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Chronic Insomnia

April 2011

Sleep deprivation in the rat: VIII. High EEG amplitude sleep deprivation.

The disk apparatus was used to deprive six rats of the portion of non-rapid eye movement (NREM) sleep with high electroencephalogram (EEG) amplitude (HS2). All HS2 deprived (HS2D) rats died or were sacrificed when death seemed imminent within 23 to 66 days. No anatomical cause of death was identified. All deprived rats showed a debilitated appearance, lesions on their tails and paws, and weight loss in spite of increased food intake. Energy expenditure (calculated from the caloric value of food, weight change, and wastes) increased to more than twice baseline values. With one exception, yoked control rats remained generally healthy. It was not clear whether the changes in HS2D rats resulted from the loss of HS2 or the general disruption of NREM sleep that accompanied this loss. Also, it was not possible to produce major HS2 loss without incurring some loss of paradoxical sleep (PS). Control studies indicated that the partial PS loss in HS2D rats could not, in and of itself, account for all the pathological effects. However, an interaction of HS2D and partial PS loss in producing pathological effects cannot be ruled out.

Sleep. 1989 Feb;12(1):53-9

Sleep deprivation in the rat: VI. Skin changes.

All rats subjected to total or paradoxical sleep deprivation by the disk apparatus developed severe ulcerative and hyperkeratotic skin lesions localized to the plantar surfaces of their paws and to their tails. Yoked control rats only occasionally developed similar appearing lesions, which were always much less severe than in deprived rats. The deprived rat lesions could not be explained by pressure, disk rotation, water immersion, infection, necrotizing vasculitis, tyrosinemia, protein deficiency, or reduced rates of mitosis. Thus, although paw and tail lesions constitute a very reliable and severe symptom of total or selective sleep deprivation in the rat that potentially could yield insights into the pathogenic mechanisms induced by sleep loss, the mediation of the lesions remains unknown.

Sleep. 1989 Feb;12(1):42-6

Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety.

BACKGROUND: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment. METHODS: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.RESULTS: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] <or=8 microg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome. CONCLUSIONS: The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.

BMC Med. 2010 Aug 16;8:51

The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia.

Objectives of this study were to investigate the effects of prolonged-release melatonin 2 mg (PRM) on sleep and subsequent daytime psychomotor performance in patients aged > or =55 years with primary insomnia, as defined by fourth revision of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. Patients (N = 40) were treated nightly single-blind with placebo (2 weeks), randomized double-blind to PRM or placebo (3 weeks) followed by withdrawal period (3 weeks). Sleep was assessed by polysomnography, all-night sleep electroencephalography spectral analysis and questionnaires. Psychomotor performance was assessed by the Leeds Psychomotor Test battery. By the end of the double-blind treatment, the PRM group had significantly shorter sleep onset latency (9 min; P = 0.02) compared with the placebo group and scored significantly better in the Critical Flicker Fusion Test (P = 0.008) without negatively affecting sleep structure and architecture. Half of the patients reported substantial improvement in sleep quality at home with PRM compared with 15% with placebo (P = 0.018). No rebound effects were observed during withdrawal. In conclusion, nightly treatment with PRM effectively induced sleep and improved perceived quality of sleep in patients with primary insomnia aged > or =55 years. Daytime psychomotor performance was not impaired and was consistently better with PRM compared with placebo. PRM was well tolerated with no evidence of rebound effects.

Int Clin Psychopharmacol. 2009 Sep;24(5):239-49

Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes.

OBJECTIVE: Melatonin, the hormone produced nocturnally by the pineal gland, serves as a circadian time cue and sleep-anticipating signal in humans. With age, melatonin production declines and the prevalence of sleep disorders, particularly insomnia, increases. The efficacy and safety of a prolonged release melatonin formulation (PR-melatonin; Circadin* 2 mg) were examined in insomnia patients aged 55 years and older. DESIGN: Randomised, double blind, placebo-controlled. SETTING: Primary care. METHODOLOGY: From 1248 patients pre-screened and 523 attending visit 1, 354 males and females aged 55-80 years were admitted to the study, 177 to active medication and 177 to placebo. The study was conducted by primary care physicians in the West of Scotland and consisted of a 2-week, single blind, placebo run-in period followed by a 3-week double blind treatment period with PR-melatonin or placebo, one tablet per day at 2 hours before bedtime. MAIN OUTCOME MEASURES: Responder rate (concomitant improvement in sleep quality and morning alertness on Leeds Sleep Evaluation Questionnaire [LSEQ]), other LSEQ assessments, Pittsburgh Sleep Quality Index (PSQI) global score, other PSQI assessments, Quality of Night and Quality of Day derived from a diary, Clinical Global Improvement scale (CGI) score and quality of life (WHO-5 well being index). RESULTS: Of the 354 patients entering the active phase of the study, 20 failed to complete visit 3 (eight PR-melatonin; 12 Placebo). The principal reasons for drop-out were patient decision and lost to follow-up. Significant differences in favour of PR-melatonin vs. placebo treatment were found in concomitant and clinically relevant improvements in quality of sleep and morning alertness, demonstrated by responder analysis (26% vs. 15%; p = 0.014) as well as on each of these parameters separately. A significant and clinically relevant shortening of sleep latency to the same extent as most frequently used sleep medications was also found (-24.3 vs.-12.9 minutes; p = 0.028). Quality of life also improved significantly (p = 0.034). CONCLUSIONS: PR-melatonin results in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency and quality of life in primary insomnia patients aged 55 years and over. TRIAL REGISTRATION: The trial was conducted prior to registration being introduced.

Curr Med Res Opin. 2007 Oct;23(10):2597-605

Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects.

Melatonin, secreted nocturnally by the pineal gland, is an endogenous sleep regulator. Impaired melatonin production and complaints on poor quality of sleep are common among the elderly. Non-restorative sleep (perceived poor quality of sleep) and subsequently poor daytime functioning are increasingly recognized as a leading syndrome in the diagnostic and therapeutic process of insomnia complaints. The effects of 3-weeks prolonged-release melatonin 2 mg (PR-melatonin) versus placebo treatment were assessed in a multi-center randomized placebo-controlled study in 170 primary insomnia outpatients aged > or =55 years. Improvements in quality of sleep (QOS) the night before and morning alertness (BFW) were assessed using the Leeds Sleep Evaluation Questionnaire and changes in sleep quality (QON) reported on five categorical unit scales. Rebound insomnia and withdrawal effects following discontinuation were also evaluated. PR-melatonin significantly improved QOS (-22.5 versus -16.5 mm, P = 0.047), QON (0.89 versus 0.46 units; P = 0.003) and BFW (-15.7 versus -6.8 mm; P = 0.002) compared with placebo. The improvements in QOS and BFW were strongly correlated (Rval = 0.77, P < 0.001) suggesting a beneficial treatment effect on the restorative value of sleep. These results were confirmed in a subgroup of patients with a greater symptom severity. There was no evidence of rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was low and most side-effects were judged to be of minor severity. PR-melatonin is the first drug shown to significantly improve quality of sleep and morning alertness in primary insomnia patients aged 55 years and older-suggesting more restorative sleep, and without withdrawal symptoms upon discontinuation.

J Sleep Res. 2007 Dec;16(4):372-80

Melatonin replacement therapy of elderly insomniacs.

Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.

Sleep. 1995 Sep;18(7):598-603

Improvement of sleep quality in elderly people by controlled-release melatonin.

Melatonin, produced by the pineal gland at night, has a role in regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 [SD 8] years) who were receiving various medications for chronic illnesses and who complained of insomnia. In all 12 subjects the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomised, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a week’s washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 [SE 4] vs 75 [3]%, p < 0.001) and wake time after sleep onset was significantly shorter (49 [14] vs 73 [13] min, p < 0.001). Sleep latency decreased, but not significantly (19 [5] vs 33 [7] min, p = 0.088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously. Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.

Lancet. 1995 Aug 26;346(8974):541-4

Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy.

PURPOSE: Melatonin, which is produced by the pineal gland at night, is an endogenous sleep regulator. Both sleep disorders and impaired melatonin production are common among the elderly. We examined the excretion of the major melatonin metabolite 6-sulfatoxymelatonin in insomnia patients aged >or=55 years and its relation with the subsequent response to melatonin therapy. METHODS: We studied 517 insomnia patients, along with 29 age-matched and 30 younger healthy volunteers. Nocturnal urinary 6-sulfatoxymelatonin excretion was assessed between 10 pm and 10 am. Three hundred and ninety-six of the insomnia patients were treated for 2 weeks with placebo and for 3 weeks with 2 mg per night of controlled-release melatonin, of which 372 provided complete datasets. Clinical response, assessed with the Leeds Sleep Evaluation Questionnaire, was defined as an improvement of 10 mm or more on the visual analog scales. RESULTS: Mean (+/- SD) 6-sulfatoxymelatonin excretion was lower in the insomnia patients (9.0 +/- 8.3 microg per night) than in volunteers of the same age (18.1 +/- 12.7 microg per night, P <0.05) and in younger volunteers (24.2 +/- 11.9 microg per night, P <0.05). About 30% of patients (112/372) excreted <or=3.5 microg of sulfatoxymelatonin per night, which is considered to be lower than normal for this age group. These “low excretors” had a significantly higher response to melatonin replacement therapy (58% [65/112] vs. 47% [122/260], P <0.05). CONCLUSION: Low nocturnal melatonin production is associated with insomnia in patients aged 55 years or older, and identifies patients who are somewhat more likely to respond to melatonin replacement.

Am J Med. 2004 Jan 15;116(2):91-5

Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human suprachiasmatic nucleus (SCN) with aging.

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is implicated in the temporal organization of circadian rhythms in a variety of physiological, endocrine and behavioral processes. There is a great deal of evidence indicating that aging is characterized by a progressive deterioration of circadian timekeeping. The present study was aimed at investigating whether there are age-related changes in circadian rhythmicity of the vasopressin (VP)-producing neurons in the human SCN. To that end brains obtained at autopsy of 39 subjects, ranging in age from 6 to 91 years, were studied. Subjects were divided into two age groups, viz. ‘young subjects’ (up to 50 years) and ‘elderly subjects’ (over 50 years). It is shown that the number of VP-immunoreactive neurons in the human SCN exhibits a marked diurnal oscillation in young, but not in elderly, people. Whereas in young subjects low VP-immunoreactive neuron numbers were found during the night period (22:00-06:00 h) and peak values during the early morning (06:00-10:00 h), the SCN of elderly people showed a reduced amplitude and a tendency for a reversed diurnal pattern with high instead of low values during the night. The findings suggest that the VP synthesis of the human SCN exhibits a circadian rhythm that is disrupted later in life.

Brain Res. 1994 Jul 18;651(1-2):134-42

Triphala promotes healing of infected full-thickness dermal wound.

BACKGROUND: Infection is a major problem in the management of wounds. Even though the development of synthetic antimicrobial agents persists, drug resistance and toxicity hinder their way. Many plants with multi-potent pharmaceutical activities may offer better treatment options, and Triphala (dried fruits of Terminalia chebula, Terminalia bellirica, and Phyllanthus emblica) are potential formulations evaluated for healing activity on infected wound as it possesses numerous activities. MATERIALS AND METHODS: Alcoholic extract of Triphala has shown in vitro antimicrobial activity against wound pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pyogenes. An ointment was prepared from the Triphala extract (10% w/w) and assessed for in vivo wound healing on infected rat model by rate of healing, bacterial count, biochemical analysis, and expression of matrix metalloproteinases.RESULTS: The treated group has shown significantly improved wound closure. Assessment of granulation tissue on every fourth day showed significant reduction in bacterial count with significant level of collagen, hexosamine, uronic acid, and superoxide dismutase in the treated group (P < 0.01). Reduction of matrix metalloproteinase expression observed in the treated group by gelatin zymography and immunoblotting confirms our in vivo assessment. CONCLUSIONS: The above results showed the antibacterial, wound healing, and antioxidant activities of Triphala ointment, necessary for the management of infected wounds. Active principles of the Triphala may be further evaluated and used as an excellent therapeutic formulation for infected wounds.

J Surg Res. 2008 Jan;144(1):94-101

Role of melatonin in the regulation of human circadian rhythms and sleep.

The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep “facilitator” in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.

J Neuroendocrinol. 2003 Apr;15(4):432-7