Role of methylxanthines in the treatment of COPD
- Carlos A Vaz Fragoso, MD
Carlos A Vaz Fragoso, MD
- Associate Professor in Medicine (Geriatrics)
- Yale University School of Medicine
The value of methylxanthines (such as theophylline) in the management of patients with chronic obstructive pulmonary disease (COPD) is controversial. Current studies, in our view, continue to support a beneficial role in selected patients [1,2]. However, methylxanthines have a narrow therapeutic index; as a result, toxicity can be a significant problem with chronic use, and careful monitoring is essential.
The role of methylxanthines in the management of patients with COPD will be reviewed here. The role of theophylline in the treatment of asthma and the management of acute exacerbations of COPD and of stable COPD are discussed separately. (See "Theophylline use in asthma" and "Management of exacerbations of chronic obstructive pulmonary disease" and "Management of stable chronic obstructive pulmonary disease".)
EFFECTS ON FUNCTIONAL IMPAIRMENT
The majority of patients with chronic obstructive pulmonary disease (COPD) seek assistance because of functional impairment. Four independent determinants of functional impairment have been identified: dyspnea ratings, exercise capacity, respiratory mechanics, and respiratory muscle strength . Dyspnea ratings appear to influence general health status to a greater extent than do physiologic data , while performance in a standardized walking test correlates best with dyspnea ratings and the quality of life [3,5]. It is within this context that the clinical indications for theophylline in COPD can be evaluated. (See "Evaluation of health-related quality of life (HRQL) in patients with a serious life-threatening illness".)
Dyspnea — One review of the efficacy of theophylline in COPD found that 6 of 10 studies cited showed an improvement in dyspnea . Furthermore, those studies that utilized the more sensitive dyspnea ratings demonstrated the greatest benefit. Five additional studies, employing either theophylline alone or combination therapy (theophylline plus aerosolized beta 2-agonists and anticholinergics) in patients with stable COPD, have subsequently been performed [7-11]. Two of these trials showed a beneficial effect of theophylline. One report, for example, randomized 38 patients with severe COPD who were treated with theophylline to either continued therapy or replacement of theophylline by placebo . The percentage of patients experiencing clinical deterioration was much lower in the group maintained on theophylline (15 versus 72 percent).
The three other studies found no beneficial effect of theophylline in the population as a whole, but noted improvement in some patients [9-11]. One report employing combination therapy concluded that, despite an overall lack of benefit, approximately one-third of patients were subjective responders in whom both dyspnea and forced expiratory volume in one second (FEV1) improved . In contrast, the subjective nonresponders failed to achieve a postbronchodilator increase in FEV1.
- Ram FS, Jardin JR, Atallah A, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respir Med 2005; 99:135.
- Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187:347.
- Wegner RE, Jörres RA, Kirsten DK, Magnussen H. Factor analysis of exercise capacity, dyspnoea ratings and lung function in patients with severe COPD. Eur Respir J 1994; 7:725.
- Mahler DA, Faryniarz K, Tomlinson D, et al. Impact of dyspnea and physiologic function on general health status in patients with chronic obstructive pulmonary disease. Chest 1992; 102:395.
- Mahler DA. How should health-related quality of life be assessed in patients with COPD? Chest 2000; 117:54S.
- Vaz Fragoso CA, Miller MA. Review of the clinical efficacy of theophylline in the treatment of chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 147:S40.
- Kirsten DK, Wegner RE, Jörres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104:1101.
- Jaeschke R, Guyatt GH, Singer J, et al. Mechanism of bronchodilator effect in chronic airflow limitation. CMAJ 1991; 144:35.
- Nishimura K, Koyama H, Ikeda A, et al. The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD. Chest 1995; 107:718.
- Waterhouse JC, Pritchard SM, Howard P. Hyperinflation, trapped gas and theophylline in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1993; 48:126.
- McKay SE, Howie CA, Thomson AH, et al. Value of theophylline treatment in patients handicapped by chronic obstructive lung disease. Thorax 1993; 48:227.
- Peleman RA, Kips JC, Pauwels RA. Therapeutic activities of theophylline in chronic obstructive pulmonary disease. Clin Exp Allergy 1998; 28 Suppl 3:53.
- Newman D, Tamir J, Speedy L, et al. Physiological and neuropsychological effects of theophylline in chronic obstructive pulmonary disease. Isr J Med Sci 1994; 30:811.
- Fink G, Kaye C, Sulkes J, et al. Effect of theophylline on exercise performance in patients with severe chronic obstructive pulmonary disease. Thorax 1994; 49:332.
- Mahon JL, Laupacis A, Hodder RV, et al. Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice. Chest 1999; 115:38.
- Tsukino M, Nishimura K, Ikeda A, et al. Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. Thorax 1998; 53:269.
- Render ML, Weinstein AS, Blaustein AS. Left ventricular dysfunction in deteriorating patients with chronic obstructive pulmonary disease. Chest 1995; 107:162.
- Barbour MM, Garber CE, Ahlberg AW, et al. Effects of intravenous theophylline on exercise-induced myocardial ischemia: II. A concentration-dependent phenomenon. J Am Coll Cardiol 1993; 22:1155.
- Gaspardone A, Crea F, Iamele M, et al. Bamiphylline improves exercise-induced myocardial ischemia through a novel mechanism of action. Circulation 1993; 88:502.
- Karpel JP, Kotch A, Zinny M, et al. A comparison of inhaled ipratropium, oral theophylline plus inhaled beta-agonist, and the combination of all three in patients with COPD. Chest 1994; 105:1089.
- Bleecker ER, Britt EJ. Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease. Am J Med 1991; 91:24S.
- Mulloy E, McNicholas WT. Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 148:1030.
- Brander PE, Salmi T. Nocturnal oxygen saturation and sleep quality in patients with advanced chronic obstructive pulmonary disease during treatment with moderate dose CR-theophylline. Eur J Clin Pharmacol 1992; 43:125.
- Martin RJ, Pak J. Overnight theophylline concentrations and effects on sleep and lung function in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 145:540.
- Berry RB, Desa MM, Branum JP, Light RW. Effect of theophylline on sleep and sleep-disordered breathing in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 143:245.
- Jubran A, Gross N, Ramsdell J, et al. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study. Chest 1993; 103:678.
- Spinelli A, Fanelli A, Gorini M, et al. Control of breathing in patients with chronic pulmonary obstructive disease: response to bamiphylline. Respiration 1991; 58:241.
- Umut S, Gemicioğlu B, Yildirim N, et al. Effect of theophylline in chronic obstructive lung disease. Int J Clin Pharmacol Ther Toxicol 1992; 30:149.
- Ram FS, Jones PW, Castro AA, et al. Oral theophylline for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; :CD003902.
- ZuWallack RL, Mahler DA, Reilly D, et al. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001; 119:1661.
- Cazzola M, Gabriella Matera M. The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: a pilot study. Respir Med 2007; 101:957.
- Rice KL, Leatherman JW, Duane PG, et al. Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. A controlled trial. Ann Intern Med 1987; 107:305.
- Barr RG, Rowe BH, Camargo CA. Methylxanthines for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2003; :CD002168.
- Duffy N, Walker P, Diamantea F, et al. Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Thorax 2005; 60:713.
- Cyr MC, Beauchesne MF, Lemière C, Blais L. Effect of theophylline on the rate of moderate to severe exacerbations among patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol 2008; 65:40.
- Devereux G, Cotton S, Barnes P, et al. Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial. Trials 2015; 16:267.
- Snow V, Lascher S, Mottur-Pilson C, Joint Expert Panel on Chronic Obstructive Pulmonary Disease of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 2001; 134:595.
- Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993; 119:1161.
- Bahls FH, Ma KK, Bird TD. Theophylline-associated seizures with "therapeutic" or low toxic serum concentrations: risk factors for serious outcome in adults. Neurology 1991; 41:1309.
- Dager WE, Albertson TE. Impact of therapeutic drug monitoring of intravenous theophylline regimens on serum theophylline concentrations in the medical intensive care unit. Ann Pharmacother 1992; 26:1287.
- Hirano T, Yamagata T, Gohda M, et al. Inhibition of reactive nitrogen species production in COPD airways: comparison of inhaled corticosteroid and oral theophylline. Thorax 2006; 61:761.
- Barnes PJ. Theophylline for COPD. Thorax 2006; 61:742.
- EFFECTS ON FUNCTIONAL IMPAIRMENT
- Exercise capacity
- Respiratory mechanics
- - Stable COPD
- - Acute exacerbation
- Respiratory muscle capacity
- EFFECT ON EXACERBATION FREQUENCY
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS
- Chronic COPD
- Acute COPD exacerbation