Major Research Findings

Integrase inhibitors have recently been positioned as first-line treatment in HIV Clinical Guidelines. However, two of these drugs, bictegravir and dolutegravir, have been associated with adverse side effects on the central nervous system, especially with sleep disturbances. 15 The objective of this study was to analyze the influence of bictegravir and dolutegravir on the sleep quality in HIV patients. 15

Sleep is essential for normal and healthy living. Lack of good quality sleep affects physical, mental and emotional functions. 9 Currently, the treatments of obesity-related sleep disorders focus more on suppressing sleep-related symptoms pharmaceutically and are often accompanied by side effects. Thus, there is urgent need for alternative ways to combat chronic sleep disorders. This study will investigate underlying mechanisms of the effects of exercise and diet intervention on obesity-related sleep disorders, the role of gut microbiota in relation to poor quality of sleep and day-time sleepiness, as well as the levels of hormones responsible for sleep-wake cycle regulation. 9

Insomnia and nightmares are common in patients with posttraumatic stress disorder (PTSD). They are associated with worse psychological and physical health and worse PTSD treatment outcomes. 16 In addition, they are resistant to PTSD treatments, which do not typically address sleep disorders. Cognitive behavioral therapy for insomnia and nightmares (CBT-I&N) and cognitive processing therapy (CPT) for PTSD are first-line treatments, but limited evidence exists guiding the treatment of individuals with all three disorders. 16 The current study randomized U.S. military personnel (N = 93) to one of three conditions: CBT-I&N delivered before CPT, CBT-I&N delivered after CPT, or CPT alone; all groups received 18 sessions. Across groups, participants demonstrated significantly improved PTSD symptoms. Because the study was terminated prematurely due to challenges with recruitment and retention, it was underpowered to answer the initially intended research questions. Nonetheless, statistical findings and relevant clinically meaningful changes were observed. Compared to participants who received CPT alone, those who received CBT-I&N and CPT, regardless of sequencing, demonstrated larger improvements in PTSD symptoms, d = -0.36; insomnia, d = -0.77; sleep efficiency, d = 0.62; and nightmares, d = -.53. Compared to participants who received CBT-I&N delivered before CPT, those who received CBT-I&N delivered after CPT demonstrated larger improvements in PTSD symptoms, d = 0.48, and sleep efficiency, d = -0.44. This pilot study suggests that treating comorbid insomnia, nightmares, and PTSD symptoms results in clinically meaningful advantages in improvement for all three concerns compared to treating PTSD alone. 16

Parasomnias are involuntary behaviors or subjective experiences during sleep. 10 Our objective was to review existing information on the presence of parasomnias in patients with addictions or during treatment for addictions. Information about parasomnias related to rapid-eye-movement (REM) and non-REM sleep in patients with addictions, while using substances or in abstinence, was reviewed. A systematic search of published articles reporting parasomnias as a consequence of drug use or abuse was conducted in the PubMed and SciELO databases. The search for the studies was performed in three phases: (1) by title, (2) by abstract, and (3) by complete text. The search was performed independently by two researchers, who then compared their results from each screening phase. Seventeen articles were found. The consumption of alcohol was reported in association with arousal disorders, such as sexsomnia and sleep-related eating disorder; and REM sleep behavior disorder was reported during alcohol withdrawal. Cocaine abuse was associated with REM sleep behavior disorder with drug consumption dream content. Overall, we found that several types of parasomnias were very frequent in patients with addictions. To avoid accidents in bedroom, legal problems, and improve evolution and prognosis; must be mandatory to include security measures related to sleep period; avoid pharmacological therapy described as potential trigger factor; improve sleep hygiene; and give pharmacological and behavioral treatments for patients with these comorbid sleep disorders. 10

Successful treatment of narcolepsy requires an accurate diagnosis to exclude patients with other sleep disorders, which have different treatments, and to avoid unnecessary complications of drug treatment. 3 Treatment objectives should be tailored to individual circumstances. Modafinil, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, selegiline, pemoline, tricyclic antidepressants, and fluoxetine are effective treatments for narcolepsy, but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness, but naps seldom suffice as primary therapy. Regular follow up of patients with narcolepsy is necessary to educate patients and their families, monitor for complications of therapy and emergent of other sleep disorders, and help the patient adapt to the disease. 3

Dexmedetomidine exerts a sedative effect by promoting the sleep pathway endogenously and producing a state similar to N2 sleep. 14 This study aimed to study the efficacy and safety of dexmedetomidine nasal spray in the treatment of postoperative sleep disturbance. 14

Fifteen children (most of whom were neurologically multiply disabled) with severe, chronic sleep disorders were treated with 2 to 10mg of oral melatonin, given at bedtime. 1 Nine had fragmented sleep patterns, three had delayed sleep onset and three others had non-specific sleep disturbance of unclear aetiology; all had failed to respond to conventional management. Nine patients had ocular or cortical visual impairment. The health, behavioural and social benefits of treatment were significant, and there were no adverse side-effects. While the response was not always complete, the study clearly showed that melatonin has an important role in the treatment of certain types of chronic sleep disorders. 1

The prevalence of sleep problems in adulthood increases with age. 4 While not all sleep changes are pathological in later life, severe disturbances may lead to depression, cognitive impairments, deterioration of quality of life, significant stresses for carers and increased healthcare costs. The most common treatment for sleep disorders (particularly insomnia) is pharmacological. The efficacy of non-drug interventions has been suggested to be slower than pharmacological methods, but with no risk of drug-related tolerance or dependency. Cognitive and behavioural treatments for sleep problems aim to improve sleep by changing poor sleep habits, promoting better sleep hygiene practices and by challenging negative thoughts, attitudes and beliefs about sleep. 4

Exogenous melatonin is commonly used for sleep disorders in older adults, and its use is increasing over time. 19 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. 19

Treatment of sleep disorders in visually impaired children is complicated by a complex pathophysiology, a high incidence of sleep disorders in this population, and a dearth of management options. 8 The significant impact on the health of these children and distress to their caregivers warrant a systematic assessment of the published literature on therapeutic approaches. 8

The prevalence of sleep problems in adulthood increases with age. 6 While not all sleep changes are pathological in later life, severe disturbances may lead to depression, cognitive impairments, deterioration of quality of life, significant stresses for carers and increased healthcare costs. The most common treatment for sleep disorders (particularly insomnia) is pharmacological. The efficacy of non-drug interventions has been suggested to be slower than pharmacological methods, but with no risk of drug-related tolerance or dependency. Physical exercise, taken regularly, may promote relaxation and raise core body temperature in ways that are beneficial to initiating and maintaining sleep. 6

Pediatric sleep disorders are a common, mainly among children with pre-existing disabilities, neurological conditions, and neurodevelopmental disorders. 17 The consequences are variable, and sleep disorders may be associated with deficits in neurocognitive performance and growth failure. Rising awareness about sleep disorders among pediatricians will improve the early diagnosis and management of these disorders. This review describes normal sleep patterns in infants and children and provide a recent update on common sleep disorders that improve the diagnosis and treatment of children with sleep disorders. 17

Investigated the treatment of bedtime problems and its generalization to night wakings. 2 Six children (M age = 35 months) and their parents participated in this study. A multiple-baseline design across subjects was employed and found that treatment instituted at bedtime was successful in relieving both bedtime disturbances and night wakings. Furthermore, significant positive changes in parental sleep and family satisfaction occurred following amelioration of the children's sleep problems. Data support recent work suggesting that chronic sleep problems in children are amenable to behavioral interventions. In addition, this method appears to be more cost-effective and less stressful for parents to implement than behavioral interventions that directly target night wakings. 2

Dissatisfaction with night sleep occurs in 45% of the population. 11 Chronic insomnia is one of the most common sleep disorders. The incidence of insomnia is estimated at 9-15%. The clinical importance of insomnia is determined by the negative impact it has on social aspects, economic performance and human health. Taking into account the prevalence of insomnia in the population and its social importance the correct diagnosis and effective treatment of insomnia is clear. 11

Sleep disturbances are extremely common (40-86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. 13 These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm - primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome - to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (-39.6 minutes) compared to placebo (-12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years. 13

The correlation between sleep and epilepsy has been argued over the past decades among scientists. 18 Although the similarities and contrasts between sleep and epilepsy had been considered, their intertwined nature was not revealed until the nineteenth century. Sleep is recognized as a recurring state of mind and body through alternating brain electrical activities. It is documented that sleep disorders are associated with epilepsy. The origin, suppression, and spread of seizures are affected by sleep. As such, in patients with epilepsy, sleep disorders are a frequent comorbidity. Meanwhile, orexin, a wake-promoting neuropeptide, provides a bidirectional effect on both sleep and epilepsy. Orexin and its cognate receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R), orchestrate their effects by activating various downstream signaling pathways. Although orexin was considered a therapeutic target in insomnia shortly after its discovery, its potential usefulness for psychiatric disorders and epileptic seizures has been suggested in the pre-clinical studies. This review aimed to discuss whether the relationship between sleep, epilepsy, and orexin is clearly reciprocal. 18

Sleep disorders, especially insomnia, are very common in different kinds of cancers, but their prevalence and incidence are not well-known. 12 Disturbed sleep in cancer is caused by different reasons and usually appears as a comorbid disorder to different somatic and psychiatric diagnoses, psychological disturbances and treatment methods. There can be many different predictors for sleep disturbances in these vulnerable groups, such as pre-existing sleep disorders, caused by the mental status in cancer or as side effect of the cancer treatment. 12

Treatment Summary

Integrase inhibitors, such as bictegravir and dolutegravir, used in HIV treatment have been associated with adverse side effects on the central nervous system, especially with sleep disturbances. 15 Further research is needed to understand the impact of these drugs on sleep quality in HIV patients. 15

Exercise and diet interventions have shown potential in improving sleep quality and addressing obesity-related sleep disorders. 9 These interventions may positively impact sleep quality, daytime sleepiness, gut microbiota, and hormone levels responsible for sleep-wake cycle regulation. 9

Sleep disorders, particularly insomnia and nightmares, are common in patients with PTSD and can negatively affect treatment outcomes. 16 Combined treatment with CBT-I&N and CPT shows promising results in improving PTSD symptoms, insomnia, sleep efficiency, and nightmares. 16

Individuals with substance abuse are more prone to various sleep disorders. 10 Safety measures, avoidance of pharmacological therapy, sleep hygiene improvement, and behavioral treatments are essential for managing sleep disorders in this population. 10

Accurate diagnosis is crucial for treating narcolepsy to exclude other sleep disorders and avoid complications from drug treatment. 3 Several medications, including modafinil, amphetamines, and tricyclic antidepressants, are effective for narcolepsy, but evidence quality varies. 3 While scheduled naps can help combat sleepiness, they are not sufficient as primary therapy. Regular follow-up is crucial for educating patients and families, monitoring for complications, and managing emergent sleep disorders. 3

Dexmedetomidine nasal spray has shown potential in safely and effectively improving sleep quality in patients after maxillofacial surgery. 14

Melatonin has demonstrated its role in treating certain types of chronic sleep disorders, particularly in children with fragmented sleep patterns, delayed sleep onset, or non-specific sleep disturbances. 1 Melatonin has proven to be beneficial for health, behavior, and social aspects in these children without any adverse effects. 1

Bright light therapy and cognitive behavioral interventions have shown promise in addressing sleep disorders in older adults. 4 Bright light therapy offers a non-pharmacological approach to improving sleep quality. 4 Cognitive behavioral therapy aims to improve sleep through modifying poor sleep habits, promoting better sleep hygiene, and addressing negative thoughts and attitudes. 4

Melatonin is a commonly used treatment for sleep disorders in older adults. 19 While it shows modest efficacy for insomnia and circadian rhythm sleep-wake disorders, its safety profile in older adults, especially for prolonged use, requires further investigation. 19

Treating sleep disorders in visually impaired children is complex due to their specific needs and limited treatment options. 8 The impact on their well-being and the burden on their caregivers necessitates a comprehensive assessment of published literature to guide therapeutic approaches. 8

Regular physical exercise has emerged as a viable non-pharmacological approach for managing sleep problems in older adults. 6 Exercise can promote relaxation and raise core body temperature, both contributing to better sleep initiation and maintenance. 6

Sleep disorders are prevalent in children, particularly those with pre-existing disabilities, neurological conditions, and neurodevelopmental disorders. 17 Early diagnosis and management of these disorders are crucial to minimize the potential consequences, including neurocognitive deficits and growth failure. 17

Treatment for bedtime problems in children can positively impact night wakings. 2 This approach not only alleviates bedtime disturbances and night wakings but also improves parental sleep and family satisfaction. 2

Complex spa treatments combined with transcranial magnetic therapy show potential in improving sleep quality for patients with chronic insomnia. 11

Sleep disturbances are prevalent in children with ASD, often emerging as the first symptom noticed by parents. 13 Addressing sleep disorders in this population requires a systematic approach, including excluding other specific sleep disorders and associated comorbidities (e.g. seizures). 13 Treatment typically involves a combination of non-pharmacological strategies, such as parental education, bedtime rituals, and behavioral interventions, followed by pharmacological interventions if necessary. 13 Melatonin plays a significant role in managing sleep disorders associated with ASD, with evidence suggesting its efficacy in treating sleep difficulties in patients with this condition. 13

Sleep and epilepsy have a complex and interconnected relationship. 18 Orexin, a wake-promoting neuropeptide, plays a significant role in both sleep and epilepsy, highlighting the potential for orexin receptor antagonists as therapeutic targets for sleep disorders and epilepsy. 18

Sleep disorders, particularly insomnia, are prevalent in cancer patients, influenced by factors such as mental status and treatment side effects. 12

Benefits and Risks

Benefit Summary

Exercise and diet interventions can potentially improve sleep quality and address obesity-related sleep disorders. 9 Combined treatment with CBT-I&N and CPT shows promise in improving PTSD symptoms, insomnia, sleep efficiency, and nightmares. 16 Melatonin has demonstrated its role in treating certain types of chronic sleep disorders, particularly in children with fragmented sleep patterns, delayed sleep onset, or non-specific sleep disturbances. 1 Bright light therapy offers a non-pharmacological approach to improving sleep quality. 4 Cognitive behavioral therapy aims to improve sleep through modifying poor sleep habits, promoting better sleep hygiene, and addressing negative thoughts and attitudes. 4 Dexmedetomidine nasal spray has shown potential in safely and effectively improving sleep quality in patients after maxillofacial surgery. 14

Risk Summary

Some integrase inhibitors, such as bictegravir and dolutegravir, have been associated with adverse side effects on the central nervous system, particularly sleep disturbances. 15 Melatonin, while generally considered safe, may pose higher risks of adverse effects in older adults. 19

Comparison Across Studies

Commonalities

Many studies highlight the diverse causes and wide-ranging impact of sleep disorders across various populations.

Differences

Studies vary significantly in terms of target populations, treatment methods, and research designs.

Consistency and Contradictions in Findings

The effectiveness of treatments for sleep disorders can vary between studies. For example, the efficacy of melatonin for sleep disorders has yielded mixed results. 19 These discrepancies may be attributed to differences in study populations, treatment approaches, and research designs.

Practical Implications and Considerations

Choosing the right treatment for sleep disorders requires individualized assessment. Factors such as symptom severity, underlying causes, lifestyle, and co-existing conditions should be carefully considered when selecting a treatment option.

Current Research Limitations

Many studies have limited sample sizes and focus on specific populations, limiting the generalizability of their findings.

Future Research Directions

Larger-scale studies involving diverse populations are needed to validate the effectiveness of treatments for sleep disorders.

Conclusion

Sleep disorders are a common concern affecting various populations, and a range of treatments has been developed to address these issues. While some treatments demonstrate promising results, the effectiveness can vary between studies. Individualized assessment and careful consideration of various factors are crucial for selecting the most appropriate treatment option for sleep disorders. Consult a healthcare professional if you are experiencing sleep problems to receive personalized guidance and find the best solution.

Treatment List

Integrase inhibitors, exercise, diet, CBT-I&N, CPT, melatonin, bright light therapy, cognitive behavioral therapy, dexmedetomidine nasal spray, transcranial magnetic therapy