The range of drugs considered in the treatment of asthma, their dosages, contraindications, and side effects are described in the BNF sections 3.1 (bronchodilators), 3.2 (corticosteroids), and 3.3 (cromoglycate and related therapy). All recommendations for treatment apply only in the absence of recognised contraindications, side effects, or interactions as documented in the BNF.

Compliance

Recommendation

Compliance with treatment is important and should be checked regularly, especially if symptom control is poor or treatment is about to be increased (D)

Inhaled short acting b₂ agonists

Recommendations

· Inhaled short acting b₂ agonists should be used on an "as required" basis to relieve symptoms (B)

· They should be used before exercise in patients who experience bronchospasm induced by exercise (A)

· As there is no good evidence of clinically important differences between different inhaled short acting b₂ agonists, patients should be treated with the cheapest preparation that they can effectively use (D)

Statements

· Inhaled short acting b₂ agonists are effective as judged by an increase in peak expiratory flow rate (PEFR) (I)

· There is no clear evidence on the issue of as required versus regular dosage of inhaled short acting b₂ agonists (I)

· From a single small study there seems to be no difference between generic and branded salbutamol (I)

· Salbutamol is effective in the treatment of exercise induced bronchospasm and is more effective than sodium cromoglycate (I)

Research question

What is the relative place of regular and as required dosing with inhaled short acting b ₂ agonists?

Evidence for statements

Statement: inhaled short acting b₂ agonists are effective as judged by an increase in PEFR (I)—The major trials in this area date from before our initial search (1984). We identified one paper that showed that salbutamol is effective.⁽¹²⁾

Statement: there is no clear evidence on the issue of as required versus regular dosage of inhaled short acting b₂agonists (I)—The three studies in this area (table 6) give contradictory findings; this may be due to patient selection, drug selection, and study design. Two studies were of salbutamol; one of fenoterol. Participants were followed for up to 24 weeks. Two studies included patients taking inhaled corticosteroids; the third excluded such patients. In all three studies, regular dosage of short acting b₂ agonists did not prevent the need for supplemental b₂ agonist. Other outcomes varied across the three studies.
 

Table 6 As required versus regular use, short acting b₂ agonist
 

Statement: from a single small study there seems to be no difference between generic and branded salbutamol (I)—Details are given in table 7.
 

Table 7 Generic versus branded short acting b₂ agonist and sodium cromoglycate
 

Statement: salbutamol is effective in the treatment of exercise induced bronchospasm and is more effective than sodium cromoglycate (I)—One small crossover trial (table 7) compared open branded salbutamol with blinded generic salbutamol and blinded branded salbutamol and found no difference between the three preparations.

Inhaled long acting b₂ agonists

We identified no studies directly examining whether inhaled long acting b₂ agonists should be used before or after inhaled anti-inflammatory drugs. Currently they are used after the introduction of inhaled corticosteroids. Salmeterol and formoterol have been grouped together, but there are differences between the two drugs, mainly the differing speed of onset of action.

Recommendations

· In most patients treated with inhaled long acting b₂ agonists asthma will be satisfactorily controlled with salmeterol 50 mg twice daily or formoterol 12 mg twice daily. If the drugs are used in higher doses attention must be paid to side effects (A)

· If patients’ symptoms are not controlled on up to 1000 mg beclometasone daily (or equivalent) then regular inhaled long acting b₂ agonists should be added to their treatment (A)

· Treatment with an inhaled short acting b₂ agonist should be continued on an as required basis (B)

· Inhaled long acting b₂ agonists should be considered if overnight relief is required (A)

· Inhaled long acting b₂ agonists should be used in preference to sodium cromoglycate or oral bronchodilators (A)

· As there is no good evidence of clinically important differences between different inhaled long acting b₂ agonists, patients should be treated with the cheapest preparation that they can effectively use (D)

Statements

· In one short term evaluation salmeterol was as safe as an inhaled short acting b₂ agonist (I)

· Inhaled long acting inhaled b₂ agonists produce significant bronchodilatation for 12 hours (I)

· Formoterol produces little additional effect in dosages beyond 12 mg twice daily (I)

· Salmeterol produces little additional effect in dosages beyond 50 mg twice daily but does produce more side effects (I)

· Salmeterol and formoterol have equivalent bronchodilator effect over 12 hours but formoterol seems to have a faster onset of action (I)

· Twice daily inhaled long acting b₂ agonist is more effective than inhaled short acting b₂ agonists used four times daily (as metered dose inhaler or a powder) in studies of populations in which a proportion of patients (usually most) were also on prophylactic treatment (I)

· In studies where all patients were on prophylactic treatment, use of inhaled long acting b₂ agonist improved control; patients could decrease their dose of inhaled corticosteroids and still experience a reduction in exacerbations, and they also showed improvements in terms of PEFR and use of inhaled short acting b₂ agonist (I)

· In one study patients on 1000 mg beclometasone or equivalent benefited from the addition of an inhaled long acting b₂ agonist rather than an increase in the dose of inhaled corticosteroid (I)

· In studies where a proportion of patients (usually most) were on prophylactic treatment the addition of a long acting b₂ agonist produced more improvement across a range of parameters than addition of sodium cromoglycate or oral bronchodilators (I)

Research questions

What is the lowest dose of inhaled corticosteroids at which patients benefit from the addition of long acting b₂ agonists?

Evidence for statements

Statement: in one short term evaluation salmeterol was as safe as an inhaled short acting b₂ agonist (I)—Castle et al studied over 25 000 patients in general practice who were randomised to salmeterol 50 mg twice daily or salbutamol 200 mg four times daily for 16 weeks.⁽¹⁸⁾ The primary outcome was mortality. There were more deaths in the salmeterol group but this did not reach significance. Only 69% of the patients were on inhaled corticosteroids. This study had negative results but no power calculation.

Statement: inhaled long acting b₂ agonists produce significant bronchodilatation for 12 hours (I)—We examined two studies (table 8).^{(19) (20)}
 

Table 8 Long acting b₂ agonists at different doses
 

Statement: formoterol produces little additional effect in dosages beyond 12 m g twice daily (I)—We examined one study (table 8).⁽²¹⁾

Statement: salmeterol produces little additional effect in dosages beyond 50 m g twice daily but does produce more side effects (I)—We examined four studies (table 8).^{(19)(22) (23) (24)}

Statement: salmeterol and formoterol have equivalent bronchodilator effect over 12 hours but formoterol seems to have a faster onset of action (I)—Only one study examined the relative effect of the two available long acting b₂ agonists (table 9).

Table 9 Comparison of different long acting b₂ agonists
 

Statement: twice daily inhaled long acting b₂ agonist is more effective than inhaled short acting b₂ agonists used four times daily (as metered dose inhaler or a powder) in studies of populations where a proportion (usually most) of patients were also on prophylactic treatment (I)—Ten studies supported this statement (table 10). They look at salmeterol and formoterol.
 

Table 10 : Long acting b ₂ agonists versus regular or as required short acting inhaled b₂ agonists: studies in which proportion of patients (usually most) are taking prophylactic treatment
 

Statements: in studies where all patients were on prophylactic treatment, use of inhaled long acting b₂ agonist improved control (I); in one study patients could decrease their dose of inhaled corticosteroids and still experience a reduction in exacerbations and improvements in terms of peak expiratory flow and use of inhaled short acting b₂ agonist (I)—Five studies examined the addition of long acting inhaled b₂ agonists to the treatment of patents on inhaled corticosteroids (table 11).  Three of these examined the effect of long acting b₂ agonists compared with placebo; two examined the effect compared with regular salbutamol. In all studies the long acting b₂ agonist group had better outcomes, though these were not consistent effects across studies.
 

Table 11 Use of long acting b₂ agonist in patients taking prophylactic treatment
 

Author	Date	Study design	Patients and setting	Intervention	Outcomes
Lai et al36	1995	Double blind crossover randomised controlled trial	25 patients with moderate to severe asthma requiring daily dose of inhaled corticosteroid between 800 and 2000 mg and oral corticosteroid of £ 20 mg prednisolone. FEV1³ 30% predicted and showing reversibility ³ 15%	Salmeterol 50 mg twice daily v salbutamol 400 mg four times daily for 2 weeks	Morning peak flow increased from 341 l/min to 363 l/min in salmeterol period and 347 l/min in salbutamol period (statistically significant baseline-salmeterol and salmeterol-salbutamol) Salmeterol period better in terms of day and night time symptom score and rescue b2 agonist use.  No difference in FEV1
Boyd et al37	1995	Double blind parallel group randomised controlled trial	55 salmeterol, 64 placebo adults with severe asthma under consideration for maintenance oral corticosteroids budesonide ³ 1500 mg/day or equivalent, ³ 2 exacerbations in past 18 months	Salmeterol 100mg twice daily plus usual prophylactic treatment v placebo plus usual prophylactic treatment for 12 weeks	No difference evening peak flow, clinic FEV1 daytime symptom scores or proportion symptom free days. Salmeterol group had better outcomes in terms of morning peak flow, night time symptom scores, proportion of symptom free nights and relief medication use.
Faurschou et al38	1996	Double blind parallel group randomised controlled trial	190 adults with moderate to severe asthma using ICS not oral corticosteroids past 4 weeks	Salmeterol 100 mg twice daily Diskhaler v salbutamol 400 mg four times daily Diskhaler for 6 weeks	Salmeterol group better in terms of morning PEF, FEV1, % symptom free nights No significant difference in symptom free days
van der Molen et al39	1997	Parallel group	239 adults symptomatic on regular ICS	Formoterol 24 mg twice daily v placebo for  24 weeks	Change in morning peak flow baseline - end point; +26l/min formoterol group; -2l/min placebo group  Use of rescue b2 agonists and symptom score decreased more in formoterol than placebo group No difference in asthma exacerbations
Wilding et al40	1997	Double blind crossover randomised controlled trial	101 adults with mild or moderate asthma  taking at least 200 mg twice daily beclometasone or budesonide	Salmeterol 50 mg twice daily v placebo, participants adjusted ICS dose according to guidelines for 6 month periods with 1 month washout	Salmeterol use allowed reduction in ICS use without increase in exacerbations or use of oral corticosteroids Salmeterol associated with higher morning and evening PEF and FEV1

 

Statement: in one study patients on 1000 mg of beclometasone or equivalent benefited from the addition of an inhaled long acting b₂ agonist rather than an increase in the dose of inhaled corticosteroid (I)—Although two studies looked at this important clinical area, one of them used an initial run in period, that while answering the specific trial question, makes it difficult to translate into routine practice (table 12).⁽⁴¹⁾ The other study showed benefit from the introduction of salmeterol in addition to beclometasone 500 mg twice daily.⁽⁴²⁾ It is not clear whether patients on lower doses of beclometasone would also benefit.
 

Table 12 Use of long acting b₂ agonist compared with increasing inhaled corticosteroids
 

Statement: in studies in which a proportion of patients (usually most) were on prophylactic treatment the addition of an inhaled long acting b₂ agonist produced more improvement across a range of parameters than addition of sodium cromoglycate, oral terbutaline, or theophylline (I)—Four studies supported this statement (table 13).  In both theophylline studies, despite attempts at dose titration, at the end of the study many patients had suboptimal serum concentrations of theophylline.
 

Table 13  Long acting b₂ agonists versus sodium cromoglycate or oral bronchodilators
 

Inhaled anti-inflammatory agents

Inhaled corticosteroids

We tend to regard inhaled corticosteroids as the first line prophylactic treatment in adults with asthma. While there is evidence to support this strategy, the number of studies supporting such a widely accepted strategy is surprisingly small. We identified no evidence on the use of inhaled corticosteroids as first line treatment.

Recommendations

· Patients requiring more than two to three doses a day of inhaled short acting b₂ agonists should be treated with inhaled corticosteroids (A)

· Inhaled corticosteroids should usually be used on a twice daily (rather than once or four times daily) basis (B)

· If symptoms are not controlled on twice daily dosing and there is concern about the total daily dose, frequency can be increased to four times daily but at the same total daily dose (A)

· If patients’ symptoms are not controlled on up to 1000 mg beclometasone daily (or equivalent) regular inhaled long acting b₂ agonists should be added (A)

· If symptoms are not controlled on standard doses (up to a daily equivalent of beclometasone 1000 mg) plus the addition of regular inhaled long acting b₂ agonists, higher doses of inhaled corticosteroids should be used up to a daily equivalent of 2000 mg beclometasone (D)

· A one to three month period of stability should be shown before slow stepwise reduction of inhaled corticosteroids is undertaken, decreasing the dose of inhaled corticosteroid by about 25-50% at each step (D)

· As there is no good evidence of clinically important differences between differing inhaled corticosteroids patients should be treated with the cheapest inhaled corticosteroid that they can effectively use and which controls their symptoms (D)

Statements

· Inhaled corticosteroids are effective (I)

· Inhaled corticosteroids can allow a reduction of oral corticosteroid dosage in patients dependent on corticosteroids (I)

· There are no clinically important differences between the effectiveness of the various inhaled corticosteroids that cannot be dealt with by adjustment of dosage (I)

· The clinical significance of differences in cortisol suppression between different agents is unclear (III)

· In patients requiring short acting b₂ agonists more than two to three times a day the addition of an inhaled corticosteroid improves peak flow and symptoms and reduces the use of inhaled short acting b₂ agonist (I)

· Inhaled corticosteroids are slightly but significantly more effective when used four times daily than when used twice daily and are more effective when used twice daily than when used once daily, though the differences in lung function are not large (I)

· In one study patients on 1000 mg equivalent of beclometasone benefited from the addition of an inhaled long acting b₂ agonist rather than an increase in the dose of inhaled corticosteroid (I)

· Symptom control is better at high compared with low doses of inhaled corticosteroids (I)

· We identified no direct evidence on when to decrease the dose of inhaled corticosteroids; one study indirectly suggested that some patients on inhaled corticosteroids may be overtreated (III)

Research questions

When and how quickly should the dosage of inhaled corticosteroids be decreased?

Is it effective to increase the dose of inhaled corticosteroids during intercurrent illnesses?

How safe are inhaled corticosteroids and what is the significance of changes in serum cortisols?

Is there a role for using inhaled corticosteroids as first line treatment?

Evidence for statements

Statement: inhaled corticosteroids are effective (I)—Seven studies showed that the addition of inhaled corticosteroids to the treatment of the study patients was beneficial (table 14). These studies that examined the effect of giving different groups different doses failed to show any consistent benefit related to dose between groups.
 

Table 14 Studies comparing inhaled corticosteroids with placebo
 

Statement: inhaled corticosteroids can allow a reduction of oral corticosteroid dosage in patients dependent on corticosteroids (I)—We identified six studies (table 15).
 

Table 15 Inhaled corticosteroids in patients dependent on oral corticosteroids
 

Statement: there are no clinically important differences between the effectiveness of the various inhaled corticosteroids that cannot be dealt with by adjustment of dosage (I)

Statement: the clinical significance of differences in cortisol suppression between different agents is unclear (III)—We identified 11 studies (table 16).
 

Table 16 Comparisons of different inhaled corticosteroids
 

Statement: in patients requiring inhaled short acting b₂ agonists more than two to three times a day the addition of an inhaled corticosteroid improves peak flow and symptoms and reduces use of short acting b₂ agonist (I)—While there may be benefit from introducing inhaled corticosteroids at a lower level of use of b₂ agonists, as suggested by the British Thoracic Society guidelines, we did not identify any evidence for or against this (table 17).
 

Table 17 Addition of inhaled corticosteroids to short acting b₂ agonists
 

Statement: inhaled corticosteroids are slightly but significantly more effective when used four times daily than when used twice daily and are more effective when used twice daily than when used once daily, though the differences in lung function are not large (I)—Five studies looked at the effectiveness of differing dosage frequencies for inhaled corticosteroids (table 18). They were all small studies and three of them had negative results but did not have a prior power calculation and are therefore at risk of type II errors. We recognise the importance of compliance with treatment (though this was not formally studied) and thought that under most circumstances twice daily dosing is appropriate.
 

Table 18 Inhaled corticosteroids—dosing frequency
 

Statement: in one study patients on 1000 mg equivalent of beclometasone benefited from the addition of a long actingb₂ agonist rather than an increase in the dose of inhaled corticosteroid (I)—We found one study.

Table 19 Increasing inhaled corticosteroids compared with addition of long acting b₂ agonist
 

Statement: symptom control is better at high compared with low doses of inhaled corticosteroids (I)—Only a surprisingly small number of studies were identified that reliably support this widely held clinical view (table 20). All of the studies examining different doses of inhaled corticosteroids look at the effect of giving different doses to different groups. As there are not large differences between groups the implications for clinical practice are not clear. No studies examined the effect of increasing the dose of inhaled corticosteroid "within patient." Therefore, this common clinical strategy is surprisingly unsupported by evidence.

Table 20 High versus low doses of inhaled corticosteroids