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A comparison of the speeds of action of salmeterol and salbutamol in reversing methacholine-induced bronchoconstriction
Pulmonary Pharmacology
(1992) 5, 133-135 PULMONARY PHARMACOLOGY
A Comparison of the Speeds of Action of Salmeterol and Salbutamol in Reversing Methacholine-induced Bronchoconstriction J. R. Beach*, C . L. Young, S . C. Stenton, A . J . Avery, E. H . Walters, D . J. Hendrick Chest Unit, Newcastle General Hospital, University of Newcastle upon Tyne, Westgate Road, Newcastle upon Tyne NE4 6BE, UK
SUMMARY : We compared the speed of action of the long acting /1-agonist salmeterol with that of salbutamol in order to assess whether reported in vitro differences are likely to have clinical significance. We used methacholine tests to produce a standardized level of bronchoconstriction and then observed the rate of recovery of FEV, towards baseline after the administration by metered dose inhaler of salmeterol 50 µg or salbutamol 200 pg-doses which are considered to have similar bronchodilator potency. Twenty asthmatic subjects participated, and a double-blind, randomized, cross-over study design was followed . Salmeterol showed a significantly slower speed of action with median recovery to 90% and 95% of the baseline FEV, (pre-methacholine) occurring after 9 .6 and 19.4 min, respectively, compared with 4 .8 and 8 .3 min, respectively, for salbutamol (P<0.01). These observations are consistent with in vitro findings and suggest that salmeterol is likely to be less satisfactory than salbutamol as a `rescue medication' for the treatment of acute episodes of bronchoconstriction.
standardized levels of bronchoconstriction . We then compared recovery rates after treatment with salmeterol 50 µg or salbutamol 200 µg . These doses, which are recommended for clinical use, have been found to have similar bronchodilator potencies2' 3 and to give similar protection (perhaps greater with salmeterol) against airway challenge with histamine or methacholine at 1 h .4,5
INTRODUCTION Short acting inhaled X3 2 -agonists such as salbutamol and terbutaline are widely used in the treatment of asthma, both as regular prophylactic medication and as `rescue medication' for the treatment of acute episodes . Inhaled formulations have been very effective in both these roles, but their relatively short duration of action (which has proved to be particularly unsatisfactory in controlling nocturnal symptoms) has stimulated the development of new longer acting preparations . The first of these long acting (3-agonists to be available in Britain is salmeterol . It has a duration of action in excess of 12 h and so needs to be taken only twice daily . While a long duration of action has clear advantages in prophylaxis, it is of much less value in rescue therapy . Much more important in this role is a rapid speed of action . In vitro work has already suggested that salmeterol has a less rapid speed of action than salbutamol,' and so there is a need to assess whether a difference is also apparent in vivo at equipotent doses, and if so whether such a difference is likely to be relevant clinically . Because it is difficult to study spontaneously occurring bronchoconstriction repeatedly in a controlled way, we decided to use methacholine tests to produce
METHODS Subjects Twenty adult asthmatic subjects of both sexes were recruited . All were able to use a metered dose inhaler correctly, and all had measurable airway responsiveness with a PD20 (dose provoking a 20% decrement in FEV,) of less than 3200 gg methacholine . b Each subject gave written informed consent and the study was approved by the local ethical committee . Subjects who had had an exacerbation of their asthma or who had required any change in their medication during the preceding 6 weeks were excluded, as were women of child bearing potential . All participants had an FEV, > 60% predicted before undergoing the methacholine test . Inhaled (3-agonists were withheld for 12 h and oral (3-agonists, theophyllines, and antihistamines for 24 h before the methacholine tests . Regularly used
* For correspondence . 0952-0600/92/020133+03 $03 .00/0
133
© 1992 Academic Press Limited
1 34
J . R . Beach et al
inhaled corticosteroids were taken at their usual time on each study day .
times are shown in Table 2 . A significant difference favouring salbutamol over salmeterol was seen in the time to recover to 90% and 95% of baseline (P< 0 .01), but not in the time to recover to 100% of baseline . There was no statistically significant difference between mean values of FEV, at the end of the 60-min study period . Figure 1 shows the mean FEV, at each time point following each treatment . It is greater following salbutamol than salmeterol throughout the 60-min recovery period . Figure 2 shows the median and the range of the difference in FEV, (FEV, following salbutamol minus FEV, following salmeterol) for the subjects at each time point . This eliminates the effect of spontaneous recovery (assuming this was essentially the same on each of the two study days) and illustrates the net benefit of one study treatment over the other . Although the median values indicate faster recovery after salbutamol, the range is wide and for a few subjects recovery occurred more quickly after salmeterol (three subjects at 90% of baseline, two at 95%, and five at 100% ; one subject only showing quicker recovery after salmeterol at every level) . There were no period or order effects .
Study protocol The study was carried out in a randomized, doubleblind, cross-over fashion, the paired investigations being performed on each of the 20 subjects 2-10 days apart at the same time of day (±2 h) . Methacholine was administered by dosimeter in doubling cumulative doses at 5 min intervals until a decrement in FEV, exceeding 20% from baseline was observed .' Each subject was then given salmeterol 50 .tg or salbutamol 200 pg from a metered dose inhaler . FEV, (mean of three satisfactory measurements) was recorded at 2 min intervals for the following 10 min and at 5 min intervals thereafter for a total of 60 min . To avoid unnecessary discomfort from exhaling to residual volume, each manoeuvre was terminated shortly after 1 s . The PD20 was derived conventionally by linear interpolation .
Statistical analysis Time taken to reattain 90%, 95% and 100% of baseline (pre-methacholine) FEV, was calculated for each subject .' Analysis of variance of ranked data was used to assess whether speeds of recovery differed between the treatment groups .'
DISCUSSION It took at least twice as long following salmeterol for median recovery of FEV, to 90% and 95% of the premethacholine baseline as it did following salbutamol (an extra 5 min and 11 min, respectively) . These figures do not, however, provide a pure comparison between the speeds of action of the two drugs because spontaneous recovery was occurring alongside their bronchodilator effects . The effect of spontaneous recovery is eliminated in Figure 2 . This shows that the differences in speeds of action are most marked over the initial 5-10 min, following which the advantage of salbutamol over salmeterol steadily declines . An earlier investigation did confirm that recovery of FEV,
RESULTS The study population comprised 15 females and five males, aged 18-75 years (mean 30 years) . Mean values for baseline FEV„ minimum FEV, following methacholine, and PD20 for the two sets of methacholine tests were very similar (Table 1) . Baseline FEV, ranged from 68 to 118% of predicted (median 93%), and PD20 ranged from 4 to 1800 pg . Median recovery Table 1
Mean values for FEV, and PD20 .
Treatment group
Baseline FEV, (1)
Minimum FEV, (1)
Geom . mean PD20 (µg)
Salmeterol Salbutamol
2.99 (2 .37-3 .25) 2.90 (2 .60-3 .20)
2 .09 (1 .87-2 .31) 2 .08 (1 .83-2 .33)
73 (32-169) 71 (33-153)
Values in parentheses are the 95% confidence intervals . Table 2
Median recovery times of FEV, in minutes to 90, 95 and 100% of baseline .
Treatment group
To 90%
To 95%
To 100%
Salmeterol Salbutamol
9 .6 (7.0-17.9) 4.8 (< 2.0-7.9)
19 .4 (10 .6-37 .1) 8 .3 (2 .8-21 .8)
26 .8 (14 .8-52 .2) 22 .3 (4 .5-48 .4)
Values in parentheses are 95% confidence intervals .
Speed of Action of Salmeterol and Salbutamol
I J I
40
20
I
60
Time (min)
Fig. 1
Mean FEV, at each time point . ( •) Salbutamol; (O)
salmeterol .
w
135
data support the conclusion that the two drugs have approximately equal bronchodilator potency at the dose levels used-there being no significant difference in mean FEV, between the two treatment days by the end of the 60-min surveillance period . If, however, protection against airway challenge is used as a measure of physiological activity, then 50 .tg of salmeterol may be equivalent to a somewhat larger dose of salbutamol than 200 µg.4,5 In any event, the two drugs are recommended (and marketed) for use in the doses used in this study . In clinical situations requiring rapid relief of asthmatic symptoms, salbutamol is consequently likely to be the more effective rescue medication . The benefit would, however, be mild or moderate rather than marked . If salmeterol were used exclusively for both prophylaxis and rescue, there might be a further disadvantage for patients already familiar with the speed of action of short acting Q-agonists such as salbutamol in that salmeterol might be taken repeatedly in acute situations in the hope of accelerating relief, leading to unduly prolonged adverse effects . We conclude that salmeterol is likely to be a less effective rescue medication than salbutamol for the rapid relief of symptoms . References
LL
-I .00 10
20
30 40 Time (min)
50
60
Fig . 2 Difference in FEV, (salbutamol minus salmeterol) at each time point. ( •) Maximum ; (C) median; (∎) minimum .
following methacholine tests is significantly faster after treatment with either salmeterol or salbutamol than after placebo .' As neither salmeterol nor salbutamol have anticholinergic properties, their bronchodilator effect after methacholine-induced bronchoconstriction must be mediated via the (3 Z adrenoreceptor (giving rise to physiological antagonism), rather than by any specific pharmacological antagonism of methacholine. While this may readily reverse bronchoconstriction attributable to airway smooth muscle contraction, it may be less effective in naturally triggered asthma where more complex mechanisms are often involved . The results we have obtained may not, therefore, be fully mirrored in the day-to-day treatment of asthma . Critical to the present evaluation are the overall bronchodilator potencies of the two drugs, i .e . do the chosen doses in fact represent the minimum doses able to achieve near maximal bronchodilation? Clinical evidence suggests this is indeed the case, 3,10 and our
1 . Brittain R T . Approaches to a long acting, selective (3 2 adrenoreceptor stimulant. Lung 1990; 169 : 111-114 . 2 . Ullman A, Svedmyr N . Salmeterol, a new long acting inhaled 0, adrenorecptor agonist: comparison with salbutamol in adult asthmatic patients . Thorax 1988 ; 43 : 674-678 . 3 . Boyd G, Anderson K, Carter R . A 12 hour placebo controlled comparison of the bronchodilator performance of salmeterol and albuterol. Am Rev Respir Dis 1990 ; 141 : A206 . 4 . Campos-Gongora H, Wisniewski A, Britton J, Tattersfield A E . Single dose comparison of inhaled salmeterol and salbutamol on airway reactivity in asthmatic patients . Eur Respir J 1990 ; 39: 114s . 5 . Derom E, Pauwels R, Van der Straeten M . Duration of the protective effect of salmeterol on methacholine challenge in asthmatics . Am Rev Respir Dis 1990 ; 141 : A469 . 6. Connolly M J, Avery A J, Walters E H, Hendrick D J . The relationship between bronchial responsiveness to methacholine and bronchial responsiveness to histamine in asthmatic subjects . Pulmon Pharmacol 1988 ; 1 : 53-58 . 7. Matthews J N S, Altman D G, Campbell M J, Royston P . Analysis of serial measurements in medical research . Br Med J 1990; 300 : 230-235 . 8. Conover W J, Iman R L . Rank transformation as a bridge between parametric and non-parametric statistics . Am Statistician 1981 ; 35 : 124-133 . 9 . Beach J R, Young C A, Walters E H, Hendrick D J . Reversal of methacholine-induced bronchoconstriction to compare speed of action of bronchodilators . Am Rev Respir Dis 1991 ; 143: A428 . 10 . Sandstrom I, Frederiksen B, Rosenhall L, Sandstrom B . Salmeterol-a dose response study with a long acting inhaled 0, agonist . Am Rev Respir Dis 1989; 139 : A64 .
Date received : 4 July 1991 Date revised : 14 August 1991 Date accepted: 28 October 1991
(1992) 5, 133-135 PULMONARY PHARMACOLOGY
A Comparison of the Speeds of Action of Salmeterol and Salbutamol in Reversing Methacholine-induced Bronchoconstriction J. R. Beach*, C . L. Young, S . C. Stenton, A . J . Avery, E. H . Walters, D . J. Hendrick Chest Unit, Newcastle General Hospital, University of Newcastle upon Tyne, Westgate Road, Newcastle upon Tyne NE4 6BE, UK
SUMMARY : We compared the speed of action of the long acting /1-agonist salmeterol with that of salbutamol in order to assess whether reported in vitro differences are likely to have clinical significance. We used methacholine tests to produce a standardized level of bronchoconstriction and then observed the rate of recovery of FEV, towards baseline after the administration by metered dose inhaler of salmeterol 50 µg or salbutamol 200 pg-doses which are considered to have similar bronchodilator potency. Twenty asthmatic subjects participated, and a double-blind, randomized, cross-over study design was followed . Salmeterol showed a significantly slower speed of action with median recovery to 90% and 95% of the baseline FEV, (pre-methacholine) occurring after 9 .6 and 19.4 min, respectively, compared with 4 .8 and 8 .3 min, respectively, for salbutamol (P<0.01). These observations are consistent with in vitro findings and suggest that salmeterol is likely to be less satisfactory than salbutamol as a `rescue medication' for the treatment of acute episodes of bronchoconstriction.
standardized levels of bronchoconstriction . We then compared recovery rates after treatment with salmeterol 50 µg or salbutamol 200 µg . These doses, which are recommended for clinical use, have been found to have similar bronchodilator potencies2' 3 and to give similar protection (perhaps greater with salmeterol) against airway challenge with histamine or methacholine at 1 h .4,5
INTRODUCTION Short acting inhaled X3 2 -agonists such as salbutamol and terbutaline are widely used in the treatment of asthma, both as regular prophylactic medication and as `rescue medication' for the treatment of acute episodes . Inhaled formulations have been very effective in both these roles, but their relatively short duration of action (which has proved to be particularly unsatisfactory in controlling nocturnal symptoms) has stimulated the development of new longer acting preparations . The first of these long acting (3-agonists to be available in Britain is salmeterol . It has a duration of action in excess of 12 h and so needs to be taken only twice daily . While a long duration of action has clear advantages in prophylaxis, it is of much less value in rescue therapy . Much more important in this role is a rapid speed of action . In vitro work has already suggested that salmeterol has a less rapid speed of action than salbutamol,' and so there is a need to assess whether a difference is also apparent in vivo at equipotent doses, and if so whether such a difference is likely to be relevant clinically . Because it is difficult to study spontaneously occurring bronchoconstriction repeatedly in a controlled way, we decided to use methacholine tests to produce
METHODS Subjects Twenty adult asthmatic subjects of both sexes were recruited . All were able to use a metered dose inhaler correctly, and all had measurable airway responsiveness with a PD20 (dose provoking a 20% decrement in FEV,) of less than 3200 gg methacholine . b Each subject gave written informed consent and the study was approved by the local ethical committee . Subjects who had had an exacerbation of their asthma or who had required any change in their medication during the preceding 6 weeks were excluded, as were women of child bearing potential . All participants had an FEV, > 60% predicted before undergoing the methacholine test . Inhaled (3-agonists were withheld for 12 h and oral (3-agonists, theophyllines, and antihistamines for 24 h before the methacholine tests . Regularly used
* For correspondence . 0952-0600/92/020133+03 $03 .00/0
133
© 1992 Academic Press Limited
1 34
J . R . Beach et al
inhaled corticosteroids were taken at their usual time on each study day .
times are shown in Table 2 . A significant difference favouring salbutamol over salmeterol was seen in the time to recover to 90% and 95% of baseline (P< 0 .01), but not in the time to recover to 100% of baseline . There was no statistically significant difference between mean values of FEV, at the end of the 60-min study period . Figure 1 shows the mean FEV, at each time point following each treatment . It is greater following salbutamol than salmeterol throughout the 60-min recovery period . Figure 2 shows the median and the range of the difference in FEV, (FEV, following salbutamol minus FEV, following salmeterol) for the subjects at each time point . This eliminates the effect of spontaneous recovery (assuming this was essentially the same on each of the two study days) and illustrates the net benefit of one study treatment over the other . Although the median values indicate faster recovery after salbutamol, the range is wide and for a few subjects recovery occurred more quickly after salmeterol (three subjects at 90% of baseline, two at 95%, and five at 100% ; one subject only showing quicker recovery after salmeterol at every level) . There were no period or order effects .
Study protocol The study was carried out in a randomized, doubleblind, cross-over fashion, the paired investigations being performed on each of the 20 subjects 2-10 days apart at the same time of day (±2 h) . Methacholine was administered by dosimeter in doubling cumulative doses at 5 min intervals until a decrement in FEV, exceeding 20% from baseline was observed .' Each subject was then given salmeterol 50 .tg or salbutamol 200 pg from a metered dose inhaler . FEV, (mean of three satisfactory measurements) was recorded at 2 min intervals for the following 10 min and at 5 min intervals thereafter for a total of 60 min . To avoid unnecessary discomfort from exhaling to residual volume, each manoeuvre was terminated shortly after 1 s . The PD20 was derived conventionally by linear interpolation .
Statistical analysis Time taken to reattain 90%, 95% and 100% of baseline (pre-methacholine) FEV, was calculated for each subject .' Analysis of variance of ranked data was used to assess whether speeds of recovery differed between the treatment groups .'
DISCUSSION It took at least twice as long following salmeterol for median recovery of FEV, to 90% and 95% of the premethacholine baseline as it did following salbutamol (an extra 5 min and 11 min, respectively) . These figures do not, however, provide a pure comparison between the speeds of action of the two drugs because spontaneous recovery was occurring alongside their bronchodilator effects . The effect of spontaneous recovery is eliminated in Figure 2 . This shows that the differences in speeds of action are most marked over the initial 5-10 min, following which the advantage of salbutamol over salmeterol steadily declines . An earlier investigation did confirm that recovery of FEV,
RESULTS The study population comprised 15 females and five males, aged 18-75 years (mean 30 years) . Mean values for baseline FEV„ minimum FEV, following methacholine, and PD20 for the two sets of methacholine tests were very similar (Table 1) . Baseline FEV, ranged from 68 to 118% of predicted (median 93%), and PD20 ranged from 4 to 1800 pg . Median recovery Table 1
Mean values for FEV, and PD20 .
Treatment group
Baseline FEV, (1)
Minimum FEV, (1)
Geom . mean PD20 (µg)
Salmeterol Salbutamol
2.99 (2 .37-3 .25) 2.90 (2 .60-3 .20)
2 .09 (1 .87-2 .31) 2 .08 (1 .83-2 .33)
73 (32-169) 71 (33-153)
Values in parentheses are the 95% confidence intervals . Table 2
Median recovery times of FEV, in minutes to 90, 95 and 100% of baseline .
Treatment group
To 90%
To 95%
To 100%
Salmeterol Salbutamol
9 .6 (7.0-17.9) 4.8 (< 2.0-7.9)
19 .4 (10 .6-37 .1) 8 .3 (2 .8-21 .8)
26 .8 (14 .8-52 .2) 22 .3 (4 .5-48 .4)
Values in parentheses are 95% confidence intervals .
Speed of Action of Salmeterol and Salbutamol
I J I
40
20
I
60
Time (min)
Fig. 1
Mean FEV, at each time point . ( •) Salbutamol; (O)
salmeterol .
w
135
data support the conclusion that the two drugs have approximately equal bronchodilator potency at the dose levels used-there being no significant difference in mean FEV, between the two treatment days by the end of the 60-min surveillance period . If, however, protection against airway challenge is used as a measure of physiological activity, then 50 .tg of salmeterol may be equivalent to a somewhat larger dose of salbutamol than 200 µg.4,5 In any event, the two drugs are recommended (and marketed) for use in the doses used in this study . In clinical situations requiring rapid relief of asthmatic symptoms, salbutamol is consequently likely to be the more effective rescue medication . The benefit would, however, be mild or moderate rather than marked . If salmeterol were used exclusively for both prophylaxis and rescue, there might be a further disadvantage for patients already familiar with the speed of action of short acting Q-agonists such as salbutamol in that salmeterol might be taken repeatedly in acute situations in the hope of accelerating relief, leading to unduly prolonged adverse effects . We conclude that salmeterol is likely to be a less effective rescue medication than salbutamol for the rapid relief of symptoms . References
LL
-I .00 10
20
30 40 Time (min)
50
60
Fig . 2 Difference in FEV, (salbutamol minus salmeterol) at each time point. ( •) Maximum ; (C) median; (∎) minimum .
following methacholine tests is significantly faster after treatment with either salmeterol or salbutamol than after placebo .' As neither salmeterol nor salbutamol have anticholinergic properties, their bronchodilator effect after methacholine-induced bronchoconstriction must be mediated via the (3 Z adrenoreceptor (giving rise to physiological antagonism), rather than by any specific pharmacological antagonism of methacholine. While this may readily reverse bronchoconstriction attributable to airway smooth muscle contraction, it may be less effective in naturally triggered asthma where more complex mechanisms are often involved . The results we have obtained may not, therefore, be fully mirrored in the day-to-day treatment of asthma . Critical to the present evaluation are the overall bronchodilator potencies of the two drugs, i .e . do the chosen doses in fact represent the minimum doses able to achieve near maximal bronchodilation? Clinical evidence suggests this is indeed the case, 3,10 and our
1 . Brittain R T . Approaches to a long acting, selective (3 2 adrenoreceptor stimulant. Lung 1990; 169 : 111-114 . 2 . Ullman A, Svedmyr N . Salmeterol, a new long acting inhaled 0, adrenorecptor agonist: comparison with salbutamol in adult asthmatic patients . Thorax 1988 ; 43 : 674-678 . 3 . Boyd G, Anderson K, Carter R . A 12 hour placebo controlled comparison of the bronchodilator performance of salmeterol and albuterol. Am Rev Respir Dis 1990 ; 141 : A206 . 4 . Campos-Gongora H, Wisniewski A, Britton J, Tattersfield A E . Single dose comparison of inhaled salmeterol and salbutamol on airway reactivity in asthmatic patients . Eur Respir J 1990 ; 39: 114s . 5 . Derom E, Pauwels R, Van der Straeten M . Duration of the protective effect of salmeterol on methacholine challenge in asthmatics . Am Rev Respir Dis 1990 ; 141 : A469 . 6. Connolly M J, Avery A J, Walters E H, Hendrick D J . The relationship between bronchial responsiveness to methacholine and bronchial responsiveness to histamine in asthmatic subjects . Pulmon Pharmacol 1988 ; 1 : 53-58 . 7. Matthews J N S, Altman D G, Campbell M J, Royston P . Analysis of serial measurements in medical research . Br Med J 1990; 300 : 230-235 . 8. Conover W J, Iman R L . Rank transformation as a bridge between parametric and non-parametric statistics . Am Statistician 1981 ; 35 : 124-133 . 9 . Beach J R, Young C A, Walters E H, Hendrick D J . Reversal of methacholine-induced bronchoconstriction to compare speed of action of bronchodilators . Am Rev Respir Dis 1991 ; 143: A428 . 10 . Sandstrom I, Frederiksen B, Rosenhall L, Sandstrom B . Salmeterol-a dose response study with a long acting inhaled 0, agonist . Am Rev Respir Dis 1989; 139 : A64 .
Date received : 4 July 1991 Date revised : 14 August 1991 Date accepted: 28 October 1991