J Neurol (2007) 254:459–464 DOI 10.1007/s00415-006-0390-x
Camila Andrade Mendes Medeiros Pedro Felipe Carvalhedo de Bruin Lı´via Ariane Lopes Maria Cecı´lia Magalha˜es Maria de Lourdes Seabra Veralice Meireles Sales de Bruin
Received: 27 March 2006 Received in revised form: 17 June 2006 Accepted: 5 July 2006 Published online: 3 April 2007
P.F.C. de Bruin Æ L.A. Lopes M.C. Magalha˜es Æ V.M.S. de Bruin (&) Dept. of Medicine Federal University of Ceara´ Rua Prof. Costa Mendes 1608 – 4 Andar CEP 60430 040 Fortaleza (Ceara´), Brazil Tel.: +55-85/32421681 Fax: +55-85/32615540 E-Mail:
[email protected] C.A.M. Medeiros Dept. of Pharmacy Federal University of Ceara´ Ceara´, Brazil M. de L. Seabra Dept. of Psychobiology Federal University of Sa˜o Paulo Sa˜o Paulo, Brazil
ORIGINAL COMMUNICATION
Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease A randomized, double blind, placebo-controlled study
j Abstract Insomnia, sleep frag-
mentation and excessive daytime sleepiness are common in Parkinson’s disease (PD) and may contribute to the reduction of cognition and alertness in those patients. Melatonin has been shown to improve sleep in several conditions. In experimental models of PD, melatonin can ameliorate motor symptoms. To evaluate the effect of melatonin on sleep and motor dysfuntion in PD, we studied 18 patients (Hoehn & Yahr I to III) from a PD clinic. Prior to treatment, motor dysfunction was assessed by UPDRS II, III and IV. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence by the Epworth Sleepiness Scale (ESS). Full polysomnography (PSG) was performed in all subjects. Patients were then randomized to receive melatonin (3mg) or placebo one hour before bedtime for four weeks. All measures were repeated at the end of treatment. On initial assessment, 14 patients (70%) showed poor
Introduction Sleep disturbances have been frequently described in Parkinson’s disease (PD) potentially leading to poor
quality sleep (PSQI > 6) and eight (40%) excessive daytime sleepiness (ESS > 10). Increased sleep latency (50%), REM sleep without atonia (66%), and reduced sleep efficiency (72%) were found on PSG. Eight patients had an apnea/ hipopnea index greater than 15 but no severe oxygen desaturation was observed. Sleep fragmentation tended to be more severe in patients on lower doses of levodopa (p = 0.07). Although melatonin significantly improved subjective quality of sleep (p = 0.03) as evaluated by the PSQI index, PSG abnormalities were not changed. Motor dysfunction was not improved by the use of melatonin. Undetected differences in motor scores and PSG findings may have been due to a small sample size and a type II error.
j Key words Parkinson’s disease Æ melatonin Æ sleep Æ polysomnography Æ sleep apnea
quality of life [1]. Insomnia, sleep fragmentation, REM-sleep behavior disorder, restless legs syndrome and sleep apnea have been described in PD [2]. These alterations and the use of dopaminergic substances
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known to have sedative properties can lead to excessive daytime sleepiness, commonly seen in these patients [3]. Patients with PD frequently use sleeping pills which may also contribute to reduce cognitive function and alertness. Melatonin, the main product of the pineal gland, is secreted during the dark hours and its synthesis and release can be acutely suppressed by exposure to bright light [4]. Melatonin favours the reentrainment of the master circadian clock located in the suprachiasmatic nucleus to the 24 hour light-dark cycle and is involved in the organization of many circadian rhythms including the sleep-wake cycle [5]. Melatonin levels may be reduced in older individuals [6]. Exogenous melatonin administration can have both chronobiotic and sleep inducing activity [7]. Beneficial effects of melatonin have been reported in circadian rhythm sleep disorders as well as in other medical and neurological conditions associated with disturbed sleep [8, 9]. Previously, melatonin has been associated with improvement of basal ganglia lesion in experimental models of PD [10, 11]. In contrast, intracerebral injection of melatonin has been described to worsen striatal lesions in rats [12]. The aim of this study was to evaluate the effect of 4 weeks of melatonin administration (3 mg) on sleep and motor disability in PD patients.
j Study Design
Patients and methods
The primary outcome measures were subjective and objective sleep quality evaluated, respectively, by the PSQI and polysomnography. PSQI has seven components, each one dealing with a major aspect of sleep: 1) subjective quality of sleep; 2) sleep onset latency; 3) sleep duration; 4) sleep efficiency; 5) presence of sleep disturbances; 6) use of hypnoticsedative medication; and 7) presence of daytime disturbances, as an indication of daytime alertness. Component six 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 [14]. Polysomnographic parameters evaluated were sleep latency, total sleep time, sleep efficiency and sleep fragmentation. Secondary outcome measures were daytime somnolence and UPDRS scores. Daytime somnolence was assessed by the ESS [15]. ESS score of 10 or more indicates excessive daytime somnolence.
j Patients Twenty consecutive PD patients of both genders with Hoehn and Yahr I to III from a PD clinic were recruited in the study. Age at onset of illness varied from 41 to 68 years (mean age 54.6 ± 8.2) and disease duration from 2 to 23 years (mean duration 7.05 ± 4.8). The diagnosis of PD was made in the presence of at least two of the following signs: tremor, rigidity and/or akinesia. All patients showed therapeutic benefit with levodopa. Individuals with supranuclear gaze palsy, signs of upper motor neuron disease, cerebellar signs, prominent autonomic dysfunction, painful or debilitating disorders, previous history stroke and cognitive impairment defined as a Mini-Mental State examination (MMSE) of less than 24 were excluded. None of the patients used beta-blockers, sedatives or antidepressants. Participants were on the same antiparkinsonian medication for the last 30 days and did not change any of their medication during the study. 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 PD. At the beginning of the study sleep quality and daytime somnolence were assessed by the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), respectively. Polysomnography was performed according to a standard clinical protocol and recordings were scored according to the standard method established by Rechtshaffen and Kales [13]. Motor disability was assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) II, III and IV at the beginning of the study by two trained examiners at the same hour of the day and one hour after levodopa ingestion. Patients were then randomized into the melatonin or placebo groups. Melatonin and placebo were supplied in identical 3-mg capsules taken in a single dose for 28 days, one hour before bedtime. Subjects were contacted by telephone once a week to check for adverse effects and compliance. Assessment of sleep quality, daytime somnolence, parkinsonian motor disability and full night polyssonography were repeated at the end of the treatment period for comparison. Patients and investigators were unaware of treatment allocation at all times.
j Outcome measures
j Statistical analysis Data were examined for normality using KolmogorovSmirnov test. Between group comparison of baseline
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Table 1 Baseline clinical characteristics of melatonin and placebo groups Melatonina (n = 8) Gender (M/F) 7/1 Age (years) Range 51–73 Mean ± SD 62.90 ± 7.78 Age at beginning of symptoms (years) Range 45–64 Mean ± SD 56.50 ± 7.44 Disease duration (years) Range 2–10 Mean ± SD 6.40 ± 2.59 Levodopa (mg/day) Range 125 – 875 Mean ± SD 600 ± 226.69
Placebo (n = 10)
P value
2
Before melatonin
After melatonin
1,5
7/3 1
50 – 70 60.70 ± 6.65
0.505
41 – 68 52.70 ± 8.90
0.314
2 – 23 7.70 ± 6.52
0.565
375 – 1250 650 ± 248.61
0.644
data were performed with unpaired Student’s t test (age, body mass index (BMI), disease duration, levodopa dose, UPDRS II to IV), chi-square test (gender) and ANOVA. The outcome measures were compared between melatonin and placebo using ANCOVA for repeated measures after adjusting for baseline differences. Statistical analysis was performed with the Statistic Package for Social Sciences (SPSS-Norusis, 1993) software for Windows. Data are quoted as mean ± SD. The level of significance was set at p < 0.05.
Results Twenty consecutive patients (16 male) with clinical diagnosis of PD were initially recruited into the study. One female patient was excluded due to a diagnosis of breast cancer and another female patient failed to comply with medication. Sixteen male and two female PD patients (mean age 61.80 ± 7.13 years; mean disease duration 7.05 ± 4.87 years; H&Y score I-III) completed the study. Eight patients were randomized to receive melatonin and ten placebo. No significant difference was found between the two groups with respect to age, disease duration, motor disability and levodopa dose at baseline (Table 1). All subjects were receiving levodopa. Other medications used were amantadine (7 patients), biperiden (4 patients), pramipexol (2 patients) and selegiline (1 patient). On initial assessment, 14 patients (70%) showed poor quality sleep (PSQI > 6) and eight (40%) excessive daytime sleepiness (ESS > 10). Increased sleep latency (50%), reduced total sleep time (50%), REM sleep without atonia (66%), increased proportional amount of REM sleep (>25% of Total Sleep Time) (39%) and reduced sleep efficiency (72%) were demonstrated by polysomnography. Eight patients (44%) had an apnea/hipopnea index greater than 15 but no severe arterial oxygen desaturation was observed.
0,5 0 Sleep quality
Sleep latency
Sleep duration
Sleep efficiency
Sleep Sleep disturbance dysfunction
Fig. 1 Melatonin improved individual components of the Pittsburgh sleep quality index in PD patients
Fifteen patients presented on-off fluctuations and they were not different regarding PSQI scores and polysomnography although there was a tendency for more sleep fragmentation in patients without motor fluctuations (ANOVA, F = 3.63, p = 0.07). Patients with on-off fluctuations were on higher dose of levodopa (708.33 ± 192.88) than those without motor fluctuations (375 ± 153.09) (ANOVA, F = 12.2, p = 0.003). Periodic leg movements (>5/h) were found in three cases. After treatment, the melatonin group showed better subjective quality of sleep compared with controls as assessed by global score and scores for the six components of PSQI (ANCOVA F = 5.40; p = 0.03) (Fig. 1). No significant difference was observed in polysomnographic measures (Table 2). A trend of improvement of total sleep time was observed in the melatonin-treated group (ANCOVA, p = 0.09) (Table 2). Motor disabilities (UPDRS II and III) and complications related to therapy (UPDRS IV) were not improved by melatonin treatment (Table 2). No adverse events were experienced by either study group.
Discussion These results show that 3 mg melatonin taken one hour before bedtime significantly improves subjective sleep quality in patients with PD. It has been shown on a recent metanalysis that melatonin can improve subjective sleep quality with little change in polysomnographic measures [16]. However, due to the small number of patients on the study and the wide variation of polysomnographic findings, a type II error may have occurred. Although sleep quality is an easily accepted clinical construct, it is a complex phenomenon. Owing to its largely subjective nature, sleep quality correlates with but is not accurately defined by, sleep laboratory measures. Subjective criteria have been reported to be superior to polysomnography in differentiating individuals with insomnia from control subjects and sleep laboratory
462
Table 2 Subjective sleep quality, daytime somnolence, polysomnographic parameters and motor disabitlity before and after 4 weeks of treatment with melatonin or placebo Melatonin (n = 8)
PSQI Range mean ± SD ESS Range mean ± SD Sleep latency (min) Range mean ± SD REM sleep latency (min) Range mean ± SD Total sleep time (min) Range mean ± SD Frequency of arousals Range mean ± SD Sleep efficiency Range mean ± SD AHI Range mean ± SD UPDRS II Range mean ± SD UPDRS III Range mean ± SD UPDRS IV Range mean ± SD
Placebo (n = 10)
ANCOVA F
p value
3–16 8.7 ± 4.0
5.4
0.03*
4–22 11.7 ± 5.3
3–21 11.5 ± 6.4
0.04
0.84
23.5–86.5 44.5 ± 22.5
3–31 17.5 ± 8.8
8–142.5 45.4 ± 40.7
0.14
0.71
81–299.5 158.0 ± 75.9
16–163.5 86.9 ± 44.7
41–158 92.8 ± 43.9
46.0–193.5 110.1 ± 58.6
0.08
0.07
174.0–379.0 264.7 ± 59.7
204.1–355.5 291.7 ± 53.0
243.5–373.0 320.1 ± 49.2
121.0–422.5 268.5 ± 96.0
3.11
0.09
2–40.8 13.6 ± 12.7
4–43.7 18.6 ± 15.92
2–31.8 14.6 ± 11.0
4–32.7 12.0 ± 6.5
1.42
0.25
29.1–94.6 73.5 ± 21.2
40.7–91.6 73.5 ± 21.2
59.1–94.2 79.2 ± 12.5
35.1–91.1 71.2 ± 18.9
1.01
0.33
4.4–49.1 23.0 ± 15.0
1.8–49.1 19.56 ± 17.0
0.8–42.6 14.8 ± 14.9
2.7–36.6 14.2 ± 12.1
0.09
0.76
2–27 13.5 ± 7.94
5–21 13.8 ± 6.2
1–31 15.3 ± 8.7
3–32 13.6 ± 9.0
0.31
0.58
3–26 16.6 ± 6.9
1–31 16.3 ± 8.7
7–40 17.2 ± 10.1
8–30 16.6 ± 8.2
0.005
0.94
0–14 5.2 ± 4.8
1–12 6.0 ± 4.4
1–13 4.8 ± 4.3
0–14 4.9 ± 4.6
0.017
0.897
Before
After
Before
After
3–17 8.3 ± 4.5
2–11 4.5 ± 3.1
4–16 9.9 ± 3.7
3–21 7.4 ± 5.5
1–21 7.7 ± 5.8
21–102 44.6 ± 7.41
Definition of Abbreviations: PSQI – Pittsburgh Sleep Quality Index; ESS – Epworth Sleepiness Scale; REM – Rapid Eye Movement Sleep; AHI – Apnea + Hypopnea Index; UPDRS – Unified Parkinson’s Disease Rating Scale
recordings provide little relevant information for confirming or excluding the presence of insomnia [17]. The significant subjective improvement in sleep demonstrated in this study may be clinically relevant for this population. However, the findings of this study must be interpreted in the context of patients affected with mild to moderate disease. There have been very few studies on the effects of melatonin in PD. Dowling and coworkers [18] found no improvement in sleep efficiency as assessed by actigraphy, after one week 5 mg melatonin administration in PD patients. Recently, the same group reported that 50 mg melatonin administration can improve sleep quality in a cross-over study of PD patients [18]. However, actigraphy is probably unreliable for the assessment of patients with motor fluctuations, such as in PD, because hypokinesia and abnormal movements can be mistaken as sleep and wake, respectively. In our series, four weeks exoge-
nous administration of melatonin did not modify motor abilities or complications related to the disease. Given the small number of patients recruited, a significant benefit of melatonin on UPDRS scores may have been missed due to a type II error. An increase of size sample and the use of patient diaries to evaluate motor function may be more sensitive and better clarify this issue. This study confirms a high frequency of poor sleep and daytime somnolence in PD patients [19]. In our data, no significant difference in sleep quality and polysomnographic measures was found between patients with and without motor fluctuations. There was a trend for more sleep fragmentation in patients without motor fluctuations and on lower dose of levodopa. Dopaminergic agents can influence sleep and it is recognized that this influence is variable and probably works on an individual basis [20–22].
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Obstructive sleep apnea without severe oxygen desaturation was common in our series. Previously, obstructive sleep apnea has been found in 20 to 43% of cases with PD [3, 23]. Long-term follow-up studies are needed to clarify the influence of sleep apnea on morbidity and mortality of PD patients. Obstructive sleep apnea may aggravate excessive daytime sleepiness in these subjects [24]. In our subjects, melatonin administration was not associated with any major complaints confirming that it is well tolerated [25]. Melatonin may prepare the individual for sleep and a reduction of body temperature may occur in association with its use [26]. Phase advance is commonly associated with aging. Phase advance may also be present in PD [27, 28] although the wide spectrum of disease severity makes it difficult to reach a consensus on this subject. The
use of a substance with sleep-inducing as well as chronobiotic properties could be advantageous in this circumstance. Bright-light exposure in the late afternoon period could theoretically improve sleep in these patients and this therapeutic alternative deserves future investigation. Our results show that daytime sleepiness is not affected by melatonin administration despite improved subjective sleep quality. Benzodiazepines, the most prescribed sleep-inducing agents, are usually associated with residual sedation that can lead to sleepiness and impairment in psychomotor performance. Daytime rhythm activities are influenced by motor fluctuations and by sleepiness in PD [29]. In summary, we confirm that structural sleep abnormalities and sleep apnea are common in PD and melatonin improves sleep quality in those patients.
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