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Nocturnal asthma: Effect of treatment with oral sustained-release terbutaline, inhaled budesonide, and the two in combination
turnal asthma: Effect of treatment wit sustained-release terbutaline, inhale esonide, and the two in combinatio maid Dahl, MD,* Bente Pedersen, Aarhus, Denmark, and Lund, Sweden
MD,* and Bjiirn Hlggliif,
Ph
The purpose of this study was to compare effect of treatment with an oral long-acting fI,-agonist (sustained-release terbutaline, Bricanyl depot), an inhaled steroid (budesonide, Pulmicort), and the combined treatment in patients with nocturnal asthma. Thirty-seven patients completed the study. During a l-week run-in period with inhaled terbutaline monotherapy, the mean nocturnal asthma score was 1 .O (+- 0.1) (corresponding to one awakening every night), and the mean overnight fall in peak expiratory Jlow rate was 27.7% ( ? 2 II). The patients were randomly entered into double-blind, crossover periods of 3 weeks each: (I) sustained-release terbutaline, 10 mg twice daily (b.i.d.), (2) sustained-release terbutaline, 10 mg b.i.d., and two puffs (400 pg) of budesonide, b.i.d., and (3) two puffs (400 pg) of budesonide, b.i.d. The combined treatment resulted in sign$cantly lower overnight fall in peak expiratory flow rate (6.9% IL 1.4 compared to 9.4% -C 2.0 during sustained-release terbutaline and 10.4% 2 1.9 during budesonide) and less nocturnal awakenings (nocturnal asthma score 0.15 ? 0.05, 0.43 t 0.09, and 0.26 & 0.06, respectively) than either single treatment alone (p < 0.05). The dtrerences between the single treatments were not sign$cant. We thus found that an inhaled steroid is as effective as a long-acting oral P,-agonist in controlling nocturnal asthma and that the combination is better. The observed difSerences were, however, small, and other studies would be required to evaluate the clinical signijcance of the present jnding. (.i rhLLERGr CLIN MMuNOL
1989;83:81I-5 .)
Patients with asthma very often experience a worsening of symptoms at night and in the early morning with a concomitant overnight reduction in airway function. I* 2 The mechanism of this “morning dip” remains uncertain. It has recently, however, been hypothesized that the comparatively large changes in airway tone at night in asthma are due to a coincidence of circadian variations in several biologic rhythms.3 Most relevant appears to be the association between the amplitude of diurnal variation in peak flow and nonspecific hyperresponsiveness, a hallmark of asthma, and the observation that hyperresponsiveness in subjects with asthma is markedly increased at night.4, ’ The most common approach in treating nocturnal
From the *Department of Respiratory Diseases, University of Aarhus, Aarbus, Denmark, and **Department of Exploratory Clinical Research, AB Draco, Lund, Sweden. Received for publication Nov. 13, 1987. Accepted for publication Oct. 20, 1988. Reprint requests: Ronald Dahl, MD, Department of Respiratory Diseases, University of Aarhus, DK-8000 Aarhus C, Denmark.
Abbreviations used
b.i.d.: Twice daily PEFR: Forced expiratory flow rate (liters per minute)
asthma has been to administer oral lo~g~act~~g bronchodilators, although it is debated whether (&agonists or methylxanthines are the most effective.6, 7 Neither bronchodilator has, however, any effect on basal nonspecific hyperresponsiveness in asthma.8*9 It would appear logical therefore to include an inhaled steroid that is the only kind of therapy that has convi~ci~~~y demonstrated a reduction in bronchial hyperresponsiveness . ‘04’ The present investigation was undertaken to compare an oral sustained-release B2-agonist (terbutaline, Bricanyl depot; Draco, Lund, Sweden), an inhaled steroid (budesonide, Pnlmicort; Draco) , and the combined therapy for the treatment of nocturna1 asthma. Testing the combination was of particular interest because of the recognition that
12
Dahl et al.
i. ALLERGYCLIN.iMMljNOL. APRIL
1989
PEFR
% predicted 100
0”
Wlorning
Evening l-22
RI T .B C
FIG. 1, A comparison of FEV,, FVC, PEFR, and percentage period (mean -t SEM). RI, run-in; T, sustained-release nation treatment; *p < 0.05, C compared to T and B,
RI T B C overnight fail in PEFR for each treatment terbutaline; 8, budesonide; C, combi-
Mean symptom .wore 3
3
iaries
Hospital visits
2
Day(O-3)
Night (O-3)
1
0
Night (O-4)
Day (O-3)
1
TBC
TBC
0
RI
T
BC
RtT
c
FIG. 2. A comparison of daytime and nocturnal asthma symptom scores recorded at each visit to the hospital and in diaries for each treatment period (mean i SEM). R/, run-in; z sustainedrelease terbutaline; f3, budesonide; C, combination treatment; *p < 0.05, C compared to T and B.
and steroids appear to have additive effect on daytime asthma and exercise-induced asthma.‘*’ I3 FurtImmore, Horn et aLI have recently demonstrated in a retrospective analysis that steroids combined with &-agonists might be very effective in treating morning dips and nocturnal symptoms. PATlENtS AND METHODS Patient selection Outpatients with mild to moderate atopic or nonatopic asthmawere seIected for this study according to the follow-
ing criteria: (1) presently treated with inhaled and/or oral p,-agonists only, (2) age between 16 and 67 years, (3) >20% improvement in FEV, after inhalation of 1.25 mg of terbutaline from a metered-dose inhaler, (4) no acute airway infecrionsiastbma exacerbations during the last 2 months, and (5) at least three overnight falls in PEFR of >20% and awakening caused by nocturnal symptoms at least three nights during a l-week run-in period.
After a I-week run-in period (we found it not possible to prolong the run-in period and to include a placebo period
because of the presence of nocturnal symptoms) with inhaled terbutaline monotherapy, patients were randomized to double-blind treatment (double-dummy technique) for four 3-week crossover periods. For two consecutive periods, treatment consisted of sustained-release ter~~tali~e tablets, 10 mg, and two puffs of inhaled placebo, b.i.d. The two other periods consisted of either sustained-release terbutaline, 10 mg, and two puffs of inhaled b~deso~~de (one puff equals 200 kg), b.i.d., or placebo and two puffs of inhaled budesonide, b.i.d. The patients were instructed to take the study medication at 8 AM and at 8 PM. Additional inhaled terbutaline, as was required, was allowed throughout the study. The study was approved by the ethical committee of Aarhus County.
Evaluation The patients reported to the hospital for clinical evahzation after the run-in period and after each of the four ITeatment periods. On each occasion, baseline spirometry (FEW, and FVC) was carried out at 8 AM before intake of any medication. The patients were also actively questioned about daytime and nighttime asthma symptoms, tremor, and palpitations, according to the following scale: 0, none; 1, mild; 2, moderate; 3, severe. After the end of the
VOLUME NUMBER
Treatment of nocturnal
83 4
asthma
I. A comparison of each treatment regimen on daytime and nocturnal adverse-e~~eri~~c~ scores recorded at each hospital visit and during the last 2 weeks in each treatment period
Hospital
Tremor Treatment period
Day
Run-in Sustained-release 0.21 r 0.08 terbutaline 0.09 rt 0.05 Budesonide 0.51 ? O.llt Combination treatment
visits
(O-3)
Diary scores
Palpitations
Night
(O-3) Night
Day
0.03 r 0.03
0.03 37 0.03
0.06 k 0.04 0.03 rtr 0.03
020 0.32 ? O.llt
020 ozto 0.05 + 0.04
DW
bigot
0.02 2 0.01 0.17 I? 0.07
0.03 rfr 0.03 0.08 + 0.06
0.07 + 0.04* 0.12 ?Z0.05
0.03 + 0.03 0 It ot
Comparisonsbetween treatments: *p < 5.55; bndesonidecompared to terbutaline alone and combination treatment. 7,~< 0.05; combination treatment comparedto terbutaline alone and budesonidealone.
study, the patients were askedwhich period treatmentthey preferred. Each patient maintained a diary. Morning and evening PEFR were recorded (Wright’s mini-peak expiratory flowmeter)before taking the medication. Daytime asthmasymptoms and daytime and nighttime adverseexperienceswere recorded according to the same 0 to 3 scale. Nighttime asthma symptomswere registered as follows: 0, no awakenings; 1%awake once; 2, awake two to three times; 3, awakefour to six times; 5, awake most of the night because of asthma symptoms. The number of puffs of inhaled terbutaline taken during the day and at night were also registered. tatistkal
analysis
The first of the two periods with active sustained-release terbutaline and inhaled placebo was considered as steroid washout and therefore not included in the analysis. Diarycard variables are presentedas daily means from the runin week and daily means for the two last weeks in each treatment period. Lung-function variables were analyzedby two-way analysis of variance, symptom and adverseexperiencescoresby Wilcoxon’s signed-ranktest, carryover effects by Wilcoxon’s rank-sum test, and preference by Friedman’s test, 5% being the chosen level of significance.
A total of 43 adult patients with asthma were entered into the study. Six patients completed only one treatmentperiod and were not included in the analysis, one patient withdrew becauseof intolerance to treatment, and another four patients withdrew becauseof severe worsening of symptoms during sustainedrelease terbutaline treatment. One patient withdrew becauseof worsening during treatment with budesonide. Thus, data from 37 patients were included in the analysis. Twenty-three patients had intrinsic
asthma, and 14 patients had extrinsic asthma. There were 23 male and 14 female patients, ranging in age from 17 to 66 years (mean age, 43.8 years) with an averageduration of diseaseof 7.9 years. At admission to the study, when the patients had not taken inhaled P,-agonists during the previous 4 hours, the mean FEV, value was 2.4 L ( ?Z 0.2) and mean WC, 3.5 L ( +- 0.2). Reversibility after inhalation of 1.25 mg of terbutaline was 25.7% (2 2.5). During the l-week run-in period, the mean nocturnal awakening score caused by asthma was I.0 ( t 0.1) (corresponding to one ‘awakening every night), and the mean overnight fall in PEF 27.7% (k 2). Evaluation Carry over effects. Becauseof the fact that treatments were randomized, the possibility that the effect of inhaled steroids can have a carryover effect into the next treatmentperiod was analyzed. effect was demonstrated(p > 0.5). Lung-function variables. There were no significant differencesin FEV, and FVC (measuredat the en each treatment period at the hospital) between the treatmentregimens. As illustrated in Fig. 1, the PEFR values (in percent of predicted normal) during the combined treatment (morning, 82.4 i 3.5; evening, 87.3 +- 3.3) were significantly higher tban during sustained-releaseterbutaline (morning, 76.1 + 3.2; evening, 80.9 2 3.O) and budesonide treatment alone (morning, 78.0 i. 4.0; evening, 84.3 ?I 3.8), consequently resulting in a significantly lower overnight fall in PEFR during the combined treatment (p < 0.05). Asthma symptoms. There were no significant differencesbetween the treatment regimens jr~ daytime
DahC et al.
J. ALLERGY
CLIN. IMFdlJNOL. APRIL 1989
Night
T
c
RI T B C
FIG. 3. A comparison of the number of puffs of inhaled terbutaline taken during the day and night of each treatment period (mean e SEMI. R/, run-in; T, sustainedrelease terbutaline; B, budesonide; C, combination treatment; *p, < 0.05, B and C compared to T.
and nocturnal asthma symptom scores recorded at hospital visits or on daytime symptoms recorded in the diaries (Fig. 2). The combination treatment, however, resulted in a significantly lower nocturnal symptom score, compared to sustained-release terbutaline treatment alone (p < 0.05). Adverse experiences. The combination treatment, presented in Table I, resulted in significantly more daytime tremor and palpitations than either treatment alone when this was specifically asked for at the hospital visits (p < 0.05). The corresponding nocturnal scores were generally considerably lower, and no such differences were demonstrated between the three regimens. Analysis of the diary adverse-experience scores revealed significantly less daytime adverse exeriences during budesonide treatment than during the two other treatment periods (p < 0.05). In contrast, when the nocturnal scores were compared, there were significantly less adverse experiences during the combined treatment compared to the two other regimens (p < 0.05). Additional medication. The concomitant daily number of puffs of inhaled terbutaline, illustrated in Fig. 3, was significantly lower during treatment with budesonide and the combination compared to the treatment period with sustained-release terbutaline (p =C0.05). The number of puffs needed during the night was significantly less during the combined
FIG. 4. Patient’s subjective preference of treatment period. T, sustained-release terbutaline; B, budesonide; C, combination treatment; *p < 0.05, B compared to 7 and C,
treatment than during the two other treatment periods (p < 0.05). Preference. The patients’ subjective preference of treatment period is illustrated in Fig. 4. Forty-three percent had no preference, 30% preferred budesonide treatment compared to 16% for the combination treatment, and 11% preferred sustained-release t~rb~taline treatment, which is significantly in favor of budesonide (p < 0.05). DISCUSSlO The importance of an adequate treatment for morning dips and nocturnal asthma is emphasized by the fact that wide diurnal variations in airway function are associated with an increased risk of sudden death at night, l5 Long-acting oral bro~~bod~ators (i.e., &agonists or methylxanthines) are undoubtedly effective, although they do not normalize the diurnal variation and do not reduce basal bronchial byperresponsiveness that might be an important ~antrib~ti~g factor. The role of inhaled steroids in the treatment of nocturnal asthma has not been systematically investigated in comparative trials, although they do reduce hyperresponsiveness. Our results demonstrate that nocturnal symptoms and morning dips can be effectively treated with both oral sustained-release terbutaline or inhaled budesonide alone. The combination of the tw-o treatments, however, elicited a further significant reduction in overnight fall in PEFR and awakenings during the night. Nocturnal adverse experiences were virtualiy absent during the combination treatment, probably be-
VOLUME NUMBER
83 4
Treatment of nocturnai asthma
REFERENCES cause of a better overall control of asthma and thus nings. This was also indicated by less need *I. Turner-Warwick M. Definition and recognition of noctttmal asthma. In: Barnes PJ, Levy .I, eds. Nocturnal asthma. London: for concomitant use of inhaled terbutaline during the Royal Society of Medicine, 1984:3. combined treatment. In the studied patients with rel2. Lewinshon HC, Cape1 LH, Smart J. Changes in forced expiatively mild asthma, the overnight fall in PEFR was ratory volume throughout the day. Br Med 3 1960;1:462. reduced from about 27% during the run-in period to 3. Barnes PJ. Circadian variation in airway function. JAMA 7% during the combined treatment, which is in the 1985;79:5. 4. Ryan 6, Latimer KM, Dolovich .I, Hargreave FE. Bronchial same range as in normal subjects.“j The differences responsiveness to histamine: relationship to diurnal variation between the treatments were small, however, and in peak flow rate, improvement after bronchodilator, and airother studies would be required to evaluate the clinical way calibre. Thorax 1982;37:432. significance of the present finding. 5. de Vries K, Goei JT, Booij-Noord H, Grie NGM. Changes during 24 hours in the lung function and histamine reactivity In contrast to what was found for nocturnal asthma, of the bronchial tree in asthmatic and bronchitic subjects. Int there were no differences between the three treatment Arch Allergy 1962;20:93. regimens on lung function measured at the hospital 6. Barnes PJ. Nocturnal asthma: mechanisms and treatment. Br visits and on daytime asthma symptoms. Daytime Med J 1984;288(6428):1397. tremor and palpitations were more frequent during the 7. Westemrann CJJ, Van Weelden BM, Laros CD. Sustainedtreatments involving sustained-release terbutaline, release terbutaline in nocturnal asthma. Allergy 1986;41:308. 8. Koeter GH, Meurs H, Jo&man JHG, Greving J, Leferink J; and daytime diary adverse-symptom scores were Sluiter HJ, de Zeew RA, de Vries K. Protective effect of oral lower during budesonide treatment compared to the oxyphenonium bromide, terbutaline, and tbeophylline against other two treatments. The use of a long-acting oral the bronchial obstructive effects of inhaled histamine, acetyl&agonist, b.i.d., is not conventional therapy for choline, and propanolol. Em J Clin Pharmacol 1984;26:435, nocturnal asthma, and therefore, the problem of 9. Kraan J, Koeter GH, vd Mark TW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of adverse experiences during the day would probably treatment with antiasthmatic drugs in patients with allergic not be encountered if inhaled ($-agonists were used asthma: a comparison between budesonide and terbutaline. during the day together with the oral dose in the J ALLERGY CLANIMMUNOL 1985;76:628. evening. 10. Hartley JPR. The effect of budesonide on bronchial hypeneactivity. In: Hogg JC, Ellul-Micallef R, Brattsand R, eds. GlucoIt is notable that significantly more patients precorticosteroids, inflammation, and hyperreactivity. Basel: ferred budesonide treatment compared to the other two Exerpta Medica, 1984: 10. treatments, a difference which cannot be explained 11. Kraan J, Koeter GH, vd Mark T, Boorsma M; Kukler J, Sluiter in terms of efficacy or adverse experiences. In this HJ, de Vries K. Dosage and time effects of inhaled budesonide respect it could be important to study the effects of on bronchial hyperreactivity. Am Rev Respir Dis 19&X:137:44. these drug regimens on diurnal rhythms in bronchial 12. Dahl R, Johansson SA. Effect on lung function of budesonide by inhalation, terbutaline s.c., and placebo given simultahyperresponsiveness. neously or as single treatments. Em J Respir Dis 1982; The results of the present study correlate well with 63(suppl 12):132. results of a retrospective analysis by Horn et a1.14 13. Henriksen JM, Dahl R. Effect of inhaled budesonide alone and demonstrating additional effects of inhaled P,-agonist in combination with low-dose terbutaline in children with exercise-induced asthma. Am Rev Respir Dis 1983;128:993. and inhaled steroid in the treatment of morning dips. 14. Horn CR, Clark TJH, Cochrane GM. Inhaled therapy reduces Our results lend further support to the concept that morning dips in asthma. Lancet 1984;1:1143. an inhaled steroid should be added to an inhaled 15. Cochrane GM, Clark THJ. A survey of asthma mortality in @,-agonist as a first-line therapy for nocturnal patients between ages 35 and 64 in the Greater London hosasthma. Adding a long-acting oral P,-agonist propitals in 1971. Thorax 1975;30:300. 16. Kerr HD. Diurnal variation of respiratory function independent vides additional benefit in patients not adequately of air quality. Arch Environ Health 1973;26:144. controlled.
MD,* and Bjiirn Hlggliif,
Ph
The purpose of this study was to compare effect of treatment with an oral long-acting fI,-agonist (sustained-release terbutaline, Bricanyl depot), an inhaled steroid (budesonide, Pulmicort), and the combined treatment in patients with nocturnal asthma. Thirty-seven patients completed the study. During a l-week run-in period with inhaled terbutaline monotherapy, the mean nocturnal asthma score was 1 .O (+- 0.1) (corresponding to one awakening every night), and the mean overnight fall in peak expiratory Jlow rate was 27.7% ( ? 2 II). The patients were randomly entered into double-blind, crossover periods of 3 weeks each: (I) sustained-release terbutaline, 10 mg twice daily (b.i.d.), (2) sustained-release terbutaline, 10 mg b.i.d., and two puffs (400 pg) of budesonide, b.i.d., and (3) two puffs (400 pg) of budesonide, b.i.d. The combined treatment resulted in sign$cantly lower overnight fall in peak expiratory flow rate (6.9% IL 1.4 compared to 9.4% -C 2.0 during sustained-release terbutaline and 10.4% 2 1.9 during budesonide) and less nocturnal awakenings (nocturnal asthma score 0.15 ? 0.05, 0.43 t 0.09, and 0.26 & 0.06, respectively) than either single treatment alone (p < 0.05). The dtrerences between the single treatments were not sign$cant. We thus found that an inhaled steroid is as effective as a long-acting oral P,-agonist in controlling nocturnal asthma and that the combination is better. The observed difSerences were, however, small, and other studies would be required to evaluate the clinical signijcance of the present jnding. (.i rhLLERGr CLIN MMuNOL
1989;83:81I-5 .)
Patients with asthma very often experience a worsening of symptoms at night and in the early morning with a concomitant overnight reduction in airway function. I* 2 The mechanism of this “morning dip” remains uncertain. It has recently, however, been hypothesized that the comparatively large changes in airway tone at night in asthma are due to a coincidence of circadian variations in several biologic rhythms.3 Most relevant appears to be the association between the amplitude of diurnal variation in peak flow and nonspecific hyperresponsiveness, a hallmark of asthma, and the observation that hyperresponsiveness in subjects with asthma is markedly increased at night.4, ’ The most common approach in treating nocturnal
From the *Department of Respiratory Diseases, University of Aarhus, Aarbus, Denmark, and **Department of Exploratory Clinical Research, AB Draco, Lund, Sweden. Received for publication Nov. 13, 1987. Accepted for publication Oct. 20, 1988. Reprint requests: Ronald Dahl, MD, Department of Respiratory Diseases, University of Aarhus, DK-8000 Aarhus C, Denmark.
Abbreviations used
b.i.d.: Twice daily PEFR: Forced expiratory flow rate (liters per minute)
asthma has been to administer oral lo~g~act~~g bronchodilators, although it is debated whether (&agonists or methylxanthines are the most effective.6, 7 Neither bronchodilator has, however, any effect on basal nonspecific hyperresponsiveness in asthma.8*9 It would appear logical therefore to include an inhaled steroid that is the only kind of therapy that has convi~ci~~~y demonstrated a reduction in bronchial hyperresponsiveness . ‘04’ The present investigation was undertaken to compare an oral sustained-release B2-agonist (terbutaline, Bricanyl depot; Draco, Lund, Sweden), an inhaled steroid (budesonide, Pnlmicort; Draco) , and the combined therapy for the treatment of nocturna1 asthma. Testing the combination was of particular interest because of the recognition that
12
Dahl et al.
i. ALLERGYCLIN.iMMljNOL. APRIL
1989
PEFR
% predicted 100
0”
Wlorning
Evening l-22
RI T .B C
FIG. 1, A comparison of FEV,, FVC, PEFR, and percentage period (mean -t SEM). RI, run-in; T, sustained-release nation treatment; *p < 0.05, C compared to T and B,
RI T B C overnight fail in PEFR for each treatment terbutaline; 8, budesonide; C, combi-
Mean symptom .wore 3
3
iaries
Hospital visits
2
Day(O-3)
Night (O-3)
1
0
Night (O-4)
Day (O-3)
1
TBC
TBC
0
RI
T
BC
RtT
c
FIG. 2. A comparison of daytime and nocturnal asthma symptom scores recorded at each visit to the hospital and in diaries for each treatment period (mean i SEM). R/, run-in; z sustainedrelease terbutaline; f3, budesonide; C, combination treatment; *p < 0.05, C compared to T and B.
and steroids appear to have additive effect on daytime asthma and exercise-induced asthma.‘*’ I3 FurtImmore, Horn et aLI have recently demonstrated in a retrospective analysis that steroids combined with &-agonists might be very effective in treating morning dips and nocturnal symptoms. PATlENtS AND METHODS Patient selection Outpatients with mild to moderate atopic or nonatopic asthmawere seIected for this study according to the follow-
ing criteria: (1) presently treated with inhaled and/or oral p,-agonists only, (2) age between 16 and 67 years, (3) >20% improvement in FEV, after inhalation of 1.25 mg of terbutaline from a metered-dose inhaler, (4) no acute airway infecrionsiastbma exacerbations during the last 2 months, and (5) at least three overnight falls in PEFR of >20% and awakening caused by nocturnal symptoms at least three nights during a l-week run-in period.
After a I-week run-in period (we found it not possible to prolong the run-in period and to include a placebo period
because of the presence of nocturnal symptoms) with inhaled terbutaline monotherapy, patients were randomized to double-blind treatment (double-dummy technique) for four 3-week crossover periods. For two consecutive periods, treatment consisted of sustained-release ter~~tali~e tablets, 10 mg, and two puffs of inhaled placebo, b.i.d. The two other periods consisted of either sustained-release terbutaline, 10 mg, and two puffs of inhaled b~deso~~de (one puff equals 200 kg), b.i.d., or placebo and two puffs of inhaled budesonide, b.i.d. The patients were instructed to take the study medication at 8 AM and at 8 PM. Additional inhaled terbutaline, as was required, was allowed throughout the study. The study was approved by the ethical committee of Aarhus County.
Evaluation The patients reported to the hospital for clinical evahzation after the run-in period and after each of the four ITeatment periods. On each occasion, baseline spirometry (FEW, and FVC) was carried out at 8 AM before intake of any medication. The patients were also actively questioned about daytime and nighttime asthma symptoms, tremor, and palpitations, according to the following scale: 0, none; 1, mild; 2, moderate; 3, severe. After the end of the
VOLUME NUMBER
Treatment of nocturnal
83 4
asthma
I. A comparison of each treatment regimen on daytime and nocturnal adverse-e~~eri~~c~ scores recorded at each hospital visit and during the last 2 weeks in each treatment period
Hospital
Tremor Treatment period
Day
Run-in Sustained-release 0.21 r 0.08 terbutaline 0.09 rt 0.05 Budesonide 0.51 ? O.llt Combination treatment
visits
(O-3)
Diary scores
Palpitations
Night
(O-3) Night
Day
0.03 r 0.03
0.03 37 0.03
0.06 k 0.04 0.03 rtr 0.03
020 0.32 ? O.llt
020 ozto 0.05 + 0.04
DW
bigot
0.02 2 0.01 0.17 I? 0.07
0.03 rfr 0.03 0.08 + 0.06
0.07 + 0.04* 0.12 ?Z0.05
0.03 + 0.03 0 It ot
Comparisonsbetween treatments: *p < 5.55; bndesonidecompared to terbutaline alone and combination treatment. 7,~< 0.05; combination treatment comparedto terbutaline alone and budesonidealone.
study, the patients were askedwhich period treatmentthey preferred. Each patient maintained a diary. Morning and evening PEFR were recorded (Wright’s mini-peak expiratory flowmeter)before taking the medication. Daytime asthmasymptoms and daytime and nighttime adverseexperienceswere recorded according to the same 0 to 3 scale. Nighttime asthma symptomswere registered as follows: 0, no awakenings; 1%awake once; 2, awake two to three times; 3, awakefour to six times; 5, awake most of the night because of asthma symptoms. The number of puffs of inhaled terbutaline taken during the day and at night were also registered. tatistkal
analysis
The first of the two periods with active sustained-release terbutaline and inhaled placebo was considered as steroid washout and therefore not included in the analysis. Diarycard variables are presentedas daily means from the runin week and daily means for the two last weeks in each treatment period. Lung-function variables were analyzedby two-way analysis of variance, symptom and adverseexperiencescoresby Wilcoxon’s signed-ranktest, carryover effects by Wilcoxon’s rank-sum test, and preference by Friedman’s test, 5% being the chosen level of significance.
A total of 43 adult patients with asthma were entered into the study. Six patients completed only one treatmentperiod and were not included in the analysis, one patient withdrew becauseof intolerance to treatment, and another four patients withdrew becauseof severe worsening of symptoms during sustainedrelease terbutaline treatment. One patient withdrew becauseof worsening during treatment with budesonide. Thus, data from 37 patients were included in the analysis. Twenty-three patients had intrinsic
asthma, and 14 patients had extrinsic asthma. There were 23 male and 14 female patients, ranging in age from 17 to 66 years (mean age, 43.8 years) with an averageduration of diseaseof 7.9 years. At admission to the study, when the patients had not taken inhaled P,-agonists during the previous 4 hours, the mean FEV, value was 2.4 L ( ?Z 0.2) and mean WC, 3.5 L ( +- 0.2). Reversibility after inhalation of 1.25 mg of terbutaline was 25.7% (2 2.5). During the l-week run-in period, the mean nocturnal awakening score caused by asthma was I.0 ( t 0.1) (corresponding to one ‘awakening every night), and the mean overnight fall in PEF 27.7% (k 2). Evaluation Carry over effects. Becauseof the fact that treatments were randomized, the possibility that the effect of inhaled steroids can have a carryover effect into the next treatmentperiod was analyzed. effect was demonstrated(p > 0.5). Lung-function variables. There were no significant differencesin FEV, and FVC (measuredat the en each treatment period at the hospital) between the treatmentregimens. As illustrated in Fig. 1, the PEFR values (in percent of predicted normal) during the combined treatment (morning, 82.4 i 3.5; evening, 87.3 +- 3.3) were significantly higher tban during sustained-releaseterbutaline (morning, 76.1 + 3.2; evening, 80.9 2 3.O) and budesonide treatment alone (morning, 78.0 i. 4.0; evening, 84.3 ?I 3.8), consequently resulting in a significantly lower overnight fall in PEFR during the combined treatment (p < 0.05). Asthma symptoms. There were no significant differencesbetween the treatment regimens jr~ daytime
DahC et al.
J. ALLERGY
CLIN. IMFdlJNOL. APRIL 1989
Night
T
c
RI T B C
FIG. 3. A comparison of the number of puffs of inhaled terbutaline taken during the day and night of each treatment period (mean e SEMI. R/, run-in; T, sustainedrelease terbutaline; B, budesonide; C, combination treatment; *p, < 0.05, B and C compared to T.
and nocturnal asthma symptom scores recorded at hospital visits or on daytime symptoms recorded in the diaries (Fig. 2). The combination treatment, however, resulted in a significantly lower nocturnal symptom score, compared to sustained-release terbutaline treatment alone (p < 0.05). Adverse experiences. The combination treatment, presented in Table I, resulted in significantly more daytime tremor and palpitations than either treatment alone when this was specifically asked for at the hospital visits (p < 0.05). The corresponding nocturnal scores were generally considerably lower, and no such differences were demonstrated between the three regimens. Analysis of the diary adverse-experience scores revealed significantly less daytime adverse exeriences during budesonide treatment than during the two other treatment periods (p < 0.05). In contrast, when the nocturnal scores were compared, there were significantly less adverse experiences during the combined treatment compared to the two other regimens (p < 0.05). Additional medication. The concomitant daily number of puffs of inhaled terbutaline, illustrated in Fig. 3, was significantly lower during treatment with budesonide and the combination compared to the treatment period with sustained-release terbutaline (p =C0.05). The number of puffs needed during the night was significantly less during the combined
FIG. 4. Patient’s subjective preference of treatment period. T, sustained-release terbutaline; B, budesonide; C, combination treatment; *p < 0.05, B compared to 7 and C,
treatment than during the two other treatment periods (p < 0.05). Preference. The patients’ subjective preference of treatment period is illustrated in Fig. 4. Forty-three percent had no preference, 30% preferred budesonide treatment compared to 16% for the combination treatment, and 11% preferred sustained-release t~rb~taline treatment, which is significantly in favor of budesonide (p < 0.05). DISCUSSlO The importance of an adequate treatment for morning dips and nocturnal asthma is emphasized by the fact that wide diurnal variations in airway function are associated with an increased risk of sudden death at night, l5 Long-acting oral bro~~bod~ators (i.e., &agonists or methylxanthines) are undoubtedly effective, although they do not normalize the diurnal variation and do not reduce basal bronchial byperresponsiveness that might be an important ~antrib~ti~g factor. The role of inhaled steroids in the treatment of nocturnal asthma has not been systematically investigated in comparative trials, although they do reduce hyperresponsiveness. Our results demonstrate that nocturnal symptoms and morning dips can be effectively treated with both oral sustained-release terbutaline or inhaled budesonide alone. The combination of the tw-o treatments, however, elicited a further significant reduction in overnight fall in PEFR and awakenings during the night. Nocturnal adverse experiences were virtualiy absent during the combination treatment, probably be-
VOLUME NUMBER
83 4
Treatment of nocturnai asthma
REFERENCES cause of a better overall control of asthma and thus nings. This was also indicated by less need *I. Turner-Warwick M. Definition and recognition of noctttmal asthma. In: Barnes PJ, Levy .I, eds. Nocturnal asthma. London: for concomitant use of inhaled terbutaline during the Royal Society of Medicine, 1984:3. combined treatment. In the studied patients with rel2. Lewinshon HC, Cape1 LH, Smart J. Changes in forced expiatively mild asthma, the overnight fall in PEFR was ratory volume throughout the day. Br Med 3 1960;1:462. reduced from about 27% during the run-in period to 3. Barnes PJ. Circadian variation in airway function. JAMA 7% during the combined treatment, which is in the 1985;79:5. 4. Ryan 6, Latimer KM, Dolovich .I, Hargreave FE. Bronchial same range as in normal subjects.“j The differences responsiveness to histamine: relationship to diurnal variation between the treatments were small, however, and in peak flow rate, improvement after bronchodilator, and airother studies would be required to evaluate the clinical way calibre. Thorax 1982;37:432. significance of the present finding. 5. de Vries K, Goei JT, Booij-Noord H, Grie NGM. Changes during 24 hours in the lung function and histamine reactivity In contrast to what was found for nocturnal asthma, of the bronchial tree in asthmatic and bronchitic subjects. Int there were no differences between the three treatment Arch Allergy 1962;20:93. regimens on lung function measured at the hospital 6. Barnes PJ. Nocturnal asthma: mechanisms and treatment. Br visits and on daytime asthma symptoms. Daytime Med J 1984;288(6428):1397. tremor and palpitations were more frequent during the 7. Westemrann CJJ, Van Weelden BM, Laros CD. Sustainedtreatments involving sustained-release terbutaline, release terbutaline in nocturnal asthma. Allergy 1986;41:308. 8. Koeter GH, Meurs H, Jo&man JHG, Greving J, Leferink J; and daytime diary adverse-symptom scores were Sluiter HJ, de Zeew RA, de Vries K. Protective effect of oral lower during budesonide treatment compared to the oxyphenonium bromide, terbutaline, and tbeophylline against other two treatments. The use of a long-acting oral the bronchial obstructive effects of inhaled histamine, acetyl&agonist, b.i.d., is not conventional therapy for choline, and propanolol. Em J Clin Pharmacol 1984;26:435, nocturnal asthma, and therefore, the problem of 9. Kraan J, Koeter GH, vd Mark TW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of adverse experiences during the day would probably treatment with antiasthmatic drugs in patients with allergic not be encountered if inhaled ($-agonists were used asthma: a comparison between budesonide and terbutaline. during the day together with the oral dose in the J ALLERGY CLANIMMUNOL 1985;76:628. evening. 10. Hartley JPR. The effect of budesonide on bronchial hypeneactivity. In: Hogg JC, Ellul-Micallef R, Brattsand R, eds. GlucoIt is notable that significantly more patients precorticosteroids, inflammation, and hyperreactivity. Basel: ferred budesonide treatment compared to the other two Exerpta Medica, 1984: 10. treatments, a difference which cannot be explained 11. Kraan J, Koeter GH, vd Mark T, Boorsma M; Kukler J, Sluiter in terms of efficacy or adverse experiences. In this HJ, de Vries K. Dosage and time effects of inhaled budesonide respect it could be important to study the effects of on bronchial hyperreactivity. Am Rev Respir Dis 19&X:137:44. these drug regimens on diurnal rhythms in bronchial 12. Dahl R, Johansson SA. Effect on lung function of budesonide by inhalation, terbutaline s.c., and placebo given simultahyperresponsiveness. neously or as single treatments. Em J Respir Dis 1982; The results of the present study correlate well with 63(suppl 12):132. results of a retrospective analysis by Horn et a1.14 13. Henriksen JM, Dahl R. Effect of inhaled budesonide alone and demonstrating additional effects of inhaled P,-agonist in combination with low-dose terbutaline in children with exercise-induced asthma. Am Rev Respir Dis 1983;128:993. and inhaled steroid in the treatment of morning dips. 14. Horn CR, Clark TJH, Cochrane GM. Inhaled therapy reduces Our results lend further support to the concept that morning dips in asthma. Lancet 1984;1:1143. an inhaled steroid should be added to an inhaled 15. Cochrane GM, Clark THJ. A survey of asthma mortality in @,-agonist as a first-line therapy for nocturnal patients between ages 35 and 64 in the Greater London hosasthma. Adding a long-acting oral P,-agonist propitals in 1971. Thorax 1975;30:300. 16. Kerr HD. Diurnal variation of respiratory function independent vides additional benefit in patients not adequately of air quality. Arch Environ Health 1973;26:144. controlled.