Long-Term Control Medications Used to Treat Asthma

Long-term control medications are taken daily on a long-term basis to achieve and maintain control of persistent asthma.

Examples of long-term controller medications include: Singulair, Flovent, Advair, Pulmicort, Symbicort and QVAR.

Go to a complete listing of asthma medications.

Long-term control medications (listed in alphabetical order) (EPR-3, p. 214):

Corticosteroids

Immunomodulators

Leukotriene modifiers

Long-acting beta-agonists (LABAs)

• LABAs are not to be used as monotherapy for long-term control of asthma.
• LABAs are used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 care or higher in children >5 years of age and adults) (Evidence A for >12 years of age, Evidence B for 5–11 years of age).
• Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths >12 years of age and adults.
• In the opinion of the Expert Panel, the beneficial effects of LABAs in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher), should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of LABAs. For patients >5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA. For patients >5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy.
• LABA may be used before exercise to prevent exercise-induced bronchospasm (EIB), but duration of action does not exceed 5 hours with chronic regular use. Frequent and chronic use of LABA for EIB is discouraged, because this use may disguise poorly controlled persistent asthma.
• In the opinion of the Expert Panel, the use of LABA for the treatment of acute symptoms or exacerbations is not currently recommended.

The Expert Panel concludes the following regarding the use of LABAs (EPR-3, p. 230):

• LABAs are used as an adjunct to ICS therapy for providing long-term control of symptoms. Of the adjunctive therapies available, LABA is the preferred treatment to combine with ICS in youths >12 years of age and adults. LABAs are not recommended for use as monotherapy for long-term control of persistent asthma.
• Use of LABA is not currently recommended to treat acute symptoms or exacerbations of asthma. Studies are underway examining the potential use of formoterol in acute exacerbations and in adjustable-dose therapy in combination with ICS.
• LABA may be used before exercise to prevent EIB, but frequent and chronic use of LABA for EIB may indicate poorly controlled asthma which should be managed with daily anti-inflammatory therapy.
• Safety issues have been raised regarding LABAs. The Expert Panel reviewed the safety data provided to the FDA Pulmonary and Allergy Drugs Advisory Committee as well as the extensive accumulation of clinical trials and meta-analyses on the use of LABA, both as monotherapy and in conjunction with ICS. The Expert Panel concluded that LABAs should not be used as monotherapy as long-term control medication in persistent asthma but that LABAs should continue to be considered for adjunctive therapy in patients >5 years of age who have asthma that requires more than low-dose ICS. For patients inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the addition of a LABA. For patients who have more severe persistent asthma (i.e., those who require step 4 care or higher), the Expert Panel continues to endorse the use of a combination of LABA and ICS as the most effective therapy.

Methylxanthines

Inhaled corticosteroids

The most potent and consistently effective long-term anti-inflammatory medications for asthma, with fewer side effects than oral corticosteroids. Used for management of persistent asthma at all levels of severity to improve symptoms and pulmonary function.

When is it used?

• Long-term prevention of symptoms; controls, reverses and keeps inflammation down.
• Reduce the need for quick-relief medications.

How does it work?

• Anti-inflammatory. Blocks late reaction to allergen and reduces airway sensitivity. Inhibits cytokine production, adhesion protein activation, and inflammatory cell migration and activation at the cellular level.
• Reverse beta₂-receptor down-regulation. Inhibits microvascular leakage.

Possible side effects

• Cough, voice changes (hoarseness), oral thrush (candidiasis)
• In high doses systemic effects may occur, although studies have not proven this, and clinical significance of these effects has not been established (e.g., adrenal suppression, osteoporosis, growth suppression, and skin thinning and easy bruising).
• Some studies of inhaled corticosteroids to treat asthma in pre-pubertal children have identified growth delay or suppression that appears to be dose-dependent; others have not. The potential small risk of adverse effects on linear growth is well balanced by efficacy. The clinical significance of the findings is unclear at this time. Monitoring growth is recommended.

• A general pdf about steroids and growth.

Other information about using this type of medication:

• Available as MDI, dry power inhaler (DPI) and nebulizer solution.
• Spacer/valved-holding chamber devices with MDIs and mouth washing after inhalation decreases the risk of oral side effects and systemic absorption.
• Preparations are not absolutely interchangeable on a mcg or per puff basis. New delivery devices may provide greater delivery to airways, which may affect dose.
• The risks of uncontrolled asthma should be weighed against the limited risks of inhaled corticosteroids. The possible but small risk of harmful effects is well balanced by their value in controlling asthma.

Oral corticosteroids

Often used to gain prompt control of poorly controlled persistent asthma, or when starting long-term therapy.

When is it used?

• For short-term (3-10 days) "burst", broad anti-inflammatory effects.
• For long-term prevention of symptoms in severe persistent or very poorly controlled asthma; controls, reverses and keeps inflammation down.

How does it work?

• Anti-inflammatory. Blocks late reaction to allergen and reduce airway sensitivity. Inhibits cytokine production, adhesion protein activation, and inflammatory cell migration and activation at the cellular level.
• Reverse beta₂-receptor down-regulation. Inhibits microvascular leakage.

Possible side effects

• Short-term use: reversible, abnormalities in sugar metabolism, increased appetite, fluid retention, weight gain, mood change, high blood pressure, peptic ulcer, and rarely aseptic necrosis of femur.
• Long-term use is associated with systemic effects: adrenal axis suppression, growth suppression, dermal thinning, hypertension, diabetes, Cushing's syndrome, cataracts, muscle weakness, and – in rare cases – impaired immune function.
• Consideration should be given to coexisting conditions that could be worsened by systemic corticosteroids, such as herpes virus infections, varicella, tuberculosis, hypertension, peptic ulcer, and Strongyloides.

Other information about using this type of medication

• Use at lowest effective dose.
• For long-term use in severe persistent or very poorly controlled asthma, fewer harmful effects have been seen with every-other-day morning dosing.

Leukotriene modifiers

May be considered an alternative therapy to low doses of inhaled corticosteroids for patients >12 years of age with mild persistent asthma, although further clinical experience and study are needed to establish their roles in asthma therapy.

When is it used?

• May be considered as alternative therapy to low doses of inhaled corticosteroids for children with mild persistent asthma, but the position of leukotriene modifiers in therapy has not been fully established. Some studies suggest that leukotriene modifiers may be effective when added to inhaled corticosteroids in the management of moderate persistent asthma (step 3) and when given the night before exercise to prevent exercise-induced bronchospasm.
• Improve symptoms and pulmonary function.
• Reduce the need for quick-relief medications.

How does it work?

• Leukotriene receptor antagonists (e.g. montelukast, zafirlukast) block LTD4 receptors; 5-lipoxygenase inhibitors (e.g. zileuton) block synthesis of all leukotrienes at the cellular level.

Possible side effects

• Elevations of liver enzymes have been reported with zileuton in some patients. Monitoring is recommended.
• In rare cases, adult patients have presented with systemic eosinophilia and vasculitis with clinical features consistent with Churg Strauss syndrome. These events usually have been associated with reducing oral corticosteroid therapy while initiating a leukotriene modifier therapy. No causal relationship has been established.

Other information about using this type of medication

• Available as tablets. Tablets should be taken at least 1 hour before or 2 hours after meals for optimum effects for zafirlukast and zileuton.
• Zafirlukast inhibits the metabolism of warfarin and increases prothrombin time; it is a competitive inhibitor of the CYP2C9 hepatic microsomal isozymes. (It has not affected elimination of terfenadine, theophylline, or ethinyl estradiol drugs metabolized by the CYP3A4 isozymes.)
• Zileuton is microsomal CYP3A4 enzyme inhibitor that can inhibit the metabolism of terfenadine, theophylline, and warfarin. Doses of these drugs should be monitored accordingly. Hepatic enzymes (ALT) should also be monitored.

Long-acting beta₂-agonists

Used together with anti-inflammatory medications for long-term control of asthma symptoms. Should not replace anti-inflammatory medications. Should never be used alone, without an inhaled corticosteroid. Not to be used to treat acute symptoms or flare-ups.

When is it used?

• To improve symptoms and reduce need for quick-relief medication.
• For long-term control of symptoms, especially nighttime symptoms.
• To prevent exercise-induced bronchospasm. However, in some patients this effect may be reduced when used daily as continuous therapy. The clinical significance of this finding is unclear.

How does it work?

• Starts working slower but lasts longer than short-acting beta₂-agonists.
• May get better symptom control when added to standard doses of inhaled corticosteroids instead of just increasing the corticosteroid dose.
• Bronchodilation: relaxes bronchial smooth muscle following adenylate cyclase activation and increases in cyclic AMP producing functional antagonism of bronchoconstriction at the cellular level.
• In vitro, inhibits mast cell mediator release, decreases vascular permeability, and increases mucociliary clearance.

Possible side effects

• Increased heart rate, shakiness, hypokalemia, prolongation of QTc interval in overdose.
• A diminished bronchoprotective effect may occur within 1 week of chronic therapy. Clinical significance has not been established.

Other information about using this type of medication:

• Available as MDI, DPI, and tablets. Inhaled long-acting beta₂-agonists are preferred because they are longer acting and have fewer side effects than time-release pills.
• Should not replace anti-inflammatory medications.
• Not to be used to treat acute symptoms or flare-ups.
• Clinical significance of potentially developing tolerance is not clear because studies show symptom control and bronchodilation are maintained.
• May provide better symptom control when added to standard doses of inhaled corticosteroid instead of increasing the corticosteroid dosage.

Long-acting Muscarinic Antagonists

Similar to LABAs, long-acting muscarinic antagonist inhalers, or LAMAs, relax the muscles of the airways to help control the symptoms of asthma.

Methylxanthines (theophylline)

Used as add-on therapy to anti-inflammatory medications for long-term control of asthma symptoms, especially nighttime symptoms.

When is it used?

• Long-term control and prevention of symptoms, especially nocturnal symptoms.
• Produces mild to moderate bronchodilation.
• Theophylline is an alternative, but not preferred, therapy for persistent asthma.

How does it work?

• Bronchodilation: Smooth muscle relaxation from phosphodiesterase inhibition and possibly adenosine antagonism (to open up the airways).
• May affect eosinophilic infiltration into bronchial mucosa as well as decrease T-lymphocyte numbers in epithelium (to slow mucus production).
• Increases diaphragm contractility and mucociliary clearance (to clear mucus from airways).

Possible side effects

• Side effects at usual therapeutic doses include stomach upset, difficulty in urination in elderly males with prostate disease, sleeplessness, and hyperactivity in some children.
• Dose-related acute toxicities include increased heart rate, nausea and vomiting, irregular heart beats (SVT), central nervous system stimulation, headache, seizures, vomiting blood, high blood sugar, and hypokalemia.
• Side effects increase with increasing levels of the medication in the body. In some children, side effects may occur with lower levels of the medication in the body.

Other information about using this type of medication:

• Available as time-release pills and capsules.
• Monitoring is required to maintain serum levels between 5 and 15 mcg/mL. Viral illnesses with fever, age, certain medications (e.g. erythromycin), and diet can increase absorption and bioavailability, which can increase levels of the medication in the body.
• Not generally recommended for asthma flare-ups. There is little proof of added benefit to optimal doses of inhaled beta₂-agonists. Blood concentration of this drug must be monitored closely.

Immunomodulators – Xolair (omalizumab):

Omalizumab (anti-IgE) is a monoclonal antibody that prevents binding of IgE to the high-affinity receptors on basophils and mast cells. Omalizumab is used as adjunctive therapy for patients ≥ 12 years of age who have allergies, and severe persistent asthma. Clinicians who administer omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur.

Adding omalizumab to ICS can:

• Reduce exacerbations and subsequent use of systemic steroid bursts
• Reduce daytime allergic asthma symptoms and nighttime awakenings
• Reduce disruptions of daily routine activities

Omalizumab is indicated for patients aged 12 years and older with:

• IgE levels between 30 and 700 IU/mL
• Positive skin test or in vitro reactivity to a perennial aeroallergen
• Allergic asthma symptoms inadequately controlled with ICS

Omalizumab is administered by subcutaneous injection and dosing is based on body weight and baseline serum total IgE concentration. All patients are required to have a baseline IgE between 30 and 700 IU/mL and body weight not more than 150 kg.

Adapted from the Guidelines for the Diagnosis and Management of Asthma, National Asthma Education and Prevention Program, National Institutes of Health, 2007