Published: May 1999


Adverse Respiratory Reactions to Long-acting Beta-agonists

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Prescriber Update 18: 24-28
May 1999

Dr. D. Robin Taylor, Senior Lecturer in Medicine, University of Otago Medical School, Dunedin

There have been occasional reports of deterioration in asthma control, and even respiratory arrest, following the commencement of a long-acting beta-agonist (Serevent, Foradil, Oxis). Several mechanisms need to be considered to explain such reactions including paradoxical bronchospasm, increased bronchial responsiveness and tolerance, but none of these has been identified in prospective studies. Practitioners using long-acting beta-agonists need to be aware of the possibility of such sporadic adverse reactions. Careful monitoring of patients is advised, particularly during the first six weeks of therapy.

The long-acting beta-agonists salmeterol (Serevent) and eformoterol fumarate (Foradil, Oxis) were introduced at a time of heightened concern about the safety of beta-agonist drugs. Clinical and epidemiological data from New Zealand had drawn attention to an association between regular use of fenoterol and poorer control of asthma and increased risk of mortality from asthma respectively.1,2 At the time, there were insufficient data to know whether or not the long-acting agents would behave similarly. These concerns prompted the Medicines Assessment Advisory Committee to recommend that these new long-acting agents be included in the Intensive Medicines Monitoring Programme (IMMP).

Impairment of asthma control possible with long-acting beta-agonists

Amongst early reports of adverse events there were two in which the patients, while on salmeterol, did not get their normal favourable response to their usual relievers (salbutamol/ipratropium). In the first, a 37-year-old male experienced increased asthma symptoms following use of inhaled salbutamol (MDI) since commencing regular salmeterol. This was objectively confirmed using spirometry: the post-salbutamol (nebulised) fall in FEV1 was 10%. In the second case, a 30-year-old female developed "resistance" to the bronchodilator effects of both salbutamol and ipratropium (MDI and nebulised) within 5 days of commencing salmeterol. The reports deserve comment and attention.

Possible mechanisms: paradoxical bronchospasm, increased bronchial responsiveness or tolerance

Attempts have been made to explain such sporadic adverse reactions. A possible cause is paradoxical bronchospasm. This phenomenon may occur in association with all inhaled medication, and its incidence is said to be as high as 4% of subjects.3 A post-inhalation fall in FEV1, accompanied by cough and wheezing, appears to be related to the physical properties of the excipients rather than the drug itself. In an earlier report of six such cases, Wilkinson et al. compared immediate changes in FEV1 when salmeterol was given either by metered dose inhaler or by Diskhaler.4 No adverse effects occurred when the salmeterol was administered by Diskhaler. The authors concluded that patients who experience paradoxical bronchospasm should use a dry powder device. However, a question that remains unanswered is why such paradoxical responses might have arisen in these cases. It is unusual when using nebulised drug therapy. Additionally, it is not clear why this would occur shortly after commencing treatment with the long-acting bronchodilators when it had not previously been noted. The balance of evidence is that while regular long-acting beta-agonists do not enhance bronchial hyper-responsiveness (BHR) in most patients, the possibility of increased BHR occurring in individual cases, as a result of drug use, can not be excluded.

These cases also raise the more important issue of tolerance. Tolerance implies that with regular or high dose usage, the response to supplementary short-acting beta-agonist use may be blunted or absent. Two aspects require consideration:

  1. Tolerance to the bronchodilator actions of short-acting beta-agonists (used as "relievers") when long-acting beta-agonists are being inhaled regularly.
    This has been investigated in many of the long-term studies of the efficacy and safety of these drugs and no clear evidence of bronchodilator tolerance has been noted.5-7 However, in more rigorously controlled conditions, improvement in lung function following the use of salbutamol is attenuated when salmeterol is being used regularly.8 In practice, the issue is probably important only in circumstances of an acute asthma attack, but controlled studies have not been carried out.
  2. Tolerance to the protective effects of short-acting beta-agonists e.g. against exercise or allergen challenges.
    Again, this phenomenon has been observed only in experimental studies.9 Its relevance in day-to-day control of asthma is not clear. Indirect evidence from a large placebo-controlled investigation carried out in New Zealand showed that during exacerbations of asthma, bronchodilator requirements among 165 asthmatics were not increased when patients were taking regular salmeterol compared to placebo.10

Rare cases of respiratory arrest reported in UK

Following the introduction of salmeterol in the United Kingdom, three cases of respiratory arrest occurring shortly after patients had been commenced on the drug were reported.11 At the same time, the United Kingdom Committee on the Safety of Medicines reported 26 cases of deterioration in asthma soon after the introduction of long-acting beta-agonists.12 Withdrawal of the drug resulted in improvement. Like the cases recorded in New Zealand, such events appear to be sporadic and rare but nevertheless cause concern. They appear to follow a pattern but do not lend themselves easily to explanation either in terms of paradoxical bronchospasm or the advent of tolerance.

More recently, an epidemiological study has provided reassurance that the introduction of the long-acting beta-agonist salmeterol has not been associated with an increase in episodes of near-fatal asthma.13 These epidemiological data offset concerns which may have arisen as a result of individual case reports.

Monitor patients during first six weeks of therapy

Long-acting beta-agonists are effective agents in controlling the symptoms of bronchial asthma in most patients. PHARMAC currently subsidises their use in patients with symptomatic moderate to severe and often unstable disease (Special Authority needed14).

Practitioners ought to be aware of the potential for deterioration in asthma control following their introduction, albeit rarely. This often occurs within the first six weeks of therapy, hence careful monitoring of patients at this time is advised. Peak flow monitoring, at least in the short term, should be encouraged. Patients should be advised to seek advice if they perceive a lack of benefit from using reliever medication.

Compliance with inhaled steroids - which may be less if the long-acting beta-agonist initially improves symptoms - should be emphasised. The long-acting agent ought to be withdrawn in the event of deteriorating asthma control in the absence of other explanations for the adverse clinical events.

Correspondence to Dr DR Taylor, Senior Lecturer in Medicine, Department of Medicine, University of Otago Medical School, PO Box 913, Dunedin phone 03 474 0999, fax 03 474 7641, e-mail

  1. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391-6.
  2. Pearce N, Beasley R, Crane J, et al. End of the New Zealand asthma mortality epidemic. Lancet 1995;345:41-4.
  3. Yarbrough J, Mansfield L, Ting S. Metered dose induced bronchospasm in asthmatic patients. Ann Allergy 1985;55:25-7.
  4. Wilkinson JRW, Roberts JA, Bradding P, et al. Paradoxical bronchoconstriction in asthmatic patients after salmeterol by metered dose inhaler. BMJ 1992;305:931-2.
  5. Tattersfield AE. Clinical pharmacology of long-acting beta-receptor agonists. Life Sciences 1993;52:2161-9.
  6. Pearlman DS, Chervinsky P, LaForce C, Seltzer SM, Southern DL, Kemp JP, et al. A comparison of salmeterol with albuterol in the treatment of mild to moderate asthma. N Engl J Med 1992;327:1420-5.
  7. D'Alonzo GE, Nathan RA, Henochowicz S, Morris RJ, Ratner P, Rennard SI. Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma. JAMA 1994;271:1412-6.
  8. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995;346:201-6.
  9. Cockcroft DW, Swystun VA. Functional antagonism: tolerance produced by inhaled beta2-agonists. Thorax 1996;51:1051-6.
  10. Taylor DR, Town GI, Herbison GP, et al. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998;53:744-52.
  11. Clark CE, Ferguson AD, Siddorn JA. Respiratory arrest in young asthmatics on salmeterol. Respir Med 1993;87:227-8.
  12. Anon. Salmeterol (Serevent) Curr Probl 1991 No 31.
  13. Williams C, Crossland L, Finnerty J, Crane J, et al. Case-control study of salmeterol and near-fatal attacks of asthma. Thorax 1998;53:7-13.
  14. New Zealand Pharmaceutical Schedule, April 1999, pg.152-3.


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