Finding the Right Mix of Asthma Meds
Finding the Right Mix of Asthma Meds
While inhaled corticosteroids remain the cornerstone of asthma management, new studies show adding medications that acutely reverse symptoms can be the best defense.
In order to create a treatment plan, clinicians must follow a stepwise regimen. For mild, moderate and severe persistent asthma, initial therapy should include an inhaled corticosteroid used daily and a short-acting inhaled beta-agonist used on an as-needed basis for the acute treatment of symptoms.1 Some experts feel that even mild intermittent patients should take inhaled corticosteroids.
A patient with well-controlled asthma should not use a short-acting inhaled beta-agonist more than two times a week for rescue therapy. More frequent use indicates the patient’s asthma is not ideally controlled. If this is the case, physicians can either increase inhaled corticosteroid dosage or add other medications, such as long-acting beta-agonists or leukotriene modifiers.
Before discussing combination therapy for persistent asthma, clinicians need to evaluate the pros and cons of increasing the patient’s dose of inhaled corticosteroids.
While there is little doubt as to the effectiveness of inhaled corticosteroids in the initial management of asthma, it’s unclear if an increase for persistent symptoms is beneficial. Sont et al. demonstrated inhaled corticosteroids dose increases resulted in a decrease in exacerbations, an improvement in FEV1 and a decrease in lung tissue eosinophilia.2 However, other studies have demonstrated no improvement in symptoms or FEV1.3,4
A significant increase in side effects is associated with higher inhaled corticosteroid doses. These include local side effects, such as oral candidiasis and dysphonia, and systemic side effects, such as decreased growth, adrenal suppression, cataracts, skin thinning and bruising, and osteoporosis. Regarding the risk of developing osteoporosis, doubling the dose of inhaled corticosteroids can result in a 0.032 g/cm decrease in spine density.5 As such, the risk/benefit ratio changes to more risk than benefit with higher doses of inhaled corticosteroids.
For patients with persistent asthma symptoms despite inhaled corticosteroid use, a potential option to improving the patient’s health is to add a long-acting inhaled beta-agonist, such as salmeterol, the only such beta-agonist available currently in the United States. Many studies have demonstrated adding this medication results in a significant improvement in asthma symptom control.
Unlike short-acting inhaled beta-agonists, which have an onset of action of minutes and a duration of four hours, salmeterol has an two-hour onset of action and a 12-hour duration of action. Therefore, it should not be used to treat acute asthma symptoms.
Greening et al. demonstrated that salmeterol, in addition to inhaled corticosteroids, was superior at increasing peak expiratory flows and improving symptoms score compared to inhaled corticosteroids alone.6 While the group receiving inhaled corticosteroids alone received 2.5 times the dose compared to the combination group, they had less control of their symptoms.
Other studies have confirmed these findings and demonstrated that combination treatments decrease rescue medication usage, increase the number of symptom-free days and decrease the number of asthma exacerbations7-9 compared to high doses of inhaled corticosteroids alone. In addition, when using this combination therapy, patients take a lower dose of inhaled corticosteroids, which could minimize potential side effects.
Several drawbacks need to be considered when adding a long-acting inhaled beta-agonist for asthma control. Salmeterol’s most common side effect is muscle cramps, which probably develop as a result of intracellular potassium shifts, and may be severe enough that patients cannot continue taking the medication. Adding another inhaler may cause compliance issues, yet these can be improved by using inhalers that combine fluticasone and salmeterol into one inhaler.
Other potential disadvantages have been proven thus far to be non-issues. Korosec et al. showed that there was no evidence of impaired response to albuterol in patients receiving salmeterol.10 Li et al. demonstrated a decrease in airway eosinophilia in patients treated with combination salmeterol and inhaled corticosteroids compared to inhaled corticosteroids alone,11 suggesting there is no inflammation masking with the long-acting inhaled beta-agonist and the possibility of salmeterol to have anti-inflammatory properties itself.
Several studies also have demonstrated that combining leukotriene modifiers and inhaled corticosteroids is better at controlling asthma symptoms compared to inhaled corticosteroids alone. Leukotrienes, especially LTC4, LTD4 and LTE4, have been found to be important mediators in asthma. Leuko-trienes are very potent bronchoconstrictors that increase mucus production and airway hyperresponsiveness, and cause airway inflammation.
Currently, three drugs are available in the United States that directly affect leukotrienes: Zileuton inhibits leukotriene production, while zafirlukast and montelukast are leukotriene receptor antagonists.
Laviolette et al. demonstrated that combining montelukast with inhaled corticosteroids was superior to inhaled corticosteroids alone and montelukast alone in improving asthma symptoms.12 Further, Virchow et al. confirmed an improvement in peak expiratory flows, FEV1, symptoms and the number of exacerbations in patients receiving zafirlukast plus inhaled corticosteroids vs. inhaled corticosteroids alone.13
While both appear to be more effective in controlling asthma symptoms than simply increasing the inhaled corticosteroid dose, one study demonstrated that combining salmeterol and inhaled corticosteroids was superior in controlling symptoms and improving peak expiratory flows than by combining zafirlukast with inhaled corticosteroids.14
Noncompliance is a potential problem for patients using leukotriene modifiers. Zileuton requires a dosage of four times daily, and zafirlukast needs to be taken twice a day on an empty stomach. Patients might comply better with montelukast, a once daily that does not require an empty stomach.
Generally, leukotriene modifiers are well-tolerated, but they may cause headache or gastrointestinal symptoms, such as abdominal cramping and diarrhea, which can limit their use. Patients taking zileuton and high doses of zafirlukast need to be monitored for hepatotoxicity. It is unclear if leukotriene modifiers cause Churg-Strauss Syndrome or if they unmask it by allowing for oral corticosteroids tapering. Regardless, the syndrome is very rare in these patients.
Adding Other Agents
Another study suggests that adding nedocromil sodium to high dose steroids might improve symptoms and peak expiratory flow.15 Nedocromil sodium is a mast cell stabilizer that is a typically well-tolerated drug with only one potential downside: inhaler compliance.
Evans et al. suggested adding low-dose theophylline (the mean plasma concentration of theophylline was 8 mg/dL) to inhaled corticosteroids would provide better control of symptoms compared to doubling the inhaled corticosteroids dose.16 The cons associated with this idea included the drug’s narrow therapeutic window, significant side effects and toxicities, multiple drug interactions and the need to periodically monitor drug levels.
While our knowledge regarding the treatment of asthma has improved greatly over the past 20 years, further research is needed to compare combinations of these and other therapies.
Dr. Kopec is assistant professor of medicine in the division of Pulmonary, Allergy and Critical Care Medicine at the University of Massachusetts Medical School, Worcester, Mass.
For a list of references, please call Tracy Schmierer at (610) 278-1400, ext. 350, or see www.Respiratory-care-sleep-medicine.advanceweb.com.