Melatonin improves sleep quality in hemodialysis patients

Introduction

Poor sleep quality (SQ) is common among patients on maintenance hemodialysis (HD).[123] SQ is important not only as a predictor of quality of life but also as a mortality risk among these patients.[45] Evidence is not conclusive about the source of sleep disturbance in these patients. However, absence of a nocturnal rise in melatonin concentration in daytime HD patients has been documented,[6] suggesting that it may be related to the degree of chronic kidney disease.[7] In contrast, some studies on HD patients have shown a relationship between supra-physiological concentrations of melatonin and its major metabolite, 6-sulfatoxymelatonin, with a diurnal rhythm in spite of insomnia, delayed sleep onset, night-time arousals and restless-leg syndrome.[8] Also, a small non-randomized trial showed significant improvements in subjective and objective sleep parameters as well as partial recovery of nocturnal melatonin rhythm after switching to in-center nocturnal HD.[9] However, other studies have shown that despite recovery of the melatonin rhythm after nocturnal HD, patients still suffered from poor sleep.[10]

Recent studies have underlined the benefit of exogenous administration of melatonin in sleep disorders in many conditions such as old adult insomnic,[11] parkisonism,[12] asthma,[13] chronic obstructive pulmonary disease (COPD)[1415] and HD patients.[16] Also, there is a promising prospect that administration of melatonin could improve anti-oxidative defence and the lipid profile.[171819]

The primary aim of this study is to investigate the efficacy of oral melatonin in improving quality of sleep in our patients on conventional daytime HD. In addition, lipid profile changes and erythropoietin (EPO) dose required after melatonin treatment are also evaluated.

Materials and Methods

Study design and protocol

This was a randomized, double-blind cross-over clinical trial [Figure 1] to evaluate the effectiveness of melatonin versus placeboin improving SQ in HD patients. The research project was approved by the Human Research Ethics Committee of the Arak University of Medical Sciences in Iran and was registered at Iranian Registry of Clinical Trials with the registration number IRCT 201108077253N1.

Close

Figure 1

Study design

Export to PPT

Patients were screened for inclusion in the study by their SQ score base on the Pittsburgh Sleep Quality Index (PSQI).[20] Inclusion criteria were age >18 years, ability to give informed consent, duration of HD >3 months, PSQI score ≥5 and adherence to regular and steady dialysis program or medication that interfere with melatonin secretion (such as beta adreno-receptors blocking drug). Exclusion criteria included known major illness (malignancy, active infection and uncontrolled heart failure), pregnancy, iron deficiency anemia, poor control diabetes mellitus (hemoglobin A_1c >7.5), current use of melatonin or known allergy of melatonin, acute medical or surgical condition that required hospitalization or operation throughout the study and dementia or psychotic disorder as diagnosed by researchers that interferes with patient's participation in this trial. All patients received daytime dialysis, and the total hours per week varied from 8 to 11.5 h.

One hundred and nineteen out of 163 patients consented to fill out the PSQI questionnaire. Eighty-seven cases (73%) had PSQI score ≥5. Finally, 82 patients who met the inclusion criteria were enrolled in this trial. Patients were randomly assigned to placebo or melatonin for 6 weeks. Melatonin (Melatonin Plus) (Schiff^®, Salt Lake City, USA) and placebo were packaged in identical 3-mg tablets. Melatonin plus has added Theanine, a natural compound found in green tea and vitamin B6 (10 mg). Dosage was set as one tablet taken at bedtime. After 6 weeks, patients underwent a 3-day washout period, followed by 6 weeks of the alternative therapy (from melatonin to placebo, and vice versa). Compliance was confirmed by pill count.

Results

Demographic data

Eighty-two consenting patients randomly took placebo or melatonin. During the course of the study, a total of 14 patients were withdrawn for reasons explained in Table 1. Sixty-eight patients (53% men; mean age of 58 ± 14 years; vintage of 6-296 months and 43% diabetics) remained in the study until completion. The majority of the subjects received HD for 4 h, three times a week. Baseline patient characteristics are shown in Table 2.

Table 1 The causes of excluding 14 patients throughout the study period

Table 2 Baseline lipid profile and hemoglobin level of the study population (n=68)

Effect of melatonin on sleep

PSQI scores were calculated at the end of 6 weeks. Significant improvements in global scores were observed in the melatonin-treated arm. Also, there was a statistically significant drop in the scores of sleep duration, sleep disturbance and sleep efficiency. In spite of improvement of subjective SQ, there was no improvement in daytime dysfunction after drug treatment. There was no meaningful difference in need for hypnotic sleep medications between groups. The global PSQI score and its components at the end of treatment are shown in Table 3. No significant differences were observed in PSQI scores by age, gender, time on HD or presence of diabetes (P > 0.05) (data not shown). There were also no serious detectable side-effects after melatonin treatment.

Table 3 Comparison of sleep quality in melatonin-treated and placebo groups

Effect of melatonin on lipid profile

There was no change in serum total cholesterol, LDL cholesterol and serum triglyceride levels throughout the study period [Table 4]. However, compared with the placebo, melatonin increased HDL cholesterol at the end of week 6 (P = 0.003).

Table 4 Comparison of lipid profile in melatonin-treated and placebo groups

Effect of melatonin on hematocrit and EPO dosage

There was no significant change in hemoglobin levels throughout the study period in both the drug treated and the placebo group [Table 5]. However, given the hemoglobin level, melatonin treatment decreased EPO dosage requirement.

Table 5 Comparison of hemoglobin values and erythropoietin requirement in melatonin-treated and placebo groups

There were also no statistically significant changes in either serum phosphorous, calcium-phosphorous product, serum parathyroid hormone or ferritin levels in both groups (P > 0.05) (data not shown).

Discussion

Melatonin is found widely in nature, ranging from unicellular organisms, plants and fungi to animals and humans.[22] In the human body, melatonin is secreted nocturnally by the pineal gland as an endogenous sleep regulator.[22] Various studies have supported the effectiveness of exogenous melatonin in sleep disorders,[12131415] insomnia,[1119] metabolic syndrome,[23] blood pressure regulation,[182425] neurodegenerative diseases[11] and disorders of oxidative damage.[1718] As complaints on poor quality of sleep are common among HD patients, we proposed to examine the effect of endogenous melatonin on SQ in these patients. In a meta-analysis, Brzezinski et al.,[26] using information derived from 17 different studies (involving 284 subjects) studied sleep-onset latency, total sleep duration and sleep efficiency. They reported that melatonin treatment can significantly improve these sleep components. However, the magnitude of this effect appears to be clinically insignificant.

Another meta-analysis by Braam et al.,[27] used nine different studies including a total of 183 individuals with intellectual disabilities. The study concluded that melatonin was effective in increasing the total sleep time and reducing the sleep latency and the number of wakes per night in patients.

In contrast, meta-analysis of the effects of melatonin in sleep disturbances, including all age groups (six randomized controlled trials with 97 participants) conducted by Buscemi et al.,[28] failed to document significant and clinically meaningful effects of exogenous melatonin on SQ, efficiency or latency. According to this analysis, melatonin did not have any effect on sleep-onset latency and sleep efficiency, SQ, wakefulness after sleep onset and the total sleep time in people with primary insomnia.

A recent study by Koch et al.,[16] suggests that melatonin may lead to an improvement of subjective and objective sleep parameters in HD patients. Using the sleep questionnaire and actigraphy, the study assessed the effect of melatonin (6 weeks melatonin 3 mg) on SQ in 20 HD patients. It concluded that melatonin treatment can significantly improve objective sleep-onset latency, sleep efficiency and actual sleep time.

Our survey was similar to that of Koch et al.,[16] except that we used only the PSQI questionnaire for assessment of SQ with a much larger sample size. Our data showed that 6-week melatonin administration improved patient-reported quality of sleep, particularly in terms of duration, disturbance and efficiency, without any impact on sleep latency and daytime dysfunction. Also, treatment with melatonin did not decrease the post-treatment need for sleep-inducing medication or hypnotics. Our results are different from those of Koch et al.,[16] where they have shown a significant improvement in sleep latency. Most studies on the effect of melatonin on SQ have failed to show any profound improvement on daytime sleepiness except the studies by Garfinkel et al.,[19] and Lemoin et al.[11] Both these studies stress the positive effect of melatonin on decreasing daytime sleepiness. Our results do not indicate any improvement in daytime dysfunction as reported by patients. Our results corroborate the findings by Nunes et al.,[14] indicating no change in daytime sleepiness despite significant improvement in global PSQI scores, sleep latency and sleep duration in COPD. In our view, the differences in findings in various studies could be explained by the variations in the duration, administered dose, sample size, heterogeneity of the selected samples and the way in which outcomes were measured.

In our study, we also monitored the lipid profile of patients after 6 weeks of melatonin or placebo prescription. Our data demonstrated significant increases in HDL cholesterol levels (P < 0.003) after melatonin treatment. In contrast, Garfinkel et al.,[19] showed no significant changes in lipid profile after 3 weeks of melatonin (2 mg) treatment in 36 type 2 diabetic patients with insomnia. Meanwhile, Koziróg et al.,[18] suggest that melatonin can decrease the LDL cholesterol without any change in HDL cholesterol in patients with metabolic syndrome.

The significant decrease in EPO dose requirements is another positive outcome associated with melatonin use in HD patients. We were unable to find any references in regards to this finding in the published literature. However, a longer follow-up period and a higher number of patients are required to really obtain data with a higher statistical power. We speculate that our results may in part be due to the anti-oxidative effect of melatonin. Herrera et al.,[17] have shown that oral consumption of melatonin can prevent oxidative stress of intravenous iron and EPO, both commonly used to treat anemia in chronic HD patients. Karimungi et al.,[29] demonstrated diurnal sensitivity in melatonin-induced hematological changes in the male albino rat. They concluded that melatonin may have a modulatory role in hematopoiesis and its rhythms.

In our study, we also attempted to control for known potential confounding variables for quality of sleep, such as major comorbidity, overt mood disorders and changes in treatment protocol, which could typically induce major changes in the target biochemical parameters (glucose, phosphorous, etc.,) However, several limitations of this report should be noted. The main limitation of this study is the absence of polysomniography or actigraphy, without which it is not possible to ascertain the exact cause of insomnia and sleep disturbance.[30] Also, subjective reports of SQ do not have a single criterion standard.

The results from the present study, showing sleep improvement and possible beneficial effect on hematopoiesis, are promising. However, this study had a relatively small sample size and a short investigation period. A longer-term multicenter study with a larger sample will be needed to further confirm the benefits of exogenous melatonin in HD patients in the future.

Conclusions

Our study suggests that melatonin may emerge as a safe, low-cost therapy for improving SQ in HD patients. The modest increase in HDL value and a decrease in the required EPO dose could be the other benefits of this treatment.