Bronchodilators, fatal asthma, rebound effect and similitude

Sir,

After the publication of my article ‘Evidence of the principle of similitude in modern fatal iatrogenic events’,[ ¹ ] new evidence was published which I brought to the attention of your readers through a Letter to the Editor.[ ² ] In a similar way to the non-steroidal anti-inflammatory drugs (NSAIDs),[ ³ ] important new studies were recently published reinforcing the hypothesis that long-acting bronchodilators (β-agonists) may increase the risk for severe or fatal asthma exacerbations, as a consequence of the irreversible paradoxical bronchospasm (rebound effect of modern pharmacology or vital reaction of the homeopathic model).

After numerous scientific protests, since GlaxoSmithKline presented the partial data of the ‘Salmeterol Multicenter Asthma Research Trial (SMART)’ at the Annual International Scientific Assembly of The American College of Chest Physicians in 2003, claiming that ‘the interim analysis was inconclusive’, the full results of the 26,355 randomized subjects were published in 2006. Exploratory analyses of each outcome event within subpopulations were conducted, finding a significant increase in respiratory-related deaths (RR 2.16, 95% CI 1.06–4.41) and asthma-related deaths (RR 4.37, 95% CI 1.25–15.34), and in combined asthma-related deaths or life-threatening experiences (RR 1.71, 95% CI 1.01–2.89) in subjects receiving salmeterol vs placebo. African-American subpopulation was particularly affected (compared with Caucasian subjects): respiratory-related deaths or life-threatening experiences (RR 4.10, 95% CI 1.54–10.90) and combined asthma-related deaths or life-threatening experiences (RR 4.92, 95% CI 1.68–14.45) in subjects receiving salmeterol vs placebo.[ ⁴ ]

In 2006, Salpeter et al published a meta-analysis of 19 randomized, placebo-controlled trials involving 33,826 participants with asthma followed for 16,848 patient-year (mean trial duration 6.0 months). Approximately 15% of the participants were African-American. The long-acting β-agonists used in the studies were salmeterol, formoterol, and eformoterol. During the trials, concomitant inhaled corticosteroids were used in approximately 53% of participants in both groups. The objective of the study was to assess the effects of long-acting β-agonists on severe asthma exacerbations requiring hospitalization, life-threatening asthma attacks, and asthma-related deaths. Subgroup analyses compared results for salmeterol and formoterol and for children and adults.[ ⁵ ]

The OR for hospitalization was 2.6 (95% CI 1.6–4.3) for long-acting β-agonists compared with placebo. The authors did not include SMART in this analysis because the investigators did not provide information on hospitalization due to asthma, just life-threatening exacerbations. When they include the SMART data on life-threatening exacerbations, the OR was 2.1 (95% CI 1.5–3.0). The risk for hospitalization was increased with salmeterol (OR 1.7, 95% CI 1.1–2.7), formoterol (OR 3.2, 95% CI 1.7–6.0), children (OR 3.9, 95% CI 1.7–8.8) and adults (OR 2.0, 95% CI 1.0–3.9).

The OR for life-threatening asthma attacks attributed to long-acting β-agonists was 1.8 (95% CI 1.1–2.9), and did not differ significantly between trials of salmeterol and formoterol or between children and adults. The OR for asthma-related deaths was obtained from the SMART (OR 3.5, 95% CI 1.3–9.3, P = 0.013). In general, the risks for severe exacerbations and asthma-related deaths were increased by 2- to 4-fold.

In terms of physiologic explanation of the phenomenon, the authors associate the regular β-agonist use with tolerance to the drugs’ effects and a worsening of disease control.[ ^6–11 ] This effect results from a negative feedback mechanism on the β-adrenergic system, an adaptive response to stimulation of receptors. Uncoupling and internalization of receptors, known as ‘desensitization’, are followed by a decrease in receptor density and receptor gene expression, known as ‘downregulation’.[ ¹² ] Regular use of β-agonists increases bronchial hyperreactivity despite maintenance of some degree of bronchodilation. These effects, along with a reduction in response to subsequent rescue β-agonists use, may worsen asthma control without giving any warning of increased symptoms.[ ^11,13 ]

Although the term ‘rebound effect’ was not used in the meta-analysis, several studies have confirmed that ‘rebound hyperreactivity’ occurs after interruption of bronchodilation (primary action; enantiopathic or antipathetic effect), with ‘rebound bronchoconstriction’ (secondary action, vital or homeostatic reaction) and a worsening of asthma.[ ^14–17 ] The authors separately evaluated trials in which more than 75% of participants were receiving concomitant inhaled corticosteroids and found that the risk for hospitalizations was still increased 2-fold (OR 2.1, 95% CI 1.3–3.4), evidencing the importance of the rebound effect in the organic physiology.

Asthma mortality rates increased worldwide in the 1960s, when inhaled β-agonists were introduced on the market,[ ^18–21 ] with a further increment in the last decade since long-acting β-agonists were introduced.[ ^22–24 ] In this meta-analysis, the absolute increase in asthma-related deaths was estimated to be 0.06–0.07% over 6 months, indicating that long-acting β-agonists cause an excess of approximately 1 death per 1000 patient-years of use. Salmeterol is one of the most widely prescribed medications on the world, with an estimated 3.5 million adults treated in the United States in 2004,[ ^25,26 ] this indicates that the salmeterol may be responsible for approximately 4000–5000 asthma-related deaths that occur in the United States each year (3.5 million adults represent, approximately, 20% of the total of asthmatic of the United States).[ ²⁷ ]

Asthma is often underdiagnosed or undertreated or inappropriately treated and approximately 350 million people worldwide currently have the disease.[ ²⁸ ] If long-acting β-agonists were used by 10% of this population, according to the modern treatment guidelines,[ ²⁹ ] we would expect 40,000–50,000 additional deaths per year in the world.

Describing the sad results that the enanthiopathic or antipathic method of treatment can cause in individuals, Hahnemann emphasized the importance of using the homoeopathic method in the treatment of the chronic diseases:

‘Had physicians been capable of reflecting on the sad results of the antagonistic employment of medicines, they had long since discovered the grand truth, that the true radical healing art must be found in the exact opposite of such an antipathic treatment of the symptoms of disease; they would have become convinced, that as a medicinal action antagonistic to the symptoms of the disease (an antipathically employed medicine) is followed by only transient relief, and after that is passed, by invariable aggravation, the converse of that procedure, the homoeopathic employment of medicines according to similarity of symptoms, must effect a permanent and perfect cure […].’ (Organon, paragraph 61).

• References

• 1 Teixeira M.Z. Evidence of the principle of similitude in modern fatal iatrogenic events. Homeopathy 2006; 95: 229-236.
• 2 Teixeira M.Z. Letter to the Editor: NSAIDs, Myocardial infarction, rebound effect and similitude. Homeopathy 2007; 96: 67-68.
• 3 Teixeira M.Z. NSAIDs, myocardial infarction, rebound effect and similitude. Homeopathy 2007; 96: 67-68.
• 4 Nelson H.S., Weiss S.T., Bleecker E.R., Yancey S.W., Dorinsky P.M. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129: 15-26.
• 5 Salpeter S.R., Buckley N.S., Ormiston T.M., Salpeter E.E. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006; 144: 904-912.
• 6 Kraan J., Koeter G.H., vd Mark T.W., Sluiter H.J., de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol 1985; 76: 628-636.
• 7 Sears M.R., Taylor D.R., Print C.G. et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391-1396.
• 8 Lipworth B.J. Risks versus benefits of inhaled beta 2-agonists in the management of asthma. Drug Saf 1992; 7: 54-70.
• 9 Wahedna I., Wong C.S., Wisniewski A.F., Pavord I.D., Tattersfield A.E. Asthma control during and after cessation of regular beta 2-agonist treatment. Am Rev Respir Dis 1993; 148: 707-712.
• 10 Suissa S., Blais L., Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near-fatal asthma. Eur Respir J 1994; 7: 1602-1609.
• 11 Salpeter S.R., Ormiston T.M., Salpeter E.E. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med 2004; 140: 802-813.
• 12 Johnson M. The beta-adrenoceptor. Am J Respir Crit Care Med 1998; 158 Pt 3 S146-S153.
• 13 van Schayck C.P., Bijl-Hofland I.D., Cloosterman S.G., Folgering H.T., van der Elshout F.J., Van Weel C. Potential masking effect on dyspnoea perception by short- and long-acting beta2-agonists in asthma. Eur Respir J 2002; 19: 240-245.
• 14 Newcomb R., Tashkin D.P., Hui K.K., Conolly M.E., Lee E., Dauphinee B. Rebound hyperresponsiveness to muscarinic stimulation after chronic therapy with an inhaled muscarinic antagonist. Am Rev Respir Dis 1985; 132: 12-15.
• 15 Vathenen A.S., Knox A.J., Higgins B.G., Britton J.R., Tattersfield A.E. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988; 1: 554-558.
• 16 de Jong J.W., van der Mark T.W., Koeter G.H., Postma D.S. Rebound airway obstruction and responsiveness after cessation of terbutaline: effects of budesonide. Am J Respir Crit Care Med 1996; 153: 70-75.
• 17 Hancox R.J., Cowan J.O., Flannery E.M., Herbison G.P., McLachlan C.R., Taylor D.R. Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment. Respir Med 2000; 94: 767-771.
• 18 Stolley P.D. Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. Am Rev Respir Dis 1972; 105: 883-890.
• 19 Baagoe K.H. The epidemic of asthma mortality in the 1960's. Aerosol spray as cause of the deaths. Ugeskr Laeger 1976; 138: 2708-2711.
• 20 Keating G., Mitchell E.A., Jackson R., Beaglehole R., Rea H. Trends in sales of drugs for asthma in New Zealand, Australia, and the United Kingdom, 1975–81. Br Med J (Clin Res Ed) 1984; 289 6441 348-351.
• 21 Mormile F., Chiappini F., Feola G., Ciappi G. Deaths from asthma in Italy (1974–1988): Is there a relationship with changing pharmacological approaches?. J Clin Epidemiol 1996; 49: 1459-1466.
• 22 Pearce N., Beasley R., Crane J., Burgess C., Jackson R. End of the New Zealand asthma mortality epidemic. Lancet 1995; 345: 41-44.
• 23 Beasley R., Pearce N., Crane J., Burgess C. Beta-agonists: What is the evidence that their use increases the risk of asthma morbidity and mortality?. J Allergy Clin Immunol 1999; 104 Pt 2 S18-S30.
• 24 Hussey P.S., Anderson G.F., Osborn R. et al. How does the quality of care compare in five countries?. Health Aff (Millwood) 2004; 23: 89-99.
• 25 Patterns of medication use in the United States 2004. A report from the Slone Survey. Boston: Slone Epidemiology Center at Boston University; 2004. Available on: ⟨ http://www.bu.edu/slone/SloneSurvey/AnnualRpt/SloneSurveyReport2004.pdf ⟩
• 26 The World Factbook. United States. Washington, DC: Central Intelligence Agency; 2005.
• 27 National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Program Description. Bethesda, MD: National Institute of Health; 2005.
• 28 Humbert M. The right tools at the right time. Chest 2006; 130 (Suppl. 01) 29S-40S.
• 29 Denlinger L.C., Sorkness C.A., Chinchilli V.M., Lemanske Jr. R.F. Guideline-defining asthma clinical trials of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network. J Allergy Clin Immunol 2007; 119: 3-11.