- Email: [email protected]
Montelukast as an adjunct to oral and inhaled steroid therapy in chronic nasal polyposis
Otolaryngology–Head and Neck Surgery (2008) 139, 682-687
ORIGINAL RESEARCH—SINONASAL DISORDERS
Montelukast as an adjunct to oral and inhaled steroid therapy in chronic nasal polyposis Rosemary A. Stewart, FRCS, Bhaskar Ram, FRCS, Garun Hamilton, MBBS, FRACP, John Weiner, MBBS, FRACP, FRCPA, and Kevin J. Kane, FRCS, FRACS, Melbourne, Australia OBJECTIVE: To examine the potential of montelukast, a leukotriene receptor antagonist, as an adjunct to oral and inhaled steroid in subjects with chronic nasal polyps. STUDY DESIGN: Prospective, randomized controlled trial. SUBJECTS AND METHODS: Thirty-eight consecutive adult patients with bilateral nasal polyps were randomized into two groups. Eighteen subjects were treated with oral prednisolone for 14 days and budenoside nasal spray for 8 weeks. Twenty subjects received similar treatment with additional oral montelukast for 8 weeks. Subjects completed a modified nasal ICSD symptom score at 8 and 12 weeks after beginning treatment and the SF-36 quality of life questionnaire at 12 weeks. RESULTS: Symptom scores improved in both groups after treatment. Subjects treated with montelukast reported significantly less headache (P ⫽ 0.013), facial pain (P ⫽ 0.048) and sneezing (P ⫽ 0.03) than controls. Four weeks after completing treatment, no significant differences were recorded. CONCLUSION: Montelukast therapy may have clinical benefit as an adjunct to oral and inhaled steroid in chronic nasal polyposis, but effects are not maintained after cessation of treatment. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
N
asal polyps are a frequently encountered problem in everyday clinical practice; however, the mechanisms that underlie polyp formation and the reason for their recurrence are incompletely understood. In recent years, there has been increasing interest in the potential role of leukotrienes, potent biological mediators produced by eosinophils, mast cells, monocytes and basophils. They are derivatives of arachidonic acid via the 5-lipoxygenase pathway. There is convincing evidence for the role of leukotrienes in the pathogenesis of asthma in that they cause bronchoconstriction, airway hyperresponsiveness, and airway inflammation.1 A number of drugs that selectively modify the leukotriene pathway (or antileukotrienes) have been developed.2 These use one of two main strategies: either inhibition of the production of leukotrienes by 5-lipoxygenase (zileuton), or by antagonism of the action of the leukotriene
at the cysLt1 receptor (montelukast, zafirlukast, panlukast). Antileukotrienes in both groups have been shown to cause clinical improvement in mild-to-moderate chronic stable asthma.3-6 However encouraging, the results of published studies do not yet provide guidelines for the optimal clinical use of antileukotrienes in asthma management.1 Leukotrienes have also been implicated in the pathology of allergic rhinitis, with measurable increases in LTC4 and LTD4 in nasal secretions of patients after nasal challenge as well as during natural allergen exposure.7 Two recent large multicenter, double-blind, placebo-controlled trials report significant improvement in symptoms and quality of life parameters in subjects with seasonal allergic rhinitis treated with montelukast.8,9 There is evidence to suggest that antileukotrienes are more effective in allergic rhinitis when given in combination with a histamine antagonist, although this may vary depending on the potency of the histamine antagonist and the potency of the disease.7 High concentrations of the leukotrienes LTC4 and LTB4 have been reported in nasal polyps in comparison with normal nasal mucosa.10,11 Indeed, it has been hypothesized that the LTC4 concentration in polyp tissue may have a prognostic value as high levels of LTC4 were found to correlate with early recurrence of polyps (within 18 months).12 Several case series have reported symptom control and improvement in nasal endoscopic findings after treatment with oral antileukotrienes.13-15 In addition, montelukast therapy has been reported to reduce the recurrence rate of nasal polyps postoperatively in subjects with aspirin sensitivity.16,17 In a blinded, placebo-controlled crossover trial that involved 24 subjects with nasal polyps, Wobst et al18 found that treatment with montelukast 10 mg daily improved symptom scores and nasal airflow on rhinomanometry, while it reduced nasal eosinophils and neuropeptides. In a recent study where montelukast was used as an “add-on” therapy in patients with asthma and nasal polyps already being treated with inhaled and topical nasal steroids, the antileukotriene caused clinical subjective improvement in a
Received April 30, 2007; revised March 24, 2008; accepted July 8, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.07.010
Stewart et al
Montelukast as an adjunct to oral and inhaled . . .
subgroup of subjects.19 Interestingly, the response was not related to aspirin sensitivity. Kutting et al20 in an uncontrolled study describe the use of montelukast as maintenance therapy in conjunction with short-term oral steroid in subjects with massive bilateral sinonasal polyposis. Seven of nine subjects experienced subjective reduction in symptoms, with consistent improvement in endoscopic and MRI findings. To date, no data have been published with respect to the effects of combined oral steroid/antileukotriene therapy compared with oral steroid alone in patients with nasal polyposis. The aim of this study is to examine the potential benefits offered by the leukotriene receptor antagonist montelukast as an adjunct to oral prednisolone in patients with chronic nasal polyps.
683
nasal polyps; if they had any contraindication to the use of oral steroid; or a history of sensitivity to any of the protocol drugs. Any previously prescribed oral steroid medication was discontinued for four weeks before commencing the trial protocol. Written consent was provided by each subject, following a full explanation of the purpose and requirements of the study by one of the authors.
Randomization Subjects thus recruited were randomized into two treatment groups with a single list of computer-generated random numbers.
Protocol
METHODS
Before commencement of treatment, subjects underwent a full ENT examination including nasal endoscopy and CT scan of paranasal sinuses and assessment by a respiratory physician with skin prick allergy testing. Subjects in group A were treated with a two-week reducing dose of oral steroid and an eight-week course of both oral montelukast and steroid nasal spray (Table 2). Subjects in treatment group B received oral and topical steroids in an identical regimen but no antileukotriene medication.
Participants Subjects were recruited from the Rhinology and Allergy outpatient clinics of the senior authors (J.W. and K.J.K.) from August 2001 to October 2002. Consecutive adult patients (aged 18 years and over) with bilateral nasal polyps that extended beyond the middle meatus confirmed by nasal endoscopy were invited to participate in the study (Table 1). Subjects were excluded if they presented with unilateral
Table 1 Baseline characteristics
Age Mean Median SD Range Gender Male Female Type of surgery No surgery Endonasal surgery External sinus surgery Turbinate resection Inferior Nasal septum on anterior rhinoscopy No septal deformity Septal deformity but no obstruction Septal deformity with obstruction Allergy test Negative Fel d 1 (cat) Rye grass Dust mite Mould mix Asthma Sensitivity to aspirin Currently smoke Exposed daily to smoke Exposed to chemicals/fumes
Group A
Group B
Total
52.5 53 13.9 24-75
53.0 50 19.9 26-80
52.8 53 16.7 26-80
12 (60%) 8 (40%)
12 (67%) 6 (33%)
24 (63%) 14 (37%)
3 16 1 1
(15%) (80%) (5%) (5%)
8 9 1 0
(44%) (50%) (6%) (0%)
11 25 2 1
(29%) (66%) (5%) (3%)
15 (75%) 2 (10%) 3 (15%)
12 (67%) 2 (11%) 4 (22%)
27 (71%) 4 (10%) 7 (18%)
6 0 5 10 2 11 1 3 2 2
12 2 5 3 2 10 2 2 3 4
18 2 10 13 4 21 3 5 5 6
(30%) (0%) (25%) (50%) (10%) (55%) (5%) (15%) (10%) (10%)
(67%) (11%) (28%) (17%) (11%) (56%) (11%) (11%) (17%) (22%)
(47%) (5%) (26%) (34%) (10%) (55%) (8%) (13%) (13%) (16%)
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Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
Table 2 Treatment protocols Group A: Prednisolone 35 mg mane reducing by 5 mg every second day over a total of 14 days Budesonide nasal spray ii metered doses to each nostril mane for 8 weeks Montelukast 10 mg mane for 8 weeks Group B: Prednisolone 35 mg mane reducing by 5 mg every second day over a total of 14 days Budesonide nasal spray ii metered doses to each nostril mane for 8 weeks
Outcome Measures Subjects completed validated questionnaires related to general quality of life (SF-36)21 and nasal symptoms (ICSD, International Classification of Sinus Disease)22 before commencement of treatment. The ICSD records patients’ symptoms of facial pain and pressure; headache; nasal blockage or congestion; nasal discharge; disturbance of smell; and overall discomfort on a 0 to 10 ordinal scale. Sinus-related headache was defined as discomfort in the frontal region, behind the eyes, or at the vertex. In addition, subjects scored their sneezing, a symptom not addressed by the ICSD score. The modified ICSD questionnaire was repeated at 8 weeks and 12 weeks from baseline and the SF-36 questionnaire again at the 12-week visit.
rhinoscopy (P ⫽ 0.47). However, 70 percent of subjects in the group who received montelukast gave a history of positive allergy testing in comparison with only 33 percent of the control group (P ⫽ 0.04). One subject in treatment group A and two in treatment group B were lost to follow-up. All other subjects completed the study. See Figure 1 for flow of participants. Results were analyzed on an intention-to-treat basis. Subjects in both treatment groups showed improvement in all of their symptoms during the eight-week treatment period (Table 3). When compared with subjects treated with steroid alone, subjects treated with montelukast showed a significantly greater reduction in symptom scores at eight weeks with respect to headache (P ⫽ 0.013), facial pain (P ⫽ 0.048), and sneezing (P ⫽ 0.03). No significant differences were recorded between the groups at this timepoint when examining nasal blockage/congestion (P ⫽ 0.31), alteration in sense of smell (P ⫽ 0.89), nasal discharge (P ⫽ 0.10), and the overall symptom score (P ⫽ 0.58). It was observed that some subjects experienced marked improvement of their symptoms throughout the course of montelukast therapy, whereas in others the benefits were marginal. No statistically significant differences in any of the symptom scores were observed between treatment groups at the 12-week time-point. In addition, there were no significant differences between the subject groups with respect to quality of life scores at 12 weeks when each of the domains of the SF-36 questionnaire were considered (Fig 2).
Statistical Analysis The baseline characteristics between the two groups were analyzed with 2 or Fisher’s exact test for categorical data and independent t test for continuous data. The differences in modified ICSD and SF-36 scores between the two groups for each domain were analyzed with repeated measures analysis of variance adjusting for age, gender, and surgery. A P value of less than 0.05 was considered statistically significant. All statistical analyses were carried out using SAS 9.1 (SAS Institute, Cary, NC).
Ethical Considerations Approval for this study was obtained from the Human Research and Ethics Committee at the Royal Victorian Eye and Ear Hospital, Melbourne.
RESULTS Of forty eligible patients, thirty-eight agreed to participate in the study and were randomized, 20 subjects to group A and 18 subjects to group B. No statistically significant differences were found between the treatment groups (Table 1) with respect to age (P ⫽ 0.94), gender (P ⫽ 0.33), or prior nasal/sinus surgery (P ⫽ 0.07) or presence of nasal septal deviation on anterior
DISCUSSION Primary Outcome When compared with subjects treated with steroid alone, subjects treated with montelukast showed a significant reduction in symptom scores at eight weeks with respect to headache, facial pain, and sneezing. However, montelukast therapy did not have a significant effect on the overall symptom score or on symptoms of nasal blockage, hyposmia, or nasal discharge, which are often the features that patients with nasal polyposis find most troublesome. The effects were not maintained at the twelve-week time-point, that is four weeks after stopping montelukast therapy. In addition, no significant differences were recorded with respect to quality of life measures at twelve weeks.
Interpretation These findings suggest that the use of montelukast may be of limited clinical benefit as an adjunct to oral and inhaled steroid therapy in patients with bilateral nasal polyposis. The lack of continuing improvement in symptoms after withdrawal of the leukotriene inhibitor indicates that treatment needs to be continued for any benefit in the long term. This is in keeping with the findings of Kutting et al20 who
Stewart et al
Montelukast as an adjunct to oral and inhaled . . .
Figure 1
685
Flow of participants.
observed recurrence of nasal polyps within 4 to 8 weeks of discontinuing montelukast therapy.
Generalizability Some subjects showed marked improvement in their symptoms when treated with antileukotriene, whereas others reported little benefit. It appears that montelukast is particularly beneficial in a subgroup of patients, whose characteristics are yet to be determined but the response does not appear to be related to aspirin sensitivity. Ragab et al19 in an open audit of
montelukast use in subjects with nasal polyps and asthma found subjective clinical improvement in 64 percent of subjects who were aspirin-tolerant and 50 percent of those who were aspirin-sensitive. In a recent uncontrolled study by Kieff and Busaba,23 patients with perennial allergic rhinitis appeared to derive more benefit from montelukast therapy than nonallergic patients, with respect to reduction in symptom scores and polyp eosinophilia. However, the authors comment that in both allergic and nonallergic groups, some patients responded dramatically to montelukast therapy whereas others did not
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Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
Table 3 Results from modified ICSD questionnaire, as mean result (with standard deviation); Scores for each domain range from 0 to 10
Nasal blockage or congestion Headache Facial pain Alternation in sense of smell Nasal discharge Sneezing Overall
Group A
Group B
Montelukast ⫹ prednisolone ⫹ budenoside nasal spray
Prednisolone ⫹ budenoside nasal spray
Baseline
Week 8
Week 12
Baseline
Week 8
Week 12
7.3 4.9 3.9 7.1 6.3 4.3 7.8
3.8 3.2 2.7 5.4 3.6 1.9 5.2
5.1 3.9 3.1 5.8 4.0 2.6 6.1
6.7 1.7 1.2 6.9 5.0 3.8 7.0
3.9 1.2 0.9 4.9 3.9 2.6 4.9
3.6 1.2 1.2 4.5 3.2 2.3 5.0
(2.5) (3.7) (4.1) (3.6) (2.9) (2.9) (1.8)
(2.2) (3.8) (3.8) (4.1) (2.4) (2.2) (2.8)
respond. Unfortunately, the subject sub-groups in our study were too small to allow meaningful analysis of this factor.
Limitations While not blinded, this is a randomized controlled study and conforms to the requirements of the Cochrane Collaboration for inclusion in any systematic review. Despite randomization of patients, more patients in the montelukast-treated group reported prior surgery than in the control group. However, this difference was not statistically significant (P ⫽ 0.07), and it was felt that it would not significantly affect their responsiveness to medical treatment. In addition, not all symptom parameters were equal within the two groups at baseline. Although both groups had recordable headache and facial pain, subjects in the montelukast treatment group expressed greater scores for these symptoms than in the control group (Table 3). While this effect might confound some of the analysis, we feel there is sufficient information from our study and others to encourage trials
(2.8) (3.8) (4.1) (3.9) (2.3) (2.5) (2.8)
(2.6) (2.5) (2.1) (3.6) (3.6) (3.4) (3.0)
(3.4) (2.5) (2.3) (4.4) (3.2) (3.0) (3.0)
(3.4) (2.8) (2.8) (4.1) (3.3) (2.8) (3.0)
with larger numbers of subjects and with a longer duration of treatment, which should result in more robust data. However, a therapeutic trial of montelukast in this difficult group of patients should be considered.
CONCLUSION Montelukast therapy may have clinical benefit as an adjunct to oral and inhaled steroid in subjects with chronic nasal polyps, but any effect is not maintained after cessation of treatment. Antileukotrienes may have a role in the long-term maintenance of bilateral nasal polyposis; however, larger randomized controlled studies are required to evaluate the effects of more prolonged therapy.
ACKNOWLEDGEMENTS The authors would like to thank Ms C. McMullen, Clinical Research Co-ordinator, Royal Victorian Eye and Ear Hospital, Melbourne; Ms S. Brenton, Respiratory Scientist, St Vincent’s Hospital, Melbourne; and Bickol Mukesh, Biostatistician, Peter MacCallum Cancer Institute, Melbourne for their assistance in completing this article.
AUTHOR INFORMATION From the Department of Otolaryngology (Drs Stewart, Ram, and Kane), Royal Victorian Eye & Ear Hospital, Melbourne; and the Department of Respiratory Medicine (Drs Hamilton and Weiner), St. Vincent’s Hospital, Melbourne. Corresponding author: Dr Rosemary Stewart, Department of ENT Surgery, Antrim Hospital, 45 Bush Road, Antrim, N. Ireland, UK BT41 2RL.
Figure 2 Results from SF-36 questionnaire. No significant difference was observed in the quality of life in all domains between montelukast and conventional treatment at 12 weeks. PF, physical functioning (P ⫽ 0.38); RP, role-physical (P ⫽ 0.38); BP, body pain (P ⫽ 0.83); GH, general health (P ⫽ 0.86); VT, vitality (P ⫽ 0.20); SF, social functioning (P ⫽ 0.68); RE, role emotional (P ⫽ 0.23); MH, mental health (P ⫽ 0.83).
E-mail address: [email protected].
AUTHOR CONTRIBUTION Rosemary A. Stewart, data collection, writing; Bhaskar Ram, study design, data collection; Garun Hamilton, data collection; John Weiner,
Stewart et al
Montelukast as an adjunct to oral and inhaled . . .
study design, editorial supervision; Kevin J. Kane, study design, editorial supervision.
FINANCIAL DISCLOSURES Montelukast was provided by Merck Pharmaceuticals, but the company did not provide any funds or other assistance, and the report was not submitted to Merck before publication. The company had no editorial control in any way over the contents of this article. No other potential conflicts of interest are declared.
REFERENCES 1. O’Byrne PM, Israel E, Drazen JM. Antileukotrienes in the treatment of asthma. Ann Intern Med 1997;127:472– 80. 2. Claesson HE, Dahlen SE. Asthma and leukotrienes: antileukotrienes as novel anti-asthmatic drugs. J Intern Med 1999;245:205–27. 3. Israel E, Cohn J, Dube L, et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. J Am Med Assoc 1996;275:931– 6. 4. Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol 1996;98:859 –71. 5. Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. ACCOLATE Asthma Trialists Group. Am J Respir Crit Care 1994;150:618 –23. 6. Reiss TF, Altman LC, Chervinsky P, et al. Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD4) receptor antagonist, in patients with chronic asthma. J Allergy Clin Immunol 1996;98:528 –34. 7. Lipworth BJ. Emerging role of antileukotriene therapy in allergic rhinitis. Clin Exp Allergy 2001;31:1813–21. 8. Nayak AS, Philip G, Lu S, et al. Efficacy and tolerability of montelukast alone or in combination with loratidine in seasonal allergic rhinitis: a multi-center, randomized double-blind placebo-controlled trial performed in the Fall. Ann Allergy Asthma Immunol 2002;88: 592– 600.
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9. Philip G, Malmstrom K, Hampel FC Jr, et al. Montelukast for treating seasonal allergic rhinitis: a randomised, double-blind, placebo-controlled trial performed in the spring. Montelukast Spring Rhinitis Study Group. Clin Exp Allergy 2002;32:1020 – 8. 10. Baenkler HW, Schafer D, Hosemann W. Eicosanoids from biopsy of normal and polypous nasal mucosa. Rhinology 1996;1:166 –70. 11. Ogino S, Irifune M, Harada T, et al. Arachidonic acid metabolites in human nasal polyps. Acta Otolaryngol Suppl 1993;501:85–7. 12. Klapan I, Culo F, Culig J, et al. Arachidonic acid metabolites and sinonasal polyposis I. Possible prognostic value. Am J Otolaryngol 1995;16:396 – 402. 13. Cohn JR, Keane WM, Branton CF. Treatment of refractory nasal polyps with leukotriene inhibitors/antagonists. J Allergy Clin Immunol 1999;103:S256 (in Soc Proc). 14. Ulualp SO, Sterman BM, Toohill RJ. Antileukotriene therapy for the relief of sinus symptoms in aspirin triad disease. Ear Nose Throat J 1999;78:604 –16. 15. Parnes SM, Chuma AV. Acute effects of antileukotrienes on sinonasal polyposis and sinusitis. Ear Nose Throat J 2000;79:18 –25. 16. DiRienzo L, Artuso A, Cerqua N. Antileukotrienes in the prevention of postoperative recurrence of nasal polyposis in ASA syndrome. Acta Otorhinolaryngol Ital 2000;20:336 – 42. 17. Grundmann T, Topfner M. Treatment of ASS-associated polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist: a prospective drug study on its anti-inflammatory effects. Laryngorhinootologie 2001;80:576 – 82. 18. Wobst B, Reichert K, Scherer H, et al. Clinical study about the effectiveness of montelukast in patients with nasal polyps with and without bronchial asthma and aspirin intolerance. Allergy 2000; 55(Suppl 63):41 (in Soc Proc). 19. Ragab S, Parikh A, Darby YC, et al. An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma. Clin Exp Allergy 2001;31:1385–91. 20. Kutting B, Nieschalk M, Brehler R. A new concept for treatment of sinonasal polyposis. Allergy 2000;11:1091–2. 21. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473– 83. 22. Lund VJ, Kennedy DW. Quantification for staging sinusitis. The Staging and Therapy Group. Ann Otol Rhinol Laryngol 1995; 104(Suppl 167):17–21. 23. Kieff DA, Busaba NY. Efficacy of montelukast in the treatment of nasal polyposis. Ann Otol Rhinol Laryngol 2005;114:941–5.
ORIGINAL RESEARCH—SINONASAL DISORDERS
Montelukast as an adjunct to oral and inhaled steroid therapy in chronic nasal polyposis Rosemary A. Stewart, FRCS, Bhaskar Ram, FRCS, Garun Hamilton, MBBS, FRACP, John Weiner, MBBS, FRACP, FRCPA, and Kevin J. Kane, FRCS, FRACS, Melbourne, Australia OBJECTIVE: To examine the potential of montelukast, a leukotriene receptor antagonist, as an adjunct to oral and inhaled steroid in subjects with chronic nasal polyps. STUDY DESIGN: Prospective, randomized controlled trial. SUBJECTS AND METHODS: Thirty-eight consecutive adult patients with bilateral nasal polyps were randomized into two groups. Eighteen subjects were treated with oral prednisolone for 14 days and budenoside nasal spray for 8 weeks. Twenty subjects received similar treatment with additional oral montelukast for 8 weeks. Subjects completed a modified nasal ICSD symptom score at 8 and 12 weeks after beginning treatment and the SF-36 quality of life questionnaire at 12 weeks. RESULTS: Symptom scores improved in both groups after treatment. Subjects treated with montelukast reported significantly less headache (P ⫽ 0.013), facial pain (P ⫽ 0.048) and sneezing (P ⫽ 0.03) than controls. Four weeks after completing treatment, no significant differences were recorded. CONCLUSION: Montelukast therapy may have clinical benefit as an adjunct to oral and inhaled steroid in chronic nasal polyposis, but effects are not maintained after cessation of treatment. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
N
asal polyps are a frequently encountered problem in everyday clinical practice; however, the mechanisms that underlie polyp formation and the reason for their recurrence are incompletely understood. In recent years, there has been increasing interest in the potential role of leukotrienes, potent biological mediators produced by eosinophils, mast cells, monocytes and basophils. They are derivatives of arachidonic acid via the 5-lipoxygenase pathway. There is convincing evidence for the role of leukotrienes in the pathogenesis of asthma in that they cause bronchoconstriction, airway hyperresponsiveness, and airway inflammation.1 A number of drugs that selectively modify the leukotriene pathway (or antileukotrienes) have been developed.2 These use one of two main strategies: either inhibition of the production of leukotrienes by 5-lipoxygenase (zileuton), or by antagonism of the action of the leukotriene
at the cysLt1 receptor (montelukast, zafirlukast, panlukast). Antileukotrienes in both groups have been shown to cause clinical improvement in mild-to-moderate chronic stable asthma.3-6 However encouraging, the results of published studies do not yet provide guidelines for the optimal clinical use of antileukotrienes in asthma management.1 Leukotrienes have also been implicated in the pathology of allergic rhinitis, with measurable increases in LTC4 and LTD4 in nasal secretions of patients after nasal challenge as well as during natural allergen exposure.7 Two recent large multicenter, double-blind, placebo-controlled trials report significant improvement in symptoms and quality of life parameters in subjects with seasonal allergic rhinitis treated with montelukast.8,9 There is evidence to suggest that antileukotrienes are more effective in allergic rhinitis when given in combination with a histamine antagonist, although this may vary depending on the potency of the histamine antagonist and the potency of the disease.7 High concentrations of the leukotrienes LTC4 and LTB4 have been reported in nasal polyps in comparison with normal nasal mucosa.10,11 Indeed, it has been hypothesized that the LTC4 concentration in polyp tissue may have a prognostic value as high levels of LTC4 were found to correlate with early recurrence of polyps (within 18 months).12 Several case series have reported symptom control and improvement in nasal endoscopic findings after treatment with oral antileukotrienes.13-15 In addition, montelukast therapy has been reported to reduce the recurrence rate of nasal polyps postoperatively in subjects with aspirin sensitivity.16,17 In a blinded, placebo-controlled crossover trial that involved 24 subjects with nasal polyps, Wobst et al18 found that treatment with montelukast 10 mg daily improved symptom scores and nasal airflow on rhinomanometry, while it reduced nasal eosinophils and neuropeptides. In a recent study where montelukast was used as an “add-on” therapy in patients with asthma and nasal polyps already being treated with inhaled and topical nasal steroids, the antileukotriene caused clinical subjective improvement in a
Received April 30, 2007; revised March 24, 2008; accepted July 8, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.07.010
Stewart et al
Montelukast as an adjunct to oral and inhaled . . .
subgroup of subjects.19 Interestingly, the response was not related to aspirin sensitivity. Kutting et al20 in an uncontrolled study describe the use of montelukast as maintenance therapy in conjunction with short-term oral steroid in subjects with massive bilateral sinonasal polyposis. Seven of nine subjects experienced subjective reduction in symptoms, with consistent improvement in endoscopic and MRI findings. To date, no data have been published with respect to the effects of combined oral steroid/antileukotriene therapy compared with oral steroid alone in patients with nasal polyposis. The aim of this study is to examine the potential benefits offered by the leukotriene receptor antagonist montelukast as an adjunct to oral prednisolone in patients with chronic nasal polyps.
683
nasal polyps; if they had any contraindication to the use of oral steroid; or a history of sensitivity to any of the protocol drugs. Any previously prescribed oral steroid medication was discontinued for four weeks before commencing the trial protocol. Written consent was provided by each subject, following a full explanation of the purpose and requirements of the study by one of the authors.
Randomization Subjects thus recruited were randomized into two treatment groups with a single list of computer-generated random numbers.
Protocol
METHODS
Before commencement of treatment, subjects underwent a full ENT examination including nasal endoscopy and CT scan of paranasal sinuses and assessment by a respiratory physician with skin prick allergy testing. Subjects in group A were treated with a two-week reducing dose of oral steroid and an eight-week course of both oral montelukast and steroid nasal spray (Table 2). Subjects in treatment group B received oral and topical steroids in an identical regimen but no antileukotriene medication.
Participants Subjects were recruited from the Rhinology and Allergy outpatient clinics of the senior authors (J.W. and K.J.K.) from August 2001 to October 2002. Consecutive adult patients (aged 18 years and over) with bilateral nasal polyps that extended beyond the middle meatus confirmed by nasal endoscopy were invited to participate in the study (Table 1). Subjects were excluded if they presented with unilateral
Table 1 Baseline characteristics
Age Mean Median SD Range Gender Male Female Type of surgery No surgery Endonasal surgery External sinus surgery Turbinate resection Inferior Nasal septum on anterior rhinoscopy No septal deformity Septal deformity but no obstruction Septal deformity with obstruction Allergy test Negative Fel d 1 (cat) Rye grass Dust mite Mould mix Asthma Sensitivity to aspirin Currently smoke Exposed daily to smoke Exposed to chemicals/fumes
Group A
Group B
Total
52.5 53 13.9 24-75
53.0 50 19.9 26-80
52.8 53 16.7 26-80
12 (60%) 8 (40%)
12 (67%) 6 (33%)
24 (63%) 14 (37%)
3 16 1 1
(15%) (80%) (5%) (5%)
8 9 1 0
(44%) (50%) (6%) (0%)
11 25 2 1
(29%) (66%) (5%) (3%)
15 (75%) 2 (10%) 3 (15%)
12 (67%) 2 (11%) 4 (22%)
27 (71%) 4 (10%) 7 (18%)
6 0 5 10 2 11 1 3 2 2
12 2 5 3 2 10 2 2 3 4
18 2 10 13 4 21 3 5 5 6
(30%) (0%) (25%) (50%) (10%) (55%) (5%) (15%) (10%) (10%)
(67%) (11%) (28%) (17%) (11%) (56%) (11%) (11%) (17%) (22%)
(47%) (5%) (26%) (34%) (10%) (55%) (8%) (13%) (13%) (16%)
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Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
Table 2 Treatment protocols Group A: Prednisolone 35 mg mane reducing by 5 mg every second day over a total of 14 days Budesonide nasal spray ii metered doses to each nostril mane for 8 weeks Montelukast 10 mg mane for 8 weeks Group B: Prednisolone 35 mg mane reducing by 5 mg every second day over a total of 14 days Budesonide nasal spray ii metered doses to each nostril mane for 8 weeks
Outcome Measures Subjects completed validated questionnaires related to general quality of life (SF-36)21 and nasal symptoms (ICSD, International Classification of Sinus Disease)22 before commencement of treatment. The ICSD records patients’ symptoms of facial pain and pressure; headache; nasal blockage or congestion; nasal discharge; disturbance of smell; and overall discomfort on a 0 to 10 ordinal scale. Sinus-related headache was defined as discomfort in the frontal region, behind the eyes, or at the vertex. In addition, subjects scored their sneezing, a symptom not addressed by the ICSD score. The modified ICSD questionnaire was repeated at 8 weeks and 12 weeks from baseline and the SF-36 questionnaire again at the 12-week visit.
rhinoscopy (P ⫽ 0.47). However, 70 percent of subjects in the group who received montelukast gave a history of positive allergy testing in comparison with only 33 percent of the control group (P ⫽ 0.04). One subject in treatment group A and two in treatment group B were lost to follow-up. All other subjects completed the study. See Figure 1 for flow of participants. Results were analyzed on an intention-to-treat basis. Subjects in both treatment groups showed improvement in all of their symptoms during the eight-week treatment period (Table 3). When compared with subjects treated with steroid alone, subjects treated with montelukast showed a significantly greater reduction in symptom scores at eight weeks with respect to headache (P ⫽ 0.013), facial pain (P ⫽ 0.048), and sneezing (P ⫽ 0.03). No significant differences were recorded between the groups at this timepoint when examining nasal blockage/congestion (P ⫽ 0.31), alteration in sense of smell (P ⫽ 0.89), nasal discharge (P ⫽ 0.10), and the overall symptom score (P ⫽ 0.58). It was observed that some subjects experienced marked improvement of their symptoms throughout the course of montelukast therapy, whereas in others the benefits were marginal. No statistically significant differences in any of the symptom scores were observed between treatment groups at the 12-week time-point. In addition, there were no significant differences between the subject groups with respect to quality of life scores at 12 weeks when each of the domains of the SF-36 questionnaire were considered (Fig 2).
Statistical Analysis The baseline characteristics between the two groups were analyzed with 2 or Fisher’s exact test for categorical data and independent t test for continuous data. The differences in modified ICSD and SF-36 scores between the two groups for each domain were analyzed with repeated measures analysis of variance adjusting for age, gender, and surgery. A P value of less than 0.05 was considered statistically significant. All statistical analyses were carried out using SAS 9.1 (SAS Institute, Cary, NC).
Ethical Considerations Approval for this study was obtained from the Human Research and Ethics Committee at the Royal Victorian Eye and Ear Hospital, Melbourne.
RESULTS Of forty eligible patients, thirty-eight agreed to participate in the study and were randomized, 20 subjects to group A and 18 subjects to group B. No statistically significant differences were found between the treatment groups (Table 1) with respect to age (P ⫽ 0.94), gender (P ⫽ 0.33), or prior nasal/sinus surgery (P ⫽ 0.07) or presence of nasal septal deviation on anterior
DISCUSSION Primary Outcome When compared with subjects treated with steroid alone, subjects treated with montelukast showed a significant reduction in symptom scores at eight weeks with respect to headache, facial pain, and sneezing. However, montelukast therapy did not have a significant effect on the overall symptom score or on symptoms of nasal blockage, hyposmia, or nasal discharge, which are often the features that patients with nasal polyposis find most troublesome. The effects were not maintained at the twelve-week time-point, that is four weeks after stopping montelukast therapy. In addition, no significant differences were recorded with respect to quality of life measures at twelve weeks.
Interpretation These findings suggest that the use of montelukast may be of limited clinical benefit as an adjunct to oral and inhaled steroid therapy in patients with bilateral nasal polyposis. The lack of continuing improvement in symptoms after withdrawal of the leukotriene inhibitor indicates that treatment needs to be continued for any benefit in the long term. This is in keeping with the findings of Kutting et al20 who
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Montelukast as an adjunct to oral and inhaled . . .
Figure 1
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Flow of participants.
observed recurrence of nasal polyps within 4 to 8 weeks of discontinuing montelukast therapy.
Generalizability Some subjects showed marked improvement in their symptoms when treated with antileukotriene, whereas others reported little benefit. It appears that montelukast is particularly beneficial in a subgroup of patients, whose characteristics are yet to be determined but the response does not appear to be related to aspirin sensitivity. Ragab et al19 in an open audit of
montelukast use in subjects with nasal polyps and asthma found subjective clinical improvement in 64 percent of subjects who were aspirin-tolerant and 50 percent of those who were aspirin-sensitive. In a recent uncontrolled study by Kieff and Busaba,23 patients with perennial allergic rhinitis appeared to derive more benefit from montelukast therapy than nonallergic patients, with respect to reduction in symptom scores and polyp eosinophilia. However, the authors comment that in both allergic and nonallergic groups, some patients responded dramatically to montelukast therapy whereas others did not
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Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
Table 3 Results from modified ICSD questionnaire, as mean result (with standard deviation); Scores for each domain range from 0 to 10
Nasal blockage or congestion Headache Facial pain Alternation in sense of smell Nasal discharge Sneezing Overall
Group A
Group B
Montelukast ⫹ prednisolone ⫹ budenoside nasal spray
Prednisolone ⫹ budenoside nasal spray
Baseline
Week 8
Week 12
Baseline
Week 8
Week 12
7.3 4.9 3.9 7.1 6.3 4.3 7.8
3.8 3.2 2.7 5.4 3.6 1.9 5.2
5.1 3.9 3.1 5.8 4.0 2.6 6.1
6.7 1.7 1.2 6.9 5.0 3.8 7.0
3.9 1.2 0.9 4.9 3.9 2.6 4.9
3.6 1.2 1.2 4.5 3.2 2.3 5.0
(2.5) (3.7) (4.1) (3.6) (2.9) (2.9) (1.8)
(2.2) (3.8) (3.8) (4.1) (2.4) (2.2) (2.8)
respond. Unfortunately, the subject sub-groups in our study were too small to allow meaningful analysis of this factor.
Limitations While not blinded, this is a randomized controlled study and conforms to the requirements of the Cochrane Collaboration for inclusion in any systematic review. Despite randomization of patients, more patients in the montelukast-treated group reported prior surgery than in the control group. However, this difference was not statistically significant (P ⫽ 0.07), and it was felt that it would not significantly affect their responsiveness to medical treatment. In addition, not all symptom parameters were equal within the two groups at baseline. Although both groups had recordable headache and facial pain, subjects in the montelukast treatment group expressed greater scores for these symptoms than in the control group (Table 3). While this effect might confound some of the analysis, we feel there is sufficient information from our study and others to encourage trials
(2.8) (3.8) (4.1) (3.9) (2.3) (2.5) (2.8)
(2.6) (2.5) (2.1) (3.6) (3.6) (3.4) (3.0)
(3.4) (2.5) (2.3) (4.4) (3.2) (3.0) (3.0)
(3.4) (2.8) (2.8) (4.1) (3.3) (2.8) (3.0)
with larger numbers of subjects and with a longer duration of treatment, which should result in more robust data. However, a therapeutic trial of montelukast in this difficult group of patients should be considered.
CONCLUSION Montelukast therapy may have clinical benefit as an adjunct to oral and inhaled steroid in subjects with chronic nasal polyps, but any effect is not maintained after cessation of treatment. Antileukotrienes may have a role in the long-term maintenance of bilateral nasal polyposis; however, larger randomized controlled studies are required to evaluate the effects of more prolonged therapy.
ACKNOWLEDGEMENTS The authors would like to thank Ms C. McMullen, Clinical Research Co-ordinator, Royal Victorian Eye and Ear Hospital, Melbourne; Ms S. Brenton, Respiratory Scientist, St Vincent’s Hospital, Melbourne; and Bickol Mukesh, Biostatistician, Peter MacCallum Cancer Institute, Melbourne for their assistance in completing this article.
AUTHOR INFORMATION From the Department of Otolaryngology (Drs Stewart, Ram, and Kane), Royal Victorian Eye & Ear Hospital, Melbourne; and the Department of Respiratory Medicine (Drs Hamilton and Weiner), St. Vincent’s Hospital, Melbourne. Corresponding author: Dr Rosemary Stewart, Department of ENT Surgery, Antrim Hospital, 45 Bush Road, Antrim, N. Ireland, UK BT41 2RL.
Figure 2 Results from SF-36 questionnaire. No significant difference was observed in the quality of life in all domains between montelukast and conventional treatment at 12 weeks. PF, physical functioning (P ⫽ 0.38); RP, role-physical (P ⫽ 0.38); BP, body pain (P ⫽ 0.83); GH, general health (P ⫽ 0.86); VT, vitality (P ⫽ 0.20); SF, social functioning (P ⫽ 0.68); RE, role emotional (P ⫽ 0.23); MH, mental health (P ⫽ 0.83).
E-mail address: [email protected].
AUTHOR CONTRIBUTION Rosemary A. Stewart, data collection, writing; Bhaskar Ram, study design, data collection; Garun Hamilton, data collection; John Weiner,
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Montelukast as an adjunct to oral and inhaled . . .
study design, editorial supervision; Kevin J. Kane, study design, editorial supervision.
FINANCIAL DISCLOSURES Montelukast was provided by Merck Pharmaceuticals, but the company did not provide any funds or other assistance, and the report was not submitted to Merck before publication. The company had no editorial control in any way over the contents of this article. No other potential conflicts of interest are declared.
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