko Takahashifor her secretarial assistance.

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4 Mauser PJ, Kreutner W, Egan RW, Chapman RW. Selectiveinhibition of peripheral histamine responses by loratadineand terfenadine. Eur3r Pharmacol 1990;182: 125-9.

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16 Makino S, Kobayashi S, Miyamoto T, Shinoda T, TakahashiS, Abe J, et al. Standard for allergen bronchial provocationtests in asthma and hypersensitivity pneumonitis.3apan TAllergol 1982;31:1074-6.

17 Bland JM, Altman DG. Statistical methods for assessingagreement between two methods of clinical meausure-ment. Lancet 1986;i:307-10.

18 Karlsson JA, Sant'Ambrogio G, Widdicombe J. Afferentneural pathways in cough and reflex bronchoconstriction._r Appl Physiol 1988;65:1007-23.

19 Eschenbacher WL, Boushey HA, Sheppard D. Alteration inosmolarity of inhaled aerosols cause bronchoconstrictionand cough, but absence of a permeant anion causes coughalone. Am Rev Respir Dis 1984;129:211-5.

20 Stone RA, Barnes PJ, Chung KF. Effect of frusemide oncough responses to chloride-deficient solution in normaland mild asthmatic subjects. Eur Respir_r 1993;6:862-7.

21 Lowry R, Higenbottam T, Johnson T, Godden D. Inhibitionof artificially induced cough in man by bronchodilators. Br_GClin Pharmacol 1987;24:503- 10.

22 Lowry R, Wood A, Higenbottam T The effect of anticholin-ergic bronchodilator therapy on cough during upper respi-ratory tract infections. Br y Clin Pharmacol 1994;37: 187-91.

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24 Boulet L-P, Milot J, Boutet M, St Geotges F, Laviolette M.Airway inflammation in nonasthmatic subjects withchronic cough. Am . Respir Crit Care Med 1994;149:482-9.

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