Abstract
Disturbed sleep is common in asthma. Melatonin has sleep-inducing activity and reportedly affects smooth muscle tone and inflammation. The aim of this study was to evaluate the effect of melatonin on sleep in patients with mild and moderate asthma. This was a randomized, double-blind, placebo-controlled study. Twenty-two consecutive women with asthma were randomized to receive melatonin 3 mg (n = 12) or placebo (n = 10) for 4 weeks. Sleep quality and daytime somnolence were assessed by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, respectively. Pulmonary function was assessed by spirometry. Use of relief medication, asthma symptoms, and morning and evening peak expiratory flow rate were recorded daily. Melatonin treatment significantly improved subjective sleep quality, as compared with placebo (p = 0.04). No significant difference in asthma symptoms, use of relief medication and daily peak expiratory flow rate was found between groups. We conclude that melatonin can improve sleep in patients with asthma. Further studies looking into long-term effects of melatonin on airway inflammation and bronchial hyperresponsiveness are needed before melatonin can be recommended in patients with asthma.
Disturbed sleep and its daytime consequences are relevant problems in the management of asthma (1). Nocturnal exacerbations usually indicate inadequate disease control and cause sleep disruption, but poor sleep quality has been reported even in individuals with well controlled stable asthma (2, 3). Drugs used for this disease, such as methylxantines and oral steroids, have also been shown to disrupt sleep (4). Failure to deal with sleep problems may lead to impaired disease control and have a great negative impact on quality of life in patients with asthma (5, 6).
Melatonin, the major product of the pineal gland, plays an important role on the regulation of human circadian rhythms and is believed to have sleep-inducing activity (7, 8). Increasing amount of evidence also suggests that melatonin is involved on the regulation of smooth muscle tone (9, 10) and that it may have immunomodulatory (11–13) and antioxidant properties (14, 15).
Exogenous melatonin administration has been shown to improve sleep quality in otherwise healthy young and elderly individuals (16, 17). There are also reports of sleep improvement after melatonin administration in some medical conditions, including patients in intensive care unit with chronic obstructive pulmonary disease and pneumonia (18). Significant side effects of short- or long-term melatonin treatment are believed to be uncommon (19).
The aim of this study was to evaluate the effect of 4 weeks of melatonin administration on sleep in women with mild and moderate asthma.
We studied 22 consecutive patients aged 18 to 60 years with mild or moderate asthma according to NAEPP criteria (20). In view of previous reports that melatonin bioavailability is nearly threefold greater in female than male subjects (21), only women were recruited into this study. Written questionnaires were administered to each patient. Individuals who gave a history of asthma exacerbation within the previous 4 weeks, respiratory diseases other than asthma, sleep disorders, use of hypnotic-sedative drugs, smokers or ex-smokers, pregnant women, women who were breastfeeding, and shift-workers were not included. No mention to psychiatric disturbance was found on review of medical records of any of the subjects. No patient was taking drugs for other medical conditions, except for a patient who used metildopa for chronic systemic arterial hypertension. The protocol was approved by the local Research Ethics Committee and written informed consent was obtained in all cases.
This was a randomized, double-blind, parallel-group, placebo-controlled study of individuals with asthma, with a 2-week run-in and a 4-week treatment period. During the run-in period, patients took a morning daily dose of inhaled steroids (beclomethasone 1,000 μg). A short-acting inhaled β2-agonist (salbutamol) was used as needed. At the end of the 2-week period, sleep quality and daytime somnolence were assessed by the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), respectively, and spirometry was performed at the lung function laboratory (22). Patients were then randomized into the melatonin or placebo group. Melatonin and placebo were supplied in identical 3-mg capsules taken in a single dose for 28 days, 2 hours before bedtime. Beclomethasone and salbutamol were kept at the same regimen as previously. Participants did not take any other oral or inhaled medication for asthma during the study. Throughout the treatment period, subjects were asked to record their morning and evening peak expiratory flow rate (PEFR, best of three attempts), the presence of asthma symptoms, and the frequency of β2-agonist inhalation. Subjects were contacted by telephone once a week to check for adverse effects and compliance. Assessment of sleep quality, daytime somnolence, and lung function were repeated at the end of the treatment period for comparison. Patients and investigators were unaware of treatment allocation at all times.
The primary outcome measure was global sleep quality, evaluated by the PSQI. This scale has seven components, each one dealing with a major aspect of sleep: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; and (7) daytime dysfunction, as an indication of daytime alertness. Component number 6 always scored zero, because patients who used hypnotic-sedative medication were not included in the study. Individuals with total PSQI score of six or more were considered poor sleepers (23).
Secondary outcome measures were: (1) daytime somnolence, assessed by the ESS (a score of 10 or more was considered indicative of excessive daytime somnolence) (24); (2) spirometric variables: FVC, FEV1, FEV1/FVC, FEF25–75, and PEFR (as percentage of the predicted values, except for FEV1/FVC); (3) diurnal and nocturnal PEFR; (4) morning to evening variation in PEFR, calculated as: [PEFR evening − PEFR morning] × 100/PEFR evening; (5) diurnal and nocturnal subjective assessment of asthma (based on a 4-point scale, where 0 indicates absence of symptoms and 3 the presence of severe symptoms); and (6) number of puffs of β2-agonist. Means for PEFR, PEFR morning to evening variation, symptoms of asthma, and number of puffs of β2-agonist were calculated for each week of treatment.
Data were examined for normality using Kolmogorov-Smirnov test. Unpaired Student's t test was used for between-group comparisons of age, body mass index (BMI) and baseline PSQI score, ESS score, and lung function. Comparisons within groups (before and after treatment) for global PSQI score, ESS score, and spirometric results were made with paired Student's t test. Additionally, melatonin and placebo groups were compared with respect to global PSQI score, ESS score, and lung function using two-way ANOVA for repeated measures. Wilcoxon test was used for within-group comparisons for each of the six parts of the PSQI. Frequency of adverse effects, asthma symptoms, and use of inhaled β2-agonist were compared by Mann-Whitney test. PEFR and morning to evening variation in PEFR for both groups were compared using unpaired Student's t test. Statistical analysis was performed with the Statistical Package for Social Sciences (25). Data are quoted as mean ± SD and the level of significance was set at p < 0.05.
Twenty-two women with mild or moderate asthma were included in the study (mean age 29.7 ± 7.7 years; mean BMI 25.0 ± 4.5 kg/m2). Twelve patients were randomized into the melatonin group and 10 into the placebo group. One subject from the melatonin group who completed the 4 weeks of treatment failed to attend the final evaluation. Data on frequency of adverse effects, morning and evening daily PEFR, morning to evening variation in PEFR, asthma symptoms, and use of inhaled β2-agonist for this patient were included in the analysis. No significant differences were found between the two groups with respect to age, BMI, PSQI score, ESS score, and lung function before the treatment phase (p > 0.05). The average bedtime during treatment period was the same for both groups (10:40 pm ± 40 min).
On initial assessment, eight patients from the melatonin group and eight patients from the placebo group were classified as poor sleepers. Excessive daytime somnolence was detected in 10 (6 from melatonin group) out of the 22 subjects.
A significant improvement in PSQI score (p < 0.001) and a trend toward a reduction in ESS score (p = 0.05) were observed after melatonin treatment, but not after placebo (Figure 1
Figure 1. Melatonin, but not placebo, significantly improved subjective quality of sleep in women with asthma. The p values shown are for the comparison of the Pittsburgh Sleep Quality Index (PSQI) score before and after treatment with melatonin or placebo. The mean values for both groups are shown as short horizontal lines.
[More] [Minimize]Placebo (n = 10) | Melatonin (n = 11) | |||||
|---|---|---|---|---|---|---|
| Before | After | Before | After | |||
| Age | 32.4 ± 13.3 | — | 27.0 ± 7.1 | — | ||
| BMI | 25.2 ± 5.2 | 25.1 ± 5.1 | 24.9 ± 4.0 | 24.8 ± 4.1 | ||
| PSQI | 8.9 ± 3.1 | 7.0 ± 3.4 | 7.4 ± 3.2 | 3.4 ± 1.8† | ||
| ESS | 7.3 ± 4.4 | 5.7 ± 3.2 | 8.9 ± 5.6 | 6.0 ± 5.1 | ||
| FVC, %pred | 92.0 ± 14.0 | 93.6 ± 14.5 | 92.8 ± 12.0 | 97.0 ± 11.4 | ||
| FEV1, %pred | 83.2 ± 16.3 | 83.0 ± 16.9 | 79.5 ± 11.3 | 82.3 ± 12.8 | ||
| FEV1, %FVC | 79.9 ± 8.3 | 79.3 ± 8.8 | 74.6 ± 13.8 | 74.0 ± 15.0 | ||
| FEF25–75, %pred | 67.8 ± 27.8 | 67.2 ± 33.1 | 61.4 ± 32.5 | 60.9 ± 30.9 | ||
| PEFR, %pred | 80.2 ± 23 | 89.0 ± 25.0* | 74.5 ± 12.4 | 86.4 ± 18.4‡ | ||
No single component of PSQI was modified by placebo (p > 0.05). On the other hand, melatonin improved subjective quality of sleep (p = 0.02), reduced sleep latency (p = 0.02), increased sleep duration (p = 0.034), and decreased daytime and sleep disturbances (p = 0.025 and 0.02, respectively).
Spirometric evaluation did not show any significant change after treatment with melatonin or placebo except for PEFR, which increased in both groups (p = 0.014 and 0.016, for melatonin and placebo, respectively) (Table 1).
There was no significant difference between melatonin and placebo groups with respect to diurnal and nocturnal PEFR, PEFR morning to evening variation, diurnal and nocturnal symptoms of asthma, and number of inhalations of β2-agonist, in any of the 4 weeks of treatment (p > 0.05; see Table 2)
1st wk | 2nd wk | 3rd wk | 4th wk | |
|---|---|---|---|---|
| Morning PEFR, l/min | ||||
| Placebo | 299.5 ± 70.8 | 300.5 ± 76.5 | 301.6 ± 77.2 | 314.3 ± 84.9 |
| Melatonin | 287.5 ± 88.8 | 295.6 ± 96.0 | 305.2 ± 94.6 | 304.1 ± 93.3 |
| Evening PEFR, l/min | ||||
| Placebo | 295.4 ± 70.7 | 303.2 ± 78.7 | 306.6 ± 78.3 | 315.4 ± 73.5 |
| Melatonin | 291.9 ± 86.7 | 291.4 ± 99.3 | 304.0 ± 99.7 | 306.7 ± 91.2 |
| PEFR morning to evening variation* | ||||
| Placebo | −1.7 ± 6.2 | 0.5 ± 5.0 | 1.4 ± 6.5 | 0.9 ± 8.0 |
| Melatonin | 1.7 ± 9.1 | −2.1 ± 6.7 | −1.0 ± 4.9 | 1.1 ± 3.3 |
| Diurnal symptoms† | ||||
| Placebo | 0.4 ± 0.3 | 0.2 ± 0.3 | 0.4 ± 0.4 | 0.3 ± 0.4 |
| Melatonin | 0.3 ± 0.4 | 0.4 ± 0.4 | 0.4 ± 0.6 | 0.2 ± 0.3 |
| Nocturnal symptoms† | ||||
| Placebo | 0.2 ± 0.3 | 0.3 ± 0.4 | 0.4 ± 0.5 | 0.3 ± 0.4 |
| Melatonin | 0.2 ± 0.3 | 0.3 ± 0.4 | 0.2 ± 0.4 | 0.1 ± 0.3 |
| Diurnal β2-agonist use | ||||
| Placebo | 0.5 ± 0.6 | 0.6 ± 0.9 | 0.6 ± 0.9 | 0.5 ± 0.7 |
| Melatonin | 0.6 ± 1.0 | 0.8 ± 1.0 | 0.7 ± 1.0 | 0.5 ± 0.7 |
| Nocturnal β2-agonist use | ||||
| Placebo | 0.3 ± 0.3 | 0.2 ± 0.4 | 0.5 ± 1.0 | 0.2 ± 0.6 |
| Melatonin | 0.3 ± 0.5 | 0.3 ± 0.6 | 0.4 ± 0.8 | 0.2 ± 0.6 |
Eight patients (five from the melatonin group) reported mild headache (p > 0.05). One patient from the placebo group complained of epigastric pain during the study period.
Our results show that 3 mg of melatonin administered 2 hours before bedtime for a period of 4 weeks can improve sleep in women with stable asthma.
In the present study, sleep quality was assessed by the PSQI, a validated questionnaire largely used for this purpose. Objective measures of sleep or daytime sleepiness were not obtained. Although sleep quality is an easily accepted clinical construct, it is a complex phenomenon. Due to its largely subjective nature, sleep quality correlates with, but is not accurately defined by, sleep laboratory measures. Indeed, it has been reported that subjective criteria are superior to polysomnography in differentiating individuals with insomnia from control subjects, and that sleep laboratory recordings provide little relevant information for confirming or excluding the presence of insomnia (26).
To our knowledge, this is the first study on melatonin and sleep in patients with asthma. Previous studies looking into melatonin effects on sleep have done so mainly in healthy volunteers or subjects with insomnia. It is generally agreed that melatonin ingested during daytime, when its endogenous levels are low, has somnogenic properties (8, 17, 27, 28). Melatonin administration near the time of habitual nocturnal sleep has yielded less consistent results. Nocturnal administration has been reported to promote sleep in a number of studies (29–31), whereas limited clinical benefit (32–34) or even an increase in wake time after sleep onset has been reported by others (35). In addition to its sleep-promoting effects, melatonin also has chronobiotic properties, that is, the ability to induce phase-shifts in the circadian clock and to reentrain desynchronized circadian rhythms (36). Both the sleep-inducing and the circadian effect may provide useful tools for improving sleep in various clinical situations (37).
The mechanisms through which melatonin exerts its hypnotic effect have not been completely clarified. Experimental evidence of melatonin action on central benzodiazepine receptors suggests that its hypnotic activity could be mediated through GABAergic mechanisms (38). However, in a clinical trial, flumazenil, a central benzodiazepine antagonist, failed to decrease the hypnotic and hypothermic effects of melatonin (39). An increase in the likelihood of sleep secondary to a muscle relaxant effect of melatonin mediated via peripheral benzodiazepine receptors has also been hypothesized (40). It has also been proposed that melatonin interaction with specific receptors in the suprachiasmatic nucleus could lead to attenuation of mechanisms responsible for promoting and maintaining cortical and behavioral arousal (41). Plasma cGMP levels show circadian variation, with peak levels being observed during nocturnal sleep (42). Melatonin administration promotes a significant increase in cGMP, with peak levels coinciding with melatonin acrophase. Moreover, peak plasma levels of cGMP and melatonin show a positive correlation with subjective sleepiness, suggesting an involvement of cGMP in melatonin hypnotic action (43).
Significant nocturnal bronchoconstriction is common in asthma and appears to be an exaggeration of the normal circadian changes in airway caliber (44). Patients with nocturnal wheezing complain of sleep interruptions and show objective reduction in sleep efficiency (45). On initial assessment, we found that despite having mild or moderate asthma and being in a well controlled stable condition, most of our subjects were poor sleepers and almost half of them showed increased subjective daytime somnolence, when compared with a normal population (23, 24). Improved subjective sleep quality associated with melatonin administration could not be correlated to any improvement in lung function or in asthma symptoms. An increase in PEFR assessed by spirometry was found in both groups. No other lung function parameter was significantly changed by melatonin treatment or by placebo.
It has long been demonstrated that melatonin can affect smooth muscle tone in a complex manner, which depends on the tissue and the species investigated. There are few studies on the effects of melatonin on airway smooth muscle. In dogs, melatonin has been shown to decrease total lung resistance, to cause bronchial muscle relaxation and to inhibit 5-hydroxytryptamine–induced bronchoconstriction (46). Inhibition of 5-hydroxytryptamine–induced bronchoconstriction was also described in tracheal muscle of cats (47). On the other hand, melatonin reportedly induced contraction of bovine bronchial smooth muscle (48). In human tissue, melatonin caused bronchial smooth muscle relaxation in surgical specimens obtained from patients suffering from bronchiectasis and lung cancer (49).
No significant adverse effects were reported by our subjects after melatonin treatment. Previously, a study looking into the safety of chronic melatonin administration in healthy subjects did not find any significant side effects (19). This was confirmed by other investigators (50). In contrast, an increase in apnea–hypopnea index, mean apnea duration, and longest apnea duration after melatonin administration has been described in 12 patients with obstructive sleep apnea syndrome treated with nasal CPAP (51). A temporal relation between melatonin use and the development of autoimmune hepatitis has been reported in a single case (52). A crossover study on the effects of chronic melatonin administration on semen quality has found a decrease in sperm concentration and reduced motility in two out of eight individuals (53).
Increased serum levels of melatonin have been found in patients suffering from rheumatoid arthritis (54). Similarly, elevated peak serum levels of melatonin have been reported in patients with nocturnal asthma. Increased levels of this hormone were found to be significantly and inversely correlated with overnight change in FEV1 in the same group of patients (55). On the other hand, melatonin has recently been shown to cause partial inhibition of the expression of nuclear factor-κB and to downregulate the inducible isoform of nitric oxide synthase activity in lung tissue, in an experimental model of asthma (56). Nuclear factor-κB is an important transcription factor in chronic inflammatory diseases, such as asthma and rheumathoid arthritis, and its activation leads to an increase in the expression of many genes responsible for proinflammatory cytokines, chemokines, and enzymes that generate inflammatory mediators, immune receptors, and adhesion molecules (57). This is an important observation, because glucocorticoids may act through nuclear factor-κB inhibition (58).
In summary, melatonin as used in this study can improve subjective sleep quality in patients with mild and moderate asthma in the absence of any significant change in pulmonary function. Further work into long-term effects of melatonin on airway inflammation is necessary before it can be safely recommended for the management of sleep disturbances in patients with asthma.
The authors are indebted to Prof. Rosa Maria Salani Mota (Department of Mathematics and Applied Statistics, Federal University of Ceará) for assistance with statistical analysis of the data.
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