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J Sleep Med > Volume 21(2); 2024 > Article
Khara, Apte, Vyas, Prajapati, Kshatriya, and Patel: The Intricacies of Insomnia: A Comprehensive Exploration

Abstract

Insomnia is a pervasive and often debilitating sleep disorder that profoundly affects health and overall well-being. This comprehensive review focuses on the historical context, clinical significance, diagnostic criteria, investigative methods, and global treatment guidelines for insomnia. Historically, references to insomnia have appeared in ancient Egyptian and Greek texts, but it was not until the 19th century that they were rigorously studied and classified. Notable individuals, including Vincent van Gogh, Franz Kafka, and Marilyn Monroe, have struggled publicly with insomnia, underscoring its widespread nature. The pathophysiology of insomnia is multifactorial, involving physiological, psychological, and environmental factors. Hyperarousal, dysregulation of the sleep-wake cycle, and neurotransmitter imbalances are central to its development. Insomnia can be categorized into acute, chronic, comorbid, idiopathic, and behavioral types. Epidemiological studies have revealed that up to 30% of adults experience insomnia, with a higher prevalence among women, older adults, and those with a lower socioeconomic status. Insomnia is associated with adverse health outcomes, including cardiovascular diseases, metabolic disorders, cognitive impairment, and increased mortality risk. The COVID-19 pandemic has exacerbated insomnia owing to stress and lifestyle changes. Diagnosis involves a comprehensive assessment, including sleep history, physical examination, and objective evaluations, such as polysomnography. Treatment combines pharmacological and non-pharmacological interventions with cognitive behavioral therapy for insomnia as the first-line approach. Pharmacotherapy includes benzodiazepines, non-benzodiazepine hypnotics, antidepressants, melatonin, and orexin receptor antagonists. Guidelines from the American Academy of Sleep Medicine and the European Sleep Research Society emphasize individualized, evidence-based treatment plans to improve sleep quality and overall health.

INTRODUCTION

Insomnia, a ubiquitous and frequently incapacitating sleep disorder, has garnered substantial attention in medical and scientific circles because of its profound impact on health and overall well-being. This review aimed to delve into the multifaceted dimensions of insomnia, including its historical context, clinical significance, diagnostic criteria, investigative methods, and treatment guidelines, on a global scale. By gaining a deeper understanding of these elements, healthcare professionals can more effectively manage and treat insomnia, ultimately enhancing patients’ quality of life.

History of insomnia

The recognition of insomnia as a medical condition dates back centuries. Early references to sleep disturbances are found in ancient texts such as the Ebers Papyrus from ancient Egypt, which details remedies for sleeplessness, and the writings of Hippocrates and Galen from ancient Greece, who emphasized the significance of sleep for maintaining health and the adverse effects of sleep deprivation [1,2]. The term “insomnia” is derived from the Latin words “in” (meaning “not”) and “somnus” (meaning “sleep”), aptly capturing the essence of the disorder—an inability to achieve adequate sleep [3]. Throughout the 20th century, the understanding and treatment of insomnia have evolved significantly, marked by advancements in sleep research, the development of polysomnography, and the recognition of insomnia as a complex condition with various etiologies and presentations [4]. In the early 20th century, researchers developed sophisticated methods for studying sleep, leading to a deeper understanding of sleep architecture and the factors that disrupt it. The invention of electroencephalography has allowed scientists to measure brain activity during sleep, providing insights into the different stages of sleep and the disruptions that occur during insomnia. This period also saw the establishment of the first sleep clinic where patients could be monitored and treated in a controlled environment [5].
Throughout history, many renowned individuals have suffered from insomnia, illustrating that this sleep disorder can affect anyone, regardless of their status or accomplishments. The brilliant yet troubled artist Vincent van Gogh is well-documented to have struggled with insomnia, frequently mentioning his sleepless nights and the distress they caused him [6]. Similarly, the prolific writer Franz Kafka’s letters and diaries reveal his constant battle with sleeplessness, which he often attributes to his overactive mind and persistent anxiety [7]. The holiday icon Marilyn Monroe’s struggle with insomnia and dependence on sleeping pills is well known, with her battle contributing significantly to her untimely death [8]. British Prime Minister Winston Churchill endured sleepless nights, coping with naps during the day and using stimulants to stay awake [9]. Celebrated author Charles Dickens wandered the streets of London during sleepless nights, finding inspiration for his novels [10]. The modern pop icon Lady Gaga openly discusses her sleeplessness, attributing it to her creative processes and the pressure of fame [11]. Actress Kim Cattrall shared her experiences with chronic insomnia, describing its debilitating effects on her life and career [12]. These famous individuals highlight insomnia as a common and severe condition that can affect anyone, regardless of their achievements or lifestyle. Their stories underscore the importance of recognizing and addressing insomnia to improve quality of life and overall health.
Presently, factors such as lifestyle changes and increased exposure to artificial light at night have contributed to the increase in insomnia cases. A modern lifestyle, with its emphasis on technology, has led to increased screen time, which significantly affects sleep patterns owing to the suppression of melatonin production by blue light.

Pathophysiology

The pathophysiology of insomnia is complex and multifactorial [3]. Insomnia results from various physiological, psychological, and environmental factors. Both mental and physical hyperarousal are considered central components of chronic insomnia. Elevated levels of cortisol and adrenocorticotropic hormone have been observed in individuals with insomnia, indicating increased hypothalamic-pituitary-adrenal axis activity [13]. Neuroimaging studies have also revealed heightened brain activity during sleep in individuals with insomnia, particularly in the areas associated with cognition and emotion [14].
Several neurobiological mechanisms have been identified to be involved in insomnia. These include dysregulation of the sleep-wake cycle, alterations in neurotransmitter systems (such as gamma-aminobutyric acid [GABA], serotonin, and norepinephrine), and genetic predispositions that may contribute to sleep disturbances. Psychological factors, including stress, anxiety, and depression, also play a significant role in the development and persistence of insomnia. Environmental factors such as noise, light, and irregular sleep schedules can exacerbate sleep difficulties.
The 3P Model for insomnia, developed by Spielman in the late 1980s, provides a comprehensive framework for understanding the multifaceted nature of insomnia by categorizing contributing factors into three distinct domains: predisposing, precipitating, and perpetuating.
Predisposing factors are underlying vulnerabilities that make an individual more susceptible to insomnia. These include genetic predispositions, personality traits, such as heightened anxiety or hyperarousal, and long-standing sleep patterns that may have been suboptimal since childhood. For example, individuals with high-strung or neurotic personality types may have a more reactive central nervous system, making them more prone to sleep disturbances in response to stress. Additionally, individuals with a family history of insomnia or other sleep disorders were more likely to develop similar issues.
The precipitating factors are specific events or changes that trigger the onset of insomnia. These can range from acute stressors, such as significant life changes (e.g., job loss, divorce, or the death of a loved one), to environmental disruptions (e.g., noise, light, or an uncomfortable sleeping environment). Health issues, including pain, chronic illnesses, and other medical conditions, can also act as precipitating factors. Even positive life events that cause excitement or stress, such as marriage or moving home, can disturb sleep patterns. The essential characteristic of the precipitating factors is that they initiate sleep disruption, transforming a person who might have previously had normal sleep into one struggling with insomnia.
Perpetuating factors include behaviors, thoughts, and lifestyle choices that sustain and exacerbate insomnia even after the initial trigger has been resolved. These factors often involve maladaptive sleep habits such as spending excessive time awake in bed, irregular sleep schedules, and overreliance on naps or stimulants such as caffeine. Cognitive aspects, including worry about sleep, negative beliefs about insomnia, and the development of a preoccupation with sleep, can perpetuate insomnia by creating a cycle of anxiety and hyperarousal, which further disrupts sleep. Additionally, behaviors aimed at compensating for lost sleep, such as sleeping or going to bed earlier, can undermine the natural sleep-wake cycle and perpetuate insomnia.
Understanding insomnia through the 3P Model helps healthcare providers develop targeted interventions by addressing not only the immediate triggers of insomnia but also the underlying vulnerabilities and self-reinforcing behaviors that maintain it. For instance, cognitive behavioral therapy for insomnia (CBT-I) is designed to modify perpetuating factors by changing maladaptive thoughts and behaviors, thereby breaking the cycle of chronic insomnia. By identifying and addressing each component of the 3P Model, treatment can be made more effective and comprehensive, ultimately leading to better sleep outcomes in individuals with insomnia.
Insomnia can be categorized into several types, primarily based on the nature of sleep disturbance. According to the 3P Model, insomnia is a progressive condition. Based on the current diagnostic criteria for the International Classification of Sleep Disorders, Third Edition (ICSD-3) [15], insomnia can be differentiated as follows: 1) sleep initiation disorders: difficulty falling asleep; 2) sleep maintenance disorders: difficulty staying asleep; 3) early morning awakening: waking up too early and unable to fall asleep; and 4) inability to fall asleep without caregivers: common in children who cannot sleep without a caregiver.

PREVALENCE AND IMPACT

Epidemiological studies have demonstrated that insomnia is a highly prevalent sleep disturbance, affecting up to 30% of the adult population at some point in their lives [4]. Insomnia often coexists with other medical and psychiatric conditions, complicating its diagnosis and management. This disorder is more common among women, older adults, and individuals with lower socioeconomic status [16]. Factors such as hormonal changes, caregiving responsibilities, and higher rates of stress and anxiety contribute to the higher prevalence of insomnia in women [15].
Insomnia is associated with several adverse health outcomes. Epidemiological data indicate that abnormal sleep patterns, including insomnia, are associated with an increased risk of cardiovascular disease, metabolic disorders, cognitive impairment, and premature mortality [4]. Furthermore, insomnia is associated with an increased risk of mood disorders, substance abuse, and other adverse health consequences [17]. Chronic insomnia can lead to significant impairment in daytime functioning, affecting personal, social, and occupational domains [18]. Insomnia significantly affects the quality of life, cognitive function, and overall health. Chronic insomnia has been linked to an increased risk of developing various medical and psychiatric conditions, including depression, anxiety, cardiovascular disease, and metabolic disorders [3]. Chronic insomnia can lead to cognitive impairments such as difficulties with attention, concentration, and memory. Cognitive deficits can affect daily functioning and reduce productivity, further exacerbating distress. Moreover, insomnia is associated with increased healthcare utilization because individuals with sleep disturbance are more likely to seek medical care for their symptoms and related conditions [19].
The impact of insomnia extends beyond individual health and influences societal and economic aspects. The economic burden of insomnia is substantial, with estimates suggesting that it accounts for significant healthcare costs and lost productivity due to absenteeism and presenteeism [20]. In the United States alone, the cost of treating insomnia is estimated to exceed $20 billion annually, with total insomnia-related costs surpassing $100 billion per year [21]. These figures underscore the urgent need for effective diagnosis and management of insomnia in clinical practice.
The COVID-19 pandemic has exacerbated the impact of insomnia. Studies have shown a surge in sleep disturbance in the general population due to disruptions in daily routines, increased stress, anxiety, and social isolation [22]. The psychological and social stressors of the pandemic, coupled with increased screen time and changes in physical activity, have significantly affected sleep patterns. Recognizing the substantial burden of insomnia and its associated comorbidities, healthcare professionals now recommend targeting insomnia for treatment, even when it co-occurs with other physical or psychiatric conditions [23].

CLINICAL ASSESSMENT

The clinical assessment of insomnia involves a comprehensive interview and gathering information about specific sleep complaints, comorbid conditions, medication use, and other relevant factors [16]. Standardized questionnaires, such as the Insomnia Severity Index (ISI) and sleep diaries, are often used to evaluate patients’ perceptions of their sleep quality and daytime functioning. Polysomnography, considered the gold standard for objective sleep evaluation, may be employed to aid in the diagnosis and to rule out other sleep disorders [24].
During a clinical assessment, it is essential to consider the patient’s sleep environment, lifestyle factors, and psychological state. Detailed sleep histories can reveal patterns and behaviors contributing to insomnia, such as irregular sleep schedules, poor sleep hygiene, and maladaptive thoughts about sleep [25]. Additionally, the assessment should include an evaluation of the patient’s medical and psychiatric history to identify underlying conditions that may exacerbate sleep disturbances [22].
Despite advancements in understanding the pathophysiology of insomnia, no universally accepted model has fully explained the heterogeneity of symptoms and complex comorbidities associated with the disorder. The multifactorial nature of insomnia necessitates a personalized approach to diagnosis and treatment, considering each patient’s unique circumstances and contributing factors.

DIAGNOSIS OF INSOMNIA

The diagnosis of insomnia is based on a comprehensive clinical assessment that includes a detailed history, physical examination, and subjective and objective sleep evaluation.

Key components of insomnia assessment

The assessment of insomnia involves several key components: 1) sleep history: a structured approach to diagnosis encompassing the duration, severity, variation, and daytime consequences of sleep disturbance; 2) physical examination: identifying underlying medical conditions that may contribute to insomnia; 3) subjective sleep assessment: tools such as sleep diaries and questionnaires such as the ISI are used to evaluate patients’ perceptions of sleep quality and daytime functioning; and 4) objective sleep assessment: employing polysomnography, the gold standard for objective sleep evaluation, to rule out other sleep disorders and provide detailed information on sleep architecture [20].

Diagnostic criteria

Diagnostic criteria for insomnia are outlined in the ICSD-3 and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [16], with some differences and similarities between the two.
According to the ICSD-3, insomnia is defined as a complaint of dissatisfaction with sleep quantity or quality associated with difficulty initiating sleep, difficulty maintaining sleep, or waking up too early despite adequate opportunity for sleep, which occurs at least three times per week and has been present for at least 3 months. The ICSD-3 also emphasizes that sleep difficulties cause significant distress or impairment in daytime functioning, such as fatigue, mood disturbances, or cognitive impairments. The ICSD-3 provides a more detailed categorization of insomnia subtypes, including chronic insomnia disorder, short-term insomnia disorder, and other insomnia disorder types.
On the other hand, the DSM-5 also requires that the sleep disturbances occur at least three times per week and have been present for at least 3 months, with significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning. However, the DSM-5 focuses more broadly on the concept of sleep-wake disorders and places insomnia within this larger category with less emphasis on specific insomnia subtypes. The DSM-5 also allows the diagnosis of insomnia when it occurs concurrently with another mental disorder, emphasizing that insomnia can be an independent condition, even when it coexists with other issues, such as depression or anxiety.
In comparison, both the ICSD-3 and DSM-5 agree on the core criteria for diagnosing insomnia, such as the frequency and duration of sleep disturbances and the requirement for significant distress or impairment. The ICSD-3 provides a more granular approach by categorizing different types of insomnia. In contrast, the DSM-5 takes a broader perspective, placing insomnia within the larger context of sleep-wake disorders and recognizing its potential overlap with other mental health conditions. The ICSD-3’s detailed subtypes may be more useful in clinical practice for identifying specific insomnia patterns, whereas the DSM-5 framework may be more practical for diagnosing insomnia in the presence of comorbid conditions.

Questionnaires

The ISI is a widely used and validated questionnaire designed to assess the severity of insomnia symptoms and their effect on daily functioning. It consists of seven items that evaluate different aspects of insomnia, including difficulties with sleep onset, sleep maintenance, early morning awakenings, satisfaction with current sleep patterns, interference with daily functioning, noticeability of sleep problems to others, and distress caused by sleep difficulties. Each item is rated on a 5-point Likert scale, ranging from 0 (no problem) to 4 (very severe problem), with a total score ranging from 0 to 28. The scores were interpreted as follows: 0–7 indicates no clinically significant insomnia, 8–14 suggests subthreshold insomnia, 15–21 indicates moderate insomnia, and 22–28 points, severe insomnia. The ISI is not only applicable in clinical settings for diagnosing insomnia but also serves as an effective tool for monitoring treatment progress and outcomes. Its brevity and ease of administration make it a popular choice in both research and practice, allowing clinicians to quickly gauge the severity of insomnia and the extent to which it affects their quality of life.
The Sleep Condition Indicator (SCI) is another prominent insomnia questionnaire recently developed to provide a brief and effective screening tool for insomnia disorders. The SCI is aligned with the DSM-5 criteria for insomnia, and it comprises eight items that explore different dimensions of insomnia symptoms. These include questions on sleep onset latency, wakefulness during the night, early morning awakenings, sleep quality, the effect of poor sleep on mood, energy levels, daytime functioning, and the chronicity of sleep difficulties. Each item was scored on a 5-point scale, similar to the ISI, with a total score ranging from 0 to 32. Higher scores indicate better sleep health, whereas lower scores indicate more severe insomnia symptoms. SCI is particularly valuable because it not only captures the severity of insomnia but also evaluates the perceived impact of sleep problems on an individual’s daily life, providing a holistic view of how insomnia affects both sleep and daytime functioning. Additionally, the structure of the SCI allows it to distinguish between transient and chronic insomnia, making it a versatile tool for clinical assessments and research purposes.
When comparing the ISI and SCI, both questionnaires were designed to assess insomnia but differed in focus and structure. The ISI is established and widely used, with a strong emphasis on the severity and impact of insomnia symptoms. The scoring system is straightforward, making it easy for clinicians to classify the severity of insomnia and monitor changes over time. The SCI, although newer, closely aligns with the DSM-5 criteria and provides a more detailed exploration of the impact of insomnia on various aspects of daily life, including mood and energy levels. The ability of the SCI to differentiate between chronic and acute insomnia makes it particularly useful for identifying cases that may require different treatment approaches. In practice, both tools are valuable, and their choice may depend on specific clinical or research needs. ISI may be preferred because of its simplicity and ease of use, especially in settings where time is limited, whereas SCI may be chosen for a more comprehensive assessment that aligns closely with the DSM-5 diagnostic criteria.

INVESTIGATIONS

A comprehensive evaluation of insomnia may involve various investigations to rule out underlying medical or psychiatric conditions and guide appropriate management strategies.

Psychological assessments

Standardized questionnaires and screening tools are used to evaluate the presence of comorbid psychiatric conditions, such as depression or anxiety, which can significantly impact sleep. Addressing these conditions is crucial for effective management of insomnia.

Blood tests

Routine blood tests may be used to assess the underlying medical conditions that could contribute to insomnia, such as thyroid disorders or anemia. Identifying and addressing these conditions can significantly improve sleep quality [22].

Actigraphy

Actigraphy involves using a wearable device to monitor sleep-wake patterns in patients. This non-invasive technique provides valuable data on sleep duration, sleep efficiency, and circadian rhythms, offering insights into the patient’s sleep behavior over extended periods [25].

Polysomnography

Polysomnography is the gold standard for objective sleep assessment. It provides detailed information on a patient’s sleep architecture, sleep stages, and potential sleep-disordered breathing. This method is particularly useful for diagnosing comorbid sleep disorders, such as sleep apnea or periodic limb movement disorders [24].

MANAGEMENT PATHWAY

The flowchart of insomnia treatment is presented in Fig. 1. The treatment approach begins with an initial assessment, which involves a comprehensive sleep history and evaluation. Standardized questionnaires, such as the ISI, are used to assess the severity of the condition.
The first-line of treatment is CBT-I. This includes several components: 1) Sleep restriction therapy: deliberately restricting the time in bed; 2) Stimulus control therapy: re-associating the bed and bedroom with sleep; 3) Relaxation techniques: progressive muscle relaxation, deep breathing, and guided imagery; and 4) Sleep hygiene education: patients are educated on healthy sleep habits.
Pharmacological treatment may be considered, as outlined in Table 1. Medications are categorized based on their effects.

Medications decreasing wakefulness

These include benzodiazepines (e.g., temazepam, lorazepam), which carry a risk of dependence and side effects, and non-benzodiazepine hypnotics (e.g., zolpidem, eszopiclone), which also have a risk of dependence.

Medications promoting sleep

Melatonin is effective for treating circadian rhythm disorders, while orexin receptor antagonists (e.g., lemborexant, suvorexant) promote sleep by inhibiting orexin neurons.

Pharmacologic treatment and mechanism of action

GABA receptor agonists

These medications, including benzodiazepines and nonbenzodiazepine hypnotics (Z-drugs), enhance the activity of GABA, a neurotransmitter that inhibits brain activity, thereby promoting sedation and sleep. These drugs are typically effective for both inducing and maintaining sleep, although their specific effects depend on the drug’s half-life and duration of action.

Melatonin receptor agonists

Ramelteon mimics the action of melatonin, a natural hormone that regulates the sleep-wake cycle. It is primarily used for sleep-onset insomnia as it helps promote the onset of sleep without causing significant next-day sedation or dependence.

Orexin receptor antagonists

These drugs block the activity of orexins, which are neuropeptides that promote wakefulness. By inhibiting these wakepromoting signals, orexin receptor antagonists help induce sleep and maintain it throughout the night, offering a dual benefit for patients with insomnia.

Antidepressants

Certain antidepressants, particularly those with strong antihistaminergic effects, such as doxepin and trazodone, are used off-label for their sedative properties. They are effective in maintaining sleep owing to their long half-lives but are generally not first-line treatments owing to the potential for side effects.

Antihistamines

Over-the-counter antihistamines such as diphenhydramine and doxylamine block histamine receptors, which affect wakefulness. These are commonly used for short-term relief of insomnia but may lead to tolerance, making them less effective over time.

Atypical antipsychotics

Drugs such as quetiapine are sometimes used off-label for their sedative effects. These drugs are not recommended as first-line treatments for insomnia because of their significant side effect profiles; however, they may be used in certain cases, particularly when other options are ineffective or contraindicated.
Although Z drugs have a lower dependence risk than benzodiazepines, they are not free from this risk and should be used with caution to avoid drug abuse.

Cognitive behavioral therapy for insomnia

CBT-I is a first-line treatment for chronic insomnia and is highly effective. This approach combines cognitive techniques, such as challenging and changing maladaptive beliefs about sleep, with behavioral strategies, including sleep restriction, stimulus control, and relaxation training. CBT-I aims to improve sleep patterns and reduce insomnia symptoms by addressing underlying psychological and behavioral factors.

Sleep restriction therapy and stimulus control therapy

Sleep restriction therapy involves limiting the amount of time spent in bed to match the actual sleep time and gradually increasing it as sleep efficiency improves. This technique helps to consolidate sleep and reduces the time spent awake in bed. Stimulus control therapy focuses on creating a strong association between bed and sleep by limiting non-sleep activities in the bedroom and establishing a consistent sleepwake schedule.

Relaxation techniques and sleep hygiene education

Relaxation techniques such as progressive muscle relaxation, deep breathing exercises, and guided imagery help reduce physical and mental arousal and facilitate sleep onset. Sleep hygiene education involves teaching patients healthy sleep habits and environmental factors that can improve sleep quality, such as maintaining a regular sleep schedule, creating a conducive sleep environment, and avoiding stimulants before bedtime [21].

RECOMMENDATIONS BY GLOBALLY PRESTIGIOUS ORGANIZATIONS

American Academy of Sleep Medicine

The American Academy of Sleep Medicine (AASM) recommends a comprehensive approach to insomnia treatment, emphasizing CBT-I as the first-line treatment. Pharmacotherapy, including benzodiazepines, non-benzodiazepine hypnotics, and orexin receptor antagonists, is recommended for short-term use or when CBT-I is not available or ineffective. The AASM guidelines also highlight the importance of individualized treatment plans that address the specific needs and preferences of each patient [21].

European Sleep Research Society

The European Sleep Research Society (ESRS) guidelines also prioritize nonpharmacological treatments, particularly CBT-I, as an initial approach for managing insomnia. Pharmacological treatments, including benzodiazepines, non-benzodiazepine hypnotics, and newer agents such as orexin receptor antagonists, are considered for short-term use or in specific cases where non-pharmacological interventions are insufficient. ESRS guidelines emphasize a stepwise approach to treatment, starting with the least invasive interventions and progressing to more intensive therapies as needed [26].

CONCLUSION

Insomnia is a prevalent and multifaceted sleep disorder with significant consequences for an individual’s overall health and well-being. A comprehensive approach to diagnosing and managing insomnia is crucial, involving a combination of clinical assessment, objective sleep evaluation, and a tailored treatment plan that addresses both pharmacological and nonpharmacological interventions. By adopting evidence-based practices and a patient-centered approach, healthcare providers can help individuals with insomnia achieve better sleep and quality of life.

Notes

Conflicts of Interest
The authors have no potential conflicts of interest to disclose.
Author Contributions
Conceptualization: all authors. Resources: all authors. Writing—original draft: Nimit Khara. Writing—review & editing: all authors.
Funding Statement
None

Acknowledgments

None

Fig. 1.
The flowchart of insomnia treatment.
jsm-240014f1.jpg
Table 1.
Pharmacologic treatment of insomnia and mechanism of action
Medication class Medication name Mechanism of action Induces sleep Maintains sleep Additional details
Benzodiazepine receptor agonists (BzRAs) Zolpidem Gamma-aminobutyric acid (GABA) receptor agonist Yes Yes Short-acting, generally used for sleep onset insomnia. Available in extended- release form for sleep maintenance.
Eszopiclone GABA receptor agonist Yes Yes Long-acting, useful for both sleep onset and maintenance insomnia. May cause a bitter aftertaste.
Zaleplon GABA receptor agonist Yes No Ultra-short-acting, ideal for sleep onset insomnia. Less effective for sleep maintenance due to short half-life.
Benzodiazepines Temazepam GABA receptor agonist Yes Yes Intermediate-acting, often used for sleep maintenance. Risk of dependence and tolerance with long-term use.
Triazolam GABA receptor agonist Yes No Short-acting, primarily for sleep onset. Higher risk of rebound insomnia.
Estazolam GABA receptor agonist Yes Yes Intermediate-acting, useful for both sleep onset and maintenance.
Melatonin receptor agonists Ramelteon Melatonin receptor (MT1/MT2) agonist Yes No Particularly useful for sleep onset insomnia. Non-sedative, minimal risk of dependence.
Orexin receptor antagonists Suvorexant Orexin receptor antagonist Yes Yes Helps both sleep onset and maintenance insomnia by promoting sleep continuity. Risk of next-day drowsiness.
Lemborexant Orexin receptor antagonist Yes Yes Similar to Suvorexant, helps with sleep onset and maintenance. Lower risk of next-day drowsiness.
Antidepressants Doxepin Histamine H1 receptor antagonist No Yes Effective for sleep maintenance due to long half-life. Low doses used specifically for insomnia.
Trazodone Serotonin 5-HT2 antagonist, alpha-1 adrenergic receptor antagonist Yes Yes Used off-label for insomnia. Sedative properties aid both sleep onset and maintenance.
Antihistamines Diphenhydramine Histamine H1 receptor antagonist Yes Yes Over-the-counter option. Sedating effect, but risk of tolerance and next-day drowsiness.
Doxylamine Histamine H1 receptor antagonist Yes Yes Similar to Diphenhydramine, used for short-term insomnia treatment.
Atypical antipsychotics Quetiapine Dopamine D2 receptor antagonist, H1 receptor antagonist Yes Yes Used off-label for insomnia. Sedative effects, but not first-line due to side effects like weight gain.

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