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CMAJ • November 30, 1999; 161 (90111)
© 1999 Canadian Medical Association or its licensors

Adjuvant therapy

Nonsteroidal inhaled anti-inflammatory agents (anti-allergic agents)

Disodium cromoglycate

There is excellent evidence that disodium cromoglycate (DSCG) therapy can reduce symptoms,1,2 disability3 and costly emergency room visits and admissions to hospital for asthma.4 The associated improvement in pulmonary function is relatively small or nil1-3,5-7 DSCG can prevent allergen-induced seasonal increases in airway responsiveness8 and, under some circumstances, may correct perennial airway hyperresponsiveness.7 However, it can neither augment nor sustain the improvement in airway responsiveness already achieved by inhaled glucocorticosteroids.5

DSCG approximates theophylline in terms of efficacy without its potential for toxicity.3,7,9 DSCG (40 mg/d) may approximate beclomethasone (400 µg/d) in efficacy10; 60 mg/d of DSCG administered by nebulization has been shown to be equivalent to 600 µg/d of inhaled triamcinolone acetonide.11 However, 80 mg/d of DSCG was inferior to 100 µg/d of fluticasone propionate over 1 year in asthmatic children aged 4-10 years.12 In patients who are less than optimally responsive to low-dose inhaled glucocorticosteroids, adding DSCG achieves no gain in symptom control.6,13-15 Also, DSCG does not facilitate the downward titration of the dose of beclomethasone in patients with persisting suppression of the hypothalamic-pituitary-adrenal axis resulting from high-dose inhaled glucocorticosteroid.15 DSCG has not demonstrated a clinically useful degree of prednisone-sparing activity.16 The addition of DSCG is less effective than the addition of salmeterol in adults with mild-to-moderate asthma regardless of whether inhaled glucocorticosteroids are taken.17

In Canada, the DSCG pressurized metered-dose inhaler contains 1 mg/puff and a minimum effective dose for DSCG is considered to be 10 mg 3-4 times daily.18,19 Thus, only the nebulizer solution (20 mg/mL) for infants or the dry powder inhaler (20 mg/capsule) for older children or adults is likely to be effective.

Nedocromil sodium

There is excellent evidence that nedocromil can reduce asthma symptoms20-24 and improve pulmonary function,20,21,23 particularly when compared with ß2-agonist use alone.24 However, airway hyperresponsiveness is not consistently lessened,25,26 and the incidence of periodic exacerbations of asthma may remain unchanged.22,27,28 Nedocromil is not a potent anti-inflammatory agent, and its regular use has little or no effect on markers of airway inflammation in people with asthma.29 In patients with mild to moderate asthma, nedocromil may facilitate reduction in theophylline use by two-thirds21 and, at a dose of 16 mg/d, may be as effective as theophylline as an add-on agent.30 Comparisons with DSCG show more, less or equivalent efficacy.31,32 Nedocromil may be substituted for 300-400 µg/d of beclomethasone23,31,33 and as much as 600 µg/d in a few patients.34 This effect is not consistently demonstrable.25,35 Nedocromil at 16 mg/d may be effective as an add-on drug in patients with a less than optimum response to low-dose beclomethasone.20,36-38 It is not effective as a substitute34,39 or add-on drug34 in patients whose asthma control is less than optimum on high-dose beclomethasone. Nedocromil's capacity to facilitate weaning a patient off prednisone is marginal at best, possibly allowing a reduction of up to 5 mg/d.28,40 During the viral season, regular treatment with nedocromil sodium in children can significantly reduce asthma symptoms associated with respiratory infections.41

Ketotifen

Ketotifen is an orally active prophylactic agent for the management of asthma and allergic disorders.42 In patients with mild asthma, compared with placebo, ketotifen can improve asthma symptoms and reduce the need for concomitant asthma drugs in 50%-70% of patients, but these effects may require 6-12 weeks of administration and the improvement in FEV1 or PEF is slight.42-44 Ketotifen appears to be less effective than DSCG in children with asthma.45 In asthmatic children requiring moderate doses of inhaled glucocorticosteroids, the addition of ketotifen did not result in any significant glucocorticosteroid-sparing effect compared with placebo.46

Theophylline and its derivatives

Theophylline has been used in the treatment of asthma for more than 50 years and, for a long time, was considered to be a first-line drug in the treatment of asthma. However, its popularity has declined in many industrialized countries, probably because theophylline has not been considered to be an anti-inflammatory agent and because it is not as good a bronchodilator as ß2-agonists. In recent years, theophylline has been relegated to third-line therapy, after ß2-agonists and, especially, inhaled glucocorticosteroids, which are now being used very early in the treatment of the condition.47,48 Nevertheless, evidence is growing to indicate that theophylline has anti-asthmatic properties other than its bronchodilator action, including anti-inflammatory and immunoregulatory properties.49-53 Therefore, further trials will be needed to clarify the role of theophylline in the treatment of asthma.49,54 In this section, we review the place of theophylline in maintenance therapy for asthma, in light of new evidence and the most recent international recommendations.48,55

Theophylline is a modest bronchodilator, but its narrow therapeutic window and high incidence of side-effects limit its use. It has the advantage of being administered orally, which may enhance compliance; also, new long-acting (12-hour) and very long-acting (24-hour) formulations result in very good serum stability. The bronchodilator effect of theophylline is proportional to the serum concentration, but on a semilogarithmic base56; thus, improvement in FEV1 is greater when serum levels increase from 28 to 55 µmol/L compared with the improvement observed when serum concentrations increase from 83 to 110 µmol/L; however, the risk of untoward side-effects is much higher in the latter case. In addition, theophylline is metabolized almost entirely by the liver and, therefore, its clearance is subject to several drug interactions (e.g., ciprofloxacin, erythromycin, cimetidine) and is influenced by various clinical conditions (fever, hepatitis, cirrhosis, cardiac failure).57 Flow charts have been developed to assist in achieving therapeutic concentrations rapidly,56 but required doses vary widely among patients and must be tailored to the individual by monitoring serum concentrations.

The main limitation to the use of theophylline is the frequency of adverse effects. The most common side-effects are headache, nausea and vomiting, abdominal discomfort, restlessness and insomnia. There may also be increased acid secretion, gastroesophageal reflux and diuresis. High serum concentrations may cause agitation, convulsions, tachyarrythmias, coma and death.57

Side-effects may be significantly reduced without compromising clinical benefit by aiming for serum concentrations of 28-55 µmol/L, rather than the previously recommended 55-110 µmol/L.49 Some studies have suggested that theophylline could cause behavioural changes and learning difficulties in children,58 but these findings have not been confirmed elsewhere.59,60 Concomitant use of theophylline and the new leukotriene antagonists may lower the serum concentration of certain of the leukotriene antagonists, but not the theophylline concentration.

In chronic trials in children, theophylline was at least as effective as sodium cromoglycate, although it causes more side-effects.7 Whereas Nassif and co-workers61 showed some additive advantage of theophylline in glucocorticosteroid-dependent children, Tinkelman and colleagues62 demonstrated that theophylline resulted in symptom control comparable to low-dose beclomethasone, but led to more bronchodilator use and more courses of systemic glucocorticosteroids. Side-effects were also observed significantly more frequently with theophylline. Thus, theophylline is not a first-line treatment.

For adults, theophylline appears to be inferior to inhaled glucocorticosteroids for primary therapy of asthma.63,64 However, the addition of theophylline can improve symptom control in patients already taking high-dose inhaled glucocorticosteroids (e.g., 1000 µg/d or more of beclomethasone or its equivalent).65 For some patients with moderate asthma who are still symptomatic despite inhaled glucocorticosteroid therapy, the combination of moderate-dose inhaled glucocorticosteroid (e.g., budesonide, 400 µg twice daily) and theophylline at serum concentrations below the currently recommended therapeutic range may produce benefits similar to those with high-dose inhaled glucocorticosteroids (e.g., budesonide, 800 µg twice daily) alone.66

There may be a subgroup of asthmatic patients who particularly benefit from therapy with theophylline - those in whom effective asthmatic control is lost when theophylline is withdrawn and will not respond to increasing doses of glucocorticosteroids.51,67 Theophylline is especially useful for control of asthma with nocturnal symptoms,68-73 but, for those who are not taking inhaled glucocorticosteroids, nocturnal symptoms may be better controlled by the addition of an inhaled glucocorticosteroid than by the addition of theophylline twice daily without inhaled glucocorticosteroids.74 However, long-acting ß2-agonists may afford better control of asthma with nocturnal symptoms75-78 and also provide better continuous symptom control and reduce the need for rescue with short-acting ß2-agonists.75-79

Original trials of theophylline were based on measurement of acute bronchodilation and suggested that therapeutic concentrations ranged from 55 to 110 µmol/L (10 to 20 µg/mL), which placed patients at higher risk of side-effects because of the various clinical conditions that can affect theophylline metabolism. More recent trials examining the nonbronchodilator actions of theophylline suggest that doses producing lower serum concentrations have significant cellular and immunomodulatory effects.49 The beneficial effects of theophylline on the cellular events associated with nocturnal asthma52 and the clinical benefits seen at low serum concentrations of theophylline66 may reflect these immunomodulating properties of theophylline.49,53

Theophylline is a nonspecific phosphodiesterase (PDE) inhibitor. However expanding knowledge of PDE isozymes indicates that PDE III is predominant in airway smooth-muscle relaxation whereas PDE IV appears to be important in inflammatory cells such as mast cells, eosinophils and T-lymphocytes.80 Future clinical trials with more specific PDE antagonists will be important in redefining the role of these agents in asthma therapy.

Anticholinergic drugs

The most commonly used anticholinergic bronchodilators are quaternary derivatives. Their potency has been examined in stable ambulatory patients using MDIs.81-83 Typically, ipratropium bromide or similar compounds cause bronchodilation more gradually than ß2-agonists, such as salbutamol, fenoterol or terbutaline. For example, ipratropium produces 50% of its bronchodilation in 3 minutes and 80% in 30 minutes, with maximal or peak effect evident only 1-2 hours after administration.81,84 Compared with anticholinergics, the adrenergic compounds (ß2-agonists) cause greater bronchodilation in the first 2-3 hours following administration. Thus, quaternary anticholinergic agents are not first-line bronchodilator therapy for most patients with asthma.

The combination of anticholinergic and adrenergic therapy appears to produce greater bronchodilation than either agent used alone. In addition, an additive effect with theophylline has been documented.83,85-88 The clinical relevance of these studies is uncertain now that the use of anti-inflammatory therapy is more widespread, but in acute asthma in both adults and children, there appears to be a clear role for combination therapy with ipratropium and ß2-agonists.89,90

The response of asthmatic patients to anticholinergic agents appears to be unrelated to their atopic status. However, Ullah and colleagues87 have suggested that these agents are more useful in older patients.87 Adrenergic receptor sensitivity declines with age, whereas the sensitivity of the cholinergic system appears to remain intact. This may make anticholinergics relatively more useful for older patients with asthma.

Recommendations

Disodium cromoglycate

• Disodium cromoglycate should not be added to an established regimen of inhaled or systemic glucocorticosteroids (level I).

• Disodium cromoglycate may be used as a less-effective alternative to short-acting ß2-agonist bronchodilators for the prevention of exertion-induced symptoms (level I).

• In children with mild symptoms, disodium cromoglycate may be an alternative to low-dose inhaled glucocorticosteroids when the patient is unwilling to take inhaled glucocorticosteroids (level I).

Nedocromil

• Nedocromil is a safe but modestly effective alternative to low-dose inhaled glucocorticosteroid in children older than 12 years and in adults with mild asthma where the fear of side-effects precludes the use of glucocorticosteroids (level I).

• Nedocromil may be considered as a less-effective alternative to short-acting ß2-agonist bronchodilators for the prevention of exertion-induced bronchospasm (level I).

Ketotifen

• Ketotifen is not recommended in first-line therapy for asthma (level II).

Recommendations

• Theophylline should not be used as first-line therapy in children or adults with asthma (level I).

• In patients whose symptoms do not respond to moderate-dose inhaled glucocorticosteroids alone, the addition of theophylline may result in asthma control that is equivalent to increasing to high-dose inhaled glucocorticosteroids alone (level II).

• Theophylline may be useful in some children requiring high-dose inhaled glucocorticosteroids (level III).

• Because theophylline has a narrow therapeutic range and potential for severe side-effects, the dose must be titrated to minimize side-effects in patients starting the drug, especially if high doses are required (level III).

Recommendations

• Anticholinergic bronchodilators are not recommended as first-line agents. They may be used as relievers for patients who are unable to tolerate ß2-adrenergic bronchodilators (level III).

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