Efficacy and safety of perioperative melatonin for postoperative delirium in patients undergoing surgery: a systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of perioperative melatonin and melatonin agonists in preventing postoperative delirium (POD). METHODS: We conducted a systematic search for randomized controlled trials (RCTs) published through December 2022. The primary outcome was efficacy based on the incidence of POD (POD-I). Secondary outcomes included efficacy and safety according to the length of hospital or intensive care unit stay, in-hospital mortality, and adverse events. Subgroup analyses of POD-I were based on the type and dose of drug (low- and high-dose melatonin, ramelteon), the postoperative period (early or late), and the type of surgery. RESULTS: In the analysis (16 RCTs, 1981 patients), POD-I was lower in the treatment group than in the control group (risk ratio [RR] = 0.57). POD-I was lower in the high-dose melatonin group than in the control group (RR = 0.41), whereas no benefit was observed in the low-dose melatonin and ramelteon groups. POD-I was lower in the melatonin group in the early postoperative period (RR = 0.35) and in patients undergoing cardiopulmonary surgery (RR = 0.54). CONCLUSION: Perioperative melatonin or melatonin agonist treatment suppressed POD without severe adverse events, particularly at higher doses, during the early postoperative period, and after cardiopulmonary surgery.

Efficacy and safety of topical rosuvastatin & melatonin vs. placebo in patients with mild to moderate plaque psoriasis: A preliminary randomized double-blinded clinical trial.

BACKGROUND: Considering the pathogenesis of psoriasis and also the anti-oxidant, immunomodulatory, and anti-inflammatory properties of rosuvastatin and melatonin, the current clinical trial aimed to evaluate the efficacy of topical rosuvastatin and melatonin in patients with mild to moderate psoriasis. METHODS: The current randomized placebo-controlled clinical trial was conducted using a 3-arm parallel group included 77 adult patients (≥18 years old) with mild to moderate plaque psoriasis. Patients were randomized into a 1:1:1 ratio to one of three groups to receive one of the three interventions: melatonin cream, 5.0% (w/w), rosuvastatin cream, 5.0% (w/w), or placebo cream with a similar transparent appearance twice a day for 12 weeks. The primary outcome was severity of the disease using Psoriasis Area Severity Index (PASI). The secondary outcomes included the Dermatological Sum Score (DSS) to assess the erythema, scaling, and plaque elevation and the Dermatology Life Quality Index (DLQI). Photographs of the lesions were also taken at the baseline and at different periodic intervals thereafter. RESULTS: Among 77 randomized patients, 52 (mean (SD) age, 40.67 (10.85) years; 22 (42.30%) men) completed the study. A significant reduction of 45% (mean (SD) of 2.67 (0.98) to 1.74 (1.12)) and 70% (mean (SD) of 2.67 (0.98) to 1.31 (1.13)) in PASI score, and 46% (mean (SD) of 2.91(1.85) to 1.57 (1.11)) and 77% (mean (SD) of 2.91 (1.85) to 0.87 (0.67)) in DSS score on days 30 and 60 with rosuvastatin cream, 5% w/w (P < 0.001) compared with baseline was observed, respectively. Also a significant decrease of 35% (mean (SD) of 2.67 (0.98) to 1.74 (1.12)) and 51% (mean (SD) of 2.67 (0.98) to 1.31 (1.13)) in PASI score, and 40% (mean (SD) of 5.00 (1.58) to 3.00 (1.76))and 61% (mean (SD) of 5.00 (1.58) to 1.92 (1.71)) in DSS score on days 30 and 60 with melatonin cream, 5% w/w (P < 0.001) compared with baseline were observed, respectively. In each of the melatonin or rosuvastatin groups, DLQI improved significantly on days 30 (P < 0.0001) and 60 (P < 0.001) while the changes in the control group were not significant. CONCLUSION: The results of this clinical trial demonstrated that topical melatonin and rosuvastatin diminished the severity of mild to moderate plaque psoriasis with a satisfactory safety profile. Future clinical trials should assess both the long-term efficacy and safety of melatonin and rosuvastatin creams in larger study populations.

Investigating the safety profiles of exogenous melatonin and associated adverse events: A pharmacovigilance study using WHO-VigiBase.

Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders. However, there are limited studies on the safety of melatonin. Therefore, we aimed to present the overall patterns of adverse events (AEs) following melatonin administration and identify potential safety signals associated with melatonin. Using VigiBase, a global individual case safety report (ICSRs) database managed by the World Health Organization (WHO), we conducted a retrospective, observational, pharmacovigilance study of melatonin between January 1996 and September 2022. Disproportionality analysis was conducted using two comparator settings: all other drugs and other sleep medications. We used multivariable logistic regression to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs) to compare the frequencies of AEs reporting between melatonin and each comparator setting. Furthermore, we assessed adverse events of special interests (AESIs) that could potentially be associated with melatonin. Signals were identified when the following criteria were met: cases ≥3, x2 ≥ 4, IC025 ≥ 0, and the lower end of the 95% CI of ROR > 2. These signals were then compared with the AE information on the drug labels provided by regulatory bodies. A total of 35 479 AE reports associated with melatonin were identified, with a higher proportion of reports from females (57.1%) and individuals aged 45-64 years (20.8%). We identified 21 AEs that were commonly detected as safety signals in the disproportionality analyses, including tic, educational problems, disturbance in social behavior, body temperature fluctuation, and growth retardation. In AESI analyses, accidents and injuries (adjusted ROR 2.97; 95% CI, 2.80-3.16), fall (2.24; 2.12-2.37), nightmare (4.90; 4.37-5.49), and abnormal dreams (3.68; 3.19-4.25) were detected as a signal of melatonin when compared to all other drugs, whereas those signals were not detected when compared to other sleep medications. In this pharmacovigilance study, exogenous melatonin showed safety profiles comparable to other sleep medications. However, several unexpected potential safety signals were identified, underscoring the need for further investigation at the population level.

[Pharmacotherapies for insomnia]. / Traitements médicamenteux de l'insomnie.

PHARMACOTHERAPIES FOR INSOMNIA. The first line of treatment in adult chronic insomnia is cognitive behavioral therapy (CBT). However, its difficult accessibility limited its use and medications are still often prescribed. Considering the drugs with marketing authorization, Z-drugs (zolpidem and zopiclone) if taken at the right hour and dosage promote sleep initiation and have less deleterious effects than benzodiazepines, especially the long-acting ones which should be avoided. This class of drugs cannot be prescribed longer than 28 days. Some antihistaminic licensed drugs are authorized as hypnotics, with a low proof of efficacy and a risk of adverse event as sedation and somnolence the next day. Their prescription should be avoided in old subjects. Some clinicians used antidepressant sedative medications, at low dosage, as hypnotic drugs but "off label", outside authorization. Now melatonin, an endogenous synchronizer of biologic rhythms, has obtained the authorization for the treatment of insomniac troubles, in subjects of at least 55 years old, in its slow- release formula, replacing the physiological decline of this hormone with aging. Melatonin is not a hypnotic, but has soporific properties, inducing sleep, improving sleep efficacy, sometimes sleep duration and morning alertness. When discontinued, it induced no withdrawal syndrome. It has shown no risk of abuse potential and no deleterious side-effects, if used at the right dose and in the absence of hepatic interaction with other compounds. Finally, a new class of hypnotics, "the orexin antagonists" has its first representative on the French market: daridorexant. The place of these molecules in the therapeutic strategy for chronic insomnia needs to be clarified.

TRAITEMENTS MÉDICAMENTEUX DE L'INSOMNIE. Le traitement de première intention des adultes atteints d'insomnie chronique est la thérapie cognitivo-comportementale. Toutefois, compte tenu des difficultés d'accès à cette thérapeutique, les prescriptions médicamenteuses restent fréquentes. Considérant les médicaments qui ont une autorisation de mise sur le marché (AMM) dans cette indication, les Z-drugs (zolpidem et zopiclone), prises à bon escient, à la bonne posologie et à la bonne heure, favorisent l'initiation du sommeil et ont moins d'effets indésirables que les benzodiapézines, notamment celles à longue durée d'action, dont la prescription doit être évitée. Cette classe de médicaments est soumise à une réglementation particulière de durée de prescription (28 jours au maximum). Certains antihistaminiques peuvent être utiles comme hypnotiques, avec un faible niveau de preuve d'efficacité et des effets indésirables, notamment sur la vigilance du lendemain ; ils sont à éviter chez les sujets âgés. Certains antidépresseurs sédatifs sont prescrits, à faible dose, hors AMM. Plus récemment, la mélatonine, synchroniseur endogène des rythmes biologiques, a obtenu une AMM dans les troubles du sommeil du sujet âgé de 55 ans ou plus, dans sa formulation à longue durée d'action, suppléant la baisse physiologique de cette hormone avec l'âge. Induisant une somnolence, elle favorise l'endormissement, l'efficacité du sommeil, peut améliorer sa durée et assure un réveil de bonne qualité, sans accoutumance, sans syndrome de sevrage, et sans effet délétère majeur si l'on fait attention à la posologie et aux interactions médicamenteuses. Enfin, une nouvelle classe de médicaments, les anti-orexines, compte un premier représentant commercialisé en France : le daridorexant. La place de ces molécules dans la stratégie thérapeutique de l'insomnie chronique devra être précisée.

Melatonin and melatonin receptor agonists in the treatment of nocturia: A systematic review.

AIM: Causes of nocturia may extend beyond primary bladder pathology and it has been commonly associated as a side effect of sleep disorders. This has led to the study of melatonin and melatonin receptor agonists as a primary treatment for nocturia hypothesized to be secondary to sleep disorders. We aim to systematically review the efficacy and reported safety of melatonin and melatonin receptor agonists in the treatment of nocturia. METHODS: A search strategy of EMBASE and Pubmed/Medline databases was utilized to identify eligible studies. Two thousand and twenty-eight unique references were identified in concordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines for systematic reviews, of which nine papers met the inclusion criteria. The Cochrane Collaboration risk of bias criteria in the open label and nonplacebo studies was used to assess bias. RESULTS: The nine studies identified included 3 randomized double-blinded placebo-controlled trials, 2 randomized non-placebo trial, and 4 prospective open-label trials. Three utilized the melatonin-receptor agonist ramelteon (8 mg) and six utilized melatonin (four 2 mg extended release, two 2 mg normal release). Nocturia improved in 8 studies varying from moderate to low efficacy related to reduction in nocturia episodes. Five studies evaluated sleep parameters finding improvement in both nocturia and sleep quality. Male subjects represented 76.8% of 371 total subjects in prospective and randomized trials. Ramelteon and melatonin were both reported as well tolerated during nocturia treatment. A meta-analysis was not able to be performed due to the heterogeneity of bladder diagnoses. CONCLUSIONS: At this time, there is insufficient evidence to routinely recommend melatonin as an effective treatment for nocturia given the limitations of current clinical studies. Randomized placebo-controlled trials and prospective open label studies in non-neurogenic populations report a trend towards nocturia improvement with good tolerability and rare side effects. Therefore, further larger scale randomized trials with focused urologic diagnoses in well-characterized patient populations are warranted.

Melatonin treatment has consistent but transient beneficial effects on sleep measures and pain in patients with severe chronic pain: the DREAM-CP randomised controlled trial.

BACKGROUND: Sleep disturbance is a major issue for patients with chronic pain. Melatonin has been shown to improve symptoms of fibromyalgia, but its efficacy in other chronic non-malignant pain conditions is not fully known. Hence, we determined the effect of melatonin in patients with severe noncancer chronic pain. METHODS: This was a randomised double-blinded crossover trial of modified-release melatonin as Circadin™ compared with placebo. Sixty male and female subjects with chronic severe pain were randomised to receive either 2 mg of Circadin™ or placebo before sleep for 6 weeks, followed by a >4 week washout, then crossing over to the other treatment. Sleep disturbance, quality, and latency were measured using three different validated sleep assessment tools. The primary outcome measure was self-reported sleep disturbance after 6 weeks of treatment. Adverse events were also recorded. RESULTS: Sleep disturbance after 6 weeks was not significantly altered by melatonin treatment, but differences between melatonin and placebo treatment periods after 3 weeks were seen: sleep disturbance (P=0.014), latency (P=0.04), overall sleep quality (P=0.004), and effect of pain on sleep (P=0.032). Pain intensity scores improved during both treatment periods (both P<0.001). There were no differences in adverse events between treatment periods. CONCLUSIONS: Circadin™ treatment did not improve sleep disturbance in patients with severe chronic pain compared with placebo at 6 weeks, but there were consistent improvements in aspects of sleep in the shorter term. Given its favourable safety profile, it could be beneficial for some patients with chronic pain. CLINICAL TRIAL REGISTRATION: ISRCTN12861060.

Melatonin as an add-on treatment for epilepsy: A systematic review and meta-analysis.

PURPOSE: Epilepsy, one severe prevalent brain disorder, primarily relies on drug treatment. However, approximately one-third of patients with epilepsy do not achieve effective control with current medications, underscoring the need for more innovative treatment approaches. Notably, melatonin has gained attention for its anti-seizure properties and favourable safety profile. This systematic review aimed to evaluate the efficacy and safety of melatonin as an add-on treatment for epilepsy. METHODS: We searched for articles published before June 2023 in Web of Science, Cochrane Library, and PubMed. We used RevMan 5.4 software to compute relative risks (RRs) and 95 % confidence intervals (CIs). Key outcomes included total sleep time, wakefulness after sleep onset, sleep latency, seizure frequency, seizure severity, and safety. The quality of randomised controlled studies (RCTs) was assessed using the Cochrane Risk of Bias tool. RESULTS: Of the 264 publications retrieved, 10 RCTs were included in the meta-analysis. Add-on melatonin treatment improved sleep latency (RR: 0.56; 95 %CI: 0.10-1.02; P = 0.02) and seizure severity (RR: 0.33; 95 %CI: 0.04-0.62; P = 0.03) compared with placebo treatment. Adverse events (increased headache severity in children with a history of migraines, bronchitis, ear infections, agitation, and urinary frequency) were reported in only one trial. CONCLUSION: This systematic review found that add-on melatonin therapy improved sleep latency and seizure severity in patients with epilepsy. However, several of the included studies did not systematically assess sleep quality, seizures, and safety and lacked long-term follow-up data. Further RCTs with extended follow-up periods are required to definitively determine the efficacy and safety of melatonin.

The Safety and Comparative Effectiveness of Non-Psychoactive Cannabinoid Formulations for the Improvement of Sleep: A Double-Blinded, Randomized Controlled Trial.

BACKGROUND: Clinical evidence on the use of cannabidiol (CBD) for sleep remains limited. Even fewer studies have tested the comparative effectiveness of cannabinoid formulations found within CBD products used for sleep or how they compare to other complementary therapies such as melatonin. METHODS: Participants (N = 1,793 adults experiencing symptoms of sleep disturbance) were randomly assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15 mg CBD or 5 mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed over a period of 5 weeks (baseline week and 4 weeks of product use) using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. A linear mixed-effects regression model was used to assess the differences in the change in sleep disturbance through time between each active product arm and CBD isolate. RESULTS: All formulations exhibited a favorable safety profile (12% of participants reported a side effect and none were severe) and led to significant improvements in sleep disturbance (p < 0.001 in within-group comparisons). Most participants (56% to 75%) across all formulations experienced a clinically important improvement in their sleep quality. There were no significant differences in effect, however, between 15 mg CBD isolate and formulations containing 15 mg CBD and 15 mg cannabinol (CBN), alone or in combination with 5 mg cannabichromene (CBC). There were also no significant differences in effect between 15 mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15 mg CBD and 15 mg CBN. CONCLUSIONS: Our findings suggest that chronic use of a low dose of CBD is safe and could improve sleep quality, though these effects do not exceed that of 5 mg melatonin. Moreover, the addition of low doses of CBN and CBC may not improve the effect of formulations containing CBD or melatonin isolate.

Melatonin Supplementation for Cancer-Related Fatigue in Patients With Early Stage Breast Cancer Receiving Radiotherapy: A Double-Blind Placebo-Controlled Trial.

BACKGROUND: Fatigue is common in patients undergoing radiotherapy (RT) and can significantly impact quality of life. Melatonin, a safe inexpensive natural supplement, may improve symptoms and attenuate the side effects of RT. The purpose of this randomized double-blind placebo-controlled phase III trial was to assess the effects of melatonin for preventing fatigue and other symptoms in patients with breast cancer undergoing RT. METHODS: Female early stage or Ductal carcinoma in situ patients with breast cancer ≥18 years of age with Eastern Cooperative Oncology Group (ECOG) performance status <3, hemoglobin ≥9 g/dL, planned for outpatient RT treatment with curative intent, were randomized 1:1 to melatonin 20 mg or placebo, orally, starting the night before RT initiation until 2 weeks post-RT. Randomization was stratified according to treatment duration (<3 weeks, ≥3 weeks) and prior chemotherapy. The primary endpoint was the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue scale), and secondary endpoints were FACIT-F subscales, Edmonton Symptom Assessment Scale (ESAS), and Patient-Reported Outcomes Measurement Information System (PROMIS) scores obtained at baseline, and 2 and 8 weeks post-RT. A 2-sided ANOVA F-test at a 4.5% significance level for the primary endpoint was used. Secondary analyses were reported using an F-test at a 5% significance level. The goal was to recruit approximately 140 patients with interim analysis planned mid-recruitment. RESULTS: Eighty-five patients were screened for eligibility; 79 patients were randomized: 40 to melatonin and 39 to placebo; 78 patients were treated and included in the interim analysis at the mid-recruitment point. Baseline patient characteristics of age, race, and ECOG performance status were similar in both arms. The treatment effect was studied using a longitudinal mixed effects model with the effect of treatment over time (treatment × time) as the primary outcome parameter. The treatment × time for FACIT-Fatigue did not demonstrate statistical significance (P-value .83) in the melatonin group compared to placebo. In addition, secondary analyses of FACIT physical, social, emotional, and functional well-being scores did not demonstrate statistical significance (P-values of .35, .06, .62, and .71, respectively). Total PROMIS scores, collected as secondary outcome reported by patients, did not demonstrate statistically significant change over time either (P-value is .34). The other secondary scale, ESAS, was analyzed for each individual item and found to be nonsignificant, anxiety (P = .56), well-being (.82), drowsiness (.83), lack of appetite (.35), nausea (.79), pain (.50), shortness of breath (.77), sleep (.45), and tiredness (.56). Depression was the only item demonstrating statistical significance with a decrease of 0.01 unit in the placebo group, a change not considered clinically significant. Melatonin was well-tolerated with no grade 3 or 4 adverse events reported. The most common side effects were headache, somnolence, and abdominal pain. No patients died while participating in this study. Two patients died within a year of study completion from breast cancer recurrence. Sixteen patients withdrew prior to study completion for various reasons including adverse events, hospitalizations unrelated to study drug, RT discontinuation, and COVID-19 precautions. CONCLUSIONS: In this double-blind placebo-controlled phase III trial, melatonin did not prevent or significantly improve fatigue and other symptoms in patients with early stage breast cancer undergoing RT. The analysis, showing little evidence of an effect, at mid-recruitment, assured early termination of the trial.

Central precocious puberty secondary to peripheral precocious puberty due to a pineal germ cell tumor: a case and review of literature.

BACKGROUND: The pineal lesion affecting melatonin is a rare cause of central precocious puberty by decreasing the inhibition of hypothalamic-pituitary-gonadal axis. Germ cell tumor secreting human chorionic gonadotropin is a rare cause of peripheral puberty. CASE PRESENTATION: A 5.8-year-old male presented facial hair and phallic growth, deepened voice, and accelerated growth velocity for 6 months. The elevated human chorionic gonadotropin level with undetectable gonadotropin levels indicated peripheral precocious puberty. Brain imaging revealed a pineal mass and further pathology indicated the diagnosis of teratoma. During chemoradiotherapy with operation, the elevated human chorionic gonadotropin level reduced to normal range, while the levels of gonadotropins and testosterone increased. Subsequently, progressing precocious puberty was arrested with gonadotrophin-releasing hormone analog therapy. Previous cases of transition from peripheral precocious puberty to central precocious puberty were reviewed. The transitions were caused by the suddenly reduced feedback inhibition of sex steroid hormones on gonadotropin releasing hormone and gonadotropins. CONCLUSIONS: For patients with human chorionic gonadotropin-secreting tumors, gonadotropin levels increase prior to sex steroid decrease, seems a sign of melatonin-related central PP related to melatonin.

Protective and therapeutic potential of melatonin against intestinal diseases: updated review of current data based on molecular mechanisms.

INTRODUCTION: Intestinal diseases, a leading global cause of mortality and morbidity, carry a substantial socioeconomic burden. Small and large intestines play pivotal roles in gastrointestinal physiology and food digestion. Pathological conditions, such as gut dysbiosis, inflammation, cancer, therapy-related complications, ulcers, and ischemia, necessitate the urgent exploration of safe and effective complementary therapeutic strategies for optimal intestinal health. AREAS COVERED: This article evaluates the potential therapeutic effects of melatonin, a molecule with a wide range of physiological actions, on intestinal diseases including inflammatory bowel disease, irritable bowel syndrome, colon cancer, gastric/duodenal ulcers and other intestinal disorders. EXPERT OPINION: Due to anti-inflammatory and antioxidant properties as well as various biological actions, melatonin could be a therapeutic option for improving digestive disorders. However, more researches are needed to fully understand the potential benefits and risks of using melatonin for digestive disorders.

Clinical efficacy and safety of melatonin supplementation in multiple sclerosis: a systematic review.

BACKGROUND: Melatonin is a neurohormone secreted predominantly by the pineal gland that is demonstrated to be associated with the pathogenesis of multiple sclerosis (MS). This research desires to evaluate the tolerability and beneficial effects of exogenous melatonin supplementations in patients with MS. METHODS: This study was executed following the PRISMA 2020 statement. Both observational and interventional studies which reported the clinical effectiveness and/or safety of melatonin supplementation in patients with MS were included in this systematic review. Ovid, PubMed, Scopus, Embase, and Web of Science databases were searched and the risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools based on study design. RESULTS: Out of 1304 results of database searches, finally, 14 articles, including 7 randomized controlled trials (RCTs), 6 case-control studies, and one quasi-experimental study, were included based on the full-text review. Included phenotypes of MS were mostly relapsing-remitting MS (RRMS) (in 11 studies); it was secondary progressive MS (SPMS) in only one study, and two other studies had a mixture of the different phenotypes. The course of treatment with melatonin supplementation was between 2 weeks and 12 months. There were no substantial safety issues. Although melatonin was associated with enhanced oxidative stress and inflammation status, concerning the clinical benefits, limited studies suggested improvements in sleep conditions, cognitive outcomes, and fatigue in MS. DISCUSSION: There are insufficient data to support the regular melatonin prescription in MS. Limitations such as the small number of included studies, the diversity of the dosage, route, and duration of melatonin administration, and the diversity of assessment tests lead to unconvincing findings in this study. There is a need for future studies to achieve a comprehensive judgment on this subject.

[Comparative study of the clinical efficacy and safety of the fixed dose combination Levroso Long with Melaxen and Diphenhydramine in patients with insomnia]. / Rezul'taty sravnitel'nogo klinicheskogo issledovaniya effektivnosti i bezopasnosti kombinirovannogo lekarstvennogo preparata Levroso Long s preparatami Melaksen i Dimedrol u patsientov s bessonnitsei.

OBJECTIVE: Evaluation of the efficacy and safety of Levroso Long (fixed dose combination (hereinafter referred to as «FDC¼) diphenhydramine and melatonin, 25 mg + 3 mg and FDC diphenhydramine and melatonin 50 mg + 3 mg, respectively, capsules with modified release, NovaMedica Innotech LLC) in comparison with diphenhydramine medicines 50 mg (Diphenhydramine tablets, DALHIMFARM OJSC, Russia) and 3 mg melatonin (Melaxen tablets, Unipharm Inc., USA) in patients with insomnia. MATERIALS AND METHODS: Material and methods. A multicenter open randomized comparative clinical trial was conducted in parallel groups. The study included 312 patients with an insomnia diagnosis verified in accordance with the DSM-IV criteria (ICD code F51.0-10) and an insomnia severity index (ICI) >8 points. The patients were randomized into 4 groups and took the following medications for 10 days: patients of group 1 - Levroso Long (25 mg diphenhydramine and 3 mg melatonin), group 2 - Levroso Long combination drug (50 mg diphenhydramine and 3 mg melatonin), Group 3 -Diphenhydramine 50 mg, 4th - Melaxen 3 mg. A comparative assessment was performed on the 7th and 10th days of therapy according to the primary endpoint - ICI, and secondary endpoints - the results of the assessment based on the Leeds Sleep Assessment Questionnaire, the Pittsburgh Sleep Quality Questionnaire, the Scale of the overall clinical impression of improvement and the analysis of the profile of adverse events (NA). RESULTS: The FDC of diphenhydramine 25 mg + melatonin 3 mg was more effective than diphenhydramine 50 mg, and FDC diphenhydramine 50 mg + melatonin 3 mg was more effective than diphenhydramine 50 mg or melatonin 3 mg on both primary and secondary endpoints. In a safety assessment, the highest incidence of adverse events (48.7%) in the diphenhydramine 50 mg group was significantly lower in groups 1 (29.5%), 2 (12.8%) and 4 (1.3%). All reported adverse events in the FDC groups were mild or moderate in severity. CONCLUSION: The study showed that Levroso Long in two dosages surpassed monotherapy with 50 mg of Diphenhydramine (50 mg) or Melaxen (3 mg) in patients with insomnia in terms of efficacy parameters. The benefit/risk ratio of the studied drug is favorable compared to monotherapy.

Efficacy and Safety of Preoperative Melatonin for Women Undergoing Cesarean Section: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

Background: Cesarean section (CS) has been linked to a number of negative effects, such as pain, anxiety, and sleeping problems. The aim of this systematic review and meta-analysis was to investigate the safety and efficacy of preoperative melatonin on postoperative outcomes in pregnant women who were scheduled for elective CS. Methods: We systemically searched 4 electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) from inception until 10 March 2023. We included randomized controlled trials (RCTs) comparing melatonin and placebo for postoperative outcomes in CS patients. For risk of bias assessment, we used the Cochrane Risk of Bias 2 tool. Continuous variables were pooled as mean difference (MD), and categorical variables were pooled as a risk ratio (RR) with a 95% confidence interval (CI). Results: We included 7 studies with a total of 754 pregnant women scheduled for CS. The melatonin group had a lower pain score (MD = -1.23, 95% CI [-1.94, -0.51], p < 0.001) and longer time to first analgesic request (MD = 60.41 min, 95% CI [45.47, 75.36], p < 0.001) than the placebo group. No difference was found regarding hemoglobin levels, heart rate, mean arterial pressure, total blood loss, or adverse events. Conclusions: Preoperative melatonin may reduce postoperative pain in CS patients without side effects. This research offers a safe and affordable pain management method for this population, which has clinical consequences. Further research is needed to validate these findings and determine the best melatonin dosage and timing.

The association of melatonin use and hip fracture: a matched cohort study.

By using propensity-score matched cohorts, we compared the risk of incident hip fracture between melatonin initiators and hypnotic benzodiazepines initiators. The initiation of melatonin was not associated with an increased risk of hip fracture. INTRODUCTION: Melatonin is hypothesized to suppress bone loss, but a previous study reported an increased risk of hip fracture among melatonin users compared with non-users, which was however susceptible to confounding by indication. This study aimed to compare the risk of hip fracture between melatonin initiators and initiators of its active comparators, i.e., hypnotic benzodiazepines. METHODS: Among individuals aged 40 years or older without a history of hip fracture or cancer in the IQVIA Medical Research Database (IMRD) in the UK (2000-2018), a propensity score-matched cohort study was conducted to examine the association of melatonin initiation vs. hypnotic benzodiazepines initiation with the risk of hip fracture. RESULTS: After propensity score matching, 9,038 patients were included (4,519 melatonin initiators and 4,519 hypnotic benzodiazepines initiators). During the entire follow-up, 41 cases of hip fracture occurred in the melatonin cohort, and 51 cases occurred in the hypnotic benzodiazepines cohort. The absolute rate difference in hip fracture between melatonin initiators and hypnotic benzodiazepines initiators was -0.8 (95% CI: -1.9 to 0.3) per 1000 person-years and the multivariable-adjusted hazard ratio (HR) of hip fracture for melatonin initiators was 0.78 (95% CI: 0.51 to 1.17). CONCLUSION: In this population-based cohort study, the risk of hip fracture among melatonin initiators was not higher, if not lower, than that among hypnotic benzodiazepines initiators.

A comparative study between the possible protective role of melatonin versus its combination with adipose derived-mesenchymal stem cells on experimentally induced diabetic retinopathy in adult male albino rats (Histological and immunohistochemical study).

Diabetes mellitus is a metabolic disorder that can cause numerous ocular issues as well as long-term effects. In our study, we evaluate the effect of melatonin on the diabetic retinal alterations in male albino rats to the effect of melatonin combined with stem cells. 50 adult male rats were equally divided into four groups control, diabetic, melatonin, and melatonin plus stem cells. STZ, 65 mg/kg in phosphate buffered was administered intraperitoneally as a bolus to diabetic group of rats. After inducing diabetes, melatonin (10 mg/kg b.wt./day) was administered orally to the melatonin group for 8 weeks. The stem cell and melatonin group got the same dosage of melatonin as the prior group. They received an intravenous injection of (3?×?106 cell) adipose-derived MSC suspended in phosphate-buffered saline at same time of melatonin ingestion. Animals from all groups had their fundics examined. Following the injection of stem cells, samples of rat retina were collected for light and electron microscopy analyses. H&E and immunohistochemically stained sections revealed a slight improvement in group (III). At the same time, group (IV) results were comparable to those of the control group, which was supported by the findings of an electron microscope. Neovascularization was visible on fundus examination in group (II), whereas it was less noticeable in group (III) and group IV. Melatonin mildly improved the histological structure of the retina in diabetic rats, and when it was combined with adipose-derived MSC, it considerably improved the diabetic alterations.

Adjuvant melatonin for uveal melanoma (AMUM): protocol for a randomized open-label phase III study.

BACKGROUND: Uveal melanoma is the most common primary intraocular tumor in adults. In Sweden, at least 100 patients are diagnosed with the disease each year. Almost half of the patients develop metastases, with a median survival time of 1 year once metastases are detected. The primary ocular tumor is typically treated with either enucleation or brachytherapy, and no adjuvant treatment is added. Melatonin is an indolamine hormone that has improved survival in previous trials with patients diagnosed with various cancers, including advanced cutaneous melanoma. Side effects have been mild. We aim to investigate if adjuvant treatment with melatonin for 5 years following diagnosis of non-metastasized uveal melanoma can decrease the occurrence of metastases. METHODS: An open-label, prospective, 5-year randomized clinical trial (RCT) will be conducted at St. Erik Eye Hospital. One hundred patients recently diagnosed with non-metastatic uveal melanoma will be randomized to either treatment with adjuvant melatonin 20 mg (4 tablets of 5 mg) at 10 pm for 5 years, or to standard follow-up (control group). The primary outcome measurement is the relative risk for having developed metastases 5 years after randomization. The secondary outcomes are overall survival, risk of developing other cancers, overall survival after detection of metastases, and differences in the occurrence of adverse events (AE) and serious adverse events (SAE) between the groups. DISCUSSION: Melatonin has been found to positively impact our immune system, inhibit angiogenesis, stimulate apoptosis in malignant cells, and act as a potent antioxidant. Previous clinical trials have used similar doses of melatonin with positive results, particularly in advanced stages of cancer. Previous animal and human studies have found the toxicity of the hormone to be low. Considering the potential benefits and limited risks of melatonin, as well as its global availability, it may be a suitable candidate for an adjuvant treatment in patients with uveal melanoma. TRIAL REGISTRATION: Our trial protocol has been approved and registered by the Swedish Medical Products Agency on June 22, 2022 (EudraCT 2022-500,307-49-00). Our trial registration number is NCT05502900, and the date of registration is August 16, 2022.

Current Insights into the Risks of Using Melatonin as a Treatment for Sleep Disorders in Older Adults.

Exogenous melatonin is commonly used for sleep disorders in older adults, and its use is increasing over time. It appears to have modest efficacy in treating insomnia and circadian rhythm sleep-wake disorders. Melatonin is commonly perceived to be a safe alternative to other hypnotics and is available without prescription in some jurisdictions. New evidence suggests that endogenous melatonin has pleomorphic effects on multiple organ systems, many of which are poorly understood. This narrative review summarizes the current evidence regarding the safety of melatonin in older adults (defined by age over 65 years). Melatonin appears to have a favorable safety profile in this population, however there is a dearth of evidence regarding the safety of prolonged use. There are several factors which increase the risk of adverse effects of melatonin in older adults, and these should be taken into consideration when prescribing to this population.