Original ArticleEffects of melatonin and bright light administration on motor and sensory symptoms of RLS
Introduction
Restless legs syndrome (RLS) is a common neurological disorder characterized by an urge to move the legs, usually accompanied or caused by unpleasant sensations which begin or worsen during periods of rest or inactivity such as lying or sitting, partially or totally relieved by movement, and worse in the evening or night than during the day [1].
A large number of these patients also have periodic leg movements during sleep (PLMS) and during wakefulness [2]. To quantify both sensory and motor manifestations of RLS during wakefulness, we developed a method called the suggested immobilization test (SIT) [3].
One of the central characteristics of RLS is the worsening of symptoms in the evening and during the night. Three studies have investigated the circadian fluctuations of RLS symptoms using the SIT [4], [5], [6] and showed that the severity of leg discomfort follows a circadian rhythm with a maximum occurring after midnight. One study [4] used a modified constant routine protocol to evaluate circadian variations of both leg discomfort and PLMW in RLS patients and controls in relation to circadian rhythms of core body temperature, melatonin secretion and subjective vigilance [7]. This study showed that the onset of melatonin secretion occurs at the same time as the worsening of symptoms at night, but salivary melatonin concentration reached its peak approximately 2 h before the acrophase of sensory or motor symptom severity. This result raised the possibility that increased melatonin secretion at night may contribute to nighttime worsening of RLS. Clinical, pharmacological, neuroimaging and neuroendocrine studies [8], [9], [10], [11], [12], [13], [14], [15], [16] suggest that decreased dopaminergic transmission may be involved in the physiopathology of RLS. Since melatonin is known to inhibit dopamine release in specific areas of the central nervous system including the striatum [17], [18], we formulated the hypothesis that the increase of melatonin at night, through its inhibition of dopamine transmission, would be responsible for the aggravation of symptoms at that time.
To test this hypothesis, we administered melatonin in the evening to see whether increased circulating levels of exogenous melatonin would increase RLS symptoms. Additionally, we exposed RLS patients to bright light in the evening, a procedure known to suppress endogenous melatonin secretion [19], [20] with the expectation that melatonin suppression would decrease the expression of RLS manifestations.
Section snippets
Subjects
Eight subjects (two men and six women; mean age ± standard deviation [SD], 53.3 ± 9.1 years; range, 38–63 years) who were drug naïve and who received a diagnosis of primary RLS participated in this study. All subjects fulfilled the four essential diagnostic criteria of RLS. They all had a severity score greater than 20 (mean of 29.1 ± 5.4, range: 20–36) on the International RLS Study Group Severity Scale [21]. They all had a habitual bedtime between 21:00 h and midnight. Exclusion criteria were the
Results
As expected, a major increase of salivary melatonin secretion was seen after oral administration of melatonin compared to baseline values (see Fig. 1). A mean melatonin concentration of 70 and 60 pg/ml was found during the first and second SIT after melatonin administration compared to 5 and 12 pg/ml in the baseline condition (p < 0.001 for both the first and the second SIT). When subjects were exposed to bright light, melatonin secretion was suppressed (mean < 5 pg/ml for both SIT 1 and 2). There
Discussion
Motor symptoms worsened during the SIT when subjects received exogenous melatonin. This result supports our hypothesis that melatonin secretion plays a role in the worsening of RLS symptoms at night. The decrease of sensory symptoms during bright light exposure is also congruent with this hypothesis, although the magnitude of this change suggests that endogenous melatonin secretion is probably not the most important contributing factor to the worsening of symptoms at night.
Why does exogenous
Limitations of the study
The results of the present study should be interpreted with caution considering the small sample size. It is also important to stress the point that subjects of the present study were severely affected with a mean RLS severity score of 29. It is possible that very severe cases are less responsive to experimental manipulation and that larger effects may be seen in subjects with milder symptoms. Severely affected patients tend to complain of sensory-motor symptoms throughout the day, suggesting a
Acknowledgment
Research supported by the Canadian Institutes of Health Research.
References (47)
- et al.
Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health
Sleep Med
(2003) - et al.
Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study – the PRELUDE study
Sleep Med
(2006) - et al.
Open-label study of the long-term efficacy and safety of pramipexole in patients with restless legs syndrome (extension of the PRELUDE study)
Sleep Med
(2008) - et al.
Dopamine inhibits melatonin release in the mammalian retina: in vitro evidence
Neurosci Lett
(2000) - et al.
The basic physiology and pathophysiology of melatonin
Sleep Med Rev
(2005) - et al.
Restless legs syndrome in end-stage renal disease
Am J Kidney Dis
(1996) - et al.
Periodic leg movements are not more prevalent in insomnia or hypersomnia but are specifically associated with sleep disorders involving a dopaminergic impairment
Sleep Med
(2000) - et al.
Periodic leg movements in sleep following treatment of obstructive sleep apnea with nasal continuous positive airway pressure
Chest
(1989) - et al.
Restless Legs Syndrome: scoring criteria for leg movements recorded during the suggested immobilization test
Sleep Med
(2001) - et al.
Correlation between putative indicators of primary restless legs syndrome severity
Sleep Med
(2007)
Day- and nighttime content of monoamines and their metabolites in the pineal gland of rat and hamster
Neurosci Lett
Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections
Brain Res
Bright light improves vitality and alleviates distress in healthy people
J Affective Disord
Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria
Mov Disord
Effects of immobility on sensory and motor symptoms of restless legs syndrome
Mov Disord
Circadian rhythm of restless legs syndrome: relationship with biological markers
Ann Neurol
Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome
Sleep
Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome
Mov Disord
Adaptation to abrupt time shifts of the oscillator(s) controlling human circadian rhythms
J Physiol
Restless legs syndrome and periodic movements in sleep: physiopathology and treatment with L-dopa
Clin Neuropharmacol
Restless legs syndrome improved by pramipexole: a double-blind randomized trial
Neurology
Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome
Sleep
Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome
Sleep
Cited by (34)
Insomnia and Other Sleep Disorders in Older Adults
2022, Psychiatric Clinics of North AmericaMelatonin in sleep disorders
2022, NeurologiaAmbient bright lighting in the morning improves sleep disturbances of older adults with dementia
2022, Sleep MedicineCitation Excerpt :For participants with RBD (n = 2), or RLS (n = 1), family members gave feedback that the wake-up time at night and the behaviors of shouting and talking during nighttime sleep were significantly improved after the light intervention. Morning bright light exposure may play a role in improving RBD and RLS by inhibiting daytime melatonin secretion, which reduces daytime sleepiness, and increases nighttime melatonin secretion [44]. Accordingly, the comparison group showed worsening sleep disturbances and circadian rhythms.
Treatment of Medical (Sleep Breathing Disorders, Restless Legs Syndrome, Periodic Limb Movement Disorder, and Narcolepsy) Sleep Problems in ADHD
2019, Sleep and ADHD: An Evidence-Based Guide to Assessment and TreatmentTreatment of Sleep-Related Movement and Circadian Rhythm Disorders, Hypersomnolence, and Parasomnias
2019, Handbook of Sleep Disorders in Medical Conditions