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 Table of Contents  
Year : 2021  |  Volume : 35  |  Issue : 2  |  Page : 48-54

Expert opinion on montelukast and acebrophylline combination in the management of asthma

1 Trustee & Founder President - Chest Council of India (CCI), Davangere-577005, Karnataka, India
2 Department of Respiratory Medicine, Programme-In-Charge and Teacher- DNB Respiratory Disease, Bombay Hospital, Mumbai, India
3 Consultant Pulmonologist, Department of Pulmonology, Ruby Hall Clinic and Modi Clinic, Pune, India
4 Consultant Pulmonologist and Sleep Specialist, Department of Respiratory and Sleep Medicines, Columbia Asia Hospital, Kolkata, India
5 Consultant Pulmonologist, Songara Chest And Allergy Clinic, MP, India
6 Consultant Pulmonologist, Nagpur Chest & Sleep Centre and Wockhardt Hospital, Nagpur, India

Date of Submission02-Feb-2022
Date of Acceptance26-Apr-2022
Date of Web Publication08-Jul-2022

Correspondence Address:
Dr. Amita Nene
Department of Respiratory Medicine, Bombay Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijaai.ijaai_4_22

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Asthma control is highly inadequate in India, with worse outcomes and poor adherence to inhaled corticosteroids (ICSs). As per the Global Initiative for Asthma guidelines, leukotriene receptor antagonist (LTRA) can be added when a low-to-moderate dose of ICS does not provide sufficient disease control. The combination of montelukast with its anti-inflammatory action and acebrophylline with its mild bronchodilator, anti-inflammatory, and mucolytic actions may be beneficial in patients with asthma. This manuscript aims to present an expert opinion to discuss the role of montelukast and acebrophylline combination in the management of asthma. An expert panel comprising nine specialists in respiratory medicine took part in a roundtable discussion to review the role of montelukast–acebrophylline combination in the management of asthma. A qualitative question-and-answer-based format was used to help facilitate the discussion. It was concurred that the montelukast and acebrophylline combination may be used if asthma symptoms remain uncontrolled with ICS and long-acting β2-agonists. This combination can also be preferred in patients with severe pulmonary obstruction along with allergic bronchopulmonary aspergillosis, in patients with asthma–chronic obstructive pulmonary disease overlap syndrome, and in patients with a history of smoking. There is adequate evidence for the role of montelukast and acebrophylline as individual drugs in asthma. However, evidence related to their combination therapy is lacking. The panel has reiterated the need for studies to evaluate the safety and efficacy of montelukast and acebrophylline combination in patients with asthma and its variants.

Keywords: Acebrophylline, asthma, cysteinyl leukotriene receptor antagonist, montelukast

How to cite this article:
Krishna N H, Nene A, Modi M, Reza T, Songara A, Deshmukh V. Expert opinion on montelukast and acebrophylline combination in the management of asthma. Indian J Allergy Asthma Immunol 2021;35:48-54

How to cite this URL:
Krishna N H, Nene A, Modi M, Reza T, Songara A, Deshmukh V. Expert opinion on montelukast and acebrophylline combination in the management of asthma. Indian J Allergy Asthma Immunol [serial online] 2021 [cited 2023 Jan 29];35:48-54. Available from: https://www.ijaai.in/text.asp?2021/35/2/48/350080

  Introduction Top

Asthma is a heterogeneous disease characterized by recurring breathlessness and wheezing episodes. It is the most common airway disease that adversely impacts the physical, mental, and social wellness of the affected.[1] According to the World Health Organization,[2] around 300 million people have asthma worldwide, of which 38 million live in India,[3] and by 2025, a further 100 million may be affected globally.[4] Although asthma is prevalent in all countries, most asthma-related deaths occur in developing countries.[2] According to the Global Asthma Report 2018, about 6% of children and 2% of adults in India have asthma.[5] The prevalence of self-reported asthma is 2% among women and 1% among men aged 15–49 years, and the prevalence rate has remained unchanged since 2015, as per the latest national report.[6] Asthma accounted for 1.9% of total death and 1.9% of total disability-adjusted life years in 2016 in India.[7]

In India, asthma control is highly inadequate, with a greater disease burden. According to the World Health Survey study, 9.6% of Indians with asthma had experienced wheezing in the last 12 months.[8] The Asia-Pacific Asthma Insight and Management (AP-AIM) study observed that 67% of asthmatics in India had experienced exacerbation during the previous year.[9] The phase 3 International Study of Asthma and Allergies in Children observed an overall prevalence of current wheeze of 6.8% among Indian children. Most importantly, more than half of the cases have severe uncontrolled asthma.[10] The AP-AIM study revealed that more than 90% of asthmatics felt that their asthma was under control in India. However, after objective assessments using the Global Initiative for Asthma (GINA) guidelines, none of the surveyed patients were reported to have controlled asthma, and about 40% of them were confirmed to have uncontrolled asthma. Moreover, the quality of life (QoL) of these patients was severely impacted by school/work absenteeism and loss of productivity by half. About half of asthma patients reported 3–10 exacerbations, and one-fifth of patients reported 11 exacerbations per year. More than 30% of patients required a hospital visit, and 7% required intensive care support.[11]

Treatment medication adherence in asthma is generally poor. It is often characterized by overuse of short-acting β2-agonist and underuse of inhaled corticosteroids (ICSs).[12] Suboptimal adherence to medication and nonaligning to treatment recommendations in asthma was frequent in most parts of the world, including Asia.[13] Nonadherence to asthma therapy often stems from patients' or physicians' perceived lack of understanding or safety issues related to ICS therapy or preference for oral therapy.[12],[13] One of the key factors for nonadherence in the Asian population is the stigma of asthma disease and limited use of inhalers due to cultural restrictions.[13] A national survey study involving Indian pulmonologists revealed that the preferred ICS + long-acting β2-agonist (LABA) treatment was prescribed in only 41% of asthma cases.[14] Similarly, a cross-sectional study has reported that 48% of patients were reluctant to undergo inhaler therapy, and 76% failed to use the inhaler correctly.[15]

Despite major advancements in understanding asthma over the years, the burden of disease is immense. Especially, asthma control in India is very poor, with worst outcomes. Therefore, treatment options that are effective and economical are urgently needed to improve asthma management in India. Considering the aforementioned literature views, this manuscript aims to discuss the role of montelukast and acebrophylline in the management of asthma and present expert opinion based on their clinical experience.

  Methodology Top

Roundtable meeting was conducted to review the role of montelukast – acebrophylline combination in the management of asthma. The committee consisted of regional experts in the field of respiratory medicine, who discussed the available evidence and clinical experiences related to montelukast and acebrophylline individually as well as combinations of both drugs in the management of asthma. A qualitative question-and-answer-based format was used to help facilitate the discussion. Recommendations were formulated based on this expert opinion for patient groups who may benefit from this combination therapy.

  Montelukast in Asthma Top

Montelukast is a widely prescribed potent, oral, specific leukotriene D4-receptor antagonist (LTRA) that mediates late-phase reaction in asthma. According to the GINA 2020 guidelines, LTRA could be added when a low-to-moderate dose of ICSs does not provide sufficient disease control.[1] The advantage of montelukast in asthma management has been evident from its ICS-sparing effect, improvement in QoL, thereby reducing the need for rescue medication, and improvement in nocturnal symptoms, lung function, and sleep quality.[16],[17] The other notable advantages of montelukast include complementing the effect of ICS in controlling asthma exacerbations, reducing the frequency of asthma exacerbations, improving the peak expiratory flow rate (PEFR) and availability as a once-daily oral formulation, lack of tolerance, and good safety profile.[18],[19]

A large body of evidence has shown that montelukast has a beneficial role in asthma management. In a real-world study in the UK, the addition of montelukast resulted in an improvement in asthma control in 66% of patients.[20] In another observational study, about 90% of patients receiving montelukast reported overall improvement of asthma with significant changes in the Asthma Control Questionnaire (ACQ) score.[21] Further, the addition of montelukast has improved both asthma control and QoL in patients inadequately controlled with ICS or ICS + LABA.[17] Two parallel, multicenter, pragmatic trials evaluated the real-world effectiveness of LTRA versus ICS for first-line asthma controller therapy or a LABA as an add-on in patients who are already on ICS therapy. At 2 months, LTRA improved asthma-related QoL similar to ICS and LABA among primary care patients.[22] [Table 1] summarizes the evidence of montelukast in asthma and asthma exacerbations.
Table 1: Evidence of montelukast in asthma and asthma exacerbations

Click here to view

  Montelukast in Specific Asthma Phenotypes Top

Real-world studies support the concept that some asthma phenotypes are more likely to benefit from montelukast therapy. Treatment with montelukast has proven to be especially useful in exercise-induced asthma and asthma associated with allergic rhinitis. It is also found to be effective in other phenotypes such as asthma – obesity comorbidity, aspirin-exacerbated respiratory disease, asthma in smokers, preschool children with asthma and wheezing disorder, asthma with small airways involvement, and elderly asthma.[24]

  LTRA in the Elderly with Asthma and Cough Variant Asthma Top

A comparative study evaluated the effectiveness of LTRA versus ICS among elderly asthmatics in a real-world setting. There was no significant difference in the risks of asthma exacerbation between the LTRA and low-dose ICS groups (hazard ratio: 0.98, 95% confidence interval: 0.65–1.54). Moreover, patients receiving LTRAs were associated with high compliance (medication possession ratio of ≥80%) as compared to those in the low-dose ICS group. Given the similar effectiveness to ICSs for reducing the risk of asthma exacerbation, LTRAs may be a reasonable treatment choice for elderly patients with mild asthma.[25]

In a small randomized study, LTRA add-on was found to be beneficial in improving cough among cough-variant asthmatics. Cough scores significantly improved in the ICS + LTRA group from 0 week to 2 weeks (P < 0.05), 4 weeks (P < 0.001), and 8 weeks (P < 0.001). However, no significant change was observed with spirometric parameters. Treatment with LTRA improved cough in patients with cough-variant asthma, even though it appeared to be ineffective in improving respiratory function.[26]

  Place of LTRA during Step-Down Approach in the Management of Stable Asthma Top

The role of LTRA as a step-down approach – decreasing the high dose of ICS for the management of asthma – is evident from multiple studies.[27] A randomized study evaluated the step-down treatment of inhaled ICS with montelukast or fluticasone + salmeterol. Symptom-free days were slightly less in the montelukast group (79%) than the fluticasone + salmeterol (83%) or fluticasone alone group (85%). Overall, 70% of patients who switched to montelukast therapy had good asthma control. However, clinically significant asthma exacerbations did not differ between the fluticasone + salmeterol group and the montelukast group.[28]

  Acebrophylline in Asthma Top

Mucolytic agents have a multitude of effects on asthma biology, including reducing respiratory tract inflammation and decreasing mucin production and goblet cell hyperplasia.[27] Acebrophylline, a novel bronchodilator, is a xanthine derivative, composed of ambroxol-theophylline-7 acetic acid. It reduces the episodic bronchial obstruction and improves the ventilatory function. Acebrophylline increases the synthesis and release of alveolar surfactant, resulting in triple action, including mucoregulation, stimulation of bronchoalveolar clearance, and anti-inflammatory and anti-interactive effects. It inhibits intracellular phosphodiesterase and causes bronchial muscle relaxation by increasing cyclic adenosine monophosphate levels. Acebrophylline also reduces the availability of phosphatidylcholine for the production of inflammatory mediators and thus produces an anti-inflammatory effect in chronic stages.[29],[30]

  Clinical Evidence in Asthma Top

Literature on the safety and efficacy of acebrophylline is scant. The available evidence indicates that acebrophylline has a beneficial role in adult patients with acute bronchitis or asthma-like bronchitis or flare-ups of chronic forms with increased bronchial secretions and cough with mucoid, mucopurulent, or purulent sputum, with or without fever. Acebrophylline has been found to be a better choice of drug in improving asthma symptoms over its individual components. Compared to ambroxol alone, acebrophylline was associated with a reduction in sputum production and sputum viscosity, with improved clinical symptoms, increased forced expiratory volume (FEV) and vital capacity, and reduced airway obstruction. When compared to theophylline alone, acebrophylline reduced the rate of bronchospastic attacks.[30] In an open-label, randomized comparative trial of mild asthma, patients in the acebrophylline group were associated with significantly greater improvements in the mean FEV1 and PEFR than the theophylline group. Cough scoring and sputum quantity also improved significantly in the acebrophylline group. Adverse effects complained in the theophylline group were mainly headache, nausea/vomiting/epigastric pain, insomnia, muscular tremors, and palpitations. Comparatively, acebrophylline had a better safety profile compared to the theophylline group.[31] The efficacy of montelukast or acebrophylline combined with ICS in the treatment of asthma was similar to that of formoterol with ICS. Significant improvement in PEFR, FEV1, and QoL was noted with all three treatment options.[32]

  Rationale for Combination of Montelukast and Acebrophylline in Asthma Top

Asthma is generally characterized by smooth muscle dysfunction and airway inflammation. Whereas, montelukast could alleviate the inflammation in asthmatics, which is associated with the release of inflammatory mediators including cysteinyl leukotrienes, histamine, kinins, and eosinophil-derived mediators.[33] Acebrophylline could potentially complement the actions of montelukast with its mild bronchodilator and mucolytic activity.[30] A randomized clinical trial with 200 patients was conducted at three centers in India, as documented in the Clinical Trials Registry-India. This study compared the safety and efficacy of a fixed-dose combination (FDC) of montelukast plus acebrophylline with montelukast alone in patients suffering from chronic asthma and reported better efficacy of the FDC compared to montelukast alone. No specific safety concerns were noted in the patient population (aged 18–64 years) with the FDC.[34]

Based on the outcomes noted in studies that evaluated montelukast and acebrophylline as individual drugs in combination with ICS, a combination of montelukast and acebrophylline can be considered as an add-on therapy to ICS, especially in patients in whom the symptoms remain uncontrolled with ICS and LABA, in the following scenarios:

  Smokers Top

A prospective study assessed the impact of acebrophylline add-on in improving QoL among asthmatics who were smokers. Of 150 smoker asthmatics included in the study, Group 1 received inhaled fluticasone 250 μg and formoterol 6 μg as a dry-powder inhaler (DPI) + acebrophylline 100 mg twice daily orally (mean age, 46.84 years) and Group 2 received inhaled fluticasone 250 μg and formoterol 6 μg (DPI) + placebo (mean age, 46.81 years). The mean FEV1, mean Mini Asthma QoL Questionnaire score, and mean ACQ score were significantly improved in the acebrophylline add-on group on days 15 and 30 compared to Group 2 patients (P < 0.05). The ACQ score of 0.000–0.75 and well-controlled asthma were observed in a high number of patients of the acebrophylline add-on group compared to Group 2 patients (P < 0.0001), suggesting a beneficial effect of acebrophylline in counteracting the adverse impact of smoking on QoL in smoker asthmatics. Further, patients in the acebrophylline add-on group had no serious adverse events.[35]

In a multicenter crossover trial, montelukast resulted in a small but significant increase in peak expiratory flow in smokers with asthma. While ICS significantly increased FEV1 among nonsmoker asthmatics, montelukast significantly increased peak flow among smoker asthmatics.[36] In a placebo-controlled randomized trial, the mean control of asthma over 6 months was significantly higher with montelukast compared to placebo (45% vs. 39%, P < 0.05). The outcomes were found to be similar between montelukast and a high dose of fluticasone. The subjects that used only fluticasone showed significant improvement in FEV1. While patients with a smoking history of fewer than 11 pack-years exhibited better benefits from fluticasone, smokers with a history of more than 11 pack-years experienced better benefits with montelukast. The findings indicated increased synthesis of leukotrienes among heavy smokers, and this subset of patients may benefit more from the use of anti-leukotrienes in controlling asthma as compared to fluticasone.[37]

  Presence of Severe Obstructive Airway Disease Top

Asthma has distinct endotypes and phenotypes with variable clinical presentation and clinical response. Especially, patients presenting with asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) have an increased disease burden and risk of exacerbations compared to individual diseases. In the studies conducted in India, the burden of ACOS was reported to be 27% in South India.[38] and 20% in North India.[39]

In a randomized trial of patients with moderate COPD, treatment with acebrophylline was associated with consistent improvement of FEV1, FEV1/FVC ratio, and FEF 25%–75% at all three scheduled visits of 0, 21, and 42 days (P < 0.05). Further, patients in the acebrophylline add-on group have a significant PEFR at day 21 compared to baseline. Acebrophylline also reduced cough, chest pain, wheeze, sputum, frequency of use of relievers, and shortness of breath considerably in a majority of the patients.[40] Besides, in patients with newly diagnosed COPD, acebrophylline significantly improved FEV1% within 7 days of treatment, and this was sustained all through the 6 weeks (P < 0.05). It also improved QoL with no cardiovascular side effects.[41]

Patients with characteristics of both COPD and asthma may more likely benefit from montelukast therapy. A retrospective study of inner-city veterans with COPD reported that 2 years of montelukast therapy significantly decreased emergency department (P = 0.03) and urgent care utilization for exacerbations (P = 0.02).[42]

In a crossover study, asthmatics likely representing ACOS subgroup, smokers had a better response to montelukast compared to ICS (Lazrus 2007). In a real-world survey, leukotriene modifiers have been prescribed frequently in patients of COPD presumed to have asthma as well.[43]

The above evidence suggests that while acebrophylline has a beneficial role in both asthma and COPD patients, montelukast has a beneficial role in asthma patients as well as asthmatics having coexistent COPD.

  Patients Unwilling to Initiate Inhaler Therapy Top

A multicenter, open-label study analyzed the treatment patterns among patients aged 6 years and above who had discontinued ICS therapy and were treated with orally administered montelukast once daily for 6 weeks. Post montelukast treatment, compliance with asthma therapy increased from 41% to 88% at week 6 (P < 0.001). Further, treatment with montelukast was associated with a significant improvement in physician satisfaction (P < 0.001) and considerable improvement in patient satisfaction at week 6. Patient satisfaction increased from 45% at baseline to 94% at week 6. No serious adverse events were reported with montelukast over the duration of the study.[44] Thus, oral therapy may benefit this subset.

  Patients with Asthma and Bronchiectasis with Associated Allergic Bronchopulmonary Aspergillosis Top

Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder encountered in patients with asthma. The disorder clinically manifests with poor asthma control, fleeting pulmonary infiltrates, and bronchiectasis. Aspergillus fumigatus is the commonest cause of ABPA, but other species are also responsible. The prevalence of ABPA in asthma in patients attending special asthma/chest clinics is about 13%, with a global burden of about 5 million cases. There are an estimated 1.4 million cases in India alone. The natural history of ABPA is characterized by recurrent exacerbations. If the disorder is not properly recognized or adequately treated, the underlying inflammatory process can progress inexorably and can cause extensive bronchiectasis with pulmonary fibrosis.[45]

Montelukast sodium, a leukotriene antagonist, was shown to increase exercise tolerance and peak flow rate in an open-label study of 11 patients with cystic fibrosis. Interestingly, the patients who benefited most had serological results positive for Aspergillus. At present, although not supported by any clinical trials, a rational approach would be to use ICSs and leukotriene modifiers for the asthma component of ABPA, as recommended by the National Institutes of Health Asthma guidelines.[46]

Along with the standard therapies, montelukast was also found to be beneficial in asthmatics who have coexisting ABPA. There are several case reports which have reported the benefits of adding a montelukast in terms of symptom relief such as dyspnea and wheezing and a marked improvement in chest X-ray upon follow-up.[47],[48]

  Expert Opinion Top

  • ICS and LABA are the first-line drugs for treatment of asthma.
  • If asthma is not controlled with the above, then an add-on combination of acebrophylline/montelukast may be prescribed under the following conditions:

    • Patient is a smoker
    • Coexisting asthma–COPD overlap
    • Severe obstructive airway disease
    • If a patient is not willing to accept inhaler therapy
    • Until patients get accustomed to inhaled medication
    • Asthma and bronchiectasis with associated ABPA.

  • In adults, the suggested dose of montelukast would be 10 mg/day and of acebrophylline would be 200 mg/day
  • The duration of therapy would depend on factors, such as stage of asthma, symptom severity, and patient response. In patients with only acute bronchitis, this combination could be prescribed for a short course of 7–10 days
  • Montelukast and acebrophylline are considered safe as individual molecules; their efficacy as a stand-alone therapy for asthma is questionable. Nevertheless, it has clinically proven efficacy as an add-on therapy to ICS and LABA
  • Acebrophylline can be useful for its mucolytic, bronchodilatory, and anti-inflammatory properties. Acebrophylline has lesser adverse effects compared to theophylline and lesser gastrointestinal symptoms and palpitations compared to doxofylline and theophylline. Further, it was also suggested that acebrophylline is preferred in the elderly, cardiac patients, and those with comorbidities.

  Conclusion Top

The combination of montelukast and acebrophylline has potential benefits in bronchial asthma. There is adequate evidence for the role of montelukast and acebrophylline as individual drugs in asthma. However, evidence related to combination therapy is lacking and requires further research. Although there is less evidence on the utility of this combination, experts believe that montelukast–acebrophylline combination could be useful in certain subsets of patients with asthma who are not well controlled with ICS-LABA and also few others who are smokers and have coexisting COPD or ABPA. This oral combination therapy may also benefit especially those patients who are still getting accustomed to their inhaled medications. However, further studies are needed to evaluate the safety and efficacy of montelukast and acebrophylline combination in patients with asthma and its variants.


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Conflicts of interest

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