INTRODUCTION — The drugs, cromolyn sodium (or cromolyn) and nedocromil, are commonly grouped together as chromones (also called cromoglycates). The chromones are listed as alternate initial controller therapies for mild asthma in national and international guidelines, although inhaled glucocorticoids (also known as inhaled corticosteroids) are the preferred agents [1,2]. The low incidence of side effects compared with inhaled glucocorticoids is a leading reason some patients prefer chromones over inhaled glucocorticoids.
This topic will review the pharmacology and use of chromones in the management of asthma. A more general discussion of asthma therapy is found separately. (See "An overview of asthma management".)
LIMITATIONS ON AVAILABILITY — Cromolyn first became available in the 1970s. At present, availability of cromoglycates varies from one country to another, due in part to the need to change the propellants used in cromoglycate metered-dose inhalers (MDIs) [3,4]. The propellant originally had been a chlorofluorocarbon (CFC). Following adoption of the Montreal protocol (an international agreement to ban CFCs), inhalers that contain hydrofluoroalkane (HFA) were developed for some drugs. HFA formulations of cromolyn are available in the United Kingdom and a Spinhaler device is available in Australia, although neither of these is sold in the United States. (See "The use of inhaler devices in adults" and "The use of inhaler devices in children".)
In the United States, neither cromolyn nor nedocromil is available in HFA-containing MDIs, and no formulation of nedocromil is marketed for asthma. As a result, the only remaining formulations for asthma are solutions of cromolyn (10 mg/mL) for nebulization. However, dry-powder inhaler formulations for cromolyn and nedocromil are available in other countries (table 1).
PHARMACOLOGY — The chromones have potent effects in preventing both early and late asthmatic responses to inhaled allergens, such as pollen, and reducing airway reactivity to a range of inhaled irritants, such as sulfur dioxide and cold air [5].
The hypothesis proposed to explain the mechanism of action of the chromones involves two related and possibly sequential processes, which act to stabilize airway mast cells and perhaps other inflammatory cells.
●First, the drugs cause phosphorylation of a cell membrane moesin-like protein that is responsible for the termination of mediator release from mast cells and probably a broad range of other cells responsible for allergic inflammation [6]. As such, chromones appear to activate a natural "turn-off switch" in the very early stages of an asthmatic response to an external noxious stimulus. This action may explain the ability of cromolyn to block the acute bronchospastic response to inhaled antigen equally effectively whether administered one minute or one hour prior to challenge [7].
●Second, chromones inhibit the activation of a chloride current in cells undergoing shape and volume changes associated with cell activation [8]. The opening of chloride channels is followed by opening of calcium channels and degranulation. Chromones affect only the chloride channels [9].
Other putative mechanisms have been proposed, including inhibition of the synthesis of immunoglobulin E (IgE) antibody by B lymphocytes and a gradual reduction in airway hyperreactivity [10,11]. Cromolyn may also prevent lung damage by acting as an oxygen-free radical scavenger [12].
Pharmacologically, cromolyn is a chromone, whereas nedocromil belongs to the structural class of pyranoquinolines. Both agents contain a chromone ring configuration (one ring in nedocromil, two in cromolyn) and they share many clinical characteristics. Both medications are potent G protein-coupled receptor 35 (GPR 35) agonists. GPR 35 is upregulated upon challenge with IgE antibody and is expressed in mast cells, basophils, and eosinophils [13].
ROLE IN ASTHMA THERAPY — The chromones have clinical utility in two distinct clinical situations: prophylactic use before exposure to a known asthma trigger and chronic use as a controller therapy.
Prevention of acute bronchoconstriction — A single treatment (one nebulized 20 mg dose of cromolyn or two or more puffs of either cromolyn or nedocromil from a metered-dose inhaler [MDI]) administered 10 to 15 minutes before an anticipated trigger exposure (ie, pollen or animals in patient allergic to these things or exercise) is usually sufficient to provide protection. For protection against stronger challenges or in more sensitive patients, inhaled beta-agonists may be administered immediately prior to the chromone because the combination is additive in benefit [14]. We know of no studies that compared the chromones with albuterol directly for the prevention of bronchoconstriction. (See "Exercise-induced bronchoconstriction".)
Cromolyn was originally introduced in Europe and later in the United States primarily for the prevention of allergic asthma (the trade name Intal was a contraction of "interferes with allergy"). The early emphasis on an allergic diathesis and the restriction of its use to the most severe asthmatics led to initial clinical confusion and disappointment. Subsequent analyses directed clinical usage toward those with milder asthma and nonallergic as well as allergic precipitants for their disease [11,15]. The chromones can be used to prevent bronchoconstriction, although they do not have bronchodilating properties for relief of acute symptoms, unlike the short-acting beta-agonists. It is therefore important to ensure that patients understand that beta-agonists should be used instead for rapid relief of symptoms.
Efficacy as long-term maintenance therapy — The chromones may also be used as antiinflammatory controller agents. The clinical efficacy of cromolyn and nedocromil is similar. Inhaled glucocorticoids are the preferred initial antiinflammatory therapy for patients of all ages with mild persistent asthma, as mentioned previously. However, the chromones are considered alternative first-line agents [1,2,11,16,17]. (See "Treatment of intermittent and mild persistent asthma in adolescents and adults".)
A 2006 systematic review examined trials comparing nedocromil with placebo in the management of chronic asthma in children [18]. Fifteen trials including 1422 children were included, most of whom had mild- or moderate-persistent asthma. The primary outcome was an improvement in symptom-free days. Short-term studies (one to three months) showed some improvements in lung function with nedocromil. Two longer-term studies (one of six months duration and another of four to six years duration) found variable improvement in symptom-free days and some improvement in lung function parameters. Overall, these findings suggested mild efficacy.
Compared with inhaled glucocorticoids — Several studies concluded that the chromones were less effective than inhaled glucocorticoids [16,19,20].
●A retrospective study compared risk of hospitalization for asthma with use of asthma medications in an analysis of 16,941 eligible adults and children in a managed healthcare setting [16]. The relative risk (RR) of hospitalization among those who received cromolyn was most reduced among children (RR = 0.8; 95% CI 0.7-0.9), although the reduction in risk was greater for those given inhaled glucocorticoids (RR = 0.5; 95% CI 0.4-0.6) after adjustment for beta-agonist dispensing.
●A trial of 1041 children with mild-to-moderate asthma, aged 5 to 12 years, randomized subjects to inhaled nedocromil (8 mg twice daily), inhaled budesonide (200 mcg twice daily), or placebo, and followed the children for four to six years [19]. Both active treatments reduced the number of urgent care visits and the frequency of prednisone use, although the effect was greater with budesonide (12 versus 16 visits per 100 person-years). Budesonide resulted in improved airway hyperresponsiveness and a smaller decrement in lung function, effects which were not seen with nedocromil.
●A 2006 meta-analysis of 25 randomized, controlled trials (1600 adults and children) compared cromolyn and inhaled glucocorticoids [20]. Inhaled glucocorticoids were more effective at improving lung function and asthma control.
Compared with other controller agents — One 12-week, open-label study randomized 333 children aged 6 to 11 with mild-to-moderate asthma to either one month of montelukast (5 mg daily) or one month of cromolyn (two puffs four times daily), with crossing over to the other treatment [21]. Daily albuterol use was reduced by 38 percent and 23 percent by montelukast and cromolyn, respectively. Parents and patients both preferred and were more compliant with montelukast. However, the brief duration of therapy in this study may have prevented patients from benefiting maximally from the cromolyn, as the chromones require one to three months to reach full efficacy. Further direct comparative trials are needed.
CLINICAL USE — An initial trial of a cromolyn or nedocromil should be one to three months in duration in order to attain full efficacy. Because chromones act solely to prevent bronchospasm and do not have acute bronchodilating capacity, some clinicians initiate therapy concomitantly with a short course of oral glucocorticoids to maximize lung function before relying on the chromone alone. This is particularly helpful for patients with excessive bronchial constriction, who may have initial difficulty inhaling medications. All patients should also have access to a short-acting beta2-agonist, such as albuterol, for relief of acute symptoms.
Choice of drug — Clinical experience has favored the use of cromolyn in younger children and nedocromil in adolescents and adults. Nedocromil generally has displayed greater potency in protecting patients against nonimmunologic stimuli and is a broader spectrum antiinflammatory agent than cromolyn [22]. However, nedocromil is no longer available in the United States.
Circumstances that might favor the choice of cromolyn (over nedocromil) include:
●Mild asthma with allergic triggers. Cromolyn is better studied in this setting [23].
●When a nebulized chromone formulation is preferred, as in asthmatics younger than five years of age. Only cromolyn is available in a solution for nebulization.
●In asthmatics who object to the taste of nedocromil (approximately one in eight patients).
Circumstances that favor the choice of nedocromil (over cromolyn) include:
●Less adherent patients in whom the initial twice daily dose of nedocromil provides a decided advantage.
●Patients already receiving an inhaled glucocorticoid, because nedocromil appears to have a more potent steroid-sparing effect than cromolyn [24-26].
Initial dosing — The maximal dose is usually used initially. A minimum of four to six weeks should be allowed to determine if there is a clinical response, and some clinicians allow up to three months. After this, the dose can be reduced to the lowest effective dose. Standard doses are listed in the table (table 1).
Cromolyn — The shift in the recommended use of chromones from severe to mild asthma has been paralleled by a reduction in dose in available formulations. Cromolyn in a metered-dose inhaler (MDI) provides a dose of 800 mcg per actuation, whereas the original formulation (a dry-powder inhaler) delivered 20 mg per dose. The change in formulation may alter the generalizability of the earlier studies to present-day products, as the lower MDI dose may not deliver the same level of clinical efficacy in severe asthma as was demonstrated with the original 20 mg formulation [17]. The 20 mg dose is only available in a solution for nebulization. (See 'Limitations on availability' above.)
Cromolyn was administered by MDI at a dose of two to four inhalations, three to four times daily initially. Cromolyn has been safely administered by inhalation in doses up to 80 mg per day (via nebulization).
Nedocromil — Hydrofluoroalkane (HFA)-based nedocromil inhalers should deliver approximately 2 mg per actuation. The usual dose is two to four puffs twice daily. Up to four puffs four times daily may be used in adults [27]. Nedocromil HFA is not available in the United States, as mentioned previously. (See 'Limitations on availability' above.)
Adverse effects — Both cromolyn and nedocromil have remarkably favorable therapeutic indices and appear to have minimal systemic absorption after inhalation. Mild local throat irritation and cough may occur. There is no known toxicity from chromone overdose and there are no known adverse drug interactions.
Idiosyncratic systemic reactions, such as myositis, anaphylactoid reactions, eosinophilic pneumonia, and acute bronchospasm have been reported, but such events appear to be extremely rare.
The favorable side effect profile of the chromones is a major factor in their selection versus inhaled glucocorticoids, theophylline, and long-acting beta-agonists. However, antileukotriene agents are also generally well-tolerated and can be administered orally. (See "Major side effects of inhaled glucocorticoids" and "Theophylline use in asthma" and "Antileukotriene agents in the management of asthma".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Asthma in adolescents and adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Trigger avoidance in asthma (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)" and "Patient education: How to use a peak flow meter (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Inhaled cromolyn and nedocromil act by preventing both early and late asthmatic responses to inhaled allergens and irritants, such as exercise and cold air. (See 'Introduction' above and 'Pharmacology' above.)
●These agents can be administered prophylactically 10 to 15 minutes before exposure to a known asthma trigger. They do not have acute bronchodilatory properties, unlike short-acting beta-agonists. (See 'Role in asthma therapy' above.)
●The chromones can also be administered regularly as antiinflammatory controller therapy in mild persistent asthma. National and international guidelines, however, recommend inhaled glucocorticoids rather than chromones as the preferred initial controller therapy in patients of all ages (Grade 1A). (See 'Efficacy as long-term maintenance therapy' above.)
●The chromones, although less effective than inhaled glucocorticoids, are virtually devoid of systemic side effects. They may be desirable alternative or additive controller agents in young children or patients who do not tolerate or do not wish to take inhaled glucocorticoids. (See 'Compared with inhaled glucocorticoids' above.)
●The efficacy of the chromones has not been compared with that of the antileukotriene agents or theophylline. (See 'Compared with other controller agents' above.)
●An initial trial of cromolyn or nedocromil for control of asthma should be one to three months in duration. The maximal dose is given initially and then tapered to the lowest effective dose. Significant adverse reactions are rare with both medications. (See 'Clinical use' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James P Kemp, MD, who contributed to an earlier version of this topic review.
