Effectiveness of Melatonin and Ramelteon for Chronic Insomnia in Older Adults: A Systematic Review and Meta-Analysis

Table of Contents

Overall Summary

Overview

This systematic review and meta-analysis evaluated the effectiveness of melatonin and ramelteon in treating chronic insomnia in older adults (50+). Researchers analyzed studies published between 1990 and 2021, focusing on sleep outcomes like total sleep time, sleep latency, and sleep efficiency. The study included 21 studies (17 for meta-analysis) from various databases, examining the impact of these treatments on objective and subjective sleep quality. Results indicated modest but significant improvements in total sleep time and sleep latency with melatonin/ramelteon compared to placebo. This suggests potential benefits for older adults with insomnia, given limited safe treatment options.

Key Findings

Strengths

Areas for Improvement

Significant Elements

Figure 1 (PRISMA Flowchart)

Description: This flowchart details the study selection process, starting from 9247 identified records and ending with 21 studies for qualitative review and 17 for meta-analysis. It visually depicts each step, including duplicate removal, screening, eligibility assessment, and reasons for exclusion, promoting transparency and allowing readers to evaluate the study selection process.

Relevance: The flowchart provides transparency and allows assessment of the study selection process. It clearly shows how the researchers arrived at their final set of studies, enabling readers to evaluate the comprehensiveness and rigor of the search and selection methodology.

Table 2 (Study Outcomes)

Description: This table summarizes the outcome measures, treatment and placebo values (including dosages), and statistical data (mean, SD, or median and IQR) for each included study. It allows readers to examine the raw data behind the meta-analysis and understand the variability of effects across studies.

Relevance: This table is crucial for understanding the study's results and provides a detailed breakdown of the outcomes measured in each included study. The presentation of treatment and placebo data for each outcome allows for direct comparisons and assessment of intervention effects. However, the lack of clear unit labeling and inconsistent data presentation (mean ± SD and median (IQR)) could be improved for better clarity and interpretation.

Conclusion

This study supports the moderate effectiveness of melatonin and ramelteon for improving total sleep time (by about 21 minutes) and sleep latency (by about 14 minutes objectively and 8 minutes subjectively) in older adults with chronic insomnia. While sleep efficiency did not show significant improvement, these findings suggest potential benefits for this population, especially considering limited safe insomnia treatment options. The study's strengths include its comprehensive search strategy and focus on a vulnerable population. Future research should explore age-related subgroup effects, clarify the clinical significance of findings (e.g., impact on daytime function), investigate optimal dosages, and compare these treatments to non-pharmacological options. This would further refine treatment guidelines and provide a more complete understanding of the long-term benefits and risks of melatonin and ramelteon for chronic insomnia in older adults.

Section Analysis

Abstract

Overview

This systematic review and meta-analysis investigated the effectiveness of melatonin and ramelteon for treating chronic insomnia in older adults. Researchers analyzed studies from 1990 to 2021, focusing on sleep outcomes like total sleep time, sleep latency, and sleep efficiency. Results showed significant improvements in total sleep time, sleep latency, and sleep quality with melatonin and/or ramelteon compared to placebo, although the effects were modest. Sleep efficiency did not show significant improvement.

Key Aspects

Strengths

Suggestions for Improvement

Introduction

Overview

Insomnia is a common sleep disorder affecting a significant portion of the American population, especially older adults. As people age, they naturally sleep less, and this, combined with age-related sleep changes, makes older adults more susceptible to insomnia. Current medications for insomnia, like benzodiazepines, have drawbacks such as cognitive impairment and fall risks. Melatonin, a hormone naturally produced in the body, and ramelteon, a melatonin receptor agonist, offer potentially safer alternatives. This review aims to analyze the effectiveness of melatonin and ramelteon in managing chronic insomnia in older adults by examining total sleep time, sleep latency, sleep efficiency, and subjective sleep quality.

Key Aspects

Strengths

Suggestions for Improvement

Materials and Methods

Overview

This section details how the researchers selected studies, searched for information, gathered data, and analyzed the results to determine the effectiveness of melatonin and ramelteon for insomnia in older adults. They used specific criteria to choose relevant studies, searched various databases, and used standardized methods to extract and analyze the data. They focused on outcomes like total sleep time, sleep latency, sleep efficiency, and sleep quality, using both objective measurements (like devices) and subjective measurements (like questionnaires).

Key Aspects

Strengths

Suggestions for Improvement

Results

Overview

This section presents the findings of the systematic review and meta-analysis on the effects of melatonin and ramelteon on sleep outcomes in older adults with chronic insomnia. The analysis included 21 studies, 17 of which were used in the meta-analysis. Results showed a moderate improvement in objectively measured total sleep time with melatonin/ramelteon. Objectively measured sleep latency was also significantly reduced. However, sleep efficiency showed high variability and no significant improvement. Subjective sleep quality was generally improved, though measured with various tools.

Key Aspects

Strengths

Suggestions for Improvement

Non-Text Elements

figure 1

This flowchart illustrates the process of identifying and selecting studies for inclusion in the systematic review and meta-analysis. It follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Initially, 9247 records were identified through database searches and other sources. After removing 3789 duplicates, 5247 records remained for title and abstract screening. Of these, 860 reports were sought for retrieval, but 791 were not retrievable. The remaining 69 full-text articles were assessed for eligibility, and 48 were excluded based on pre-defined criteria. This left 21 studies for the qualitative systematic review, of which 17 met the criteria for inclusion in the quantitative meta-analysis.

First Mention

Text: "Of 5247 studies identified, 17 studies met the inclusion criteria for MA. Study sample size ranged from 10 to 829 with the mean age ≥55 years."

Context: This sentence, located in the abstract, provides the first mention of the number of studies included in the meta-analysis, referencing the PRISMA flowchart which details the selection process.

Relevance: This flowchart is crucial for understanding how the researchers arrived at the final set of studies included in their analysis. It provides transparency and allows readers to assess the rigor and comprehensiveness of the literature search and selection process.

Critique
Visual Aspects
  • The flowchart is clear and easy to follow, adhering to PRISMA guidelines.
  • The use of different shapes (boxes and diamonds) to represent different stages of the process is helpful.
  • The numerical values at each stage clearly show the number of studies included and excluded.
Analytical Aspects
  • The flowchart clearly outlines the reasons for excluding studies, enhancing transparency.
  • The visual representation makes it easy to understand the overall selection process.
  • The flowchart could be improved by adding a brief explanation of the specific databases and grey literature sources searched.
Numeric Data
  • Records identified: 9247
  • Duplicates removed: 3789
  • Records screened: 5247
  • Reports sought for retrieval: 860
  • Reports not retrieved: 791
  • Reports assessed for eligibility: 69
  • Studies excluded: 48
  • Studies included in qualitative review: 21
  • Studies included in meta-analysis: 17
table 1

Table 1 summarizes the characteristics of the 21 studies included in the systematic review. It provides details such as author, year of publication, country of origin, study design, sample size, participant demographics (age, gender), study setting, presence of comorbid conditions, duration of therapy, and the drug/dose used (melatonin or ramelteon). This information helps to understand the context and variability of the studies included in the review.

First Mention

Text: "Table 1 shows characteristics of the studies included in the systematic review."

Context: This sentence, located at the beginning of the Results section on page 5, introduces Table 1 and its purpose.

Relevance: This table is essential for understanding the characteristics of the included studies, which can influence the overall results of the meta-analysis. It allows readers to assess the generalizability and potential biases of the included studies.

Critique
Visual Aspects
  • The table is well-organized and easy to read, with clear column headings.
  • The use of abbreviations (e.g., RCT, SD) is explained, which improves clarity.
  • The table could be improved by using consistent formatting for numerical values (e.g., always reporting age as mean ± SD).
Analytical Aspects
  • The table provides a comprehensive overview of the key characteristics of the included studies.
  • The inclusion of information on study design, sample size, and patient characteristics is helpful for assessing the quality and relevance of the studies.
  • The table could be enhanced by providing more details about the specific insomnia outcomes measured in each study.
Numeric Data
  • Number of RCTs: 16
  • Number of crossover studies: 3
  • Number of open-label studies: 5
  • Total number of subjects in meta-analysis: 2462
  • Minimum sample size: 20
  • Maximum sample size: 829
table Table 2

Table 2 summarizes the outcome measures used in the included studies, including total sleep time (TST), sleep latency (SL), and sleep efficiency (SE). It presents the results for both the treatment (melatonin or ramelteon) and placebo groups, often specifying the dosage used. The table uses a mix of mean ± standard deviation and median (interquartile range) to present the data. It also includes changes in subjective sleep measures from baseline for some studies.

First Mention

Text: "Table 2 summarizes types of outcome measurement techniques used and outcomes for TST, SL and SE in the included studies."

Context: Fifteen studies described subjective outcomes, among which five studies had both subjective and objective measures. Four studies reported descriptive sleep quality only, and are therefore excluded from the meta-analysis.

Relevance: This table is crucial for understanding the results of the meta-analysis. It provides the raw data on sleep outcomes from individual studies, allowing readers to see the variability in effects and the basis for the calculated SMDs. It also highlights the different measurement techniques used, which is important for interpreting the overall findings.

Critique
Visual Aspects
  • The table could be improved by consistently using one method of data presentation (either mean ± SD or median with IQR) for each outcome to avoid confusion.
  • Clearer labeling of units within the table itself (e.g., 'TST (minutes)', 'SL (minutes)') would enhance readability.
  • Using visual cues like bolding or shading to highlight statistically significant differences would make key findings stand out.
Analytical Aspects
  • While the table presents the data, it lacks context. Explaining the clinical significance of the observed differences in TST, SL, and SE would make the results more meaningful.
  • The table could benefit from a brief explanation of why some studies used mean ± SD while others used median (IQR). This would address potential differences in data distribution.
  • Including the sample size for each group (treatment and placebo) within the table would provide additional context for interpreting the results.
table Table 1

Table 1 describes the characteristics of the studies included in the systematic review. It provides information on the study author, year of publication, country, study design, total sample size, average patient age, gender distribution, study setting, presence of comorbid conditions, duration of therapy, and the drug and dose used in each study.

First Mention

Text: "Table 1 shows characteristics of the studies included in the systematic review."

Context: There were 16 RCTs, among which three used crossover study design, and five an open-label study. A total of 2462 subjects were involved in the 17 studies included in meta-analysis. Sample size ranged from 20 to 829 with the mean age of all included studies being 55 years and older, thirteen studies involved majority female patients, and eight studies reported comorbid conditions. Most of the studies (57%) were conducted in outpatient settings (n = 12), followed by long term care settings (n = 2). Melatonin doses ranged from 0.3 mg to 6 mg in fourteen studies, while ramelteon doses ranged from 4 mg to 8 mg in seven studies.

Relevance: This table provides essential background information on the included studies. It allows readers to assess the diversity of the studies in terms of design, population characteristics, interventions, and settings, which is important for understanding the generalizability of the meta-analysis results.

Critique
Visual Aspects
  • The table is dense and could be visually improved by grouping related information (e.g., study characteristics, patient characteristics, intervention details) into separate sections.
  • Using abbreviations consistently (e.g., 'RCT' for randomized controlled trial, 'SD' for standard deviation) would save space and improve readability.
  • Highlighting key information, such as the drug and dose used, would make it easier to scan the table and quickly find relevant details.
Analytical Aspects
  • The table could be more informative by including a column indicating the primary outcome measure used in each study. This would help readers quickly assess the relevance of each study to the overall review.
  • Providing a brief summary of the main findings of each study within the table would enhance its value and make it a more standalone resource.
  • Explaining the rationale for including studies with different designs (e.g., RCTs, open-label studies) would strengthen the methodology section.
table Table 1. Cont.

This table provides further details on the characteristics of the studies included in the systematic review. It lists the study author and year, country of origin, study design, total number of participants (N), mean patient age with standard deviation, percentage of male and female participants, study setting, presence of concurrent diseases, duration of therapy, and drug/dose used.

First Mention

Text: "Table 1 shows characteristics of the studies included in the systematic review."

Context: The results section begins by describing the characteristics of the included studies, including the number of randomized controlled trials (RCTs), study design, and patient demographics.

Relevance: This table is crucial for understanding the context of the studies included in the meta-analysis. It provides detailed information about the study populations, interventions, and settings, allowing for a better understanding of the overall results and potential sources of heterogeneity.

Critique
Visual Aspects
  • The table is dense and could benefit from visual separation of rows and columns to improve readability.
  • Using abbreviations (like N for sample size and SD for standard deviation) without explanation might confuse some readers.
  • Consider using color-coding to highlight different study designs or interventions.
Analytical Aspects
  • While the table provides descriptive statistics for each study, it lacks information about the statistical methods used within each study. This information would be helpful in assessing the quality of the evidence.
  • The table could benefit from a summary row showing the overall characteristics of the included studies (e.g., total number of participants across all studies, average age across all studies).
  • It would be helpful to include a column indicating the type of insomnia addressed in each study (sleep-onset, sleep-maintenance, or both).
Numeric Data
table Table 2. Study Outcomes.

This table presents the outcomes of the included studies, focusing on Total Sleep Time (TST), Sleep Latency (SL), and Sleep Efficiency (SE). It's organized by study author and year, and includes the outcome measures used, treatment and placebo values (with dosages specified where applicable), and data presented as mean ± standard deviation or median (IQR). It also includes 'Change in subjective total sleep time from baseline' and 'Change in subjective sleep latency from baseline' for some studies.

First Mention

Text: "Table 2 summarizes types of outcome measurement techniques used and outcomes for TST, SL and SE in the included studies."

Context: After presenting the study characteristics in Table 1, the results section then details the outcomes of the studies in Table 2, including the types of outcome measures used and the results for TST, SL, and SE.

Relevance: This table is essential for understanding the main findings of the systematic review and meta-analysis. It presents the actual results of the included studies, allowing for comparison between treatment and placebo groups and assessment of the effectiveness of melatonin and ramelteon on various sleep parameters.

Critique
Visual Aspects
  • The table is quite large and complex, making it difficult to grasp the key findings at a glance. Consider splitting it into smaller, more focused tables, one for each outcome measure.
  • The use of both mean ± SD and median (IQR) within the same columns can be confusing. Choose a consistent reporting method or clearly explain the reason for using different methods.
  • Using abbreviations like PSQI and LSEQ without explanation might make the table less accessible to a general audience.
Analytical Aspects
  • The table could benefit from a summary row at the bottom, showing the overall mean difference between treatment and placebo for each outcome measure. This would make it easier to see the overall effect of the interventions.
  • While the table shows the results for different dosages of melatonin and ramelteon, it doesn't explicitly compare the effectiveness of different dosages. A separate analysis of dose-response relationships would be informative.
  • The table includes both objective and subjective outcome measures, but it doesn't clearly distinguish between them. Using different formatting or labeling could improve clarity.
Numeric Data
table 2. Cont.

Table 2. Cont. provides further details on the outcomes of different studies examining the effects of melatonin and ramelteon on sleep parameters. The table includes the study author and year, outcome measure, total sleep time (mean and standard deviation), sleep latency (mean and standard deviation), and sleep efficiency (mean and standard deviation). Some data is presented as median and interquartile range (IQR). The table also includes 'Change in subjective sleep latency from baseline' for some studies. Dosages of ramelteon are specified where applicable.

First Mention

Text: "Table 2 summarizes types of outcome measurement techniques used and outcomes for TST, SL and SE in the included studies."

Context: The text discusses the different outcome measures used in the included studies, such as total sleep time, sleep latency, and sleep efficiency, and how they were measured, both objectively and subjectively. It mentions that Table 2 provides a summary of these measures.

Relevance: This table is crucial for understanding the specific outcomes of the included studies and how the interventions (melatonin and ramelteon) affected sleep parameters compared to placebo. It provides the raw data upon which the meta-analysis is based.

Critique
Visual Aspects
  • The table could benefit from clearer labeling of units for each column (e.g., minutes for sleep time and latency, percentage for sleep efficiency).
  • Consistent use of either mean ± SD or median (IQR) would improve readability. Currently, the table mixes both formats within the same columns.
  • Visually separating treatment and placebo data within the table (e.g., using shading or different font styles) would make comparisons easier.
Analytical Aspects
  • While 'Change from baseline' data is included, it's not always clearly labeled as such. Explicitly stating 'Change from baseline' in the relevant column headers would improve clarity.
  • The table could be more informative by including the p-values for the differences between treatment and placebo groups for each study.
  • Providing a brief explanation of the clinical significance of the observed differences would enhance the table's value.
Numeric Data
  • Total Sleep Time (Treatment): 438 minutes
  • Total Sleep Time (Placebo): 444 minutes
  • Sleep Latency (Treatment): 1.6 minutes
  • Sleep Latency (Placebo): 1.4 minutes
  • Sleep Efficiency (Treatment): 84.1 percentage
  • Sleep Efficiency (Placebo): 86.2 percentage
figure 2. Objective Sleep Outcomes

Figure 2, titled 'Objective Sleep Outcomes,' presents forest plots visualizing the results of a meta-analysis on three objective sleep measures: Total Sleep Time (TST), Sleep Latency (SL), and Sleep Efficiency (SE). Each forest plot displays the standardized mean difference (SMD) for individual studies, represented by squares, along with their 95% confidence intervals (CIs) shown as horizontal lines. The size of each square corresponds to the study's weight in the analysis. A diamond at the bottom of each plot represents the overall pooled effect size. The x-axis represents the SMD, with negative values favoring placebo and positive values favoring the treatment (melatonin or ramelteon). The figure also provides numerical data for each study, including SMD, CI limits, Z-value, p-value, and a measure of heterogeneity (I²).

First Mention

Text: "The forest plots as shown in Figure 2 (objective measures) examine the effect of melatonin and/or ramelteon on TST."

Context: This sentence introduces Figure 2, which displays the results of the meta-analysis on objective sleep outcomes, starting with Total Sleep Time.

Relevance: This figure is central to the study's findings, visually summarizing the effects of melatonin and/or ramelteon on objective sleep outcomes. It allows for a quick comparison of the treatment effects across different studies and provides the overall pooled effect size for each outcome.

Critique
Visual Aspects
  • The figure could be improved by adding labels directly on the forest plots to indicate the treatment and placebo groups on the x-axis.
  • Using different colors or shading for the squares representing melatonin and ramelteon studies would enhance visual differentiation.
  • Including the study names next to the squares would make it easier to connect the visual data with the information in Table 2.
Analytical Aspects
  • While the figure provides I² values for heterogeneity, it lacks a brief explanation of what these values mean. Adding a sentence explaining that higher I² indicates greater heterogeneity would be helpful.
  • The figure could benefit from a visual representation of the overall significance of the pooled effect size, perhaps by using asterisks or shading the diamond if the p-value is less than 0.05.
  • A brief comment on the clinical significance of the observed SMDs would add valuable context to the figure.
Numeric Data
table Table 3

Table 3 presents the risk of bias assessment for 16 randomized controlled trials (RCTs) included in the meta-analysis. The table assesses bias across five domains: Randomization, Deviations from Intended Intervention, Missing Outcome Data, Measurement of Outcome, and Selection of Reported Results. Each study's risk of bias is categorized as 'high,' 'low,' or 'some concerns' within each domain and overall. The table uses symbols to represent these categories: a filled circle (⊕) for low risk, a half-filled circle (⊘) for some concerns, and an empty circle (⊙) for high risk.

First Mention

Text: "Risk of bias findings of the 16 studies included in the meta-analysis with RCT study design are presented in Table 3."

Context: The authors are discussing the risk of bias assessment for the included studies.

Relevance: This table is crucial for understanding the validity of the meta-analysis results. By assessing the risk of bias in the included studies, the authors provide transparency about the potential limitations and trustworthiness of the evidence.

Critique
Visual Aspects
  • The symbols used (⊕, ⊘, ⊙) are visually distinct and easy to differentiate, aiding quick interpretation.
  • The table is well-organized, with clear column headings and consistent formatting.
Analytical Aspects
  • The table provides a detailed breakdown of risk of bias across different domains, allowing readers to assess the potential impact of bias on specific aspects of the studies.
  • The overall risk of bias assessment provides a concise summary of the potential threats to validity for each study.

Discussion

Overview

This section discusses the findings of the systematic review and meta-analysis on melatonin and ramelteon for insomnia in older adults. The key finding is that these treatments moderately improve total sleep time (about 21 minutes longer) and sleep latency (falling asleep about 14 minutes faster based on objective measures and 8 minutes faster subjectively) compared to placebo. Sleep efficiency did not improve significantly. The discussion also compares this review to previous research and addresses potential reasons for variability in study results, such as different doses, treatment durations, and sample sizes.

Key Aspects

Strengths

Suggestions for Improvement

Conclusions

Overview

This study supports the moderate effectiveness of melatonin and ramelteon, a melatonin receptor agonist, for improving total sleep time and reducing sleep latency in older adults with limited safe insomnia treatment options. These may be safer alternatives to traditional sleep medications like benzodiazepines, which have significant safety concerns.

Key Aspects

Strengths

Suggestions for Improvement

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