Theophylline-Improved Swallowing Reflex in Elderly Nursing Home Patients

To the Editor: Swallowing disorders are common in the elderly and cause significant morbidity and mortality due to aspiration bronchitis and pneumonia.¹ Although theophylline is one of the most widely prescribed treatments for respiratory diseases, its mode of action still remains uncertain.² There are two well-characterized cellular actions of theophylline.² One is the inhibition of phosphodiesterases, and the other is the antagonizing receptor-mediated action of adenosine. Recent studies showed that theophylline removes tonic inhibition by adenosine on dopaminergic neurotransmission, resulting in the improvement of dopamine metabolism disorders.^3,4 Because dopamine supplementation improves the swallowing reflex in patients with dysphagia due to cerebral infarctions,⁵ whether theophylline improves the swallowing reflex in elderly patients with impaired swallowing was investigated.

Of the residents in the two nursing homes near Sendai, the stable patients without chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD), bronchial asthma, and pulmonary fibrosis were selected. In all of the 85 patients who met the criterion and gave informed consent, the latent time of swallowing reflex (LTSR) was assessed. A bolus injection of 1 mL distilled water into the pharynx through a nasal catheter induced the swallowing reflex, which was evaluated using latency of response, timed from injection to the onset of swallowing.⁵ The mean±standard error LTSR was 12.0±2.1 for the 85 patients. Due to the potential risk of aspiration of medicine in patients with very severe dysphagia, patients with mild to moderate dysphagia were focused on. Therefore, patients with a LTSR of greater than 15 seconds and less than 5 seconds were excluded, resulting in selection of 64 patients. All of them could take oral medicine. The patients were randomly assigned to the theophylline group or placebo group using a random-numbers table and were investigated for 1 month. One patient from the control group was excluded from analysis because he died from stroke before the study finished. Finally, 32 patients in the theophylline group of mean age 84.6 (range 72–94) and 31 patients in the placebo group of mean age 82.2 (range 71–95) were analyzed.

Subjects in the theophylline group took theophylline (200 mg/d) for 28 days, and subjects in the placebo group took the placebo (2 tablets/d) during the same period. LTSR was measured at 10:00 a.m. in both groups before and 14 and 28 days after the theophylline or placebo medication was started. Cognitive function and activities of daily living (ADL) were also investigated at baseline and Day 28 using the Mini-Mental State Examination (MMSE)⁶ and the Barthel index,⁷ respectively.

There were no significant differences at baseline for age, LTSR, MMSE, or ADL score between the placebo group and the theophylline group. When the change of LTSR over time was compared between the placebo and theophylline group, two-way repeated analysis of variance revealed a differential changing pattern between the groups (P<.005) (Figure 1). There was no significant difference in LTSR between the time points in the placebo group, whereas in the theophylline group, LTSR at 28 days showed significantly lower values than baseline (P<.001 using the Wilcoxon signed rank test). In a comparison between the groups at each time point, LTSR did not show a significant difference at 14 days, whereas at 28 days, LTSR in the theophylline group was significantly lower than in the placebo group (P<.001 using Mann-Whitney test). Compared with the placebo group, the odds ratio of improvement of LTSR was 12.5 (95% confidence interval=3.8–41.3; P<.001 using Fisher exact test) for the theophylline group. Twenty-eight days of theophylline and placebo medication did not have a significant effect on MMSE or ADL score.

Figure 1

Latent time (s=seconds) of swallowing reflex in elderly nursing home patients treated with theophylline (n=32; closed circle) or placebo (n=31; open circle) during the follow-up period. Values are expressed as mean±standard error. ^*P<.001 versus placebo group at 28 days using Mann-Whitney test. ^†P<.001 versus theophylline group at 0 days (baseline) and 14 days using the Wilcoxon signed rank test.

The study suggested that theophylline could improve the impairment of swallowing reflex in the elderly. Impaired swallowing physiology often predisposes the patient to various respiratory diseases, including COPD.⁸ High prevalence of aspiration pneumonia in patients with COPD has been reported.⁹ Moreover, aspiration is suggested to be a cause of COPD exacerbation in some patients.¹⁰ Although the role of impaired swallowing on aspiration pneumonia in COPD remains to be determined, theophylline may contribute better control of COPD not only by its action as a bronchodilator, but also as a drug to improve swallowing in the elderly. Recently, selective inhibition of phosphodiesterase-4 has been highlighted as a target for drug development in respiratory diseases,² but the effect of theophylline on the central nervous system might be also important for control of respiratory diseases in elderly patients.