Asthma Treatment Types: Part 2 — Advanced and Combination Therapies
▶ Advanced asthma therapy: overview
When basic inhaler therapy is not enough, a range of add-on treatments can improve asthma control: combination ICS+LABA inhalers, LAMA bronchodilators, montelukast tablets, theophylline, and — for severe uncontrolled asthma — biologic injections targeting specific inflammatory pathways. This guide covers Steps 3–5 of the NICE NG245 stepwise approach and the specialist therapies available in the UK.
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Start Asthma Consultation →Recap: Steps 1–3 of Asthma Treatment
In Part 1 of our asthma treatment guide, we covered Steps 1–3 of the NICE/BTS stepwise approach:
- Step 1 — SABA reliever inhaler only (for very mild, infrequent symptoms)
- Step 2 — Add a daily low-dose ICS preventer inhaler
- Step 3 — Add a LABA — usually as a combination ICS+LABA inhaler, ideally using MART therapy
This guide covers what happens when standard ICS+LABA therapy is not enough — Steps 4 and 5, including combination inhalers in depth, LAMA add-on, montelukast, theophylline, oral steroids, and biologic therapies for severe asthma.
Before stepping up treatment, always verify: correct inhaler technique, treatment adherence, elimination of modifiable triggers (smoking, allergen exposure), and accuracy of diagnosis. Poor control often reflects suboptimal use of existing therapy rather than an inherent need for more medication.
Combination ICS+LABA Inhalers in Detail
Combination inhalers are the most commonly used step-up treatment in asthma. They contain both an inhaled corticosteroid (for inflammation control) and a long-acting beta-2 agonist (for sustained bronchodilation). They are used daily as maintenance therapy — not for acute symptom relief (unless using MART with a formoterol-containing inhaler).
The main combination inhalers available in the UK:
| Brand | ICS | LABA | Device | Frequency | MART? |
|---|---|---|---|---|---|
| Fostair 100/6 | Beclometasone 100mcg | Formoterol 6mcg | pMDI or Nexthaler DPI | Twice daily + as needed (MART) | Yes |
| Fostair 200/6 | Beclometasone 200mcg | Formoterol 6mcg | pMDI or Nexthaler DPI | Twice daily | No (higher dose) |
| Symbicort 200/6 | Budesonide 200mcg | Formoterol 6mcg | Turbohaler DPI | Twice daily + as needed (MART) | Yes |
| Symbicort 400/12 | Budesonide 400mcg | Formoterol 12mcg | Turbohaler DPI | Twice daily | No |
| Seretide 125 | Fluticasone 125mcg | Salmeterol 25mcg | Evohaler pMDI | Twice daily | No |
| Seretide 250 Accuhaler | Fluticasone 250mcg | Salmeterol 50mcg | Accuhaler DPI | Twice daily | No |
| Relvar Ellipta 92/22 | Fluticasone furoate 92mcg | Vilanterol 22mcg | Ellipta DPI | Once daily | No |
| DuoResp Spiromax | Budesonide 160mcg | Formoterol 4.5mcg | Spiromax DPI | Twice daily + as needed (MART) | Yes |
Key principle: LABAs must never be used without an ICS in asthma. Monotherapy LABA is associated with increased risk of severe asthma attacks and death. Combination inhalers ensure both components are always taken together.
MART: Maintenance and Reliever Therapy in Practice
MART (Maintenance and Reliever Therapy) uses a single combination ICS+formoterol inhaler for both regular daily maintenance and as an on-demand reliever. This is possible because formoterol has a rapid onset (like salbutamol) in addition to its long duration of action.
Why MART is clinically superior to traditional fixed-dose ICS+LABA plus separate SABA:
- Every extra puff taken for symptoms delivers an additional dose of ICS — providing anti-inflammatory cover at exactly the moment it is most needed (during an exacerbation)
- Reduces total number of inhalers to one, improving adherence
- Strong evidence from randomised trials showing 30–50% reduction in severe exacerbation rates vs fixed-dose ICS+LABA + SABA
- NICE NG245 recommends MART as the preferred Step 3 strategy in adults
MART dose limits (as per NICE NG245 / product licences):
- Fostair 100/6 MART: 1–2 puffs maintenance twice daily + up to 6 additional as-needed puffs per day (max 8 puffs/day total)
- Symbicort 200/6 MART: 1–2 inhalations twice daily + up to 6 additional as needed (max 12 inhalations/day)
MART-eligible inhalers must contain formoterol as the LABA. Seretide (salmeterol) cannot be used as MART because salmeterol has a slow onset and is not suitable for acute relief.
LAMA Add-On Therapy (Tiotropium)
Long-acting muscarinic antagonists (LAMAs) block muscarinic receptors in the airways, reducing bronchoconstriction and mucus secretion. They have a sustained effect over 24 hours and are taken once daily.
Tiotropium (Spiriva Respimat) is the LAMA licensed for asthma in the UK. It is approved as add-on therapy for adults aged 18+ with symptomatic asthma who remain uncontrolled on ICS+LABA (Step 4). Key points:
- Reduces the frequency and severity of exacerbations as add-on to ICS+LABA
- Administered once daily via Respimat soft mist inhaler (2.5mcg per actuation, 2 actuations once daily)
- Side effects: dry mouth (most common), constipation, urinary retention (rare)
- Caution in narrow-angle glaucoma and bladder outflow obstruction
Montelukast (Leukotriene Receptor Antagonist)
Montelukast (Singulair) is an oral tablet taken once daily at night. It works by blocking leukotriene receptors — reducing the effects of inflammatory chemicals that cause airway narrowing and mucus production. It is a completely different class of drug from corticosteroids or bronchodilators.
Montelukast is particularly useful for:
Allergic Asthma
Leukotrienes play a central role in allergen-driven airway inflammation. Particularly useful when asthma co-exists with allergic rhinitis (hay fever) — montelukast treats both conditions simultaneously.
Exercise-Induced Asthma
Strong evidence for reducing exercise-induced bronchoconstriction. Can allow some patients to reduce pre-exercise inhaler use.
Aspirin-Sensitive Asthma
NSAIDs trigger asthma in a subset of patients via leukotriene overproduction. Montelukast is particularly beneficial in this subgroup.
Neuropsychiatric side effects: Montelukast carries a warning for rare neuropsychiatric effects — mood changes, agitation, sleep disturbance, and (very rarely) suicidal ideation. The MHRA advises patients and carers to report any behavioural or mood changes to their prescriber. The risk is greatest in children and young adults.
Theophylline
Theophylline is an oral bronchodilator and mild anti-inflammatory agent used as add-on therapy at Step 4. It is a methylxanthine drug that works by inhibiting phosphodiesterase enzymes, resulting in smooth muscle relaxation and bronchodilation.
Theophylline has a narrow therapeutic index — the difference between therapeutic and toxic plasma levels is small. Toxic levels cause nausea, vomiting, palpitations, seizures, and arrhythmias. Blood level monitoring is mandatory.
Because of its side effect profile, theophylline is now used less frequently than in the past — it is generally reserved for patients who cannot tolerate other add-on treatments or who have persistent benefit that justifies monitoring. Serum theophylline levels should be maintained at 10–20 mg/L.
Important drug interactions that affect theophylline levels include: ciprofloxacin, erythromycin, allopurinol (increase levels); rifampicin, carbamazepine, phenytoin, smoking (decrease levels).
Oral Corticosteroids
Oral corticosteroids (prednisolone) are used in two contexts in asthma:
- Short courses for acute exacerbations: Typically 40mg prednisolone for 5 days. Rapidly controls airway inflammation during a flare and reduces the risk of relapse. Relatively few side effects from short courses.
- Maintenance oral steroids: Used at Step 5 in severe asthma not controlled on all other treatments. The lowest effective dose is used, and patients are monitored for osteoporosis, diabetes, hypertension, adrenal suppression, and other long-term steroid side effects. Always paired with calcium/vitamin D supplementation and a bisphosphonate if long-term use.
Long-term oral corticosteroids carry significant risks including osteoporosis, diabetes, hypertension, adrenal suppression, cataracts, weight gain, and increased infection risk. The development of effective biologic therapies has dramatically reduced the need for maintenance oral steroids in severe asthma — always explore biologic eligibility before committing to long-term oral steroids.
Biologic Therapies for Severe Asthma
Biologic therapies are injectable monoclonal antibodies that target specific inflammatory molecules involved in severe asthma. They represent a major advance for the minority of people with severe, treatment-resistant asthma and have enabled many patients to reduce or eliminate oral corticosteroid use.
Biologics currently approved for asthma in the UK:
| Drug (Brand) | Target | Asthma Type | Administration |
|---|---|---|---|
| Mepolizumab (Nucala) | Anti-IL-5 | Severe eosinophilic asthma (≥300 eosinophils/µL) | SC injection every 4 weeks |
| Benralizumab (Fasenra) | Anti-IL-5Rα | Severe eosinophilic asthma (≥300 eosinophils/µL) | SC injection q4w (first 3 doses), then q8w |
| Dupilumab (Dupixent) | Anti-IL-4Rα (blocks IL-4 and IL-13) | Severe eosinophilic or OCS-dependent asthma | SC injection every 2 weeks |
| Tezepelumab (Tezspire) | Anti-TSLP | Severe asthma (regardless of phenotype) | SC injection every 4 weeks |
| Omalizumab (Xolair) | Anti-IgE | Severe allergic (IgE-mediated) asthma | SC injection every 2–4 weeks |
Biologics are initiated and supervised by specialist severe asthma centres. Patients are assessed against strict eligibility criteria (including blood eosinophil count, IgE levels, and OCS use). Response is reviewed at 12–16 weeks — treatment is continued only if there is a clinically meaningful benefit.
Biologic therapy can transform lives in severe asthma. Studies show reductions in exacerbation rates of 50–70% and oral steroid dose reduction or elimination in many patients. If you have severe asthma that is not controlled on high-dose inhaled therapy and/or requires frequent oral steroids, ask your GP for a referral to a specialist asthma centre.
Bronchial Thermoplasty
Bronchial thermoplasty (BT) is a non-pharmacological bronchoscopic procedure available for adults with severe asthma not controlled on optimal medical therapy. A catheter is passed into the airways via a bronchoscope and delivers controlled radiofrequency energy to the airway walls, reducing the bulk of the smooth muscle layer.
By reducing airway smooth muscle mass, thermoplasty decreases the degree of bronchoconstriction that can occur during asthma triggers. Three treatment sessions are required (each treating a different region of the lungs) at 3-week intervals. There is a risk of short-term asthma worsening during and after each session.
Thermoplasty is reserved for a small, carefully selected group of severe asthma patients at specialist centres. Long-term (5-year) data shows sustained reduction in exacerbation rates and improvements in quality of life.
The Stepwise Approach Revisited
All treatment decisions should follow a structured review process:
- 1
Assess control and identify barriers
Before stepping up, ensure: correct technique (re-check at every review), adequate adherence, absence of modifiable triggers (smoking, allergens, occupational exposures), and accuracy of diagnosis.
- 2
Step up treatment as needed
Move to the next step if asthma is not controlled after 4–8 weeks at the current step. Follow NICE NG245 pathway — Step 2 (ICS) → Step 3 (ICS+LABA/MART) → Step 4 (add LAMA/montelukast/increase ICS) → Step 5 (high-dose + biologics/OCS).
- 3
Step down after 3 months of good control
Once asthma has been well controlled for 3 months, attempt to reduce treatment to the lowest effective dose. Stepping down reduces side effect risk and confirms the minimum treatment required. Step down slowly — typically one step at a time with a 3-month washout between reductions.
For a comprehensive overview of asthma — causes, symptoms, diagnosis and all treatment options — see our complete asthma condition guide. [Pillar page — link to be activated on publication]
Frequently Asked Questions
What are combination inhalers for asthma?
Combination inhalers contain both an inhaled corticosteroid (ICS) and a long-acting beta-2 agonist (LABA) in a single device. Used as daily maintenance therapy when a preventer alone is insufficient. Examples: Fostair (beclometasone + formoterol), Seretide (fluticasone + salmeterol), Symbicort (budesonide + formoterol). Those containing formoterol can also serve as a reliever (MART approach).
What are biologic therapies for asthma?
Biologic therapies are injectable monoclonal antibodies targeting specific inflammatory pathways in severe asthma. UK-approved examples include mepolizumab (anti-IL-5), benralizumab (anti-IL-5 receptor), dupilumab (anti-IL-4/13), tezepelumab (anti-TSLP), and omalizumab (anti-IgE). They are reserved for severe uncontrolled asthma and supervised by specialist centres. They can reduce exacerbation rates by 50–70% in suitable patients.
What is montelukast used for in asthma?
Montelukast is a leukotriene receptor antagonist (LTRA) taken as a daily oral tablet. It is add-on therapy at Step 3+ particularly useful for allergic asthma, exercise-induced symptoms, and aspirin-sensitive asthma. It is generally well tolerated but carries a rare risk of neuropsychiatric side effects — any mood changes should be reported to your prescriber.
What is theophylline used for in asthma?
Theophylline is an oral bronchodilator used as add-on therapy at Step 4. It has a narrow therapeutic index and requires regular blood level monitoring. Side effects at toxic levels include nausea, palpitations, and seizures. It is used less frequently now than in the past due to the availability of safer alternatives, but remains an option in difficult-to-treat asthma.
References
- NICE (2024). Asthma: diagnosis, monitoring and chronic asthma management. NG245. nice.org.uk/guidance/ng245
- SIGN/BTS (2023). British Guideline on the Management of Asthma. SIGN 158.
- Chupp GL et al. (2017). Efficacy of mepolizumab add-on therapy on health-related quality of life. Lancet Respiratory Medicine.
- NICE (2023). Tezepelumab for treating severe refractory asthma. TA824.
- Thomson NC et al. (2011). Bronchial thermoplasty: indications, contraindications, and effectiveness. Therapeutic Advances in Respiratory Disease.