Demonstration by placebo response in asthma by means of exercise testing☆

It has been suggested that some placebo interventions might be associated with larger clinical effects than others. In a systematic review, we investigated whether there is evidence from direct comparisons in randomized clinical trials including two or more placebo groups supporting this hypothesis.

Eligible trials were identified through electronic database searches and citation tracking up to February 2013. Placebo interventions in a trial were categorized into a more intense and a less intense intervention based on complexity, invasiveness, or route of administration and time needed for application.

Twelve studies with 1,059 patients receiving placebo met the eligibility criteria. Studies were highly heterogeneous regarding patients, interventions, outcomes, and risk of bias. Seven studies did not find any significant differences between the more intense and the less intense placebo intervention, four studies found differences for single outcomes, and one study consistently reported significantly larger effects of the more intense placebo. An explorative meta-analysis yielded a standardized mean difference −0.22 (95% confidence interval: −0.46, 0.02; P = 0.07; I² = 68%).

In the studies included in this review, more intense placebos were not consistently associated with larger effects than less intense placebos.

Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing.

To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist.

In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (≥20% postexercise decrease in forced expiratory volume in 1 second [FEV₁]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV₁ from preexercise baseline during 60 minutes after the 2-hour challenge.

At 2, 12, and 24 hours after dosing, the maximum decrease in FEV₁ was 10.8% ± 7.9%, 8.4% ± 7.5%, and 8.3% ± 7.3% for montelukast and 22.3% ± 13.1%, 16.1% ± 10.2%, and 16.9% ± 11.7% for placebo, respectively (P ≤ .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo (P ≤ .001); mean (95% confidence interval) differences were −26.8 minutes (−35.1 to −18.4 minutes), −16.0 minutes (−22.9 to −9.2 minutes), and −17.4 minutes (−24.9 to −9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV₁ during 60 minutes after exercise was smaller after montelukast (P ≤ .001); montelukast protected more patients against EIB (P ≤ .001). Fewer patients required postexercise β-agonist rescue at 2 hours after dosing with montelukast (P = .03).

Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.

We aimed to compare the protective effect of single doses of 4·5 and 9 μ g of formoterol fumarate (F), 0·5 mg terbutaline sulphate (T) and placebo (P), all via Turbuhaler^®, against exercise-induced bronchoconstriction (EIB) in children.

Twenty-seven asthmatic children, showing a fall of ≥20% in FEV₁after a standardized exercise challenge test (ECT) combined with cold air (−10°C) inhalation, were randomized in this cross-over, double-blind study. They had a mean age of 12·6 years (range 8–17 years), mean baseline FEV₁90% (73·9–105·6%) of predicted normal value. Seventeen children used inhaled glucocorticosteroids (120–750 μ g day⁻¹). ECTs were performed 15 min and 4, 8, and 12 h after drug administration.

F significantly reduced the fall in FEV₁after ECT to 5·4% (15 min), 5·2% (4 h), 8·2% (8 h) and 9·3% (12 h) after 4·5 μ g, and 2·5%, 3·0%, 5·0% and 5·4% after 9 μ g, compared with a fall of 18·4%, 15·7%, 15·6% and 16·5% in FEV₁after P. The fall after T was 3·3%, 11·6%, 14·4% and 19·1% after 15 min, 4, 8 and 12 h respectively. The difference between F and T was statistically significant from 4 h and onward (P -value for all comparisons <0·05).

Children using a single dose of either formoterol Turbuhaler 4·5 or 9 μ g had significantly better bronchoprotection against repeated exercise challenge up to 12 h compared with placebo and from 4 h onward compared with terbutaline Turbuhaler^®0·5 mg.

Objective: To determine the effects of zafirlukast on exercise-induced bronchoconstriction in children. Study design: Exercise challenges were done 4 hours after single oral doses of zafirlukast or placebo were administered in asthmatic children (6 to 14 years) treated with β₂ -agonists alone. Subjects randomized to treatment had a ≥20% decrease in forced expiratory volume in 1 second (FEV₁ ) after a screening challenge. In a randomized, double-blind, 3-way, crossover design, group 1 (n = 20) received placebo and 5 and 20 mg zafirlukast, and group 2 (n = 19) received placebo and 10 and 40 mg zafirlukast. Maximal percentage fall in FEV₁ , area under the curve, and time to recovery of FEV₁ to within 5% of baseline after the challenge were compared with analysis of variance. Results: Mean values for maximal fall in FEV₁ ranged from –8.7% ± 1.7% to –11.1% ± 1.9% after zafirlukast compared with –17.1% ± 1.8% and –16.3% ± 1.9% after placebo. Differences from placebo for fall in FEV₁ and area under the curve were significant (P ≤ .05) after 5, 20, and 40 mg zafirlukast and approached significance (P ≤ .08) after 10 mg zafirlukast. After all zafirlukast doses, recovery times (means of 5 to 7 minutes) decreased significantly (P ≤ .05) and by approximately half compared with placebo (11 and 14 minutes). Safety assessments did not differ among treatments. Conclusion: Four hours after dosing, zafirlukast attenuated exercise-induced bronchoconstriction in children. (J Pediatr 1999;134:273-9)

Objective: To determine whether montelukast, a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction (EIB) in 6- to 14-year-old children with asthma.

Study design: Double-blind, multicenter, 2-period crossover study. Children (n = 27) with forced expiratory volume in 1 second (FEV₁ ) ≥70% of the predicted value and a fall in FEV₁ ≥ 20% after exercise on 2 occasions. Patients received montelukast (5-mg chewable tablet) or placebo once daily in the evening for 2 days in crossover fashion (at least 4 days between treatment periods). Standardized exercise challenges were performed 20 to 24 hours after the last dose in each period. End points included area above the postexercise percent fall in FEV₁ versus time curve (AAC_0-60min ), maximum percent fall in FEV₁ from pre-exercise baseline, and time to recovery of FEV₁ to within 5% of pre-exercise baseline.

Results: Montelukast significantly reduced AAC_0-60min (265 vs 590 % · min for montelukast and placebo, respectively, P ≤ .05; ~59% protection relative to placebo) and the maximum percent fall (18% vs 26% for montelukast and placebo, respectively, P ≤ .05). Montelukast treatment resulted in a shorter time to recovery (18 vs 28 minutes for montelukast and placebo, respectively, P = .079).

Conclusions: Montelukast attenuates EIB at the end of the dosing interval in 6- to 14-year-old children with asthma. (J Pediatr 1998;133:424-8)

In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma.

In a double-blind, crossover pilot study, we randomly assigned 46 patients with asthma to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention. Using a block design, we administered one each of these four interventions in random order during four sequential visits (3 to 7 days apart); this procedure was repeated in two more blocks of visits (for a total of 12 visits by each patient). At each visit, spirometry was performed repeatedly over a period of 2 hours. Maximum forced expiratory volume in 1 second (FEV₁) was measured, and patients' self-reported improvement ratings were recorded.

Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV₁, as compared with approximately 7% with each of the other three interventions (P<0.001). However, patients' reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P<0.001).

Although albuterol, but not the two placebo interventions, improved FEV₁ in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma. However, from a clinical-management and research-design perspective, patient self-reports can be unreliable. An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. (Funded by the National Center for Complementary and Alternative Medicine; ClinicalTrials.gov number, NCT01143688.)

In patients with asthma, an active bronchodilator improved lung function; two inactive treatments and no intervention had no effect. The same patients reported subjective improvements after both inactive and active interventions but not after no intervention at all.

Placebo effects (i.e., benefits resulting from simulated treatment or the experience of receiving care) are reported to improve signs and symptoms of many diseases in clinical trials and in clinical practice.¹ On this basis, the accepted standards for clinical-trial design specify that the effects of active treatment should ideally be compared with the effects of placebo.2, 3 Despite this common practice, it is unclear whether placebo effects observed in clinical trials (or those that presumably occur in clinical care) influence both objective and subjective outcomes and whether placebo effects differ from the natural course of disease or regression to the . . .