CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 9, SEPTEMBER1994
PATIENT COMPLIANCE WITH BRONCHODILATOR THERAPY IN ASTHMA WILLIAM W. STORMS University of Colorado Health Sciences Center, Colorado Springs, Colorado
ABSTRACT A s t h m a is a c o m m o n disease caused by i n f l a m m a t i o n o f the a i r w a y s a n d c h a r a c t e r i z e d by cough, shortness of breath, chest tightness, and wheezing. R e c o m m e n d e d daily t h e r a p y for m o d e r a t e l y severe a s t h m a includes a n i n h a l e d a n t i - i n f l a m m a t o r y m e d i c a t i o n t o g e t h e r with an inhaled beta2-agonist bronchodilator for acute symptoms. Betaa d r e n e r g i c r e c e p t o r a g o n i s t s given by i n h a l a t i o n - - i n p a r t i c u l a r , agonists selective for beta2-receptors in the a i r w a y s - - a r e a safe a n d effective m e t h o d for c o n t r o l o f a s t h m a s y m p t o m s . However, n o t all p a t i e n t s can t a k e i n h a l a t i o n t h e r a p y , some because of difficulties in h a n d l i n g t h e m e t e r e d - d o s e inhaler, others b e c a u s e of i m p a t i e n c e or l a c k of discipline. F o r those p a t i e n t s unable or u n w i l l i n g to comply w i t h i n h a l a t i o n t h e r a p y , the a d m i n i s t r a t i o n o f an o r a l b r o n c h o d i l a t o r , such as t h e o p h y l l i n e , or an oral beta2-agonist, such as a l b u t e r o l , m a y be helpful. The s u s t a i n e d - r e l e a s e f o r m u l a t i o n o f a l b u t e r o l m a y be given on a twice-daily basis; this improves p a t i e n t c o m p l i a n c e while providing p r o l o n g e d b r o n c h o d i l a t i o n and s y m p t o m control. This is p a r t i c u l a r l y useful for c h i l d r e n and the elderly or for p a t i e n t s whose active schedules do not p e r m i t frequent dosing d u r i n g t h e day.
Asthma is a chronic inflammatory condition of the airways characterized by episodic coughing, shortness of breath, chest tightness, and wheezing. Symptoms are due to variable airways obstruction associated with an exaggerated response to various bronchoconstrictor stimuli (allergens, irritants, drugs, food additives, respiratory infections, exercise, and cold air). 1'2 In asthma, there is increased sensitivity in the airways of patients, as evidenced by an increase in the response to inhaled bronchoconstricting agents. It is important to recognize that bronchoconstriction is not the cause of asthma but the result of various stimuli, both specific and nonspecific, and that asthma is a disease of airways inflammation. Since the
Address correspondenceto: William W. Storms, MD, The Allergy and Asthma Center, 2709 North Tejon, Colorado Springs, CO 80907. Received for publication on July 13, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1038
primary underlying pathology of asthma is inflammation, the cornerstone in the management of moderate-to-severe disease is daily inhaled antiinflammatory medications, such as corticosteroids, cromolyn sodium, or nedocromil, supplemented with as-needed inhaled short-acting inhaled beta2-agonist bronchodilators for acute symptoms. Patients with mild disease may be treated effectively with a beta-agonist, such as albuterol, given only when needed. 1's-5 Asthma had previously been regarded as an inconvenient disease but not as a life-threatening disease. Yet prevalence, severity, and mortality appear to be increasing worldwide, especially among children. 6'7 In the United States, asthma is the most common childhood disease, afflicting an estimated 3 to 8 million children younger than 17 years of age and causing more emergency room visits, hospital admissions, and school absenteeism than any other disease. The prevalence in this age group rose approximately 50% in the 1980s. s Asthma is viewed as a disease that should be managed on an outpatient basis, yet asthma-related inpatient hospital services alone cost well over a billion dollars annually. In 1990, the total cost of asthma--both direct costs for patient management and indirect costs for lost days at school and work--was estimated at $6.2 billion. 9 Reducing the underlying inflammatory process and preventing acute symptoms are the primary goals of pharmacotherapy for asthma, which, in turn, will help reduce emergency room visits, hospitalizations, and other costs associated with the disease. The "Guidelines for the Diagnosis and Management of Asthma" promulgated in the United States by the National Asthma Education Program stress the prophylactic use of inhaled anti-inflammatory agents to control asthma, thereby reducing the need for emergency room visits and hospitalizations. 1° Ultimately, asthma-related deaths are also minimized. 1° Although chronic, daily, inhaled anti-inflammatory medications are the mainstay for preventive management of outpatient asthma, bronchodilators still have an important role in the treatment of not only acute exacerbations of asthma but also the chronic daily control of symptoms. The remainder of this article will focus on the bronchodilators that are used in asthma therapy. BRONCHODILATOR THERAPY FOR ASTHMA
B eta-A gonists Beta-adrenergic receptor agonists, particularly those agonists selective for beta2-receptors found primarily in the airways, are potent bronchial smooth muscle relaxants. Because of their ability to rapidly reverse bronchoconstriction, these drugs are widely used for "rescue" during acute attacks and for preventing exercise- and allergen-induced asthma. 4'11 1039
BRONCHODILATOR THERAPY IN ASTHMA
Nearly half of all prescriptions written for patients with mild-to-moderate asthma are for beta2-agonists, and perhaps half of the remaining prescriptions are for theophylline preparations, even though the "Guidelines for the Diagnosis and M a n a g e m e n t of Asthma" recommend anti-inflammatory inhalers for the chronic treatment of asthma. 11'12 A number of oral beta2-agonist formulations are available, including sustained-release formulations; however, delivery by inhalation offers faster onset of action and less risk of systemic side effects (nervousness, tremor). 3'13 Oral beta2-agonists can be used effectively in those patients who have difficulty with inhalation therapy. Oral beta2-agonists are easier to use than oral theophylline, since there is no need to monitor serum levels.a,4,13 Questions about the safety of some beta-agonists arise periodically. The concern is that the regular use of these agents m a y be detrimental to asthma control, and that they may increase the risk of death from asthma. An increase in asthma-related deaths during the 1960s was found to be associated with the widespread use of inhalers delivering isoproterenol, a potent and relatively nonselective beta-agonist. 3 An increase in mortality in New Zealand during the 1970s was associated with the use of (and possibly overreliance on) fenoterol, a selective beta2-agonist. 14-16 A casecontrol study in Canada also found that fenoterol inhalation therapy increased the risk of fatal and near-fatal a s t h m a s 'is In both New Zealand and Canada, the increased mortality associated with beta-agonists was primarily in patients with severe disease. In a meta-analysis of six casecontrol studies, Mullen et a119 found a weak but statistically significant association between beta2-agonist use and death from asthma. The analysis included a total of 364 patients who used beta2-agonists and 1388 controls who did not. The association in this study was seen only when the drug was administered by nebulizer; there was no association between beta2-agonist use and death when the drugs were administered by metered-dose inhaler (MDI). Nebulized beta2-agonist therapy is generally used for patients with severe or intractable asthma who require high doses of m e d i c a t i o n . E v e n so, t h e i n c r e a s e d risk of d e a t h was of small magnitude. 19 Many have felt that beta2-agonists are probably not directly responsible for the increases in asthma morbidity and mortality, but that their increased use may just be a marker for more severe disease. 1'1s'19 Patients with severe and potentially fatal asthma require more beta2-agonist to relieve symptoms and m a y require administration of high doses via nebulizer. It is possible that patients tend to equate symptom control with disease control, thus delaying the use of anti-inflammatory agents and allowing the disease to progress. Physicians and patients alike should be alerted to worsening disease when beta2-agonists are used with increasing frequency. 1'4'1s'2° The frequency of use of a beta2-agonist can be a way for 1040
patients to monitor their asthma; when use is frequent (I>3 times per day or >13 days per week), the patient is instructed to call the physician for an increase in daily prophylactic therapy.
Choosing a Beta2-Agonist Formulation The most widely used beta2-agonist preparations are inhaled. Oral beta2-agonists (immediate release and sustained release) are used less frequently. The most popular device for inhalation therapy is the MDI. Usually these devices are of standard design, although new inhalers are being introduced with dry powder delivery systems to take the place of chlorofluorocarbon propellants (which are to be phased out by 1995 under the Montreal Accord).~ For some, manipulating the MDI is a complex process--exhale fully, spray, inhale slowly, hold breath, and exhale--and often as little as 5% to 10% of the medication actually travels beyond the pharynx. Even when patients use the technique recommended by the Food and Drug Administration--which calls for placing the mouthpiece in the mouth and sealing it with the lips--most of the medication lands on the posterior wall of the oropharynx. In addition to knowing how to use inhalers, patients using both corticosteroid and beta2-agonist inhalers must distinguish between the two and must know which one to use regularly and which to use for quick relief. 13'21 The new long-acting beta2-agonist bronchodilator salmeterol provides effective therapy for patients with chronic asthma, especially those who experience nocturnal symptoms of the disease. Unlike other inhaled beta2agonists available to date that are used on an as-needed basis to rapidly control bronchoconstriction, salmeterol cannot be used for relief of acute symptoms. It is primarily indicated for the relief of nocturnal asthma or as twice-daily therapy for moderately severe asthmatic patients who are taking multiple drugs. Salmeterol should not be used as monotherapy for asthma. There are two categories of patients who cannot manage beta-agonist inhalation therapy and thus are candidates for oral therapy: patients who are unable to cope with the MDI such as the elderly and young children, and patients who are unwilling to comply with a complex treatment regimen. Even patients who claim they are capable of using MDIs may be using them incorrectly. Therefore, clear instructions (either oral or written) with respect to the inhaler technique are essential. Other important points to consider when prescribing the use of an inhaler are to remind the patient that in addition to assessing the amount of medication remaining in the canister by the recommended "sink or float" method, an inhaler should be kept in reserve that is fresh and full. It has often occurred that patients use an inhaler until it is spent, thereby receiving diminishing doses toward the 1041
BRONCHODILATORTHERAPY IN ASTHMA
end of the canister's life expectancy. Also, maintenance of the canister (ie, keeping it clean and patent and at the proper temperature) should be emphasized.
Patients Who Have Problems with Compliance Another category of patients who may do poorly on inhaled betaagonists are those who do not comply with therapy in spite of being capable of using MDIs correctly. Noncompliance rates are high with every type of therapy for all different diseases. An estimated 40% of any given physician's patients do not follow the recommendations they are given, and the physician probably is unaware of this situation because the patients themselves do not divulge the information. 22 The psychology of noncompliance is complex. In the case of asthma, some patients are casual about the disease, some resent the disease, some resent being told what to do, some are not convinced that therapy makes that much difference, some forget or delay therapy, some are too busy to bother, and some regularly misplace their inhalers and lack a backup. In children, embarrassment at using an inhaler during school in the presence of peers may make the child ill at ease and therefore be the cause of the child's noncompliance. Noncompliance with inhalation therapy is thought to be an important cause of persistent morbidity from asthma. 23-25 In one study of patient compliance with a standardized incremental regimen of inhaled albuterol, measurements of albuterol levels in urine were made in 30 patients who had the largest improvement with therapy and in 30 patients whose airflow obstruction failed to improve. Urine concentrations of albuterol rose as expected over the 9-month period in the patients who responded to therapy and were significantly higher than urine levels in patients who did not respond. 24
Candidates for Oral Beta-Agonist Bronchodilator Therapy Directing the noncompliant patient to inhale a beta2-agonist as n e e d e d - - w h i c h requires the patient to keep track not only of symptoms b u t also of the MDI and its m a i n t e n a n c e - - m a y be a difficult task for physicians. Such patients would probably do better on the regular administration of an oral formulation, particularly one that need be administered only twice a day. A good choice is a sustained-release formulation of albuterol (Proventil Repetabs ®* or Volmax®t) that can be administered once every 12 hours. Proventil Repetabs contain 4 mg of albuterol (2 mg in * Trademark: Schering Corporation, Kenilworth, New Jersey. Trademark: Muro Pharmaceutical, Inc., Tewksbury, Massachusetts. 1042
the coating for immediate release and 2 mg in the core for release after several hours). Onset of effective bronchodilation is within 30 minutes, peak effects occur within 2 to 3 hours, and duration of action is up to 12 hours. 26 This biphasic delivery results in sustained blood levels of albuterol for up to 12 hours. Volmax contains either 4 mg or 8 mg of albuterol and provides sustained blood levels of albuterol for 12 hours through the use of an osmotic pump delivery system; this slow-release system depends on the ambient osmolarity of the intestinal lumen. The elderly, particularly those receiving multiple drug therapy, m a y benefit from oral beta-agonists. For patients who have difficulty using an MDI, even with a spacer unit, the use of an oral albuterol formulation ensures the delivery of sustained therapeutic drug levels. The sustainedrelease action may obviate the need for younger patients to use an MDI during school, thereby reducing the number of visits to the school nurse for medication administration. Sustained-release tablet formulations can also benefit those patients who find the use of an MDI a problem, including patients who travel or those who have outdoor jobs that make taking multiple doses inconvenient. Some patients m a y become disruptive or abusive when confronted by their physician about noncompliance issues. When using a sustainedrelease formulation, these patients need not be questioned as rigorously about their compliance methods as those who might be on a four-times-aday regimen. As compared with the newly approved, long-acting beta2-agonist salmeterol, Proventil Repetabs are easier to use (oral administration versus inhalation), especially for elderly patients, and are more cost effective. Based on a recommended dose of 2 puffs twice-daily, the average daily cost for salmeterol therapy is approximately $1.60 compared with $1.16 for Proventil Repetabs (2 tablets per day). 27
Theophylline Methylxanthines such as theophylline and aminophylline have a long history as antiasthma agents, though their use has declined with regard to primary therapy. By inhibiting phosphodiesterase, these agents maintain intracellular levels of cyclic adenosine monophosphate, which results in relaxation of bronchial smooth muscle. Methylxanthines also improve diaphragmatic contractility, which may be useful in patients with chronic airflow obstruction. Compared with beta2-agonists, methylxanthines have only modest effects on mediator release, on exercise-induced asthma, and on histamine-induced bronchoconstriction. 3'4'2s Intravenous aminophylline is still fairly widely used in emergency rooms and hospitals to treat severe acute attacks, 29'3° while oral theophylline is widely used for outpatient maintenance therapy, especially for nocturnal asthma. Theophylline 1043
BRONCHODILATOR THERAPY IN ASTHMA
is relatively inexpensive and is available in slow-release formulations and in a wide range of tablet strengths. Its main disadvantages are that it has a very narrow therapeutic window and that it is sometimes difficult to maintain patients on an adverse e v e n t - f r e e regimen. To be clinically effective, theophylline must achieve a plasma concentration of at least 7 to 10 ~g/mL but, at 20 ~g/mL, the drug causes considerable toxicity (nervousness, irritability, tremor, insomnia, nausea, hypokalemia, hyperglycemia, tachycardia, cardiac arrhythmias, and seizures). Current practice standards favor a theophylline blood level of 7 to 15 ~g/mL. Even within the therapeutic range, nausea and jitteriness are common complaints. 3'4'2s In addition to the narrow margin of safety, theophylline may be complicated to use. Absorption is variable and affected by the presence of food, particularly fat, in the gut. Its pharmacodynamics and pharmacokinetics are influenced by a number of factors, including the presence of other diseases and illnesses and concomitant drug therapy. The plasma half-life is prolonged in patients with heart or liver disease, obesity, certain viral and bacterial infections, and fever, whereas the half-life is shortened in smokers, persons on high-protein/low-carbohydrate diets or xanthine-free diets, and in patients with cystic fibrosis or hypothyroidism. Concomitant therapy with cimetidine, erythromycin, and the fluoroquinolone antibiotics m a y slow theophylline clearance to the extent that toxic concentrations develop. Because theophylline has a narrow therapeutic window, serum concentrations must be monitored during both acute care and long-term maintenance.3,4.11,12, 2s
Anticholinergic Drugs Because some aspects of asthma may be due to vagal-mediated stimulation of bronchial smooth muscle that causes bronchospasm and increased mucus secretion, anticholinergic drugs m a y be of benefit to some patients. Inhaled agents such as ipratropium are now favored over older agents such as oral atropine. However, because of their relatively short duration, agents such as ipratropium must be given three or four times daily and are not conducive to enhancing patient compliance. CONCLUSION
The "Guidelines for the Diagnosis and Management of Asthma" recommend that inhaled anti-inflammatory medications be prescribed for patients with moderate-to-severe disease and that they be supplemented with an inhaled bronchodilator as needed to control symptoms. 1° A beta2agonist such as albuterol given by inhalation provides rapid reversal of bronchoconstriction and excellent control of the symptoms of mild, moderate, and severe asthma. However, a beta-agonist is not sufficient as sole 1044
therapy for moderate-to-severe chronic asthma; indeed, the need for regular use of any beta-agonist should signal both patient and physician that inhaled anti-inflammatory agents are indicated. A substantial number of patients cannot manage beta-agonist inhalation therapy, some because they lack the coordination to manipulate the MDI, and some because they lack the time or patience to comply with a complicated therapeutic regimen. For those patients who are unable or unwilling to cope with inhalation therapy, simplifying the treatment regimen by providing a long-acting beta2-agonist in the form of a convenient, easy-to-swallow tablet may improve compliance. An oral bronchodilator, particularly one such as theophylline or sustained-release albuterol, maintains bronchodilation with minimal effort and ability on the part of the patient. Oral bronchodilator therapy remains an important component of a comprehensive treatment strategy for asthma. References: 1. Weinberger SE. Recent advances in pulmonary medicine. NEJM. 1993;328:1389-1397. 2. Kemp JP. Approaches to asthma management. Arch Intern Med. 1993;153:805-812. 3. Frew AJ, Holgate ST. Clinical pharmacology of asthma: Implications of treatment. Drugs. 1993;46:847-862. 4. Skorodin MS. Pharmacotherapy for asthma and chronic obstructive pulmonary disease: Current thinking, practices, and controversies. Arch Intern Med. 1993;153:814-829. 5. Barnes PJ. Asthma: What is there left to find out? BMI. 1993;307:815-816. 6. Weiss KB, Wagener DK. Changing patterns of asthma mortality: Identifying target populations at high risk. J A M A . 1990;264:1683-1687. 7. Gergen PJ, Weiss KB. Changing patterns of asthma hospitalization among children: 1979-1987. J A M A . 1990;264:1688-1692. 8. Zamula E. Childhood asthma. FDA Consumer. 1990;24:11-13. 9. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. NEJM. 1992;326:862-866. 10. National Heart, Lung, and Blood Institute. Guidelines for the diagnosis and management of asthma: National Asthma Education Program. Expert Panel Report. J Allergy Clin Immunol. 1991;88:425-534. 11. Busse W. Asthma in the 1990s: A new approach to therapy. Postgrad Med. 1992;92:177190. 12. Littlejohns P, Ebrahim S, Anderson R. Treatment of adult asthma: Is the diagnosis relevant? Thorax. 1989;44:797-802. 13. Kemp JP, Meltzer EO. ~2-adrenergic agonists--oral or aerosol for the treatment of asthma? J A s t h m a . 1990;27:149-157. 14. Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: Case-control study. Lancet. 1989;1:917-922. 1045
15. Pearce N, Grainger J, Atkinson M. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax. 1990;45:170-175. 16. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-87: A further case-control study. Thorax. 1991;46:105-111. 17. Spitzer WO, Suissa S, Ernst P, et al. The use of [~-agonists and the risk of death and near death from asthma. NEJM. 1992;326:501-506. 18. Burrows B, Lebowitz MD. The [~-agonist dilemma. NEJM. 1992;326:560-561. 19. Mullen M, Mullen B, Carey M. The association between ~-agonist use and death from asthma. JAMA. 1993;270:1842-1845. 20. Castle W, Fuller R, Hall J, Palmer J. Serevent national surveillance study: Comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator therapy. BMJ. 1993;306:1034 - 1037. 21. Editor. Is there an easier way to use my asthma inhaler? Patient Care. 1991;25:83-84. 22. DiMatteo MR. Enhancing patient adherence to medical recommendations. JAMA. 1994; 271:79-83. 23. Mayo PH, Richman J, Harris HW. Results of a program to reduce admissions for adult asthma. Ann Intern Med. 1991;112:864-871. 24. Horn CR, Clark TJ, Cochrane GM. Compliance with inhaled therapy and morbidity from asthma. Respir Med. 1990;84:67-70. 25. Editor. Are you taking the medicine? Lancet. 1990;335:262-263. 26. Physicians' Desk Reference. Montvale, NJ: Medical Economics Data Production Company; 1994:2169-2170. 27. Drug Topics Red Book. Montvale, NJ: Medical Economics Data Production Company; 1994. 28. Aronson JK, Mardman M, Reynolds DJM. Theophylline. BMJ. 1992;305:1355-1358. 29. McFadden ER. Methylxanthines in the treatment of asthma: The rise, the fall, and the possible rise again. Ann Intern Med. 1991;115:323-324. 30. Wrenn K, Slovis CM, Murphy F, et al. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med. 1991;115:241-247.