Mid afternoon inhaler use may improve nighttime asthma control

A single daily preventer dose of inhaled corticosteroid (beclomethasone), taken mid afternoon, may be the best timing for effective asthma control as it suppresses the usual nocturnal worsening of symptoms more effectively than dosing regimens at other times of the day, suggest the results of a small clinical trial published in the journal Thorax.

If the findings are confirmed in larger studies, this approach may lead to better clinical outcomes for patients without increasing unwanted steroidal side effects or medical costs, suggest the researchers.

Aligning the timing of drug treatment with the body clock, known as chronotherapy, can enhance the therapeutic effects of medicines, say the researchers. 

This may be particularly important in asthma, which has a distinct daily rhythm, with the cardinal effects of airflow obstruction and airway inflammation peaking overnight, when 80% of fatal asthma attacks occur, they explain.

Drawing on their previously published research, showing enhanced immune cell responsiveness to steroids mid afternoon, the researchers wanted to find out if a single dose of preventer inhaler at this time would better suppress the usual nocturnal worsening of asthma symptoms than either morning or standard twice-daily dosing, and without increasing the risk of steroidal side effects.

Twenty five people (aged 18-65) with confirmed mild to moderate asthma lasting at least a year, and common respiratory allergies to cat hair, dust mites, or grass pollen, were randomly assigned to one of three dosing regimens for 28 days each.

These comprised a single daily dose of 400 µg beclomethasone between 0800 and 0900 hours; the same once daily dose between 1500 and 1600 hours; and a twice daily dose of 200 µg beclomethasone between 0800 and 0900 hours and between 20.00 and 21.00 hours. 

At the end of each 28 day period, participants swapped their dosing regimen after a 14 to 21 day gap until all three trial arms had been completed. 

Spirometry readings and blood biomarkers (inflammatory cells, levels of cortisol and salbutamol from reliever inhalers) were measured every 6 hours for 24 hours at the start and end of each of the 28 day periods.

Twenty one people (84%), all of whom had similar sleep-wake cycles, completed all three of the trial arms.

Compared with baseline measurements, all the treatment arms improved night time lung function. But the timing of the improvement differed according to the dosing regimen. The largest Improvement, measured at 22:00 hours, was associated with the once daily mid afternoon dose (100 ml more than the morning dose).

Similarly, all the dosing regimens suppressed airway inflammation compared with baseline levels. And this was significantly lower at 22.00 and 0400 hours with the once daily mid afternoon dose than it was with the twice daily dose. 

There was no difference in cortisol levels between the three dosing regimens, compared with baseline levels, suggesting that there was no additional impairment in the body's ability to produce the hormone-a potential side effect of inhaled steroid treatment. 

The researchers acknowledge the small number of participants involved and the short length of their study, but suggest that the findings might form the basis of further larger trials.

"Our findings further support the hypothesis that the optimal timing of [inhaled corticosteroid] administration is at 16:00, coincident with enhanced glucocorticoid sensitivity at that time," they say. 

"The notion that the onset of the inflammatory cascade begins mid-afternoon may also explain the findings we observed, and the attenuation of the predictable rhythmic recruitment of airway inflammatory cells at this time point may abolish the subsequent excessive nocturnal dip in lung function in asthma," they suggest.

In a linked editorial, Drs Richard Russell and Nicola Smallcombe of, respectively, the King's Centre for Lung Health, King's College London,and the Royal Free London NHS Foundation Trust, point out that the mid afternoon dosing regimen did not result in better symptom control.

But they explain: "This lack of translation to patient outcomes may be attributed to the short duration of the follow-up period, the small numbers, and the relatively low symptom burden of participants at baseline, so there was no headroom for improvement."

Because participants had mild to moderate asthma, and long acting beta agonist inhalers-recommended in the latest treatment guidelines-weren't included, the results might not be applicable more widely, they suggest.

"Additionally, when one considers the translation of these findings into clinical practice, with adherence to asthma therapies being the greatest challenge – around 30–40% of the general population struggles with inhaler compliance – introducing a specific time for inhaler use could potentially complicate matters further," they surmise.

But they conclude: "This study offers promising insights into the potential benefits of using chronotherapy with inhaled corticosteroids for asthma patients. We believe that this is most likely to benefit those with more severe asthma, where marginal gains in lung function and a reduced eosinophil count are more likely to translate into better control and risk reduction."