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Norris SL, McNally TK, Thakurta S. Drug Class Review: Quick-relief Medications for Asthma: Final Report Update 1 [Internet]. Portland (OR): Oregon Health & Science University; 2008 Oct.

Introduction

Asthma

Asthma is a chronic inflammatory disorder of the airways. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, cough, and other symptoms. These episodes are usually associated with widespread and variable airflow obstruction. This obstruction is often reversible, either spontaneously or with treatment. Airway inflammation also increases bronchial hyper-responsiveness to a variety of stimuli, resulting in increased susceptibility to bronchospasm. In addition to bronchospasm and inflammation, some patients also experience airway remodeling, which leads to more severe and persistent disease. Airway reversibility may be incomplete in some patients.1, 2

Asthma is diagnosed when 1) the patient has episodic symptoms of airflow obstruction; 2) airflow obstruction is at least partially reversible; and 3) alternative diagnoses are excluded. Asthma most often begins in childhood and in these children is frequently associated with atopy. Asthma can, however, develop at any time in life and can be related to allergens or can be nonallergic (or intrinsic).2

The 2004 National Health Interview Survey3 estimated that 10.5% (30.2 million) of the United States’ population have been diagnosed with asthma. These include 9.9% (21.3 million) of adults 18 years and over and 12.2% (8.9 million) of children under age 18 years. Among children in the US, 5.4% (4.0 million) had at least 1 asthma attack in the past 12 months; for adults the figure was 3.6% (7.7 million). Prevalence of asthma increased from 1980 to 1996. In 1996 new measures of asthma prevalence were adopted. These measures suggest that prevalence of asthma remained relatively stable from 1997 to 2004.3

Asthma medications fall into 2 general classes: medications for long-term control and medications for quick relief of airflow obstruction and symptoms.1, 2 Persons with persistent asthma require long-term controller and quick relief medications. Long-term controller medications include corticosteroids, cromolyn sodium and nedocromil, methylxanthines, leukotriene modifiers, and long-acting beta2-agonists.1, 2 Medications for quick relief of bronchoconstriction and acute symptoms include short-acting beta2-agonists and anticholinergics.

Exercise-induced asthma

Exercise-induced asthma is characterized by coughing, wheezing, shortness of breath, and chest tightness during or after exercise.4 Exercise-induced asthma is associated with airway obstruction after exercise, as indicated by a decrease in the volume of air forcefully expired in 1 second (forced expiratory volume in 1 second, FEV1). In exercise-induced bronchospasm exercise precipitates airway obstruction, but lung function is normal at rest.4 The term exercise-induced asthma sometimes refers to persons who have exacerbation of their chronic asthma during exercise. We use the term exercise-induced asthma to encompass both this condition and exercise-induced bronchospasm.1

The mechanisms underlying exercise-induced asthma are not well understood. The hyperosmolarity hypothesis proposes that water loss from the airway causes hypertonicity of airway cells, leading to release of inflammatory mediators and subsequent bronchoconstriction.4 Another hypothesis suggests that hyperventilation leads to cooling of airway cells, and after exercise the rewarming process leads to dilatation of bronchiolar vessels accompanied by fluid exudation, mediator release, and bronchoconstriction.

Exercise-induced asthma can affect elite and recreational athletes. Prevalence is reported as 17% in athletes participating in winter Olympics,4 35% among athletes competitive in cold weather sports,4 and 9% among school children.4

Treatment focuses on avoidance of the particular activities that precipitate bronchospasm, adequate warm-up periods, and pharmacologic therapy. The last of these usually consists of an inhaled short-acting beta2-agonist 15 minutes prior to exercise.4 Additional, daily therapy may be required for management of underlying chronic asthma.

Inhaled beta2-agonists

Beta2-agonists act mainly to relax airway smooth muscle by stimulating beta2-receptors, which in turn increase cyclic AMP and produce functional antagonism to bronchoconstriction.2 Beta2-agonists may also have anti-inflammatory properties, as suggested by in vitro experiments.5

The short-acting beta2-agonists relax airway smooth muscle and increase airflow within 30 minutes1 and last 4 to 5 hours. They are the drug of choice for treating acute asthma symptoms and exacerbations and are used for preventing exercise-induced bronchospasm. The short-acting beta2-agonists are not recommended for regularly scheduled, daily use.1

The United States Food and Drug Administration announced on March 31, 2005, that albuterol metered-dose inhalers using chlorofluorocarbon propellants must no longer be produced, marketed, or sold in the United States after December 31, 2008, as they deplete stratospheric ozone.1 Numerous clinical studies have demonstrated that albuterol hydrofluoroalkane 134a formulations have safety and efficacy comparable to albuterol chlorofluorocarbon formulations.6–8

A hydrofluoroalkane metered-dose inhaler containing levalbuterol (Xopenex HFA®) was approved in December 2005 for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease.

Inhaled anticholinergic agents

Anticholinergic (antimuscarinic) agents such as ipratropium bromide have been used in the treatment of acute and chronic asthma. These drugs act on muscarinic receptors to inhibit the effects of acetylcholine, thus causing smooth muscle relaxation. In asthma, ipratropium bromide is less potent and its bronchodilation slower than beta2-agonists, but its effects last up to 6 hours.9 In a 2000 Cochrane review Plotnick and colleagues10 concluded that a single dose of an anticholinergic agents is not effective in the treatment of mild and moderate asthma, and is insufficient for acute exacerbations. They noted, however, that addition of multiple doses of anticholinergic agents to beta2-agonists improves lung function and avoids hospital admission in some patients.

Scope and Key Questions

The purpose of this review is to compare the benefits and harms of short-acting beta2-agonists and ipratropium bromide used for quick relief of asthma symptoms. For the original report we included long- and short-acting beta2-agonists for the treatment of asthma (including exercise-induced asthma) and chronic obstructive pulmonary disease. For Update 1 we were asked to focus only on short-acting drugs for quick relief of asthma symptoms (quick-relief medications for asthma). Therefore, for this report we included from the original report only sections that relate to short-acting beta2-agonists. We included short-acting beta2-agonists used on a regular basis in the original report, and we also updated that information in Update 1. We added ipratropium bromide to the review, and we did not include studies of chronic obstructive pulmonary disease. We also did not update metaproterenol for Update 1, per the request of our participating organizations.

The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and, based on these, the eligibility criteria for studies. These preliminary questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians and patients. The participating organizations approved the following key questions to guide this review:

Key Questions

  1. What are the comparative efficacy and effectiveness of quick-relief medications used to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm?
  2. What are the comparative incidence and severity of adverse events reported from using quick-relief medications to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm?
  3. Are there subgroups of patients for which quick-relief medications used to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm differ in efficacy, effectiveness, or frequency and severity of adverse events?
Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Cover of Drug Class Review: Quick-relief Medications for Asthma
Drug Class Review: Quick-relief Medications for Asthma: Final Report Update 1 [Internet].
Norris SL, McNally TK, Thakurta S.
Portland (OR): Oregon Health & Science University; 2008 Oct.

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