Insomnia Abstracts 6




(Buysse, 2013) Download
IMPORTANCE:  Insomnia is one of the most prevalent health concerns in the population and in clinical practice. Clinicians may be reluctant to address insomnia because of its many potential causes, unfamiliarity with behavioral treatments, and concerns about pharmacologic treatments. OBJECTIVE:  To review the assessment, diagnosis, and treatment of insomnia in adults. EVIDENCE REVIEW:  Systematic review to identify and summarize previously published quantitative reviews (meta-analyses) of behavioral and pharmacologic treatments for insomnia. FINDINGS:  Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, accompanied by symptoms such as irritability or fatigue during wakefulness. The prevalence of insomnia disorder is approximately 10% to 20%, with approximately 50% having a chronic course. Insomnia is a risk factor for impaired function, development of other medical and mental disorders, and increased health care costs. The etiology and pathophysiology of insomnia involve genetic, environmental, behavioral, and physiological factors culminating in hyperarousal. The diagnosis of insomnia is established by a thorough history of sleep behaviors, medical and psychiatric problems, and medications, supplemented by a prospective record of sleep patterns (sleep diary). Quantitative literature reviews (meta-analyses) support the efficacy of behavioral, cognitive, and pharmacologic interventions for insomnia. Brief behavioral interventions and Internet-based cognitive-behavioral therapy both show promise for use in primary care settings. Among pharmacologic interventions, the most evidence exists for benzodiazepine receptor agonist drugs, although persistent concerns focus on their safety relative to modest efficacy. Behavioral treatments should be used whenever possible, and medications should be limited to the lowest necessary dose and shortest necessary duration. CONCLUSIONS AND RELEVANCE:  Clinicians should recognize insomnia because of its effects on function and health. A thorough clinical history is often sufficient to identify factors that contribute to insomnia. Behavioral treatments should be used when possible. Hypnotic medications are also efficacious but must be carefully monitored for adverse effects.


Chronic insomnia: a practical review.
            (Rajput and Bromley, 1999) Download
Insomnia has numerous, often concurrent etiologies, including medical conditions, medications, psychiatric disorders and poor sleep hygiene. In the elderly, insomnia is complex and often difficult to relieve because the physiologic parameters of sleep normally change with age. In most cases, however, a practical management approach is to first consider depression, medications, or both, as potential causes. Sleep apnea also should be considered in the differential assessment. Regardless of the cause of insomnia, most patients benefit from behavioral approaches that focus on good sleep habits. Exposure to bright light at appropriate times can help realign the circadian rhythm in patients whose sleep-wake cycle has shifted to undesirable times. Periodic limb movements during sleep are very common in the elderly and may merit treatment if the movements cause frequent arousals from sleep. When medication is deemed necessary for relief of insomnia, a low-dose sedating antidepressant or a nonbenzodiazepine anxiolytic may offer advantages over traditional sedative-hypnotics. Longterm use of long-acting benzodiazepines should, in particular, be avoided. Melatonin may be helpful when insomnia is related to shift work and jet lag; however, its use remains controversial.


Sleep complaints: Whenever possible, avoid the use of sleeping pills.
            (2008) Download
1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of "stimulus control". This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness and altered vigilance, and atropinic effects; (9) Case-control studies showed a statistical link between benzodiazepine use in early pregnancy and birth defects such as cleft lip. In contrast, data on the use of doxylamine during pregnancy are reassuring; (10) Other sedative psychotropics have not been adequately tested in this setting or have been shown to have a negative risk-benefit balance; (11) In practice, patients who complain of poor-quality sleep should be given appropriate information on the mechanisms of normal sleep and related misconceptions, on the best methods for getting to sleep, and on the dangers of sedative psychotropics (dependence, withdrawal syndrome). When prescribing or dispensing a benzodiazepine to a woman of child-bearing age, the risk of birth defects, although not clearly demonstrated, must be mentioned.

Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians.
            (Asnis et al., 2015) Download
Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about "sleep-related complex behaviors", e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects.

Insomnia From Drug Treatments: Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information.
            (Doufas et al., 2017) Download
OBJECTIVE:  To determine whether drugs used to treat diverse conditions cause insomnia symptoms and whether their prescription information is concordant with this evidence. METHODS:  We conducted a survey of meta-analyses (Cochrane Database of Systematic Reviews) and comparisons with package inserts compiled in the Physicians' Desk Reference (PDR). We identified randomized controlled trials (RCTs) in which any drug had been evaluated vs placebo and sleep had been assessed. We collectively referred to insomnia-related outcomes as sleep disturbance. We also searched the PDR to identify any insomnia symptoms listed for drugs with RCT evidence available. RESULTS:  Seventy-four Cochrane systematic reviews corresponding to 274 RCTs assessed 88 drugs in 27 different conditions, providing evidence on 109 drug-condition pairs. Of these 88 drugs, 5 decreased sleep problems and 19 increased sleep problems; 64 drugs had no nominally statistically significant effect on sleep. Acetylcholinesterase inhibitors, dopamine agonists, and selective serotonin reuptake inhibitors were the drug classes most importantly associated with sleep disturbance. Of 35 drugs that included disturbed sleep as an adverse effect in the PDR, only 14 had RCT evidence supporting such effect, and 2 had evidence of increasing and decreasing sleep problems in RCTs, although this was not shown in the PDR. We identified weak concordance between the PDR and RCTs (weighted κ=0.31; P<.001). CONCLUSION:  The RCTs offer substantial evidence about the common effects of drugs on the risk of sleep disturbance; currently, prescription information only partially agrees with the available randomized evidence.

Sleep neurobiology from a clinical perspective.
            (España and Scammell, 2011) Download
Many neurochemical systems interact to generate wakefulness and sleep. Wakefulness is promoted by neurons in the pons, midbrain, and posterior hypothalamus that produce acetylcholine, norepinephrine, dopamine, serotonin, histamine, and orexin/hypocretin. Most of these ascending arousal systems diffusely activate the cortex and other forebrain targets. NREM sleep is mainly driven by neurons in the preoptic area that inhibit the ascending arousal systems, while REM sleep is regulated primarily by neurons in the pons, with additional influence arising in the hypothalamus. Mutual inhibition between these wake- and sleep-regulating regions likely helps generate full wakefulness and sleep with rapid transitions between states. This up-to-date review of these systems should allow clinicians and researchers to better understand the effects of drugs, lesions, and neurologic disease on sleep and wakefulness.


Treatment options for insomnia.
            (Ramakrishnan and Scheid, 2007) Download
The frequency of sleep disruption and the degree to which insomnia significantly affects daytime function determine the need for evaluation and treatment. Physicians may initiate treatment of insomnia at an initial visit; for patients with a clear acute stressor such as grief, no further evaluation may be indicated. However, if insomnia is severe or long-lasting, a thorough evaluation to uncover coexisting medical, neurologic, or psychiatric illness is warranted. Treatment should begin with nonpharmacologic therapy, addressing sleep hygiene issues and exercise. There is good evidence supporting the effectiveness of cognitive behavior therapy. Exercise improves sleep as effectively as benzodiazepines in some studies and, given its other health benefits, is recommended for patients with insomnia. Hypnotics generally should be prescribed for short periods only, with the frequency and duration of use customized to each patient's circumstances. Routine use of over-the-counter drugs containing antihistamines should be discouraged. Alcohol has the potential for abuse and should not be used as a sleep aid. Opiates are valuable in pain-associated insomnia. Benzodiazepines are most useful for short-term treatment; however, long-term use may lead to adverse effects and withdrawal phenomena. The better safety profile of the newer-generation nonbenzodiazepines (i.e., zolpidem, zaleplon, eszopidone, and ramelteon) makes them better first-line choices for long-term treatment of chronic insomnia.



Cannabis, Cannabinoids, and Sleep: a Review of the Literature.
            (Babson et al., 2017) Download
PURPOSE OF REVIEW:  The current review aims to summarize the state of research on cannabis and sleep up to 2014 and to review in detail the literature on cannabis and specific sleep disorders from 2014 to the time of publication. RECENT FINDINGS:  Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications.

Valerian for sleep: a systematic review and meta-analysis.
            (Bent et al., 2006) Download
Insomnia affects approximately one-third of the adult population and contributes to increased rates of absenteeism, health care use, and social disability. Extracts of the roots of valerian (Valeriana officinalis) are widely used for inducing sleep and improving sleep quality. A systematic review of randomized, placebo-controlled trials of valerian for improving sleep quality is presented. An extensive literature search identified 16 eligible studies examining a total of 1093 patients. Most studies had significant methodologic problems, and the valerian doses, preparations, and length of treatment varied considerably. A dichotomous outcome of sleep quality (improved or not) was reported by 6 studies and showed a statistically significant benefit (relative risk of improved sleep = 1.8, 95% confidence interval, 1.2-2.9), but there was evidence of publication bias in this summary measure. The available evidence suggests that valerian might improve sleep quality without producing side effects. Future studies should assess a range of doses of standardized preparations of valerian and include standard measures of sleep quality and safety.

Marijuana use patterns and sleep among community-based young adults.
            (Conroy et al., 2016) Download
Marijuana is the most commonly used recreational drug in the United States. Research on the relationship between marijuana and sleep is still in its infancy. The study examined differences in sleep characteristics between a community sample of daily users, non-daily marijuana users, and non-users. A total of 98 subjects (45 M; 53 F) participated. The mean age was 22.3 (standard deviation = 3.0). There were 53 females and 55% of the sample was Caucasian. Recruitment was done online and via print advertisements in the community. Groups were categorized as non-daily users (n = 29), daily users (n = 49), and non-user controls (n = 20). Sleep was characterized by the Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale, and the Morningness Eveningness Questionnaire. A standard cut off score of >10 for the Insomnia Severity Index was found in 38.8% of daily users, 10.3% of non-daily users, and 20% of non-users. Pittsburgh Sleep Quality Index scores in daily users (7.0+/-3.8) were higher than non-daily (4.9+/-3.2) and non-user controls (5.0+/-3.7), p = .02. Insomnia Severity Index scores in daily users (7.9+/-6.1) were higher than non-daily (5.1+/-4.3) and non-user controls (4.3+/-4.8), p = .01. Covariate adjusted regression analyses revealed mean Pittsburgh Sleep Quality Index and Insomnia Severity Index scores were significantly lower for non-daily users and controls relative to the daily users. When adjusting for depression and anxiety, these unique associations were not significant. There were no differences in the Epworth Sleepiness Scale or Morningness Eveningness Questionnaire. Daily marijuana users endorsed more sleep disturbance than non-daily users. Future studies should consider mood in the relationship between marijuana use and sleep.



Asnis, GM, M Thomas, and MA Henderson (2015), ‘Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians.’, Int J Mol Sci, 17 (1), PubMed: 26729104
Babson, KA, J Sottile, and D Morabito (2017), ‘Cannabis, Cannabinoids, and Sleep: a Review of the Literature.’, Curr Psychiatry Rep, 19 (4), 23. PubMed: 28349316
Bent, S, et al. (2006), ‘Valerian for sleep: a systematic review and meta-analysis.’, Am J Med, 119 (12), 1005-12. PubMed: 17145239
Buysse, DJ (2013), ‘Insomnia.’, JAMA, 309 (7), 706-16. PubMed: 23423416
Conroy, DA, et al. (2016), ‘Marijuana use patterns and sleep among community-based young adults.’, J Addict Dis, 35 (2), 135-43. PubMed: 26727193
Doufas, AG, et al. (2017), ‘Insomnia From Drug Treatments: Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information.’, Mayo Clin Proc, 92 (1), 72-87. PubMed: 27842706
España, RA and TE Scammell (2011), ‘Sleep neurobiology from a clinical perspective.’, Sleep, 34 (7), 845-58. PubMed: 21731134
Rajput, V and SM Bromley (1999), ‘Chronic insomnia: a practical review.’, Am Fam Physician, 60 (5), 1431-8; discussion 1441. PubMed: 10524487
Ramakrishnan, K and DC Scheid (2007), ‘Treatment options for insomnia.’, Am Fam Physician, 76 (4), 517-26. PubMed: 17853625
(2008), ‘Sleep complaints: Whenever possible, avoid the use of sleeping pills.’, Prescrire Int, 17 (97), 206-12. PubMed: 19536941