Effects of Theophylline Withdrawal in Severe Chronic Obstructive Pulmonary Disease

doi:10.1378/chest.104.4.1101

Chest

Volume 104, Issue 4, October 1993, Pages 1101-1107

https://doi.org/10.1378/chest.104.4.1101 Get rights and content

To determine the value of theophylline in the maintenance therapy of patients with severe chronic obstructive pulmonary disease (COPD), we conducted a trial of theophylline therapy withdrawal in 38 clinically stable patients with severe COPD (FEV₁ <60 percent) predicted. Symptoms, lung function, blood gases, and 6-min walking distance were assessed on days 1 and 2. Quality of life and overall dyspnea were scored using four different clinical rating scales. Theophylline therapy was continued in 20 patients and replaced by placebo from day 3 on in the remainder; measurements were repeated on days 5 and 6. Withdrawal of theophylline therapy resulted in significant (p<0.05) deterioration in lung function, exercise performance, and two indices of overall dyspnea, and a significant increase in scoring of symptoms and auscultation findings. Individual analysis revealed a clinically relevant deterioration in 72 percent of patients from whom theophylline therapy was withdrawn, while only 15 percent of patients receiving theophylline exhibited deterioration. No major side effects were observed. Our data show that about half of the patients with severe COPD can be considered as theophylline responders. The response of these patients to withdrawal of theophylline therapy suggests that the clinical effectiveness of this drug cannot be explained exclusively by bronchodilation. Due to the inherent difficulties in predicting response to theophylline, its effectiveness in patients with severe COPD should be determined individually, including assessment of exercise performance and ratings of dyspnea.

Section snippets

Patients

We stdied 39 patients aged 40 to 80 years. Diagnosis followed the guidelines of the American Thoracic Society.¹¹ Patients were included on the basis of the following criteria: (1) history of prolonged cigarette smoking and gradual progression of dyspnea on exertion over many years; (2) no history of atopy; (3) stable clinical condition as judged by discharge from hospital being planned within the next week; (4) absence of other major medical problems such as congestive heart failure, liver

Patients

We studied 39 patients who fulfilled the inclusion criteria. Randomization resulted in 18 patients being assigned to the placebo group and 21 being assigned to the theophylline group. One male patient in the theophylline group did not complete the study due to an acute exacerbation unrelated to the study. Mean age ± SD of the 38 patients who completed the study was 66.2±8.2 years, with no significant difference between groups. Two patients in the placebo group and one patient in the

Discussion

The present study demonstrates small but significant deteriorations in lung function, PaCO₂, exercise performance, symptoms and auscultation, and two indices of overall dyspnea 2 days after theophylline therapy withdrawal. Analysis of individual data reveals clinically relevant deterioration after withdrawal of theophylline therapy in more than half of the patients.

Theophylline has been a first-line drug in the treatment of chronic obstructive airway disease for decades. In recent years, it has

Acknowledgment

This investigation was part of the doctoral thesis of R. E. Wegner.

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2021, Encyclopedia of Respiratory Medicine, Second Edition
In addition to β₂-agonists, anticholinergics and corticosteroids, several other classes of drug are used in the treatment of asthma and COPD. These include cromones in asthma patients, antagonists or inhibitors of various inflammatory mediators (histamine, leukotrienes), theophylline and other methylxanthines, selective phosphodiesterase inhibitors, immunomodulators (such as methotrexate, gold, cyclosporin), specific immunotherapy for allergic asthma and mucoregulators, particularly in COPD. Overall, these drugs are less effective than the major classes of inhaled drug and often have side effects that limit their dose if the drugs are given systemically. Some recent developments of drugs that are close to approval are also discussed.
Chronic Obstructive Pulmonary Disease: A Palliative Medicine Review of the Disease, Its Therapies, and Drug Interactions
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Citation Excerpt :
Another systematic review of theophylline in COPD found that only six of 10 studies cited showed an improvement in dyspnea.65 Similarly, improvement in exercise performance is not always observed with theophylline use.66–72 Theophylline is a medication with a very narrow therapeutic window, with significant toxicities potentially occurring even in the high end of the safe range.64
Despite significant advances in treatment, chronic obstructive pulmonary disease (COPD) remains a chronic and progressive disease that frequently leads to premature mortality. COPD is associated with a constellation of significant symptoms, including dyspnea, cough, wheezing, pain, fatigue, anxiety, depression, and insomnia, and is associated with increased morbidity. Palliative care is appropriate to support these patients. However, historically, palliative care has focused on supporting patients with malignant disease, rather than progressive chronic diseases such as COPD. Therapies for COPD often result in functional and symptomatic improvements, including health-related quality of life (HRQL), and palliative care may further improve symptoms and HRQL. Provision of usual palliative care therapies for this patient population requires understanding the pathogenesis of COPD and common disease-targeted pharmacotherapies, as well as an approach to balancing life-prolonging and HRQL care strategies. This review describes COPD and current targeted therapies and their effects on symptoms, exercise tolerance, HRQL, and survival. It is important to note that medications commonly used for symptom management in palliative care can interact with COPD medications resulting in increased risk of adverse effects, enhanced toxicity, or changes in clearance of medications. To address this, we review pharmacologic interactions with and precautions related to use of COPD therapies in conjunction with commonly used palliative care medications.
Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes
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Low-dose theophylline is also effective in improving responses to ICSs in active smokers with asthma who have a poor response to low-dose ICSs.142 Previous studies have shown that controlled withdrawal of theophylline therapy causes worsening of both severe asthma and COPD, indicating that this is likely to be an effective therapeutic approach.143,144 The tricyclic antidepressant nortriptyline also increases HDAC2 activity and reverses steroid resistance by directly inhibiting PI3Kδ.145
The recognition that there are some patients with features of asthma and chronic obstructive pulmonary disease (COPD) has highlighted the need to develop more specific treatments for these clinical phenotypes. Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on T_H2 cells antagonists. Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen-activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty. Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long-acting β₂-agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness.
Theophylline inhibits the cough reflex through a novel mechanism of action
2014, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Despite current COPD guidelines indicating that theophylline is of limited value in the routine management of COPD, many controlled clinical trials support its utility in patients with stable COPD24,25 and also observed worsening of the clinical state when theophylline was withdrawn. Furthermore, it has also been recommended for the treatment of cough in patients with COPD.8,26 In children and adults with poorly controlled asthma, theophylline significantly improved symptom scores for cough and wheeze compared with placebo,7 and it has been shown to be effective for treating angiotensin-converting enzyme inhibitor–related cough.9
Theophylline has been used in the treatment of asthma and chronic obstructive pulmonary disease for more than 80 years. In addition to bronchodilator and anti-inflammatory activity, clinical studies have suggested that theophylline acts as an antitussive agent. Cough is the most frequent reason for consultation with a family doctor, and treatment options are limited. Determining how theophylline inhibits cough might lead to the development of optimized compounds.
We sought to investigate the inhibitory activity of theophylline on vagal sensory nerve activity and the cough reflex.
Using a range of techniques, we investigated the effect of theophylline on human and guinea pig vagal sensory nerve activity in vitro and on the cough reflex in guinea pig challenge models.
Theophylline was antitussive in a guinea pig model, inhibited activation of single C-fiber afferents in vivo and depolarization of human and guinea pig vagus in vitro, and inhibited calcium influx in airway-specific neurons in vitro. A sequence of pharmacological studies on the isolated vagus and patch clamp and single-channel inside-out experiments showed that the effect of theophylline was due to an increase in the open probability of calcium-activated potassium channels. Finally, we demonstrated the antitussive activity of theophylline in a cigarette smoke exposure model that exhibited enhanced tussive responses to capsaicin.
Theophylline inhibits capsaicin-induced cough under both normal and “disease” conditions by decreasing the excitability of sensory nerves through activation of small- and intermediate-conductance calcium-activated potassium channels. These findings could lead to the development of optimized antitussive compounds with a reduced side effect potential.
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Nonetheless, xanthines are recognised as being clinically effective in both asthma and COPD patients, showing benefit that is complementary to existing drug classes. There is now good evidence in the literature that xanthines can exhibit both bronchodilator and anti-inflammatory actions in patients with asthma [1,2] or COPD [3,4] and several studies have described worsening of asthma and COPD when xanthines are withdrawn, even in patients taking concomitant glucocorticosteroids [5,6]. However, xanthines have a very narrow therapeutic window (exhibiting a wide range of side effects and many drug/drug interactions) which has been ascribed to the fact that xanthines are non-selective phosphodiesterase (PDE) inhibitors, as well as having other pharmacological actions such as adenosine receptor antagonism.
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Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD
2010, Chest
Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD.
To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 μg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8–12.4 mg/L).
In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV₁% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD.
Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD.
clinicaltrials.gov; Identifier NCT00241631

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Chest

Clinical Investigations: COPD/AsthmaEffects of Theophylline Withdrawal in Severe Chronic Obstructive Pulmonary Disease

Section snippets

Patients

Patients

Discussion

Acknowledgment

Chest

Chest

Chest

Chest

Chest

Chest

Lancet

Efficacy of theophylline in ‘irreversible’ airflow obstruction

Ann Intern Med

Sustained-release theophylline reduces dyspnea in nonreversible obstructive airway disease

Am Rev Respir Dis

A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease

N Engl J Med

Bronchodilator treatment for partially reversible chronic obstructive airways disease

Thorax

Bronchodilators in chronic air-flow limitation: effects on airway function, exercise capacity, and quality of life

Am Rev Respir Dis

A comparative trial of ipratropium bromide (Atrovent), controlled release theophylline (Phyllocontin), and a combination of these in patients with reversible airflow obstruction

Br J Clin Pract

Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease

Am J Med

Clinical Investigations: COPD/Asthma
Effects of Theophylline Withdrawal in Severe Chronic Obstructive Pulmonary Disease