Ordinary and high ose ipratr perennial nonallergic rhinitis

Transcription

1 Ordinary and high ose ipratr perennial nonallergic rhinitis ium in J. Kirkegaard,* N. Mygind,** F. Mmlgaard,*** B. Grahne,**** E. Holopainen,**** H. Malmberg,**** K. Brmndbo,***** and T. Rejne***** Aalborg and Copenhagen, Denmark, Helsinki, Finland, and Oslo, Norway The aim of the present study was to test the efficacy of the topically active cholinoceptor antagonist, ipratropium, in the treatment of rhinorrhea in perennial nonauergic rhinitis, with special reference to identification of subgroups of responders and increased efficacy from high-dose therapy. Thirty-six adult patients with watery rhinorrhea as a dominant ~ymptom completed the study, which consisted of a 2-week run-in period followed by two 3-week treatment periods with placebo and ipratropium in an ordinary dosage (80 Ixg four times a day) in a double-blind, crossover design, and, finally, an open 2-week period with high-dose therapy (4~ txg four times a day). The number of nose blowings was 47% lower during treatment with ipratropium in the ordinary dosage than during the placebo period (p < 0.001). There was an additional reduction during high-dose therapy that was slight but statistically sign~fiz'ant (p < 0.05). Ipratropium had no effect on the number of sneezes or on nasal blockage index~ During ordinary-dose therapy, side effects were slight and confined to the nose, whereas the high-dose therapy caused unpleasant nasal dryness and, in a few cases, systemic side effects. It was not possible to separate responders from nonresponders by case history, physical examination, or nasal methacholine testing. It is concluded that intranasal ipratropium is effective in the treatment of watery rhinorrhea in perennial nonallergic rhinitis and that 320 ~g a &tv is sufficient in most patients. (J ALLERGY CLIN IMMUNOL 1987:79:585-90) Intranasal atropine has been used for the treatment of watery rhinorrhea in allergic and viral rhinitis,l but the claimed efficacy has not been documented by placebo-controlled trials. In addition, atropine is readily absorbed, and there is a risk of systemic side effects. 2 Ipratropium bromide (ipratropium) is a cholinoceptor antagonist that, as a quaternary ammonium compound, is poorly absorbed from mucous membranes.3.4 It was primarily developed as a bronchodilator, since inhalation of the drug relaxes bronchial smooth muscle without systemic side effects. 5' 6 No adverse effect on bronchial mucus production or mucociliary transport function has been demonstrated during long-term therapy with inhaled ipratropium in ordinary doses for asthma (400 p,g qid). 7 Laboratory studies later demonstrated that ipratro- TABLE I. Provoking factors (percent of patients) Cold air 82 Hot soup 60 Dust 46 Tiredness 34 Exercise 29 Alcohol 26 Spicy food 26 Vacuum cleaning 23 Food 20 Pollen 20 Flowers 14 Analgesics 14 Animals 6 Psychic 3 From the *Department of Otolaryngology, Aalborg Hospital, **Otopathological Laboratory, Department of Otolaryngology, Rigsh~italet, Copenhagen, ***Medical Department, Boehringer tngelheim, Copenhagen, Denmark, ****Department of Otolaryngology, Central Hospital, Helsinki, Finland, and *****Department of Ototaryngology, Rikshospitalet, Oslo, Norway. Received for publication May 21, Accepted for publication Sept. 17, Reprint requests: Niels Mygind, M.D., Otopathological Laboratory, Department of Otolaryngology, Rigshospitalet, DK-2100 Copenhagen. Denmark. Abbreviation used qid: Four times a day plum can block methacholine-induced hypersecretion in the nose, 8 and clinical trials demtmstrated a reduction of rhinorrhea in perennial rhinitis when the drug was administered as a nasal aerosol in a dosage of 320 Ixg qid. 9 The antirhinorrhea effect in published

2 586 Kirkegaard et al. J. ALLERGY CLIN. IMMUNOL APRIL 1987 TABLE II. Self-assessment method for recording nasal blockage* Assessment Score TABLE III. Blockage index based on patient self-assessment (see Table II) Self-assessment score Both sides One side Other side Blockage index Breathing through the nose/nostril Free and easy 0 Uneasy but can be continued 1 Difficult and cannot be continued 2 Completely abolished 3 *After examination of both nasal cavities together, each cavity is assessed separately by occluding the other nostril gently but tightly with a thumb TABLE IV. List of symptoms that are likely and unlikely adverse effects from a cholinoceptor antagonist Run-in Ipratropium Ipratropium period Placebo (80 Ixg qid) (400 I~g qid) Uneasiness 14 (3.4) 28 (7.0) 19 (5.2) 25 (6.2) Diarrhea 11 (2.6) 11 (3.6) 11 (2.4) 11 (2.8) Palpitation 6 (0.4) 11 (2.4) 14 (3.2) 11 (2.6) Headache 50 (17.1) 44 (18.4) 39 (16.9) 31 (14.1) Nausea 3 (1.0) 17 (4.8) 11 (3.8) 19 (4.6) Abdominal pain 19 (4.0) 19 (7.3) 11 (5.8) 25 (5.8) Dryness of mouth* 39 (21.6) 28 (17.6) 42 (23.2) 78 (50.0) Dizziness 11 (5.0) 19 (9.5) 19 (8.5) 22 (10.3) Blurred vision 6 (4.2) 8 (6.4) 8 (6.4) 14 (11.1) Constipation 19 (7.3) 14 (10.1) 14 (11.2) 25 (13.7) Dysuria* 3 (0.2) 6 (4.4) 11 (5.0) 28 (14.1) Dryness of nose*'t 25 (8.1) 36 (15.8) 61 (31.2) 72 (49.6) Heating 14 (1.8) 11 (3.8) 19 (4.8) 22 (5.2) The results of the questionnaire are presented as the percent of patients having the symptoms and as the percent of all days with the symptom (in parentheses). *p < 0.01 for column 1 versus column 4, and column 2 versus column 4. tp < 0.05 for column 2 versus column 3. studies has varied from good, ~~ 11t0 moderate, 9. 12, 13 to marginal. 14, 15 The aim of the present study was to determine whether responders and nonresponders to ipratropium in an ordinary dosage (320 ~g qid) can be identified from clinical symptoms and signs or based on the secretory response to a nasal methacholine test. In addition, we wanted to discover whether the apparent lack of efficacy in some patients could be due to a too low dosage of ipratropium; another object was to define the maximum efficacy of this type of therapy in rhinitis. Therefore, a very large ipratropium dosage was administered, even though adverse effects, not acceptable in clinical practice, could be expected. PATIENTS AND METHODS Patients Consecutive adult patients referred to departments of otolaryngology for perennial nouallergic rhinitis and watery rhinorrhea as a dominant symptom entered the study. They all complained of nonseasonal, nasal symptoms that were present on most days, requiring daily therapy, and which had lasted for at least 1 year. They were skin test negative to a standard series of aeroallergens (ALK, Copenhagen, Denmark). Patients were not included if they (1) were pregnant, (2) used other types of medicine that could affect trial results, (3) had large polyps, or (4) had gross anatomic abnormalities hindering the use of intranasal medication. All patients gave informed consent to participate, and the protocol was approved by the relevant ethical committees.

3 VOLUME 79 Ipratropium in perennial nonallergic rhinitis 587 NUMBER 4 TABLE V. Average daily number of nose blowings in 36 patients Ipratropium Ipratropium Patient no. Run-in period Placebo (80 Ixg qid) (400 lxg qid) t4.9 4, i l ~9, , li~ [3, , /2, , i) , ], ,4 [ t0~ [ ~, ~ , , , , , ,1 Median ,0 Mean ,6 13,3 SEM P <0.001 <0,05 Thirty-nine patients entered, and thirty-six patients completed the trial: one patient lost his score card, one failed to fill it in properly, and one patient did not take medication in the last treatment period. The mean age was 51 years (range 19 to 84 years). There were 18 women and 18 men. ~ n of the study After a 2-week run-in period, patients were treated for 3 weeks with ipratropium in an ordinary dose (80 p.g qid) or placebo in a double-blind crossover design, which was followed by a 2-week open assessment of ipratropium, administered in a large dose (400 o,g qid). Run-in period All antirhinitis medication was stopped 2 weeks before the trial medication was started, and the patients filled in diary cards during this run-in period. [h'~r~rr~lvt exa "mmclions All patients completed a detailed symptom questionnaire. including questions about the nature and severity of symp-

4 588 Kirkegaard et al. J. ALLERGY CLIN. IMMUNOL. APRIL 1987 TABLE VI. Percent of ipratropium responders (i.e., patients with I> 50% reduction of nose blowings) based on comparisons with the run-in period and with the placebo period Run-in period Placebo period No. (%) No. (%) Placebo 4/36 (14) Ipratropium 15/36 (42) 15/36 (42) (ordinary dose) Ipratro'pium 18/36 (50) 23/36 (64) (large dose) toms, the most troublesome symptom, and provoking factors (Table I). The patients stated that they sneezed on average 8V2 times a day, blew their nose 40 times, and had symptoms on average 91/2 hours a day. The nasal discharge was predominantly (85%) nonpurulent (clear and watery/mucoid). The disease had lasted an average of 14.9 years (2 to 45 years). An intranasal methacholine test was performed, af'aer an ordinary ear, nose, and throat examination, by spraying 12 mg of methacholine into each nostril with subsequent sampling of nasal discharge*; the mean volume produced during a 15-minute period was 1.0 ml (range 0.2 to 2.7 ml). The nasal mucociliary clearance was studied by measuring the time between the placing of a saccharine particle on the inferior turbinate (1 cm from the front edge) and until the volunteer experienced a sweet taste in the mouthl6; the test was repeated after each treatment period. Drugs Ipratropium and placebo were supplied as coded, pressurized canisters by Boehringer Ingelheim, Copenhagen, Denmark. The canisters were equipped with a nozzle and delivered 20 I~g of aerosolized ipratropium per actuation. The daily dose was two puffs in each nostril (one in the upper and one in the lower part) four times daily (total dally dose, 320 I~g). High-dose ipratropium aerosols, delivering 100 tzg per actuation, were administered in a similar way (total daily dose, 1600 p,g); they were specially made and supplied by Boehringer Ingelheim, Ingelheim, West Germany. Effect parameters Diary cards were filled in during the entire study period. Patients recorded the number of sneezes and nose blowings continuously in 2-hour periods; they were told not to sniff but only to blow the nose. They assessed nasal blockage bidaily (Tables II and III). A questionnaire about side effects was completed morning and evening. Some of the symptoms listed were well-known side effects from a cholinoceptor antagonist, and some were not (Table IV). Statistics Since neither the number of sneezes nor the number of nose blowings followed a normal distribution, the nonparametric Wilcoxon signed-rank test for paired data with two-sided alternatives was used. To reduce day-to-day variation in symptoms and the risk of mass significance, comparisons were made between median values for the last week of each period only. The chi-square test was used for side effects. RESULTS There were striking differences between patients during the run-in period with the average number of nose blowings ranging from 3.6 to 373 per day. The results of ipratropium treatment on rhinorrhea are presented in Table V. The number of nose blowings was 47% lower during normal-dose ipratropium treatment than during placebo therapy (p < 0,01). There was an additional, but slight, reduction during high-dose therapy (p < 0.05). The response to ipratropium varied considerably between individuals. Four different types of response can be described. (1) Some patients had few symptoms and probably did not require treatment (Nos. 3, 7, 11, 12, 13, 42, 54, and 61). (2) Some patients had nose blowings that apparently were unresponsive to the treatment (Nos. 32, 43, 52, and 57). (3) Many patients obtained sufficient relief from ipratropium in the normal dose (Nos. 1, 6, 9, 10, 18, 20, 35, 41,49, and 55). (4) A few patients with severe symptoms needed high-dose ipratropium for proper symptom control (Nos. 4 and 50). Twelve patients could not easily be referred to one of these groups. The number of patients who were considered to be ipratropium responders is presented in Table VI in order to illustrate an impression of the overall usefulness of the drug. There was no correlation between the percentual reduction of nose blowings during ipratropium treatment and any of the following parameters: duration of disease, severity of symptoms, percentage of secretion that was watery, provoking factors, and secretory response to a methacholine test. Ipratropium in normal and in large dose had no effect on the number of sneezes or the nasal blockage index (Table VII). The possible side effects from medication are listed in Table IV. Patients on both ordinary and high-dose ipratropium therapy had an increased frequency of nose dryness, whereas only those on high-dose therapy developed mouth dryness and difficulties in urination. The figures suggested a slight but nonsignificant increase in the occurrence of blurred vision during high-dose therapy. Ipratropium, ordinary dose and

5 VOLUME 79 Ipratropium in perennial nonallergic rhinitis 589 NUMBER 4 TABLE VII. Average daily number of sneezes and blockage index (mean + SEM) Run-in Ipratrepiurn Ipratropium period Placebo (80 p.g (lid) (400 ~g qid) No. of sneezes , ~ ().b Blockage index , (~ ~ 0.2 large dose, had no demonstrable effect on the nasal mucociliary transport (Table VIII). DISCUSSION We used detailed recording of the number of nose blowings and not the ordinary 0, 1, 2, and 3 system (no, slight, moderate, and severe symptoms). It was possible to hav~ the patients adhere to this practice for 10 weeks. The diary cards disclosed that patients claiming to suffer from rhinorrhea, in fact, blew their noses from a few to more than 100 times a day. This information is essential when patients are compared in drug trials, important for exact evaluation of therapy, and is also useful in clinical practice. A questionnaire filled in before the trial revealed a 100% overestimation of symptom severity. The present trial confirms earlier studies of the efficacy of intranasal ipratropium in perennial nonallergic rhinitis. 9-H' 13 The overall result was better in our study than in some of the other studies ~4' ~5 that may be related to the relatively high age of the patients and the cold weather during the trial period (Nordic winter); ipratropium is very effective in cold air-induced rhinorrhea. ~7 The significant reduction in the number of nose blowings demonstrates that at least one half of the discharge is a reflex-mediated product from nasal glands and probably more, because it is unlikely that a nasal spray can reach all of the 100,000 seromucous glands t8 in the nose. It is unknown whether anterior serous glands ~9 and Bowman's glands contribute to rhinorrhea, and if they do, whether they respond to a cholinoceptor antagonist. Discharge from goblet cells, transudation, tears, and secretion from paranasal sinuses cannot be expected to be reduced by ipratropium. Unfortunately, none of the parameters studied were able to separate responders from nonresponders. Consequently, a therapeutic trial with symptom recording is necessary in clinical practice, It must be emphasized that ipratropium is only effective on one rhinitis symptom, namely, watery rhinorrhea, in contrast to antihistamines, cromolyn, and steroids. The manner in which ipratropium is administered in clinical trials, i.e.. as a fixed dose four times daily, is, in our opinion, not the best way to treat many of TABLE VUl. Saccharine transport time (minutes) (mean ~- SEM) After After B~lot~ After ila~tlau illtattll~m t.uttmqmt placebo (N ~qkl) 1~ l~ll:qld) 14.9 ~ , I the patients, Characteristically, the symptoms vary considerably, and treatment should follow this variation. Patients with periodic symptoms may only need the spray occasionally. In the more severe cases, when dally medication is indicated, the diurnal variation should be taken into account. As a general rule, there is most nasal discharge in the morning~~ later during the day, there may be intermittent reflex-mediated symptoms, induced by a series of stimuli (Table 1). In these patients, it appears preferable to start with a full dose of ipratropium (i.e., 80 ~g) early in the morning; if the symptoms are not controlled, this dose can be repeated once or perhaps twice at intervals of 30 minutes. Later, the spray can be used as required, preferably before known exposure to provoking factors. 9 The normal dally dose of 320 p~g of ipratropium will, as the only side effect, cause some nasal dryness if symptoms are not severe enough to match the dosage. Control of severe morning symptoms can therefore be at the expense of nasal dryness in the aftemoon and evening, since it is a very long-acting drug (18 to 24 hours). ~ A saline spray can be helpful in that situation. Our trial demonstrated that a few patients with very severe symptoms are not controlled by a daily dose of 320 txg, and a larger dosage may be tried in these few cases. Systemic adverse effects occurred in some patients at 1600 ~g, which is therefore too large a dose for clinical practice. It is likely that a large dose may only be necessary for a period, since clinical experience has suggested that the ipratropiurn dose can be reduced after continuous therapy for some months.,o.,~z Theoretically, this may be. due to the fact that constant treatment inhibits an increase in glandular size and in the activity of enzymes that syn-

6 590 Kirkegaard et al. J. ALLERGY CLIN. IMMUNOL. APRIL 1987 thesize mucus. 23' 24 There is no evidence that a cholinoceptor antagonist can cause rhinitis medicamentosa after long-term usage:2; this side effect is well known from prolonged use of ct-adrenoceptor agonists. It has been demonstrated earlier 25 that a single in- tranasal spraying of 80 ixg of ipratropium does not have any demonstrable effect on the mucociliary transport rate measured by the saccharine test. The results of the present study confirm and extend this observation because treatment for 14 days did not reduce the saccharine transport time significantly, even when the daily dose was 320 Ixg or 1600 ixg. The latter is astonishing, since many of the patients complained of a dry nose during high-dose therapy. REFERENCES 1. Jackson RT, Teichgraeber J. Low-dose topical atropine for rhinorrhea. Arch Otolaryngol 1981;107: Weiner N. Atropine, scopolamine, and related antimuscarinic drugs. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman's the pharmacological basis of therapeutics. New York: Macmillan, 1980: Deckers W. The chemistry of new derivatives of tropane alkaloids and the pharmacokinetics of a quaternary compound. Postgrad Med J 1975;51(suppl 7): Engelhardt A, Klupp H. The pharmacology and toxicology of a new tropane alkaloid derivative. Postgrad Med J 1975; 51 (suppl 7): Poppius H, Salorinne Y. Comparative trial of a new anticholinergic bronchodilator, Sch 1000, and salbutamol in chronic bronchitis. Br Med J 1973;4: Baigelman W, Chodosh S. Bronchodilator action of the anticholinergic drug ipratropium bromide (Sell 1000) as an aerosol in chronic bronchitis and asthma. Chest 1977;71: Pakes GE, Brogden RN, Heel RC, Speight TM, Avery GS. Ipratropium bromide: a review of its pharmacological properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs 1980;20: Borum P. Nasal methacholine challenge: a test for measurement of nasal reactivity. J ALLERGY CLIN IMMUNOL 1979; 63: Borum P, Mygind N, Larsen FS. Intranasal ipratropium: a new treatment for perennial rhinitis. Clin Otolaryngol 1979;4: 407- I Malmberg H, Grahne B, Holopainen E, Binder E. Ipratropium (Atrovent) in the treatment of vasomotor rhinitis in elderly patients. Clin Otolaryngol 1983;8: Dolovich J, Kennedy L, Kazim F, Vickerson F. Ipratropium bromide (Atrovent) nasal spray in vasomotor rhinitis [Abstract]. J ALLERGY CLIN IMMUNOL 1985;75: Jokinen K, Sipila P. Intranasal ipratropium in the treatment of vasomotor rhinitis. Rhinology 1983;21: Van Haacke NP, Moore-Gillon V, Capel LH. Double-blind crossover trial of ipratropium and placebo in chronic rhinorrhoea. Lancet 1983;287: Bok HE, Van Winjngaarden HA, Comelissen PJG. Intranasal ipratropium bromide for paroxysmal rhinorrhoea. Eur J Respir Dis 1983;64: Sjogren I, Juhasz J. Ipratropium in the treatment of patients with perennial rhinitis. Allergy 1984;39: Andersen I, Lundqvist G, Proctor DF. Human nasal mucosal function in a controlled climate. Arch Environ Health 1971 ;23: Cerkez V, Ostberg B, Winther B, Mygind N. Effect of highdose ipratropium on watery rhinorrhea in the common cold [in press]. Ann Otol 18. Tos M. Goblet cells and glands in the nose and paranasal sinuses. In: Proctor DF, Andersen 1, eds. The nose: upper airway physiology and the atmospheric environment. Amsterdam: Elsevier Biomedical, 1982: Bojsen-Mr F. Glandulae nasales anteriores in the human nose. Ann Otol Rhinol Laryngol 1965;74: Munch E, SCborg M, Nc~rresleth'IT, Mygind N. A comparative study of dexchlorpheniramine maleate sustained-release tablets and budesonide nasal spray in seasonal allergic rhinitis. Allergy 1983;38: Borum P. Intranasal ipratropium: inhibition of methacholineinduced hypersecretion. Rhinology 1978;16: Borum P, Mygind N, Larsen FS. lpratropium treatment for rhinorrhoea in patients with perennial rhinitis. An open followup study of efficacy and safety. Clin Otolaryngol 1983;8: Baker AP, Chakrin LW, Wardell JR. Chronic cholinergic stimulation of canine respiratory tissue: its effect on the activities of glycosyltransferase and release of macromolecules. Am Rev Respir Dis 1975;t 11: Sturgess J, Reid L. The effect of isoprenaline and pilocarpine on a bronchial mucus-secreting tissue and pancreas, salivary glands, heart, thymus, liver, and spleen. Br J Exp Pathol 1973;54: Ohi M, Sakakura Y, Mural S, Miyoshi Y. Effect of ipratropium bromide on nasal mucociliary transport. Rhinology 1984; 22:241-6.