Uniphyl

We compared the effects of evening administration of sustained-release theophylline (Uniphyl) and qid inhaled [[beta].sub.2]-agonist (salbutamol, two 100-[mu]g puffs) on sleep quality and nocturnal oxygen saturation in 20 patients with COPD. Patients with [FEV.sub.1] less than 70% predicted and [FEV.sub.1]/FVC ratio less than 70% were eligible to participate in this double-blind, crossover study, with 2-week treatment arms. Patients recorded morning and evening peak flow and symptoms in a daily diary. On the last day of each treatment period, overnight polysomnography was done. Spirometric indexes were measured before retiring and on awakening. Patients spent less time at less than 9o% oxygen saturation (51[+ or -]92 min vs 72[+ or -]105 mini p=0.03) during theophylline treatments than during salbutamol treatment. There was a smaller overnight decrease in [FEV.sub.1] (0.04 L vs 0.13 L; p=0.04) after theophylline than after salbutamol treatment. [FEV.sub.1]/FVC ratio and maximum expiratory flow at 50% of vital capacity (V50) increased overnight with theophylline and decreased with salbutamol (p=0.014, 0.025). Morning peak expiratory flow rate was higher with theophylline (4.0[+ or -]1.7 L/s) than with salbutamol (3.6[+ or -]1.8 L/s; p=0.004). The duration of patient-reported nocturnal wheezing was lower with theophylline than with salbutamol (p=0.006). There were no differences between treatments in sleep quantity, efficiency, staging, or subjective quality. We conclude that, compared with salbutamol, evening administration of once-daily theophylline results in better nocturnal oxygen saturation and an improvement in the overnight change in pulmonary function, without affecting sleep architecture, in patients with COPD. (CHEST 1996; 110:648-53)

Key words: COPD; polysomnography; salbutamol; sleep quality; theophylline

Abbreviations: PEFR=peak expiratory flow rate, REM=rapid eye movement; STC=serum theophylline concentration; TIB=time in bed; TST=total sleep time; V50=maximum expiratory flow at 50% of vital capacity

Patients with COPD complain often of poor sleep quality and these complaints have been substantiated by the objective findings of several investigators. Leitch et al[1] contrasted the sleep architecture of COPD patients with that of normal subjects. COPD patients had longer sleep latency, more frequent arousals, more frequent sleep stage changes and, as a consequence, poorer sleep efficiency than normal volunteers. Similar findings have been reported by Fletcher and colleagues[2] and Brezinova and coworkers.[3] Arand et al[4] reported that the frequent arousals seen during sleep in patients with COPD correlated with subjective complaints of excessive daytime sleepiness.

Several studies have highlighted the importance of nocturnal desaturation in the sleep fragmentation of patients with COPD. In a study by Fleetham et al,[5] 40% of nocturnal arousals were related temporally to oxyhemoglobin desaturation. However, supplemental oxygen did not decrease arousals even though the saturation was raised to near normal levels. By contrast, Kearley and coworkers[6] reported that supplemental oxygen improved sleep efficiency to 80% in a population of COPD patients whose sleep efficiency was just 52% while they breathed room air. Confirming these findings, Calverley et al[7] found that the administration of oxygen at 2 L/min via nasal prongs during sleep improved mean nocturnal oxygen saturation (from 53 to 90%), decreased sleep onset latency, and increased all stages of sleep, including rapid eye movement (REM) and slow-wave sleep.

Unfortunately, transient nocturnal desaturation is common among patients with COPD, even those with adequate daytime saturation values. Treatment of all such patients with supplemental oxygen would be prohibitively expensive, prompting a search for alternative forms of therapy. Sustained-release theophylline preparations could reduce nocturnal desaturation by means of their respiratory stimulant and bronchodilator properties and of particular interest is the observation by Mulloy and McNicholas[8] that theophylline improved oxygenation and reduced trapped gas volume in patients with severe COPD.

Fleetham and coworkers[9] studied the effects of theophylline on sleep in patients with COPD, and found a reduction in both total sleep time (TST) and REM sleep, and an increase in arousal frequency with theophylline compared with control nights. Similarly, Mulloy and McNicholas[8] found theophylline to decrease sleep duration in patients with COPD, although the proportions of TST spent in various sleep stages were not significantly different from placebo treatment. In contrast, Berry et al[10] found no differences between theophylline and placebo in TST, sleep latency, sleep efficiency, amount of time spent in various sleep stages, and REM sleep in patients with COPD. The latter two studies evaluated the effects of multiple daily doses of theophylline preparations that provide relatively constant serum theophylline concentrations throughout the day and night. A once-daily preparation, administered in the evening, has been shown to improve morning pulmonary function in patients with COPD compared with a twice-daily formulation.[11] Our study was therefore designed to compare the effects of a once-daily theophylline preparation (Uniphyl) and an inhaled [beta]-agonist (salbutamol) on sleep efficiency, staging and quality of sleep, overnight changes in pulmonary function, and nocturnal respiratory parameters, including arterial oxygen saturation, apneas, and hypopneas.

Materials and Methods

Patients in clinically stable conditions with COPD who had not been hospitalized within 1 month were eligible to participate in this randomized, double-blind, crossover study of theophylline and inhaled salbutamol. Blindness was maintained by the use of matching placebos. Men and women 18 years of age and older with [FEV.sub.1] below 70% of predicted, [FEV.sub.1]/FVC ratio below 70%, and an increase in [FEV.sub.1] of 15% or less in response to 200 [mu]g (2 puffs) of inhaled salbutamol were eligible. Patients with significant hypoxemia requiring supplemental oxygen therapy and those who would not be able to tolerate polysomnographic evaluation without supplemental oxygen were not eligible for the study. Patients with documented sleep disorders such as sleep apnea or narcolepsy were also excluded. Patients were informed about the study and signed a written consent form. The study was approved by the research and ethics boards of each of the two participating research centers.

Patients were asked to withhold treatment with theophylline for 36 h and inhaled [beta]-agonists for 6 h before baseline pulmonary function tests at the initial visit. Patients meeting all inclusion and exclusion criteria then underwent a 1-week run-in treatment period during which each individual's optimal once-daily theophylline dosage was determined. Doses were titrated to achieve trough serum concentrations of 37 to 66 [mu]mol/L (6.7 to 12.0 mg/L). Before recruitment or during this 1-week theophylline treatment period, patients underwent a 1-night acclimatization polysomnogram. Immediately following the [FEV.sub.1] reversibility test at approximately 8 AM, patients were given half their usual theophylline dose (Uniphyl; Purdue Frederick; Pickering, Ontario, Canada). Patients were discharged from the clinic and were instructed to take the daily theophylline dose with food at 6 PM on day 1 and day 2 of the study. On day 3, patients returned to the clinic prior to their next scheduled theophylline dose at 6 PM for measurement of trough serum theophylline concentrations (STCs). Patients with STCs between[37] and 66 [mu]mol/L continued in the study. For those patients whose STCs did not fall within this range, the dose of theophylline was adjusted and trough theophylline measurements were repeated after another 3 days of dosing to obtain a value between 37 and 66 [mu]mol/L. During the active treatment arms of the study, the patient received this dose of theophylline (as Uniphyl, 400- to 600-mg tablets, Purdue Frederick) or a matching placebo. The dose of scheduled inhaled salbutamol by metered-dose inhaler (or placebo) was 200 [mu]g (2 puffs) taken at 7 AM, 1 PM, 6 PM, and 11 PM (or bedtime). An open-label inhaled salbutamol was provided for "rescue" use on an as needed basis.

In addition to the study medications, patients continued their use of inhaled or oral corhcosteroids at the dose established prior to study entry. The dose of oral steroids did not exceed 10 mg/d of prednisone or equivalent. Concomitant use of ipratropium bromide was not permitted during the course of the study. Daily diaries were maintained by patients throughout the study period to record the following: (1) peak expiratory flow rate (PEFR), twice daily before medication use; (2) number of puffs of open-label rescue salbutamol inhaler; (3) frequency and severity of wheeze, cough, sputum production, and shortness of breath measured on a 5-point scale (0 = none; 1 = mild; 2 = moderate ; 3=severe; and 4=very severe) ; duration of symptoms recorded on a 4-point scale (0=none; 1=occasional; 2=frequent; and 3=continuous); (4) subjective evaluation of the previous night's sleep quality on a 4-point scale (0=poor; 1=fair; 2=good; 3=excellent); (5) fumes for sleep onset and awakening; and (6) any adverse events experienced.

Each active treatment arm of the double-blind, crossover study lasted approximately 2 weeks (allowable range, 12 to 16 days), and there was no washout period between phases. On the evening before the last day of each phase, patients were admitted to the sleep laboratory for evening and morning pulmonary function testing and polysomnographic evaluation, including oximetry throughout the night. Flow-volume spirometry was performed just before the scheduled 6 PM dose of theophylline or inhaled salbutamol, before the evening polysomnographic evaluation, and again the next morning at 7 AM immediately before the morning dose of inhaled salbutamol (or placebo). The following sleep parameters were recorded and analyzed: TST, total time in bed (TIB), sleep efficiency (TST/TIB), percentage of time spent in each stage, sleep latency, REM latency, wake time after sleep onset, and number of sleep stage changes. For respiratory parameters, the number of apneas (cessation of air flow for 10 s or longer) and hypopneas (greater than 50% decrease in tidal volume for 10 s or longer) were recorded, and the percentile distribution of oxygen saturation by time spent at each level of saturation was analyzed. The apnea, hypopnea, and apnea plus hypopnea indexes were calculated by dividing the number of apneas, hypopneas, and apneas plus hypopneas by the number of hours of TST (number of events per hour of sleep).

Statistical Analysis

Data from the one-night acclimatization study in the sleep laboratory were not analyzed. All other individual patient data from pulmonary function tests, polysomnography evaluations, and symptom scores were analyzed using analysis of variance appropriate for a 2x2 crossover design testing for the effects of treatment, study period, and sequence of treatment administration on each of the outcome variables Ratio and percentage scores were converted to ranks prior to analysis. since there was no washout period between the two active treatment phases, the data for duration and severity of symptoms and PEFR for the first 5 days were not included in the analysis to avoid any carryover effects Statistical significance was defined as p[less than or equal to]0.05 for a two-tailed hypothesis.

Results

Twenty patients (8 men and 12 women) were enrolled at the two participating research centers. Nineteen patients completed both phases of the crossover study, with 1 patient withdrawing due to reported side effects of upset stomach, headache, chest tightness, and insomnia after 2 days of phase 1, the theophylline treatment arm. Ten patients were receiving theophylline prior to the study while nine were not. Five patients were smokers; 15 were ax-smokers and their mean duration of disease was 14[+ or -] 15 years. The mean age of enrolled patients was 66[+ or -]8 years (range, 46 to 83 years). The mean [FEV.sub.1] was 1.18[+ or -]0.48 L, and the mean baseline [FEV.sub.1]/FVC ratio was 51.3+ 14.9%. The mean daily dose of theophylline was 550 mg (range, 400 to 800 ma) with a mean trough STC of 51.3[+ or -]9.4 [mu]mol/L (9.2[+ or -]1.7 mg/L).

Overnight changes in mean spirometric values are presented in Table 1. There was a significantly smaller decrease in overnight [FEV.sub.1] during the theophylline treatment arm than during the salbutamol phase (p=0.04). Similarly, overnight changes in [FEV.sub.1]/FVC ratio and [V.sub.50] were significantly different between the two treatments (p=0.014 and 0.025, respectively), with both parameters increasing with theophylline and decreasing with salbutamol. There were no other significant differences in spirometric values, but morning PEFR recorded daily by the patients was significantly higher while receiving theophylline than salbutamol (p=0.004). Nighttime symptoms scores tended to be lower during theophylline than during salbutamol treatment; these differences were statistically significant for the duration and severity of wheezing (p<0.006) (Table 2).

[TABULAR DATA 1-2 OMITTED]

Mean values for sleep-related and respiratory parameters are listed in Table 3. There were no significant treatment differences in TST, TIB, sleep efficiency, sleep latency, awake time after sleep onset, and the number of sleep stage changes. In addition, there were no differences between treatments with respect to the proportion of time spent in each of the sleep stages (Fig 1) or in subjective estimates of sleep quality (mean score, 2.32[+ or -]0.41, theopohylline; 2.44[+ or -]0.41, salbutamol). The total number of apneas and hypopneas was relatively small. Although not statistically significant, there were more apneas (12.7 vs 8.5) and hypopneas (25.3 vs 14.9) during salbutamol treatment than theophylline treatment. The apnea/hypopnea index also tended to be higher during salbutamol than during theophylline therapy. Patients spent significantly less time in oxygen saturation levels less than 90% (51[+ or -]92 min) during theophylline therapy than during salbutamol therapy (72[+ or -]104 mini p=0.03), and more time at oxygen saturation levels greater than 95% (108[+ or -]125 min vs 78[+ or -]112 mini p=0.0956, marginally significant) (Table 4). [TABULAR DATA 3-4 OMITTED]

Discussion

This study has demonstrated that evening administration of a once-daily theophylline preparation results in less overnight arterial oxygen desaturation and better overnight pulmonary function than four-times-daily inhaled salbutamol. These pulmonary benefits were achieved with no impairment of sleep quality.

Previous studies on the effect of theophylline on sleep quality have yielded conflicting information. Some studies have reported deterioration in sleep quality[8,9,12,13] while others have found no such effect.[10,14-16] Fitzpatrick et al,[14] reported that therapeutic levels of theophylline given for a period of 2 weeks to normal subjects had no significant effect on subjective or objective sleep quality in terms of sleep efficiency, sleep onset latency, or sleep architecture compared with placebo. Berry and coworkers[10] compared the effect of theophylline and placebo in patients with COPD. They found no significant quantitative or qualitative differences between theophylline and placebo. Similar lack of effect of theophylline on sleep quality and quantity has been reported with two theophylline preparations that provided different overnight theophylline concentrations[15] and in comparison to a long-acting [beta]-agonist.[16] In contrast, other studies examining the effect of theophylline on sleep in healthy volunteers have reported deterioration of sleep quality compared with placebo. Okudaira et al[12] found theophylline to delay the rhythm timing for sleep/wake patterns, while Kaplan and coworkers[13] found theophylline to increase significantly the number of arousals and decrease TST. Studies in patients with CoPD[8,9] have reported theophylline to decrease sleep duration and increase arousal frequency. In our study, theophylline did not have any adverse effect on subjective or objective measures of sleep quality compared with salbutamol. There were no significant treatment differences in TST, TIB, sleep efficiency, sleep latency, wake time after sleep onset, and number of sleep stage changes. In addition, there were no differences between treatments with respect to the proportion of time spent in each of the sleep stages.

Patients in our study spent significantly less time at oxygen saturation values of 90% or less with theophylline than with salbutamol therapy. This finding is consistent with results reported by Fleetham et al,9 Mulloy and McNicholas,[8] and Berry et al[10] in COPD. Each study reported higher nocturnal oxygen saturation levels with theophylline therapy compared with placebo. Significantly lower transcutaneous carbon dioxide levels were also seen when patients took theophylline.[8-10] Zwillich and colleagues[16] compared the effect of theophylline with bitolterol, a [beta]-agonist with a longer duration of action than salbutamol. They reported that the time spent at an oxygen saturation value greater than 4% below the awake control value was significantly less with theophylline. Our study extends these findings by showing that evening administration of a once-daily theophylline preparation improves oxygenation when compared with active therapy with a short-acting [beta]-agonist.

Beneficial effects of theophylline on pulmonary function in patients with COPD have been well documented.[10,11,15,17,18] The results of our study also show significantly better overnight pulmonary function compared with inhaled salbutamol, as measured by [FEV.sub.1] and [FEV.sub.1]/FVC ratios and morning PEFR.

We found that, in comparison to salbutamol, once-daily theophylline provided better overnight oxygenation and an improvement in the overnight change in pulmonary function without any difference in sleep quality. In contrast to our results, Fleetham and colleagues[9] reported that patients with COPD suffered a reduction in TST and an increase in arousal frequency when given theophylline. This occurred despite improvements in overnight oxygenation. There may be several reasons for the apparent differences between the results of our study and those that have reported an impairment in sleep quality resulting from theophylline. First, the studies may have employed different patient populations. Individuals differ in their response to xanthine therapy and patients who have previously received and tolerated theophylline may be less likely to exhibit sleep problems when tested objectively. Patients with COPD may also have differed in their degree of baseline sleep disturbance and overnight hypoxemia. Patients with intermittent mild hypoxemia may be less likely to exhibit sleep impairment with theophylline therapy because it reduces their hypoxemia. Second, different studies of theophylline therapy may have arrived at different conclusions based on the dose, duration of therapy, and the formulation of theophylline used. Theophylline preparations differ markedly in their chronopharmacology, and this may be exploited to maximize clinical benefit. For example, Martin and colleagues[19] have reported that a once-daily sustained-release theophylline preparation produces better overnight oxygenation than a twice-daily formulation without interfering with sleep quality for nocturnal asthmatics. It was hypothesized that the once-daily formulation given in the evening produced higher peak levels of theophylline overnight when needed, whereas the twice-daily preparation tended to maintain constant serum theophylline levels throughout the 24 h. The results of our study confirm the clinical utility of this chronotherapeutic approach to COPD treatment.

Although our study compared two commonly prescribed treatment regimens in COPD, it may not have tested the most optimal bronchodilator regimen, given the short duration action of salbutamol. We did not compare once-daily theophylline therapy with ipratropium bromide or with a long-acting inhaled beta-agonist or the combination of theophylline and an inhaled regimen. Further studies may help identify the most optimal bronchodilator therapy in such patients. In the interim, it appears that patients with significant COPD who suffer mild overnight arterial oxygen desaturation, despite the use of inhaled salbutamol, can benefit from evening administration of a once-daily theophylline preparation.

[Figure 1 ILLUSTRATION OMITTED]

REFERENCES

[1] Leitch AG, Clancy LJ, Leggett RJE, et al. Arterial blood gas tensions, hydrogen ion and electroencephalogram during sleep in patients with chronic ventilatory failure. Thorax 1976; 31:730-35

[2] Fletcher EC, Martin RJ, Monlux RD. Disturbed EEG sleep patterns in chronic obstructive pulmonary disease [abstract]. Sleep Res 1982; 11:186

[3] Brezinova V, Catterall JR, Douglas NJ, et al. Night sleep of chronic ventilatory failure and age matched controls: number and duration of the EEG episodes of intervening wakefulness and drowsiness. Sleep 1982; 2:123-30

[4] Arand DL, McGinty DJ, Littner MR. Respiratory patterns associated with hemoglobin desaturation during sleep in chronic obstructive pulmonary disease. Chest 1981; 86:183-90

[5] Fleetham J, West P, Mezon B. Sleep, arousals, and oxygen desaturation in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 126:429-33

[6] Kearley R, Wynne JW, Block AJ, et al. The effect of low flow oxygen on sleep-disordered breathing and oxygen desaturation: a study of patients with chronic obstructive lung disease. Chest 1980; 78:682-85

[7] CaveAey PMA, Brezinova V, Douglas NJ, et al. The effect of oxygenation on sleep quality in chronic bronchitis and emphysema. Am Rev Respir Dis 1982; 126:206-10

[8] Mulloy E, McNicholas V`T. Theophylline improves gas exchange during rest, exercise and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 148:1030-36

[9] Fleetham JA, Fera T, Edgell G, et al. The effect of theophylline therapy on sleep disorders in COPD patients [abstract]. Am Rev Respir Dis 1983; 127(suppl):A85

[10] Berry RB, Desa MM, Branum JP, et al. Effect of theophylline on sleep and sleep disordered breathing in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 143:245-50

[11] Rivington RN, Calcutt L, Hodder RV, et al. Safety and efficacy of once-daily Uniphyl tablets compared with twice-daily TheoDur tablets in elderly patients with chronic airflow obstruction. Am J Med 1988; 85(suppl 1B):48-53

[12] Okudaira N, Kripke DF, Mullaney DJ. Theophylline delays human sleep phase. Life Sci 1984; 34:933-38

[13] Kaplan J, Fredrickson PA, Renaux SA, et al. Theophylline effect on sleep in normal subjects. Chest 1993; 103:193-95

[14] Fitzpatrick MF, Engleman HM, Boellert F, et al. Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects. Am Rev Respir Dis 1992; 145:1355-58

[15] Martin RJ, Pak J. Overnight theophylline concentrations and effects on sleep and lung function in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 145:540-44

[16] Zwilich CW, Neagley SR, Cicutto L, et al. Nocturnal asthma therapy: inhaled bitolterol versus sustained-release theophylline. Am Rev Respir Dis 1989; 139:470-74

[17] Kirsten DK, Wegner RE, Jorres RA, et al. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104:1101-07

[18] Murciano D, Auclair M-H, Pariente R, et al. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989; 320:1521-25

[19] Martin RJ, Cicutto LC, Ballard RD, et al. Circadian variations in theophylline concentrations and the treatment of nocturnal asthma. Am Rev Respir Dis 1989; 139:475-78

(*) From the Walter C. Mackenzie Health Sciences Centre, University of Alberta Edmonton (Dr. Man), the Asthma Centre of the Toronto Hospital and University of Toronto (Dr. Chapman), and Purdue Frederick Pickering, Ontario (Drs. Ali and Darke). Supported in part by a research grant from Purdue Frederick Pickering, Ontario. Manuscript received April 25, 1995; revision accepted April 3, 1996. Reprint requests: Dr. Drake, 575 Granite Ct, Pickering, Ontario, Canada LIW 3W8

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