Is the increase in bronchial responsiveness or FEV1 shortly after cessation ofβ2 -agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting β2-agonists

ArticleinRespiratory Medicine 96(3):155-62 · April 2002with167 Reads
Impact Factor: 3.09 · DOI: 10.1053/rmed.2001.1243 · Source: PubMed
Abstract

Regular use of beta2-agonists might result in increased bronchial hyper-responsiveness (BHR) and decreased forced expiratory volume in 1 sec (FEV1). It has been suggested that these possible detrimental effects are not a real deterioration of the disease, but that it might be only a transient (rebound) effect shortly after discontinuing this regular use. Moreover, these effects are thought to occur especially during short-acting and not during long-acting beta2-agonists use. The aim of this study was to invest gate whether a rebound effect (a pharmacological deterioration effect diminishing after several hours) in FEV1 and PC20 (concentration of histamine causing a 20% fall in FEV1 with regard to baseline) occurred after cessation of regular use of beta2-agonists, and whether this occurred both after short-acting and long-acting beta2-agonists. Allergic asthmatic patients (n = 134) were randomly allocated to the use of a short-acting (salbutamol), a long-acting beta2-agonist (formoterol) or placebo for 12 weeks (double-blind, double-dummy). No other asthma medication was allowed, including inhaled corticosteroids. At the start and every 4 weeks later FEV and PC20 were measured, each time at least 12 h after the last doses of study medication, which is in the possible rebound period. To investigate whether a (transient) rebound effect occurred, parameters were additionally measured at least 72 h later after discontinuation of the study medication. After 12 weeks of short-acting beta2-agonist use, a drop was seen in FEV1 from 85.6 (+/- 2.21)% predicted to 78.8 (+/- 2.9)% predicted, measured 15 h (median) after the last doses of medication. This was significantly different compared to placebo. When measured 168 h (median) later FEV1 recovered to 85.5 (+/- 2.4)% predicted, comparable to baseline. PC20 decreased with -1.17 (+/- 0.44) doubling dose after 12 weeks of short-acting beta2-agonist use, measured 15 h after the last doses of medication, which was significantly different compared to placebo. However, 168 h later PC20 recovered slightly with +0.55 (+/- 0.34) doubling dose, but this value was still lower compared to placebo. In contrast, during long-acting beta2-agonist and placebo use no significant changes were seen. In conclusion, the use of short-acting beta2-agonists resulted in a transient (rebound) effect in FEV while the effects on PC20 may point to a real deterioration of the disease. Long-acting beta2-agonist and placebo use showed no changes. We conclude that a mono-therapy of short-acting and not of long-acting beta2-agonists might have deleterious effects in asthma.

Full-text

Available from: Chris van Weel, Mar 18, 2015
Is the increase in bronchial responsiveness or FEV
1
shortly after cessation of b
2
-agonists re£ecting a real
deterioration of the disease in allergic asthmatic
patients? A comparison between short-acting and
long-acting b
2
-agonists
C. P.VAN SCHAYCK
*w
,S.G.M.CLOOSTERMAN
*
,I.D.BIJL-HOFLAND
*
,H.VAN DEN HOOGEN
*
,
H. Th. M. F
OLGERING
z
AND C.VAN WEEL
*
*Department of General Practice,University of Nijmegen, Nijmegen,
w
Department of General Practice,University of
Maastricht, Maastricht and
z
Department of Pulmonary Diseases, University of Nijmegen, Nijmegen,The Netherlands
Abstract Regular use of b
2
-agonists might result in increased bronchial hyper-responsiveness (BHR) and decreased
forced expiratory volume in1sec (FEV
1
).It has been suggested thatthese possible detrimental e¡ects are not a real de-
terioration ofthe disease, butthatit might be only a transient (rebound) e¡ect shortlyafterdiscontinuing thisregularuse.
Moreover, these ects are thought to occur especially during short-acting and not during long-acting b
2
-agonists use.
The aim of this study was to investigate whether a rebound ect ( a pharmacological deterioration ect diminishing
after several hours) in FEV
1
and PC
20
(concentration of histamine causing a 20 % fall in FEV
1
with regard to baseline) oc-
curred after cessation of regular use of b
2
-agonists, and whether thisoccurredboth after short-actingandlong-acting b
2
-
agonists. Allergic asthmatic patients (n=134) were randomly allocated to the use of a short-acting (salbutamol), a long-
acting b
2
-agonist (formoterol) or placebo for12 weeks (double-blind, double-dummy).No other asthma medication was
allowed, includinginhaled corticosteroids. Atthe start and every 4 weekslater FEV
1
and PC
20
weremeasured, eachtime
at least 12 h after the last doses of study medication, which is in the possible rebound period. To investigate whether a
(transient) rebound ect occurred, parameters were additionally measured at least 72 h later after discontinuation of
the study medication. After 12 weeks of short-acting b
2
-agonist use, a drop was seen in FEV
1
from 85?6(72?21) % p re -
dicted to 78?8(72?9)% predicted, measured15 h (median) after the lastdoses ofmedication.This was signi¢cantly der-
entcomparedto placebo.Whenmeasured168 h (median) later FEV
1
recovered to 85?5(72?4)% predicted, comparableto
baseline.PC
20
decreased with 1?17 ( 70? 44) doublingdose after12 weeks of short-acting b
2
-agonist use, measured15 h
after the last doses of medication, which was signcantly derent compared to placebo.However,168 h later PC
20
re-
covered slightly with +0?55 (70?34) doubling dose, butthis value was stilllower compared to placebo.In contrast, during
long-acting b
2
-agonist andplacebo useno signi¢cantchangeswere seen.Inconclusion, theuse ofshort-acting b
2
-agonists
resulted in a transient (rebound) e¡ect in FEV
1
while the e¡ects on PC
20
may pointto a real deterioration ofthe disease.
Long-acting b
2
-agonist and placebo use showedno changes.We conclude that a mono-therapy of short-acting andnot of
long-acting b
2
-agonists might have deleterious e¡ects in asthma.r 2002 Elsevier Science Ltd
doi:10.1053/rmed.2001.1243, available online at http://www.idealibrary.com on
Keywords short-acting b
2
-agonists; long-acting b
2
-agonists, asthma; tolerance; FEV
1
;PC
20.
INTRODUCTION
In the last 5^10 years, interest in the possibly detrimen-
tal e¡ects of chronic b
2
-agonist use for treating asthma
has increased. It started with the observation that the
increase in asthma deaths may have been causally asso-
ciated with treatment with b
2
-agonists (1,2). Moreover,
several studies observed adverse e¡ects during regular
b
2
-agonist use, such as increased bronchial hyper-
responsiveness (3^5), increased decline in lung function
(6) or decreased overall control of asthma (7).Other stu-
dies have suggested that patients may be most sensitive
in the period a few hours after cessation of b
2
-agonist
treatment since bronchial responsiveness has shown to
Received 28 June 2001, accepted in revised form 2 October 2001and
published online 18 January 2002.
Correspondence should be addressed to: Prof.C. van Weel,
Department of General Practice,University of Nijmegen, P. O. Box 9101,
6500 HB Nijmegen, The Netherlands. Fax: +31 24 3541862; E-mail:
C.vanWeel@hsv.kun.nl
Vol. 96 (2002) 155^162
Page 1
increase (3^5,8,9) and forced expiratory volume in 1sec
(FEV
1
) to decrease at this time (5,7,9), while these e¡ect
diminished several hours later (4,9). This period shortly
after cessation is referred to as the rebound period
(4,9). Studies that reported a deterioration in bronchial
hyper-responsiveness (BHR) or FEV
1
during regular use
of a b
2
-agonist, usually measured these parameters a
few hours after the last doses of the short-acting b
2
-
agonist, to avoid still existing bronchodilatating e¡ects
of these b
2
-agonists (functional antagonism). It has been
suggested that this observed deterioration is not a real
deterioration of the disease due to regular b
2
-agonist
use, but merely the result of measuring in this rebound
period. It is thought that this rebound ect is largely ex-
tinguished after 72 h. Moreover, it has been hypothesized
that this rebound e¡ect especially occurs after the regu-
lar use of short-acting b
2
-agonists and not after the use
of long-acting b
2
-agonists (10,11).
In this study we investigated the e¡ects of regular use
of short-acting and long-acting b
2
-agonists for 12 weeks
in allergic asthmatic patients. Patients were not allowed
to use inhaled corticosteroids, so that the isolated ef-
fects of regular b
2
-agonists use could be assessed. Sub-
jects were measured each time at least 12 h after the
last dose of study medication, so each time in the possi-
ble rebound period. We additionally investigated what
the development is in these parameters, after a longer
cessation period (at least 72 h). Therefore, at the end of
the12-week study medication period FEV
1
and PC
20
(the
concentration of histamine causing a 20% fallin FEV
1
with
regard to baseline) were measured an extra time, at
least 72 h after discontinuing the study medication, to
avoid possible rebound ects. By adding this last mea-
surements, we are able to determine whether possibly
detrimental e¡ects of short-acting b
2
-agonists are only
due to a rebound e¡ect and are not re£ecting a real wor-
sening of asthma.
METHODS
Patients
Asthmatic patients were selected by their GP for this
study. They used no inhaled steroids or were able to
cease this medication, to study the isolated e¡ects of
chronic use of b
2
-agonists and the e¡ects of discontinu-
ing this medication. Selection procedures were de-
scribed in detail elsewhere (12). The Medical Ethical
Committee of the Medical Centre Dekkerswald, Univer-
sity of Nijmegen, approved the study protocol, and all pa-
tients gave a written informed consent.
Design
This study was a randomized, double-blind, double-dummy,
placebo-controlled clinical trial of 12? 5 weeks. Selected
patients were randomly allocated to the use of a short-
acting [salbutamol (mdi), 200 mg qid] or long-acting [for-
moterol (mdi), 12 mgbid]b
2
-agonist, or placebo,
resulting in three study-groups (Fig. 1). Patients started
with a 4 -week run-in period, in which no changes took
place. After this period patients ceased all their pulmon-
ary medication if used (inhaled corticosteroids, cromo-
glycates, bronchodilators, etc) and were instructed to
use only the rescue medication on demand (Berodual
s
,
Boehringer Ingelheim Alkmaar, The Netherlands). Bero-
dual
s
was chosen because it predominantly contains
ipratropium bromide (40 mg, anti-cholinergic bronchodi-
lator) and a low dose of fenoterol hydrobromide (100 mg).
So, use of b
2
-agonsists as rescue medication was pre-
vented as much as possible during the study. The amount
of bronchodilator usage was carefully recorded. This was
followed by an 8 -week washout period, to adjust patients
to the cessation of their medication. After these 8 weeks
patients received the study medication (double-blind, dou-
ble-dummy)andwereinstructedtousethemedicationfor
12 weeks (rescue medication use was still allowed and was
carefully recorded). After this 12-week study period, sub-
jects discontinued the use of the study medication and
were instructed to use no b
2
-agonists until the next mea-
surement at the lung function laboratory, which was at
least 72 h after the last dose of study medication.
Lung function measurements
Spirometry and bronchial hyper-responsiveness (BHR)
were measured during inclusion, at the start of the study
medication period and after every 4 weeks of follow-up,
each time at least12 h after the last dose of study medica-
tion. Furthermore, at the end of the12-week study med-
ication period an additional measurement was done at
least 72 h after the last dose of study medication. Spiro-
metric parameters (FEV
1
, reversibility of FEV
1
15 min a f ter
inhaling 400 mg of salbutamol) were measured by means
of a Microspirometer (HI-298, Chest Corporation, To-
kyo, Japan) (13). Reversibility of FEV
1
was calculated as
percentage of the pre-bronchodilator value.
BHR was determined by stepwise inhalation of increas-
ing concentrations of histamine solution, according to
the ERS standard (tidal breathing method) (14). Doubling
concentrations of histamine acid phosphate, from 0? 03 to
16? 0mgml
1
were administered.The concentration of in-
haled histamine, causing a 20% fall in FEV
1
with regard to
baseline (PC
20histamine
) was obtained from the log-con-
centration response curve by linear interpolation. After
spontaneous recovery to 90% or more of the pre-hista-
mine value, bronchodilator response was measured be-
fore and15 min after 400 mgsalbutamol(mdi).
Analysis
PC
20
values were
2
log transformed to achieve a normal
distribution. Di¡erences could then be interpreted as
15 6 RESPIRATORY MEDICINE
Page 2
doubling doses. FEV
1
is presented as percentage of the
predicted value (ERS/ECSC standard) (15). Measure-
ments at the start of the medication period served as
baseline values (week 0). Derences between week 0
and week12, week12 and week13, and week13 and week
0 were calculated. It was tested whether these changes
di¡ered between the three medication groups by Stu-
dent’s t-test. Next, within each medication group, values
were compared by Students paired t-test (week 0 vs.
week 12, week 12 vs. week 13 and week 0 vs. week 13).
Changes are presented as mean (7
SEM), and the signi¢-
cance level was set at 5%.
RESULTS
Patients
Two hundred and four patients started the washout peri-
od (Table 1). During this period 42 subjects dropped out,
consequently 162 patients started the medication period.
During this medication period ¢ve subjects dropped-out
because they had to restart their IC use before the ¢rst
follow-up measurement (short-acting: 2, long-acting: 0,
placebo: 3). Five subjects stopped taking the study medi-
cation within 4 weeks after the start (short-acting: 2,
long-acting: 1, placebo: 2). Seven patients dropped out
due to motivational factors within 4 weeks after the start
(short-acting: 5, long-acting: 1, placebo: 1). Consequently
those 17 subjects performed only the baseline measure-
ment, and 145 subjects completed the study medication
period.Of these145 patients,134 underwent themeasure-
ment at least 72 h after discontinuing b
2
-agonists, 44 in
the short-acting b
2
-agonists group, 46 in the long-acting
b
2
-agonists group and 44 in the placebo group.The other
11 p a t i e n t s w e r e n o t a b l e t o d o t h i s m e a s u r e m e n t , d u e t o
planning problems (e.g. work, holiday) or due to motiva-
tional problems. There was no selective dropout. Patient
characteristics of these 134 patients are presented in
Table 2. There were no di¡erences between the three
groups in baseline characteristics.
Time after discontinuing study medication
and rescue medication
The median hours of discontinuing the rescue medica-
tion before each measurements was 15 h (25^75 percen-
tile: 12^17 h) for the short-acting group, 15 h (25 ^75
percentile: 14 ^18 h) for the long-acting group and 15 h
(25^75 percentile: 12^18?5h) for the placebo group.
These data con¢rm that during regular use of the study
medication (week 0 t/m week 12), patients were mea-
sured in the possible rebound period. They were mea-
sured on average 168 h (25 ^75 percentile: 144 ^192 h)
later after discontinuing this use (week 13), which is as-
sumed to be outside the rebound period.
There was no excessive use of rescue medication
in each of the three study groups (Table 3). Moreover,
FIG.1.
COMPARISON BET WEEN SHORT-ACTING AND LONG-ACTING 157
Page 3
the use of rescue medication was also discontinued
at an appropriate time before each measurement
(Table 4).
Changes in FEV
1
and PC
20
The drop in FEV
1
from week 0 to week 12 in the shor t-
acting b
2
-agonists group was signi¢cantly greater com-
pared with the drop in the placebo group in this period
[di¡erence 5?4(72?4)% predicted, P=0? 026, see Fig. 2].
After 1 week of discontinuing of study medication, an in-
crease in FEV
1
compared to week 12 was observed. This
increase was signi¢cantly greater compared to this in-
crease in the placebo group [di¡erence: 5?2(72?1)% pre -
dicted, P=0? 015 ].
PC
20
decreased after12 weeks of short-acting b
2
-ago-
nist use. This decrease was signcantly greater than the
decrease after placebo use in this period [di¡erence:1?06
(70? 47) doubling dose, P=0? 032, see Fig. 3]. After 1
week of discontinuing this study medication an increase
in PC
20
compared to week 12 was observed of 0?55
(70?34) doubling doses, while the placebo group
showed a decrease in this period [0?58 (70?31) dou-
bling dose].These changes from week12 to week13 were
signi¢cantly di¡erent [1?13 ( 70? 46) doubling dose,
P=0? 016] between the short-acting b
2
-agonist and
placebo group.
There were no di¡erences in changes in FEV
1
and PC
20
between placebo and long-acting b
2
-agonist use, for
both the period week 0 to week 12 (15 h after the last
dose), and the period week12^week13 (1week after dis-
continuing).
TABLE 1. Number of subjects and drop-outs during the study
Study period
Start
washout
Star t
medication
period
End
medication
period
One week
after
discontinuing
No of patients remained in the study 204 162 145 134
No drop-outs in preceding period 42 17 11
Lack of motivation/planning problems 19 7
Deterioration of asthma (need of inhalation corticosteroids) 23 5
Stopped using study medication 5
TABLE 2. Baseline characteristics ofthe three medication groups.Means (and standard deviation) are given
Short-acting Long-acting Placebo P-value
(n=44) (n=46) (n=44)
Ge nd er ( M/ F ) 26/18 2 2/ 24 2 2/ 2 2 0 ?529
Age (yrs) 34?3(9?8) 33?1(11?6) 36?2(11?9) 0? 402
Height (cm) 176?7(10?0) 175 ?8(8?3) 174 ?3(8?9) 0? 460
PC20
*
(mg ml
1
)1? 09 (0?582?04) 1?08 (0?631 ? 86) 1?23 (0?682? 20) 0?948
FEV
1
(% reference) 85?6(14?7) 83?6(15?2) 81 ?1(18?6) 0? 447
Reversibility
w
12 ?0(5?117 ? 7) 12?5(5?520?3) 13 ?4(7?925?2) 0 ?366
*Geometric mean (95% con¢dence interval).
w
Median (25^27 percentile), tested with Kruskal^Wallis.
TABLE 3. Use of 40 mg ipratropiumbromide plus 100 mg fenoterol in numbers of capsules (of Berodual
s
)perdaypresentedas
median (inter-quartile range) tested with Kruskal^Wallis
Short-acting Long-acting Placebo P-value
Wa sh - o ut 0 ?10 (0 ?001? 00) 0? 09 (0? 000? 41) 0?25 (0?001?13) 0 ?573
0^4 weeks 0?00 (0? 000?52) 0? 00 (0? 000?39) 0?04 (0?000?38) 0?853
4^8 weeks 0? 00 (0? 001?10) 0 ?00 (0?000?39) 0?05 (0? 000?79) 0?385
8^12 weeks 0? 07 (0? 001? 00) 0?00 (0? 000?21) 0 ? 02 (0? 000?65) 0?17 3
12^13 weeks 0? 00 (0? 001?00) 0?00 (0? 000?21) 0 ? 00 (0?000?43) 0?578
15 8 RESPIRATORY MEDICINE
Page 4
The drop in FEV
1
of 6? 8(7 2?1)% predicted, from
week0toweek12intheshort-actingb
2
-agonist group
was signcantly greater when compared with this
change in the long-acting b
2
-agonist group in this period
[di¡erence: 6?0(72?4)% predicted, P=0? 016). Af ter 1
week of discontinuing the study medication, FEV
1
in the
short-acting b
2
-agonist group increased with
6?7(71?8)% predicted from week 12 to week 13. This in-
crease was also signi¢cantly greater when compared
with the long-acting group (di¡erence: 5?6(72? 2)% pre-
dicted, P=0? 013). PC
20
decreased with 1?17 ( 70? 44)
doubling doses from week 0 to week 12 in the short-act-
ing b
2
-agonist group. The long-acting b
2
-agonists group
showed an increase in PC
20
to 0?24 (70?28) doubling
doses in this period, which was signi¢cantly derent
from the decrease in the short-acting group (di¡erence:
1?42 (70?51) doubling dose, P=0? 007). After 1 week of
discontinuing the study medication (week 12^ week 13),
PC
20
increased in the short-acting b
2
-agonist group and
TABLE 4. Number of patients using 40 mg ipratropiumbromide plus 100 mg fenoterol in each medication group and number of
hours of discontinuing 40 mg ipratropiumbromide plus 10 0 mg fenoterol (median+25^75 percentile) before each measurement, by
these patients (99 means 40 mg ipratropiumbromide plus100 mg fenoterol discontinued longer than 99 h)
Week 0 Week 4 Week 8 Week12 Week13
Short-acting (n=44) n=28 n=18 n=19 n=24 n=15
85?5h 44? 0h 36?0h 44? 0h 18?0h
(17 ?399?0) (18 ?099?0) (9 ?099?5) (10?599?0) (11?099?0)
Long-acting (n=46) n=31 n=15 n=18 n=18 n=9
72?0h 38?0h 99?0h 85?0h 44? 0h
(16 ?099?0) (15?099?0) (48 ?099?0) (48?099?0) (14 ?099?0)
Placebo (n=44) n=29 n=21 n=26 n=18 13
99?0h 40? 0h 99?0h 25?0h 18?0h
(45 ?099?0) (13 ?599?0) (15?099?0) (14 ?591 ?5) (11?599?0)
FIG.2. FEV
1
% predicted (SEM) during the study medication
period and1week after discontinuing the studymedication, pre-
sented as changes compared to baseline. P-values within groups
are presented. (a) Short-acting (&) vs.placebo(&), (b) long-
acting (&) vs.placebo(&).
FIG.3. PC
20
[doubling doses (SEM)] during the study medi-
cation period and 1 week after discontinuing the study medica-
tion, presented as changes compared to baseline. (a) Short-
acting (&) vs.placeto(&), (b) long-acting (&) vs.placebo(&).
COMPARISON BET WEEN SHORT-ACTING AND LONG-ACTING 159
Page 5
decreased in the long-acting b
2
-agonist group [di¡er-
ence: 1?33 (70?51) doubling dose, P=0? 011].
DISCUSSION
This study showed that after regular use of short-acting
b
2
-agonists for 12 weeks, FEV
1
was decreased, when
measured shortly after discontinuing this medication.
However, when this medication was discontinued
for 168 h, values returned to baseline. This indicated a
transient (rebound) e¡ect in FEV
1
shortly after
discontinuing short-acting b
2
-agonists, which disap-
peared after several hours (in this case a median of
16 8 h). P C
20
showed a decrease during regular use of
short-acting b
2
-agonists as well, when measured
shortly after the last dose. However, after 168 h of dis-
continuing, PC
20
values are still signi¢cantly lower. So,
this deterioration in PC
20
seems not only a result of a
rebound ect, but might be a re£ection of a real dete-
rioration of the disease during regular use of short-act-
ing b
2
-agonists. These e¡ects were not seen during
long-acting b
2
-agonist use and also not during placebo
use for FEV
1
.
Wahedna et al. (9) showed a fall in FEV
1
after 11h of
cessation of albuterol, which recovered after 59 h.
Additionally, he showed an increase in BHR after cessa-
tion of b
2
-agonists use, but this lasted for at least 59 h
(9).Our study clearly con¢rms the ¢ndings of Wahedna
et al. on FEV
1
values and PC
20
values during a prolonged
period, as we found that this decrease in PC
20
was
even still present after 168 h. Therefore, it is question-
able whether there is only a rebound decrease in
PC
20
after discontinuing regular short-acting b
2
-
agonist use. These results might indicate that there is a
more persistent increase in bronchial hyper-respon-
siveness after regular use of b
2
-agonists use or in
other words, it might point to a real deterioration of
the disease due to the regular use of short-acting
b
2
-agonists.
It has been hypothesized before, that a rebound in-
crease in BHR exclusively occurs after regular use of
short-acting b
2
-agonists (10). Both Cheung et al. (16) and
Ya t e s et al. (17) found no rebound increase in BHR during
regular long-acting b
2
-agonists use of salmeterol and for-
moterol, respectively, while Vathenen et al.(4)and
Wahedna et al. (9) showed a rebound increase in BHR
after regular short-acting b
2
-agonists use of respectively
terbutaline and albutamol. These studies did not directly
compare the e¡ects of both short-acting and long-acting
b
2
-agonists use, and have di¡erent study designs, which
makes a direct comparison dicult. In our study we did
compare the use of those two types of b
2
-agonists in the
same study, and we clearly con¢rm these observations.
These ¢ndings are probably of clinical importance,
although no clear pathophysiological mechanism can ex-
plain them at the moment. An anti-in£ammatory e¡ect
of long-acting b
2
-agonists has been suggested (18,19), and
this absence of deleterious and rebound e¡ects during
long-acting b
2
-agonist use might be an argument in fa-
vour of some anti-iammatory properties of long-act-
ing b
2
-agonists. Moreover, in this study we observed
that the PC
20
increased during long-acting b
2
-agonists
use and dropped signi¢cantly after discontinuing this
medication for 168 h, which might also support this sug-
gestion.
The time of measurement after the last doses of
study medication might theoretically have in£uenced
our data. Patients had to discontinue their medication
for at least 12 h during the study medication period. It
has been suggested in literature that long-acting b
2
-
agonists have e¡ects beyond 12 h (20). So, it might be
that in the long-acting b
2
-agonist group medication
was still partly active at the time of measurement,
which might result in slightly elevated values. The med-
ian time of stopping the study medication in the total
long-acting b
2
-agonists group was 15 h at all occasions.
To get an indication whether long-acting b
2
-agonists
were active during the measurement15 h after disconti-
nuing, we analysed subjects that stopped their medica-
tion for at least 24 h at week 12 separately. Analyses of
these subgroups did not result in di¡erent ¢ndings, im-
plicating that the b
2
-agonist activity was probably mar-
ginal at the time of measurement for the whole long-
acting b
2
-agonist group.
In this study we measured only twice after disconti-
nuing b
2
-agonists, shortly after discontinuing and a
median of 168 h after discontinuing, and not repeatedly.
Furthermore, we measured subjects not exactly at the
same time schedule, so inter-individual variation
was possible. In the studies of Vathenen et al. (4) and
Wahedna et al. (9), all subjects were measured several
times after cessation of b
2
-agonists and all patients
were measured exactly at the same time after cessa-
tion.Therefore, in those studies it was possible to eval-
uate the time-response curve of measured parameters
after discontinuing b
2
-agonists. Although this has not
been done in our study, we have performed an addi-
tional analysis on patients that discontinued short-act-
ing b
2
-agonists at least 72 h, but shorter than 168 h,
and patients that discontinued this drug longer than
168 h. Both the shor t stoppers and the long’ stoppers
showed the same tendency on changes in FEV
1
and
PC
20
, as was shown here for the total short-acting b
2
-
agonist group. Therefore the negative ect on PC
20
was even present in patients measured more than
168 h (1 week) after discontinuing the short-acting b
2
-
agonists. This con¢rms that the e¡ects on FEV
1
are re-
versible and that e¡ects on PC
20
might re£ect a real de-
terioration.
The rebound decrease in FEV
1
shortly after the last
dose of short-acting b
2
-agonists, is thought to be due to
16 0 RESPIRATORY MEDICINE
Page 6
a down-regulation of b
2
-receptors on airway smooth
muscles (21,22). The increase in BHR might also be a re-
sult of this phenomenon, but may also be due to b
2
-re-
ceptor down-regulation on in£ammatory cells such as
mast cells (21,22). This latter phenomenon is thought to
result in reduced protection (tolerance) against direct
and indirect stimuli, resulting in increased in£ammation
(21). The latter hypothesis might explain why FEV
1
re-
covers after168 h and why BHR does not.The down-reg-
ulation on the smooth muscle might recover quicker
than on in£ammatory cells. In other words the rebound
ect in FEV
1
suggest that the ects of regular b
2
-ago-
nists seems to point to a more pharmacological cause for
FEV
1
, whereas the e¡ects on PC
20
seems more than a
pharmacological phenomenon alone: an increase in in-
£ammation with a longer duration seems to have oc-
curred.
In this study we assessed the e¡ects of b
2
-agonists use
alone. Therefore, use of other asthma medication, espe-
cially inhaled corticosteroids, was not possible. In this
way we could investigate the isolated e¡ects of b
2
-ago-
nist, during regular use and also after stopping this use.
Because regular treatment with b
2
-agonists is not ad-
vised as a mono-therapy in guidelines, but only with ad-
ditional treatment of inhaled corticosteroids, it is
interesting to know what these e¡ects are when inhaled
corticosteroids are used at the same time. The possible
down-regulation of b
2
-receptors is thought to be re-
versed or even prevented by treatment with (inhaled)
glucocorticoids, probably because it increases b
2
-recep-
tor transcription in human lung (23). This in turn might
prevent the possible detrimental e¡ects during or after
cessation of regular b
2
-agonist use. In a follow-up which
was recently published (12), we could show that the per-
ception of bronchoconstriction was improved during ad-
ditional use of inhaled steroids.
In summary, this study directly compared cessation of
regular use of short-acting and long-acting b
2
-agonists.
It was found that a rebound decrease of FEV
1
and
increase in BHR occurred, when measured a few
(14 ^17) h after cessation of short-acting b
2
-agonists.
However, the deterioration in FEV
1
was recovered after
168 h while the increase in BHR was still present after
168 h, which might indicate a real deterioration of the
disease. These e¡ects were not seen after cessation of
regular use of long-acting b
2
-agonists and placebo.
Long-acting b
2
-agonists seem to have a di¡erent e¡ect
on bronchial hyper-responsiveness than short-acting
b
2
-agonists.
Acknowledgements
This study was supported by the Dutch Asthma Founda-
tion, by Novartis Pharma, by 3M Pharma Industries, and
by Boehringer Ingelheim.We would like to thank Prof. P.J.
Sterk, Leiden University Medical Centre, for his advice
after reading the manuscript.We gratefully acknowledge
the co-operation of the four lung function technicians in
measuring lung function and bronchial hyper-responsive-
ness of the patients.
REFERENCES
1. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and
death from asthma in New Zealand, 1981^7: a further case-control
study.Thorax 19 91; 46:105 ^111.
2. Spitzer WO, Suissa S, Ernst P, et al.Theuse of b-agonists and therisk
of death and near death from asthma. N Engl J Med 19 92 ; 326: 501^
506.
3. Kraan J, Koe
«
ter GH, van Mark T W, Sluiter HJ, Vries KD. Changes in
bronchial hyperactivity induced by 4 weeks of treatment with anti-
asthmatic drugs in patients with allergic asthma: a comparison be-
tween budesonide and terbutaline. J Allergy Clin Immunol 1985; 76:
628 ^ 636.
4. Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tatters¢eld AE. Re-
bound increase in bronchial responsiveness after treatment with in-
haled terbutaline. Lancet 19 8 8 ; 12: 554 ^558.
5. van Schayck CP, Graafsma SJ,Visch MB, Dompeling E, van Weel C,
van Herwaarden CLA. Increased bronchial hyperresponsiveness
after inhaling salbutamol during1year is not caused by subsensitiza-
tion to salbutamol.J Allergy Clin Immunol 19 9 0 ; 86: 793^ 800.
6. van Schayck CP, Dompeling E, van Herwaarden CLA, et al. Bronch-
odilator treatment in moderate asthma or chronic bronchitis: con-
tinuous or on demand? A randomised controlled study. Br Med J
19 91; 303: 1426^1431.
7. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist
treatment in bronchial asthma. Lancet 19 9 0 ; 336: 13 91^ 13 9 6 .
8. Kerrebijn KF, van Essen-Zandvliet EE, Neijens HJ. ect of long-
term treatment with inhaled corticosteroids and beta-agonists on
the bronchial responsiveness in children with asthma. JAllergyClin
Immunology 19 8 7; 79: 653^ 659.
9. Wahedna I, Wong CS, Wisniewski AFZ, Pavord ID, Tatters¢elf AE.
Asthma control during and after cessation of regular b
2
-agonist
treatment. Am Rev Respir Dis19 93 ; 14 8 : 707^712.
10. Lipworth BJ. Airway subsensitivity with long-acting b
2
-agonists. Is
there cause for concern? Drug Safety 19 97; 16 : 295 ^308.
11. Cloosterman S, Bijl-Ho£and ID, van Herwaarden CLA, et al.Apla-
cebo controlledclinical trial of regular monotherapy with short-act-
ing and long-acting b
2
-agonists in allergic asthma. Chest 2001; 119 :
13 0 6 ^ 1315 .
12. Bijl-Hand ID, Cloosterman SGM, Folgering HThM, van den Elsh-
out FJJ, van Weel C, van Schayck CP. Inhaled corticosteroids, com-
bined with long-acting b
2
-agonists, improve the perception of
bronchoconstriction in asthma. Am J Respir Crit Care Med 2001;
16 4 : 76 4 ^769.
13. Dompeling E, van Schayck CP, Folgering H, van Hoogen HJM, van
Weel C. Accuracy, precision and linearity of the portable £ow-vo-
lume meter Microspiro HI-298. Eur Respir J 19 91; 4: 612 ^ 615.
14. Sterk PJ, Fabbri LM, Quanjer PH, et al. Airway responsiveness: stan-
dardized challenge testing with pharmacological, physical and sensi-
tizing stimuli in adults. EurRespirJ19 93: 6: 53 ^ 83.
15. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R,Yernault J.
Lung volumes and forced ventilatory £ows. EurRespirJ19 93 ; 6: 5^40.
16. Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH,
Sterk PJ. Long-term e¡ects of a long-acting b
2
-adrencoceptor ago-
nist, salmeterol, on airway hyperresponsiveness in patients with
mild asthma. N Engl J Med19 9 2 ; 327: 11 9 8 ^ 1 2 0 3 .
17. Yates DH, Sussman HS, Shaw MJ, Barnes PJ, Chung KF. Regular for-
moterol treatment in mild asthma: E¡ect on bronchial responsive-
COMPARISON BET WEEN SHORT-ACTING AND LONG-ACTING 161
Page 7
ness during and after treatment. Am J Respir Crit Care Med 19 95 ; 152 :
1170 ^1174.
18. Barnes PJ. A new approach to the treatmentof asthma.N Engl J Med
1989; 321: 1517^1527.
19. TwentymanOP,FinnertyJP,HarrisA,PalmerJ,HolgateST.Protec-
tion against allergen-induced asthma by salmeterol. Lancet 19 9 0 ;
336: 1338^1342.
20. van Maesen FP, Smeets JJ, Gubbelmans HLL, Zweers PGMA.
Bronchodilator e¡ect of inhaled formoterol vs salbutamol over 12
hours.Chest 19 9 0 ; 97: 590 ^594.
21. Cockcroft DW, McParland CP, Britto SA, Swystun VA, Rutherford
BC. Regular inhaled salbutamol and airway responsiveness to aller-
gen. Lancet 19 93 ; 342: 833^ 837.
22. O’Connor BJ, Aikman SL, Barnes PJ.Tolerance to the nonbroncho-
dilator e¡ects of inhaled b
2
-agonists in asthma. N Engl J Med 19 9 2 ;
327: 120 4 ^12 0 8.
23.MakJCW,NishikawaM,ShirasakiH,MiyayasuK,BarnesPJ.
Protective e¡ects of a glucocorticoid on downregulation of pul-
monary b
2
-adrenergic receptorsin vivo.JClin Invest19 95 ; 96: 99^106.
162 RESPIRATORY MEDICINE
Page 8
    • "The chronic use of SABA was associated with an increased risk of an acute exacerbation that required an emergency department visit or hospitalization.[18–20] Also, a decrease in lung function after stopping chronic use have been reported with a regular use of SABA.[2122] "
    [Show abstract] [Hide abstract] ABSTRACT: A wide range of medications are now available for the treatment of asthma and selection of the optimal treatment combination of agents is essential. This study was designed to evaluate a self-reported drug prescribing pattern for asthma among Nigerian doctors in general practice. It was a cross-sectional survey conducted among general practitioners in six states of Nigeria. For acute severe asthma, 75.9% of the doctors prescribed intravenous methylxanthines, which was combined with oral or inhaled short-acting β(2) agonists (SABA) by 56.3% of them. Systemic steroids were prescribed mainly via the intravenous route by 58.8% of them. Aberrant drugs such as antibiotics, antihistamines, and mucolytics were prescribed by 25.6% of them. For long-term, follow-up treatment of asthma, oral steroids, and oral SABA were commonly prescribed, while inhaled corticosteroids (ICS) and ICS/LABA (long acting beta agonists) were infrequently prescribed. Aberrant drugs such as analgesics, antimalaria, and antihistamines were prescribed by 22.8% of them. About 48% of the doctors had never attended any form of update training on asthma management, whereas, only 16.3% attended update training on asthma within the last year preceding this study. Awareness of international guidelines on asthma treatment was poor among them with only 16.4% being able to mention any correct guideline on asthma management. The poor anti-asthma prescribing behavior among these doctors is associated with a low level of participation at update training on asthma management and poor awareness of asthma guidelines. The Nigerian Medical Association and the Nigerian Thoracic Society should urgently address these problems.
    Full-text · Article · Apr 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Regular use of long acting beta-2 agonist bronchodilator agents in chronic asthma combined with regular preventer medication gives effective asthma control in adults and adolescents. Patients with chronic asthma are generally treated with a 'preventer medication' to reduce the underlying airways inflammation but often require 'relief' bronchodilators for symptoms. Treatment with regular long acting beta-agonist bronchodilator agents, such as salmeterol (Serevent) or formoterol (Foradile, Oxis) resulted in fewer asthma symptoms by day or night, less relief bronchodilator medication requirement, better lung function, a lower risk of acute worsening of asthma and better quality of life. There were no major adverse effects.There is less information on asthma control in patients who do not use a regular 'preventer medication' or in children under twelve years.
    No preview · Article · Feb 2003 · Cochrane database of systematic reviews (Online)
  • [Show abstract] [Hide abstract] ABSTRACT: Background: The regular administration of beta(2)-agonists may be associated with the development of tolerance to their effects. Purpose: To assess the effect of regular beta(2)-agonist use on respiratory function and beta(2)-receptor function in asthmatic patients. Data Sources: Comprehensive searches of the EMBASE, MEDLINE, and CINAHL databases from 1966 to June 2003 and references of identified articles and reviews. Study Selection: Randomized, placebo-controlled trials that studied at least 1 week of regular beta(2)-agonist administration in patients with asthma and did not allow "as-needed" beta(2)-agonist use in the placebo group. Data Extraction: Outcomes measured in the active treatment and placebo groups were the change in FEV, in response to treatment and subsequent beta(2)-agonist administration, the provocative concentration of bronchoconstrictive agents causing a 20% reduction in FEV1 (PC20), and in vitro variables of leukocyte beta(2)-receptor function. Data Synthesis: Pooled results of 22 trials showed that regular beta(2)-agonist use, compared with placebo, did not change the mean FEV, after treatment or the net FEV, treatment effect but substantially reduced the following: the peak FEV, response to subsequent beta(2)-agonist administration (change, -17.8% [95% CI, -27.2% to -8.5%]); the FEV, dose response to subsequent beta(2)agonists (-34.8% [CI, -45.7% to -24%]); the PC20 to combined bronchoconstrictive stimuli (-26% [CI, -37% to -11%]); and leukocyte beta(2)-receptor density (-18.3% [CI, -31.6% to -5.1%]), binding affinity (-23.1% [CI, -39.4% to -6.8%]), and in vitro response to isoproterenol (-32.7% [CI, -56.5% to -9.0%]). Conclusion: Regular beta(2)-agonist use for at least 1 week in patients with asthma results in tolerance to the drug's bronchodilator and nonbronchodilator effects and may be associated with poorer disease control compared with placebo.
    No preview · Article · May 2004 · Annals of internal medicine
Show more

Similar publications

Discover more