Hancox R J, Cowan J O, Flannery E M, Herbison G P, McLachlan C R, Taylor D R
Department of Medicine, University of Otago, Dunedin, New Zealand.
Respir Med. 2000 Aug;94(8):767-71. doi: 10.1053/rmed.2000.0820.
There is uncertainty about the development of airway tolerance to beta-agonists and the phenomenon of rebound bronchoconstriction on beta-agonist withdrawal. We have recently completed a study of the regular terbutaline and budesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flows. The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500-1000 microg four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 weeks following a 4 week single-blind placebo washout. Ipratropium was used for symptom relief. No other asthma medication was permitted during either the treatment or wash-out periods. Evaluable data were obtained from 52 subjects for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the baseline peak flows during the last 2 weeks of the preceding washout. The peak flow changes on stopping terbutaline were also analysed. Mean morning peak flow was not significantly different during terbutaline treatment when compared to either baseline or placebo treatment. Evening peak flows were significantly higher during terbutaline treatment [mean increase 23.1 l min(-1) (95% CI = 18.8, 27.4)]. Analysis of the peak flow changes on a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19.2 and 13.41 min(-1) [increases of 25.0 and 17.31 min(-1) in comparison with the corresponding values during placebo (P<0.01)] followed by a return to baseline. The increase in evening peak flows was also greater for the first 2 days of treatment than for the remainder of the treatment period (P<0.01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the following morning of 21.6 l min(-1) (P<0.05 compared to placebo). The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the development of tolerance to the bronchodilator effect of terbutaline. Similarly, the fall in morning peak flows on treatment withdrawal suggests rebound bronchoconstriction. These effects are likely to be mediated by downregulation of the beta-receptor during treatment. The clinical significance of these changes is uncertain in view of the stability of overall asthma control during terbutaline treatment, but sudden withdrawal of beta-agonist treatment could conceivably lead to a deterioration in asthma control.
气道对β-激动剂产生耐受性的发展以及β-激动剂撤药后出现的反跳性支气管收缩现象尚存在不确定性。我们最近完成了一项关于哮喘患者常规使用特布他林和布地奈德治疗的研究。我们报告了开始和停止特布他林治疗对早晚峰值流速影响的观察结果。该研究是一项随机四组、双盲、交叉对照试验，比较了常规吸入特布他林（每日4次，每次500 - 1000微克）、布地奈德、联合治疗以及匹配的安慰剂。在为期4周的单盲安慰剂洗脱期后，每种治疗均持续6周。异丙托溴铵用于缓解症状。在治疗期或洗脱期均不允许使用其他哮喘药物。从52名受试者获得了安慰剂和特布他林治疗的可评估数据。将特布他林治疗期间早晚平均峰值流速的变化与前一洗脱期最后2周的基线峰值流速进行比较。还分析了停止特布他林治疗后的峰值流速变化。与基线或安慰剂治疗相比，特布他林治疗期间早晨平均峰值流速无显著差异。特布他林治疗期间晚上峰值流速显著更高[平均增加23.1升/分钟(95%可信区间 = 18.8, 27.4)]。按天分析峰值流速变化显示，治疗的前2天早晨峰值流速最初增加，分别为19.2和13.4升/分钟[与安慰剂期间相应值相比增加25.0和17.3升/分钟(P<0.01)]，随后恢复到基线。治疗的前2天晚上峰值流速的增加也大于治疗期的其余时间(P<0.01)。停止特布他林治疗后的次日早晨，平均早晨峰值流速降至基线以下21.6升/分钟(P<0.05，与安慰剂相比)。治疗的前2天早晨峰值流速的暂时增加以及晚上峰值流速大于预期的升高表明对特布他林的支气管扩张作用产生了耐受性。同样，治疗撤药后早晨峰值流速的下降表明出现了反跳性支气管收缩。这些效应可能是由治疗期间β受体下调介导的。鉴于特布他林治疗期间哮喘总体控制的稳定性，这些变化的临床意义尚不确定，但β-激动剂治疗的突然撤药可能会导致哮喘控制恶化。
