Abstract
Rationale: Unblinded studies have shown improvements in airway hyperresponsiveness with chronic nadolol in steroid-naive patients with asthma.
Objectives: To assess the effects of chronic nonselective β-blockade as add-on to inhaled corticosteroids (ICS) in patients with asthma.
Methods: A double-blind randomized placebo-controlled crossover trial of propranolol in patients with mild-to-moderate asthma receiving ICS was performed. Participants underwent a 6- to 8-week dose titration of propranolol or placebo as tolerated to a maximum of 80 mg per day. Tiotropium was given for the first 4 to 6 weeks of each treatment period.
Measurements and Main Results: Primary outcome was methacholine challenge. Secondary outcomes included histamine challenge, pulmonary function, mini-asthma quality of life questionnaire (mini-AQLQ), and asthma control questionnaire (ACQ). Eighteen patients completed (mean [SEM]): age, 36 (4) yr; FEV1%, 93 (2); ICS, 440 (66) μg/d. No significant difference was observed in methacholine or histamine challenge after exposure to propranolol versus placebo. For methacholine challenge, the doubling dilution difference was 0.04 (95% confidence interval [CI], −0.56 to 0.63), P = 0.89. Albuterol recovery at 20 minutes after histamine challenge was partially attenuated by propranolol versus placebo: FEV1% mean difference, 5.28 (95% CI, 2.54–8.01), P = 0.001. After chronic β-blockade there was a small worsening in FEV1 % predicted of 2.4% (95% CI, −0.1 to 4.8), P = 0.055. No difference was found for ACQ or mini-AQLQ.
Conclusions: This is the first placebo-controlled study to assess the effects of chronic nonselective β-blockade in asthma, showing no significant effect of propranolol compared with placebo on either methacholine or histamine airway hyperresponsiveness and no change in ACQ or AQLQ.
Clinical trial registered with www.clinicaltrials.gov (NCT01074853).
β-Blockers are avoided in asthma due to the risk of potential bronchospasm. Despite these concerns, open-label studies have suggested that there may be a potential therapeutic role for β-blocker use on airway hyperresponsiveness (AHR) in asthma, with studies to date being performed in steroid-naive patients with asthma.
Our placebo-controlled trial assesses the effects of chronic nonselective β-blockade as add-on to inhaled corticosteroids in patients with stable persistent asthma, reporting no significant effect of propranolol compared with placebo on AHR, with no significant change in asthma control or quality of life, but with only partial attenuation of acute albuterol recovery after challenge.
Discovered in 1964 by the late Nobel Laureate Sir James Black, propranolol is an example of a nonselective β-blocker, which revolutionized the treatment of hypertension and ischemic heart disease due to negative inotropic and chronotropic effects (1). However, during this early period of drug discovery, concerns grew with reports of potentially severe bronchospasm in patients with asthma after β-blocker use, especially on acute exposure to high doses (2). The use of β-blockers, regardless of selectivity, is thus contraindicated in asthma. Despite these concerns, coprescription of β-blockers and β-agonists in asthma has been reported (3). Furthermore, a metaanalysis of cardioselective β-blocker use in reactive airways disease has shown that although there was a mean 7.5% fall in FEV1 after single dosing, no significant fall in FEV1 was seen with chronic β-blocker use (4).
The evolution of the management of heart failure has shown the paradox between acute and chronic effects of β-adrenoceptor antagonism. Despite the potentially acute deleterious effects on cardiac function in heart failure, chronic β-blocker use results in beneficial effects on both ejection fraction and morbidity and mortality (5). The ability to tolerate β-blockers in heart failure was achieved by gradually increasing the dose, and as a result β-blockers are now considered part of standard therapy. This heart failure paradox prompted some researchers to reexamine the putative therapeutic role of β-blockade in asthma, questioning whether, despite the potential acute deleterious effects, there were any benefits of chronic β-blockade. This hypothesis was also fueled by emerging data suggesting chronic exposure to long-acting β-agonists may worsen asthma control due to β2-adrenoceptor down-regulation and associated desensitization of response, in turn pointing to the possibility that that antagonist of the agonist might be beneficial in causing the opposite effects (6, 7).
The first evidence in support of this hypothesis was derived from studies using the ovalbumin-sensitized mouse model of asthma, with chronic exposure to nadolol producing bronchoprotection against methacholine challenge (a direct-acting cholinergic spasmogen that induces airway hyperresponsiveness [AHR]), in conjunction with reduced airway inflammation and mucous metaplasia, and simultaneous up-regulation of airway β2-adrenoreceptors (8–10). These initial studies led to two open-label pilot studies in steroid-naive patients with asthma, with chronic nadolol dosing achieving significant improvements in methacholine-induced AHR compared with baseline (11, 12). These results might appear to be counterintuitive, since anticholinergic medication prevents β-blocker–induced bronchoconstriction (13). Hence, one would predict that β-blockers would increase rather than decrease cholinergic tone, therefore resulting in augmented methacholine responsiveness. This in turn questions as to whether the previously observed reduction in methacholine response with β-blockers is specific to the cholinergic pathway per se, or whether attenuated AHR to other spasmogens not acting through the muscarinic receptor, such as histamine, would also be demonstrated.
We first of all investigated the safety of acute exposure to propranolol in patients with asthma, and, reassuringly, we showed that nebulized albuterol and ipratropium bromide produced a full recovery of pulmonary function after acute β2-adrenoceptor blockade and sequential histamine-induced bronchoconstriction (14).
To assess the putative effects of propranolol on AHR, we decided to use both methacholine and histamine challenge to evaluate different signaling direct-acting pathways on airway smooth muscle. Due to ethical concerns regarding the safety of propranolol, especially on initial exposure, we decided to evaluate effects of β-blockade in stable patients with asthma controlled on inhaled corticosteroid (ICS), to mitigate the risk of potentially inducing acute bronchoconstriction in the presence of untreated asthmatic inflammation. To further reduce this risk of propranolol-induced bronchoconstriction, we also covered patients in the up-titration phase with concomitant tiotropium. With these reassurances, we have now examined the safety and effects of chronic propranolol use versus placebo in patients with mild-to-moderate asthma taking ICS. Some of the results of this study have been previously reported in the form of an abstract (15).
A double-blind randomized placebo-controlled crossover trial was performed (Figure 1). The Tayside Medical Research Ethics Committee gave approval before commencement of the trial. The study was registered with http://www.clinicaltrials.gov (NCT01074853).
Figure 1. Study diagram. Shown are procedures performed at each study visit. S: screen visit. Spirometry, methacholine bronchial challenge, exhaled nitric oxide (FeNO), heart rate (HR), and blood pressure (BP) were performed. V1: first observed dose of propranolol or placebo. Spirometry, HR, and BP were performed before and after dosing. V2: histamine bronchial challenge (with concomitant tiotropium) with staged albuterol and ipratropium recovery. Spirometry, HR, and BP performed before challenge and after recovery. V3: methacholine bronchial challenge with staged albuterol and ipratropium recovery. Spirometry, HR, and BP were performed before challenge and after recovery. V4: histamine bronchial challenge (without concomitant tiotropium) with staged albuterol and ipratropium recovery. Spirometry, HR, and BP were performed before challenge and after recovery. FeNO was performed before challenge. V5: crossover of treatment limbs. First observed dose of propranolol or placebo. Spirometry, HR, and BP were performed before and after dosing. V6: histamine bronchial challenge (with concomitant tiotropium) with staged albuterol and ipratropium recovery. Spirometry, HR, and BP were performed before challenge and after recovery. V7: methacholine bronchial challenge with staged albuterol and ipratropium recovery. Spirometry, HR, and BP were performed before challenge and after recovery. V8: histamine bronchial challenge (without concomitant tiotropium) with staged albuterol and ipratropium recovery. Spirometry, HR, and BP were performed before challenge and after recovery. FeNO was performed before challenge. ICS = inhaled corticosteroid.
[More] [Minimize]Patients with persistent mild-to-moderate asthma, aged between 18 and 65 years, with FEV1 greater than 80% predicted and diurnal FEV1 variation less than 30%, who were taking ICS less than or equal to 1,000 μg beclomethasone per day or equivalent were recruited. Participants were required to demonstrate AHR to methacholine bronchial challenge with a provocation concentration causing a 20% fall in FEV (PC20) less than 8 mg/ml. Participants were all nonsmokers. Exclusion criteria included: an asthma exacerbation within the last 6 months, resting systolic blood pressure less than 110 mm Hg, heart rate less than 60 bpm, history of arrhythmias, and concurrent negative chronotropic medications.
After a screening visit to assess eligibility, a 1- to 2-week run-in period to assess asthma disease stability was performed using electronic domiciliary FEV1 measurements, before randomization. Participants continued their normal dose of ICS throughout the study. Participants who usually took a combination inhaler of ICS and long-acting β2-agonist (LABA) were switched to the equivalent dose of ICS only for the duration of the study. For reliever use, participants were issued with both ipratropium bromide and albuterol to be used in a staged fashion as required (i.e., ipratropium as first-line reliever, followed if necessary by albuterol as second line).
Participants underwent initial dose titration with either propranolol or matched placebo at weekly intervals (10 mg twice daily, 20 mg twice daily, 80 mg long-acting once daily) as tolerated over a 2- to 4-week period, based on the dose titration algorithm (see online data supplement).
After the first dose of propranolol or placebo, and at every subsequent up-titration visit, participants were observed within the department for 3 hours, with serial pulmonary function recorded. Once the maximal dose of propranolol or placebo was established, the treatment was then continued for a further 4 weeks (plateau phase). Tiotropium was given concurrently throughout the dose titration period and for the first 2 weeks of the plateau phase. In total, each treatment limb (including dose titration and plateau phase) continued for a minimum of 6 weeks and maximum of 8 weeks of randomized treatments.
Participants were seen at weekly intervals for assessment of FEV1 domiciliary measurements, spirometry, blood pressure, and heart rate. Participants’ symptoms and physiological measurements were considered, and randomized treatment was titrated up or down accordingly. Blinding and randomization were performed by St May’s Pharmaceutical Unit, Cardiff and Vale University LHB, Wales, UK.
The primary outcome, methacholine challenge PC20 followed by sequential albuterol and ipratropium bromide reversibility, was performed at the end of each treatment period. Histamine challenge PC20 with reversibility was performed after 2 weeks of plateau phase with concurrent tiotropium and 4 weeks of plateau phase (i.e., with no concurrent tiotropium). At each bronchial challenge visit, participants had sequential measurements of heart rate and blood pressure recorded, before and after albuterol. After completion of the first treatment limb, participants received their usual ICS alone for a 2-week period before crossover. Participants were allowed to continue any antihistamines and leukotriene receptor antagonists throughout the study, with the exception of stopping for 5 days before any bronchial challenge test visit.
Spirometry was performed in accordance with published guidelines (16). A SuperSpiro spirometer (Micro Medical, Kent, UK) was used. A Mefar dosimeter was used for methacholine and histamine bronchial challenges. The PC20 was calculated.
Data were assessed for normality with the Shapiro-Wilk test and box plots. The primary outcome was methacholine PC20. The null hypothesis was that there was no significant difference in methacholine PC20 after propranolol compared with placebo. An a priori calculation predicted 16 patients would ensure 80% power, with an α error of 0.05 (two tailed), to detect a minimal important difference of one doubling dilution shift in methacholine PC20. For methacholine and histamine challenge, data were logarithmically transformed before analysis and then calculated as doubling dose/dilution change from placebo. For all outcomes, comparisons were made by a multifactorial analysis of variance model, including sequence, visit, treatment, and patient effects, with Bonferroni corrections for pairwise comparisons. For albuterol and ipratropium bromide recovery after bronchial challenge testing, areas under the time response curve for percentage change from baseline were calculated. All analysis was performed using SPSS version 18.
Twenty-one participants were randomized, of whom 18 participants (10 women, 8 men) completed per protocol. Mean age (SEM) was 36 (4) years. Seventeen participants achieved dose titration to the maximal propranolol dose. Baseline characteristics are shown in Table 1. Three participants withdrew during the study due to practical difficulties in completing study visits, symptomatic hypotension (103/62 mm Hg), and lower respiratory tract infection (Figure 2).
| Subject/Sex | Age, yr | FEV1% | FEV1/FVC Ratio | Methacholine PC20, mg/ml | BDP Equivalent Daily Dose, μg | Concurrent Medications |
|---|---|---|---|---|---|---|
| 1/F | 21 | 92 | 0.78 | 0.92 | 400 | LABA, A, NS |
| 2/F | 64 | 99 | 0.71 | 2.48 | 400 | LABA, LT, NS |
| 3/F | 31 | 85 | 0.75 | 0.99 | 500 | A, LT |
| 4/M | 48 | 85 | 0.68 | 2.0 | 500 | LABA, LT |
| 5/F | 65 | 103 | 0.69 | 0.71 | 200 | — |
| 6/M | 29 | 98 | 0.71 | 1.36 | 100 | — |
| 7/M | 57 | 106 | 0.81 | 3.45 | 1,000 | NS |
| 8/M | 20 | 91 | 0.76 | 3.71 | 400 | — |
| 9/F | 19 | 91 | 0.83 | 0.67 | 400 | A |
| 10/M | 19 | 90 | 0.85 | 1.73 | 200 | A |
| 11/F | 25 | 91 | 0.85 | 2.4 | 200 | A |
| 12/F | 50 | 88 | 0.67 | 1.13 | 400 | A, NS |
| 13/M | 57 | 88 | 0.76 | 2.19 | 200 | A, NS |
| 14/F | 22 | 102 | 0.82 | 0.67 | 800 | — |
| 15/M | 35 | 95 | 0.83 | 5.42 | 800 | LABA, NS |
| 16/F | 46 | 91 | 0.72 | 0.31 | 1,000 | LABA |
| 17/F | 21 | 85 | 0.75 | 3.31 | 200 | — |
| 18/M | 25 | 86 | 0.76 | 0.1 | 200 | LABA, A |
| Mean (SEM) | 36 (4) | 93 (2) | 0.76 (0.01) | 1.32 (0.81–2.15)* | 440 (66) |
No significant difference was observed in methacholine challenge PC20 after chronic propranolol exposure compared with placebo: geometric mean, 2.57 mg/ml (95% confidence interval [CI], 1.13–5.85) versus 2.50 mg/ml (95% CI, 1.14–5.50) (i.e., a mean doubling dilution difference [DDD] of 0.04 [95% CI, −0.56 to 0.63], P = 0.89) (Figure 3). After 2 weeks of chronic dosing with propranolol while receiving concurrent tiotropium, no significant difference was seen with histamine challenge PC20 for propranolol versus placebo: geometric mean, 2.11 mg/ml (95% CI, 1.33–3.33) versus 2.52 mg/ml (95% CI, 1.64–3.85) (i.e., a DDD of 0.26 [95% CI, −0.36 to 0.87], P = 0.39) (Figure 4).
Figure 3. The effect of chronic treatment with propranolol on methacholine provocation concentration causing a 20% fall in FEV (PC20). Data for each participant are displayed as the doubling dose in methacholine PC20 values between propranolol versus placebo. Mean doubling dilution difference: 0.04 (95% confidence interval, −0.56 to 0.63), P = 0.89.
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Figure 4. The effect of chronic treatment with propranolol on histamine provocation concentration causing a 20% fall in FEV (PC20) with and without tiotropium. (A) Histamine challenge with concurrent tiotropium. Mean doubling dilution difference: 0.26 (95% confidence interval, −0.36 to 0.87), P = 0.39. (B) Histamine challenge without concurrent tiotropium. Data for each participant are displayed as the doubling dose in histamine PC20 values between propranolol versus placebo. Mean doubling dilution difference: 0.42 (95% confidence interval, −0.09 to 0.93), P = 0.10.
[More] [Minimize]After the cessation of tiotropium for 14 days, after a further 2 weeks of chronic dosing with propranolol, no significant difference was seen with histamine challenge PC20 for propranolol versus placebo: geometric mean, 1.73 mg/ml (95% CI, 1.10–2.73) versus 2.32 (95% CI, 1.65–3.27) (i.e., a DDD of 0.42 [95% CI, −0.09 to 0.93], P = 0.10) (Figure 4).
Albuterol-induced chronotropic response, measured at the end of each study period, (i.e., recovery after histamine challenge, study visit four or eight) was significantly blunted after propranolol in comparison with placebo: mean difference, 25 bpm (95% CI, 14–37), P < 0.001. Resting heart rate was also significantly lower after chronic propranolol dosing: mean difference, 5 bpm (95% CI, 1–9), P < 0.001.
No differences were seen for supine systolic or diastolic blood pressure at the end of each study period (visit four or eight) for placebo versus propranolol: mean difference, 3 mm Hg (95% CI, −1 to 7), P = 0.11, and 2 mm Hg (95% CI, −2 to 5), P = 0.26.
After methacholine challenge, staged recovery to nebulized albuterol and ipratropium showed a significant overall difference between propranolol and placebo: area under the curve (AUC) (%⋅min) (SEM), 4,077.4 (102) versus 4,362.5 (102); mean difference, 285.1 (95% CI, 34.6–535.7), P = 0.028. No significant difference was seen at 20 minutes after albuterol for propranolol versus placebo: FEV1% predicted mean difference, 5.05 (95% CI, −0.13 to 10.24), P = 0.055 (Figure 5).
Figure 5. Albuterol and ipratropium recovery after methacholine challenge. Data are displayed as mean (95% confidence interval). The overall difference is displayed for area under the curve (%⋅min), propranolol versus placebo. P = 0.028.
[More] [Minimize]Comparisons of recovery after histamine challenges while receiving concurrent tiotropium showed a significant difference in staged albuterol and ipratropium recovery for propranolol versus placebo: AUC (%⋅min) (SEM), 4,082.9 (94) versus 4,413.6 (97); mean difference, 330.8 (95% CI, 208.8–452.8), P = 0.01. Furthermore, at 20 minutes after albuterol, the response was significantly different for propranolol versus placebo: FEV1% predicted mean difference, 4.94 (95% CI, 1.10–8.79), P = 0.015 (Figure 6).
Figure 6. Albuterol and ipratropium recovery after histamine challenge with and without concurrent tiotropium. (A) Histamine challenge with concurrent tiotropium. The overall difference is displayed for area under the curve (%⋅min), propranolol versus placebo. P = 0.01. (B) Histamine challenge without concurrent tiotropium. Data displayed as mean (95% confidence interval). The overall difference is displayed for area under the curve (%⋅min), propranolol versus placebo. P = 0.016.
[More] [Minimize]After the cessation of tiotropium, after a further 2 weeks of chronic dosing with propranolol, there remained a significant difference versus placebo in staged albuterol and ipratropium recovery: AUC (%⋅min) (SEM), 4,061.8 (94) versus 4,363.7 (99); mean difference, 301.8 (95% CI, 190.5–413.1), P = 0.016. A significant difference was present at 20 minutes after albuterol for propranolol versus placebo: FEV1% predicted mean difference, 5.28 (95% CI, 2.54–8.01), P = 0.001 (Figure 6).
FEV1% predicted before methacholine challenge, without concurrent tiotropium, (study visit three or seven) showed a fall with propranolol versus placebo amounting to 4.3% (95% CI, −0.6 to 9.2), P = 0.08. Measured at the end of each study period (i.e., study visit four or eight), before histamine challenge, there was a decrease in FEV1% predicted of 2.4% (95% CI, −0.1 to 4.8), P = 0.055 without tiotropium, and a decrease of 3.2% (95% CI, 0.05–6.3), P = 0.046 with concomitant tiotropium (at study visit two or six).
In terms of airway inflammation measured by fractional exhaled nitric oxide, there was no significant difference after propranolol versus placebo: geometric mean (SEM), 28.0 ppb (10.1) versus 25.3 ppb (7.6), amounting to a geometric mean fold difference of 1.11 (95% CI, 0.70–1.16), P = 0.41.
At study baseline, mean ACQ and AQLQ were 0.83 (95% CI, 0.6–1.06) and 5.99 (95% CI, 5.62–6.32), respectively. At the end of the study period, no significant difference was found between propranolol versus placebo for ACQ: mean difference, 0.18 (95% CI, −0.23 to 0.58), P = 0.79. Furthermore, no significant difference was seen in the mini-AQLQ: mean difference, 0.14 (95% CI, −0.19 to 0.46), P = 0.84. Greater reliever use was seen while receiving propranolol; however, this difference was not significant: mean difference, 4 puffs (per treatment limb) (95% CI, −4 to 12), P = 0.29.
The purpose of our study was to assess the effects of chronic propranolol in patients with stable persistent asthma as add-on therapy to ICSs. In terms of the primary outcome, we showed no significant effect of carefully titrating propranolol compared with placebo on either methacholine or histamine AHR, although there was significant partial attenuation of the post-challenge recovery response to acute albuterol. Moreover, chronic propranolol treatment was not associated with any significant worsening of asthma control or quality of life, albeit in carefully selected steroid-treated stable patients with asthma.
Previous open-label studies have shown attenuation of methacholine AHR with nadolol compared with baseline in steroid-naive patients with asthma (11, 12), in contrast to the present study wherein no effect on AHR was seen in patients already receiving ICSs. One possible explanation might be that concomitant corticosteroids in the present study might have resulted in prior up-regulation of β2-adrenoceptors, as has been previously shown in vivo (17, 18). Thus, the presence of corticosteroid might conceivably have masked any subtle effects due to propranolol induced up-regulation (19). Another possibility is that concomitant ICS had already attenuated AHR (20), such that one would be unlikely to detect any further improvement with propranolol given its relatively weak antiinflammatory activity. In vitro studies have shown a corticosteroid-sparing effect of β-blockers (21), such that one might see an additive effect of propranolol on AHR when used in patients receiving a lower dose of ICS. However, if, for example, it transpired that propranolol improves AHR compared with placebo but only in steroid-naive patients with asthma, then one could cogently argue that this is clinically much less important, because it is unlikely that one would give a β-blocker as first-line controller therapy instead of ICS.
Although using β-blockers in asthma may at first sight seem counterintuitive, there is evidence to suggest that chronic LABA therapy with ICS use results in down-regulation and subsensitivity of the β2-adrenoceptor (22, 23), sometimes with worsening asthma control (24, 25). Therefore, the paradox for potential β2-adrenoceptor up-regulation and increased sensitivity after chronic β-blocker use in asthma is intriguing (6). As LABAs are only prescribed in patients with asthma in conjunction with ICS, when examining the effects of chronic β-blocker use in asthma, it could be argued that this should also be performed as add-on therapy to preexisting ICS, as was the case in the present trial. Moreover, because this was the first ever placebo-controlled trial with propranolol, due to potential ethical concerns, we elected to enroll patients who were already controlled on ICS, rather than risking acute bronchospasm in steroid-naive patients. Unlike previous open-label chronic dosing studies with nadolol in steroid-naive patients (11, 12), we showed no attenuation of AHR to methacholine after chronic propranolol compared with placebo when added to ICS. Pointedly, even when using a spasmogen such as histamine acting via a different pathway to methacholine, we still showed no difference in comparison to placebo, regardless of presence or absence of concurrent tiotropium use.
In the absence of any worsening of AHR, it could be assumed that the presumed deleterious chronic effects of β2-blockade in asthma might conceivably result in increased airway tone. At the final visit before histamine challenge we observed a small worsening in FEV1% predicted after propranolol compared with placebo, amounting to a 2.4% difference; this was despite systemic β2-blockade being evident as attenuation of albuterol-induced tachycardia. There was, however, a small but significant worsening of albuterol recovery after histamine challenge with or without the presence of concomitant tiotropium. The same blunting of response was seen with albuterol recovery after methacholine challenge. The rationale for using concurrent long-acting anticholinergic therapy was to obviate any initial worsening of airway caliber during the initial up-titration with propranolol (13), when patients would be most vulnerable before adaptive β2-adrenoceptor up-regulation had occurred, which is believed to take at least 2 weeks with propranolol on peripheral blood mononuclear cell cAMP response to isoprenaline (26, 27). However, data on β2-adrenoceptor binding density on peripheral blood mononuclear cells with propranolol has shown near maximal up-regulation after only 2 days, reaching a peak after 10 days (19).
When reviewing historic case reports of β-blocker use in patients with asthma, the greatest concerns of bronchoconstriction have been with acute dosing. We have previously demonstrated that nebulized albuterol and ipratropium can achieve a full recovery of pulmonary function after histamine challenge testing despite the presence of 10 or 20 mg of propranolol given as single acute dose in steroid-treated patients with asthma (14). In the present study we have shown by means of slow dose titration that doses of propranolol up to 80 mg can be well tolerated in patients with stable steroid-treated persistent asthma, without any associated deleterious effects on ACQ or AQLQ. Indeed, the mean differences in either ACQ or AQLQ were well within the accepted minimal important difference of 0.5 units for both outcomes. This finding alone would challenge current clinical equipoise that patients with asthma should never be given a β-blocker, let alone a nonselective agent like propranolol (28). This in turn may suggest that, as in heart failure, chronic β-blockade can be given relatively safely to patients with controlled asthma taking ICS, when given by a gradual dose escalation regime, while allowing the β2-adrenoceptors to adapt.
Although we have not seen any significant deleterious effects of chronic propranolol dosing within our carefully chosen patients with asthma, we also failed to see any beneficial effects in comparison to placebo control. Despite propranolol and nadolol both being nonselective β-blockers, whether the use of the former has affected our findings is unclear. In this regard, both drugs exhibit in vitro inverse agonist activity (i.e., an ability to effectively switch off the receptor) as well as acting as conventional competitive receptor antagonists (29). Propranolol exhibits a slightly higher β2-adrenoceptor binding affinity compared with nadolol, although nadolol appears to be a stronger inverse agonist (30). Nonetheless, we observed evidence of marked systemic β2-adrenoceptor blockade as evidenced by complete blunting of the albuterol-induced heart rate response by propranolol.
In conclusion, we have shown in a placebo-controlled study of carefully selected stable steroid-treated patients with asthma that careful titration of nonselective β-blockers may be safe to use without any worsening of AHR and only a small effect on prechallenge pulmonary function, along with partial attenuation of post-challenge albuterol recovery.
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Funded by the Chief Scientist Office for Scotland grant CZB/4/716.
The Chief Scientist Office for Scotland had no other role in the trial, except for supplying finance and peer reviewing the original grant application. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Author Contributions: P.M.S., P.A.W., W.J.A., and B.J.L. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201212-2206OC on April 17, 2013
Author disclosures are available with the text of this article at www.atsjournals.org.
