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EPIDEMIOLOGY AND CLINICAL PRESENTATION OF INSOMNIA

Insomnia is the most prevalent of all sleep disorders: an estimated 30% to 50% of adults report symptoms of insomnia and 10% of adults meet the criteria for insomnia disorder defined by the Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (DSM-5).^1-4 Insomnia complaints are 1.5 times more common in women than in men and the prevalence of insomnia increases with age and the presence of chronic diseases.^1,3 Insomnia may be diagnosed any time an individual reports daytime impairment related to difficulty falling asleep (DFA), difficulty maintaining sleep (DMS), or early morning awakening (EMA). Insomnia may be situational, short-term, episodic (1-3 months), or persistent (≥ 3 months), and it frequently co-occurs with a medical, psychiatric, or sleep disorder.¹ For example, approximately 50% of patients with sleep apnea complain of insomnia.³ When a patient complains of insomnia, a thorough evaluation to identify and treat all comorbidities concurrently is essential for positive treatment outcomes.^3,5

According to the National Ambulatory Medical Care survey, more Americans are seeking treatment for insomnia than ever before. The survey showed a 13% increase in the number of office visits for insomnia, growing from 4.9 million visits in 1999 to 5.5 million visits in 2010. The number of office visits for any sleep disturbance increased by 29%, growing from 6,394,000 visits in 1999 to 8,237,000 visits in 2010. Perhaps the most striking finding was the 293% increase in the number of prescriptions given for sleep medications (also known as "hypnotics") during office visits, growing from 5.3 million in 1999 to 20.8 million in 2010. The greatest increase in sleep-aid prescribing over the 11-year period was attributed to the 430% increase in prescriptions for the "Z-hypnotics"– zolpidem, eszopiclone, and zaleplon.⁴ Z-hypnotic prescribing surpassed prescribing of benzodiazepines (e.g., triazolam, temazepam, lorazepam) for sleep complaints beginning in 2002. In 2006, the co-prescribing of benzodiazepines and Z-hypnotics increased significantly, particularly in patients over 65 years of age and in those with anxiety, depression, and insomnia.⁶

Improved patient education regarding insomnia treatment is needed in order to improve public safety. According to a study conducted from 2003 to 2008 that tracked 409,171 adults in an integrated health system in Washington State, individuals who received new prescriptions for hypnotics were at significantly greater risk for automobile crashes. For the top 3 prescribed hypnotics, the increased crash risk compared to non-use of hypnotics was highest for zolpidem (hazard ratio [HR] = 2.20, 95% confidence interval [CI] = 1.64, 2.95), followed by trazodone (HR = 1.91, 95% CI = 1.62, 2.25); the risk was lowest for temazepam (HR = 1.27, 95% CI = 0.85, 1.91). The risk estimates are equivalent to driving with blood alcohol concentration levels between 0.06% and 0.11%, which is synonymous with driving drunk.⁷

Increased prescribing of zolpidem, coupled with its inherent central nervous system (CNS) depressant effects, likely led to it being the psychiatric medication with the greatest number of cases of emergency department visits for adverse events in the United States (U.S.) between 2009 and 2011. Accidental injury from adverse events including falls, confusion, and delirium were associated with zolpidem.⁸ All benzodiazepine receptor agonists (BzRAs), including Z-hypnotics, are known to cause adverse effects such as excessive sedation, loss of coordination, and poor memory; several studies now associate their use with overall increased mortality. Compared to no use of prescription medications for sleep, regular use of BzRAs as hypnotics has been associated with a 1.5 to 2 times greater risk of dementia, fractures, and overall increased mortality from chronic health conditions, including cancer.^9,10

Pharmacists are perfectly positioned to promote safe and effective treatment for insomnia and there is evidence that pharmacist counseling is effective for helping patients make better health care decisions regarding insomnia. One example is the Eliminating Medications through Patient Ownership of End Results (EMPOWER) study. As part of EMPOWER, community pharmacists and physicians collaborated to educate almost 300 patients over 65 years old about the risks of taking benzodiazepines for anxiety and insomnia for longer than 3 months. In 30 pharmacies across Canada, pharmacists provided patient education on the risks of benzodiazepine use and described a standard tapering schedule; a control group of patients received usual care but no direct education. Discontinuation of long-term benzodiazepines was achieved in 27% of the intervention group and in only 5% of the control group.¹¹

This 2-unit continuing education program aims to give pharmacists the tools to assist patients and providers with individualizing safe and effective treatments for insomnia.

Insomnia’s impact on health and well-being

The benefits of getting sufficient quantity and quality of sleep through as-needed or short-term (< 1-3 months), judicious use of hypnotics outweigh the risks for most individuals. The National Institute of Health recommends getting 7 to 8 hours of sleep per night to maintain good health, yet the National Health and Nutrition Examination Survey, last completed in 2008, revealed that 37% of Americans get fewer than 7 hours of sleep per night.² The importance of adequate sleep in maintaining health has been increasingly appreciated: sleep deprivation contributes to a number of molecular, immune, and neural changes that play roles in disease development.^2,4,10 For example, lack of adequate sleep triggers the release of pro-inflammatory cytokines and decreases the body’s antioxidant defense responses. Both of these mechanisms lead to cell injury and the development of disease.² Individuals who get 6 hours or fewer of sleep per night (approximately 27% of the U.S. population) are at the greatest risk for adverse health outcomes including obesity, type 2 diabetes, cancer, cardiovascular disease, ischemic stroke, anxiety, and depression.¹⁰ Short sleep duration (< 5 hours per night) has been found to increase the risk of obesity by 1.5 times, with a 0.35 kg/m² increase in body mass index for every 1 hour reduction in sleep.² Impaired glucose tolerance and the development of type 2 diabetes is correlated with a sleep duration of less than 6 hours per night according to several large observational studies.^2,4 Breast cancer, colorectal cancer, and prostate cancer are among the cancers associated with chronically short sleep duration. Alterations in autonomic nervous system function related to insufficient sleep have been shown to increase pulse and blood pressure, which increases cardiovascular morbidity and mortality.^2,12

Sleep deprivation is associated with decreased alertness, slowed reaction time, and drowsy driving. The Centers for Disease Control and Prevention analyzed data regarding drowsy driving in 92,102 adults in 10 states and Puerto Rico in 2011 and 2012 and found that 4% of participants reported falling asleep while driving in the previous 30 days. Adults who reported usually sleeping no more than 6 hours per day were more likely to fall asleep while driving than adults who slept 7 hours or more.¹³ Drowsy driving is a contributing factor in up to 20% of traffic accidents.²

Determining the type and causes of insomnia

The first step in assessing a patient’s insomnia is to determine the type of insomnia he or she experiences; next, the patient should be assisted in determining possible causes and contributing factors for the insomnia. The pharmacist should query whether the sleep problem involves DFA, DFS, EMA, or a combination of these. Questions such as, "How do you feel during the day: refreshed or fatigued?" are necessary to evaluate impairment caused by the insomnia. The pharmacist should also ask about medications (e.g., psychostimulants, bupropion, corticosteroids), comorbid conditions (e.g., anxiety, chronic pain), or jet lag that could contribute to insomnia and about lifestyle issues that could cause insomnia (e.g.. poor sleep hygiene, use of electronics at night).^3,14 Figure 1 is adapted from the National Sleep Foundation’s sleep diary; this type of log can help patients record information that is useful for assessing causes of insomnia and making positive interventions to improve sleep. The full sleep diary can be accessed at the National Sleep Foundation’s website.¹⁵

Figure 1. Sample Sleep Diary to Record Quality and Quantity of Sleep and Factors Influencing Sleep15

Date:

Complete in the morning How many minutes did it take to fall asleep? How many times did I wake during the night? What woke me up in the night? How many hours did I sleep? How did I feel upon awakening? (e.g., refreshed, somewhat refreshed, fatigued) Complete at the end of the day What medications did I take today? When did I eat meals and what did I eat? Did I take naps? How long did I nap? How much alcohol did I drink and when did I drink it? When did I exercise and what type of exercise was it?

Environmental factors, such as excessive noise or lack of comfortable surroundings have long been known to contribute to poor sleep. A representative sample of the U.S. population rated these factors in the 2014 National Sleep Foundation’s "Sleep in America" poll. Not surprisingly, 41% of adults and 34% of children described evening activities, particularly those involving electronics (i.e., smart phones, computers, televisions), as the top reason for not getting a good night’s sleep.¹⁶ Artificial white and blue light from electronics can decrease the formation and release of natural melatonin and interfere with the suprachiasmatic nucleus and its ability to properly regulate the sleep/wake cycle.¹⁷ The suprachiasmatic nucleus – commonly known as the biological clock – responds with wakefulness to external light and it signals the pineal gland to release melatonin during external darkness or nighttime. Other top reasons for poor sleep reported in the poll were temperature (i.e., too hot or too cold), noise, light, and pets.¹⁶ The American Medical Association and the National Sleep Foundation recommend shutting down electronics 2 to 3 hours before bedtime in order to give the brain time to prepare for sleep.^16,17

There is a bidirectional relationship between medical or psychiatric conditions and insomnia. Insomnia is 5 times more likely to occur in individuals with anxiety or depression and at least 2 times as likely in individuals with chronic medical conditions (e.g., heart disease, gastroesophageal reflux, chronic obstructive pulmonary disease, diabetes) or primary sleep disorders (e.g., sleep apnea, restless legs syndrome, narcolepsy).^1,3,5 Studies show that 29% to 67% of older adults with insomnia have obstructive sleep apnea, and sleep lab referral is recommended in obese patients over 50 years old with chronic sleep complaints.⁵ Continuous positive airway pressure can improve sleep maintenance and daytime functioning in people with sleep apnea.^3,5 An average of 50% to 60% of persons with an alcohol or substance use disorder report that chronic insomnia greatly increases the risk for relapse.¹⁸ Untreated insomnia can impact recovery from all of these disorders; therefore, insomnia should be treated concurrently with all medical, psychiatric, sleep, and substance use disorders,^1,2,5,18 and patients should be encouraged to work with their care providers to optimize treatment for all causes of insomnia. Table 1 presents medical and psychiatric conditions that often present with insomnia and provides evidence-based recommendations for treatment.

Table 1. Select Medical and Psychiatric Conditions Commonly Associated With Insomnia: Clinical Correlates and Practical Evidence-based Recommendations for Management3,10,12,14,18-24
Medical/Psychiatric Condition Associated with Insomnia	Clinical Correlates (type of insomnia, associated symptoms, assessments)	Evidence-based Recommendations for Treatment
Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD), pediatric	DFA; may need less sleep than patients without ASD or ADHD Investigate and address medication causes of insomnia (i.e., stimulants) and treat comorbid anxiety and depression	Optimize treatment for ASD or ADHD; establish bedtime routine Consider melatonin 3-6 mg 1-2 hours before bedtime BzRAs are ineffective in this population
Anxiety disorder (generalized, social, situational)	DFA, DMS; associated with worries, muscle tension, and multiple physical complaints (e.g., weakness, indigestion, headache)	Consider CBT, exercise, Tai Chi, and yoga Optimize antidepressant and dose Consider short-term hypnotic
Bipolar disorder	Decreased need for sleep; sleep deprivation can trigger mania	Optimize medications (e.g., lithium, valproate, antipsychotic) Consider BzRA for short-term use
Cancer	DFA, DMS; chronic pain and steroid use can interfere with sleep	Consider CBT, relaxation techniques, and pain management Consider short-term hypnotic
Cardiovascular disease	DFA, DMS; autonomic instability can disturb sleep Assess for sleep-disordered breathing/apnea and uncontrolled pain	Consider CBT and relaxation techniques Consider short-term BzRA Exercise caution with trazodone due to hypotension risk
Chronic pain	DFA, DMS Investigate neuropathic and musculoskeletal pain; assess for associated anxiety and depression	Consider CBT Optimize pain control Consider interactions between hypnotics and opioids or other sedating agents
Dementia	Circadian-rhythm dysregulation (i.e., daytime sleep/awake at night)	Consider natural light therapy in afternoon, exercise as tolerated, massage, soft music, and relaxation Consider melatonin 1-3 mg 2 hours before bedtime
Depression	DFA, DMS, EMA; may be associated with anxiety Screen for suicidal thoughts	Consider CBT Optimize treatment for depression Consider short-term BzRA or trazodone
Diabetes	DFA, DMS; may be associated with glucose dysregulation and neuropathy	Consider CBT Optimize treatment for diabetes and neuropathic pain Consider short-term hypnotic
Perimenopause/menopause	DFA, DMS; may be associated with temperature dysregulation and frequent awakenings	Consider venlafaxine and/or hormonal interventions, short-term BzRA, and/or CBT
Post-traumatic stress disorder (PTSD)	Severe global sleeplessness; DFA, DMS, nightmares	Consider CBT Avoid BzRAs and suvorexant Optimize PTSD treatment with antidepressant or prazosin
Sleep apnea	DFA, DMS; less restful sleep, snoring, gasping for air; frequently comorbid with obesity, hypertension, and diabetes; risk for sleep apnea increases with age	Refer to sleep lab for polysomnography Avoid sedating agents until apnea effectively treated with CPAP
Alcohol or substance use disorder	DFA, DMS; dysregulated circadian rhythm; may be associated with anxiety	Encourage substance use recovery Avoid BzRAs and suvorexant Consider trazodone, gabapentin, or tricyclic antidepressant if patient is in recovery
BzRA, benzodiazepine receptor agonist; CBT, cognitive behavioral therapy; CPAP: continuous positive airway pressure; DFA: difficulty falling asleep; DMS: difficulty maintaining sleep; EMA: early morning awakening.

INSOMNIA TREATMENTS

According to the Agency for Healthcare Research and Quality (AHRQ), multimodal cognitive behavioral interventions and short-term (as needed or < 1-3 months) hypnotic therapy are both effective for increasing the quantity and quality of sleep to improve health outcomes.¹⁰ The AHRQ sought to better inform providers and consumers regarding evidence-based treatments for insomnia and, to this end, AHRQ’s scientists analyzed 3,572 citations, 169 randomized controlled trials, and 12 observational studies that examined cognitive behavioral treatments, and pharmacologic interventions to generate an executive summary on the management of insomnia disorder.¹⁰ Investigators considered cognitive behavioral interventions (i.e., cognitive behavioral therapy [CBT]), U.S. Food and Drug Administration (FDA)-approved hypnotic medications, and complementary and alternative treatments for insomnia. Evidence was insufficient to draw conclusions about comparative effectiveness among intervention classesm (i.e., psychological vs. pharmacologic) or combination interventions (i.e., psychological combined with pharmacologic vs. pharmacologic alone). Data analysis revealed that multimodal CBT, eszopiclone, zolpidem, and suvorexant had the strongest evidence for improving short-term global and sleep outcomes in the adult population. These treatments decreased the time to fall asleep by approximately 10 to 45 minutes, decreased wakefulness after sleep onset by 10 to 45 minutes, and increased total sleep time by 20 to 90 minutes.¹⁰ The report did not consider medications commonly used but not FDA approved for insomnia such as lorazepam and trazodone. There was insufficient evidence of safety and efficacy to recommend complementary treatments such as massage, yoga, acupressure, valerian, or kava-kava for the treatment of insomnia.¹⁰

Non-pharmacologic treatment

Multimodal CBT for insomnia typically requires 6 to 10 sessions that may be delivered over 3 to 6 weeks. This mode of treatment leads to remission of insomnia in 45% to 55% of individuals.^3,5 The components of multimodal CBT for insomnia are described in Table 2. The process involves a clinician guiding a motivated patient through lifestyle changes, sleep restriction, stimulus control, and cognitive and behavioral treatments. In order to notice significant improvement in insomnia, a patient must engage in self-care, which includes following sleep hygiene recommendations and adhering to the recommendations of the clinician guiding CBT.^3,5 Advantages of multimodal CBT include an avoidance of potentially adverse effects related to medication. Remission of insomnia with CBT can be long-lasting and some studies show benefit up to 3 years after treatment.³ Disadvantages include the challenge of obtaining a referral to a clinician trained in CBT for insomnia and the time and effort required of the patient to achieve recovery from insomnia.^3,5

Table 2. Non-pharmacologic Interventions for Insomnia3,5,10,25
Psychological or Behavioral Intervention	Description
Sleep hygiene education	Establishes lifestyle choices that improve sleep (e.g., keep bedroom dark, quiet, and comfortable; avoid spicy food before bed; limit alcohol to 1-2 drinks early in evening; shut down electronics 2-3 hours before bedtime)
Relaxation training	Teaches deep breathing and progressive muscle relaxation Reduces somatic tension and decreases negative thoughts
Stimulus control	Establishes consistent sleep patterns (e.g., go to bed only when sleepy; avoid television, computer, or electronics in bed)
Sleep restriction	Limits time in bed to sleep time (e.g., get out of  bed if not asleep in 15 minutes)
Brief behavioral intervention	Combines stimulus control and sleep restriction
Cognitive therapy	Addresses worries, stressors, and dysfunctional beliefs about sleep Includes thought journaling (i.e., keeping paper and pen next to bed to write down thoughts) to avoid rumination
Multimodal cognitive behavioral therapy	Combines education, sleep restriction, stimulus control, cognitive therapy, and sleep hygiene

Pharmacologic treatment options

Prescription remedies for insomnia have superior efficacy over nonprescription treatments, and, for this reason, sleep experts recommend the short-term use of prescription remedies for insomnia when rapid restoration of sleep is desired and while lifestyle changes and multimodal CBT are implemented.^3,5,26 The choice and dosing of prescription hypnotic agents should consider comorbidities, sex, age, type of sleep complaint, and concurrent medications.

Benzodiazepine receptor agonists

Together, the Z-hypnotics – zolpidem, eszopliclone, and zaleplon – are the most commonly prescribed hypnotics in the U.S. They typically induce sleep within 30 minutes and may prevent nighttime awakening for many patients. Also, due to their selectivity for omega-1 receptors, they do not have the reinforcing anxiolytic property of nonselective BzRAs, such as triazolam or temazepam, when given at recommended doses. Zolpidem and eszopiclone have been demonstrated as safe and effective in patients with comorbid depression and anxiety disorders taking concomitant antidepressant medications.^3,5,12 On the basis of their pharmacokinetic profiles, triazolam has been deemed effective for inducing sleep and temazepam for maintaining sleep. The use of triazolam is limited by rebound insomnia when it is discontinued, even after 7 to 10 days of regular use. Temazepam’s long half-life may cause next-day impairment.⁵

There is no evidence to support the effectiveness of BzRAs for insomnia in pediatric patients.^19,21,24 The elderly are at increased risk for confusion and falls from BzRAs compared to younger adults, particularly when BzRAs are combined with other CNS-active agents.^3,5,22

Suvorexant

Suvorexant, an orexin receptor antagonist, is the newest prescription hypnotic approved for use in adults with insomnia characterized by DFA and DMS. By blocking orexin receptors in the hypocretin system (the wakefulness part of the hypothalamus), somnolence ensues; the action is similar in patients whose hypocretin/orexin receptors malfunction and cause narcolepsy. Cataplexy, sleep paralysis, and hypnagogic hallucinations were reported in suvorexant clinical trials at doses above the recommended range, but these were considered uncommon to rare occurrences. Due to suvorexant’s unique mechanism, it may be associated with less amnesia and fewer gait disturbances than BzRAs.^26-28 Comparative studies with other hypnotics are needed to further confirm its place in therapy. Suvorexant should not be given to patients with existing psychiatric illness until studies demonstrate safety and efficacy in this population.²⁸

Ramelteon

Ramelteon is a prescription melatonin agonist with the ability to induce sleep and increase total sleep time in adults and the elderly. It has the advantage of no abuse potential, but its lack of sedating properties compared to BzRAs has led to low patient acceptance. An AHRQ analysis did not find it to be as effective as zolpidem, eszopiclone, or suvorexant. Preliminary studies in small numbers of patients show that ramelteon may be beneficial for insomnia in patients with alcohol and substance use disorders.^5,12,18

Antidepressants

Trazodone is not FDA approved for insomnia, but it is the most commonly prescribed sedating antidepressant for insomnia due to considerable evidence showing that 50 to 150 mg given 30 minutes before bedtime can induce and maintain sleep in patients with and without comorbid depression or anxiety.^5,3,23 Trazodone has a low risk of toxicity in overdose, but it carries risks of dizziness and next-day impairment; rarely, priapism may occur. A metabolite of trazodone, meta-chlorophenylpiperazine, is believed to be responsible for dysphoria and/or irritability the day after trazodone administration.²⁹ Mirtazapine is less well-studied for insomnia, but 7.5 to 15 mg at night may be effective to induce and maintain sleep. Doxepin 3 to 6 mg is FDA approved for insomnia in adults. It is well-tolerated in the elderly, but its long onset of inducing sleep (2-3 hours) limits patient acceptance.^3,26

Other prescription medications used for insomnia

Prazosin is a well-established treatment for insomnia and nightmares associated with post-traumatic stress disorder (PTSD). The dose of prazosin ranges from 1 to 10 mg per night and should be slowly titrated on the basis of patient tolerability.^3,12,20 If a patient does not recover from the insomnia after prazosin treatment, it could indicate that the PTSD is not being effectively treated. In this case, the patient should be referred to a PTSD specialist for trauma-focused CBT.²⁰

The enacarbil form of gabapentin is FDA approved for restless legs syndrome. At doses of 900 to 1800 mg per day given in divided doses, gabapentin may also be effective for insomnia associated with alcohol dependence.^18,30 Antipsychotics such as quetiapine or olanzapine are not recommended for insomnia unless the patient also has bipolar disorder or schizophrenia: the risk of metabolic side effects outweighs potential benefits. In addition, elderly patients with dementia have a high risk of mortality, including stroke-related mortality, from the use of antipsychotics.^18,26,31

Adverse effects of insomnia treatments

Tables 3 and 4 compare dosing, pharmacokinetic properties, and adverse effect profiles of FDA-approved hypnotics and other agents commonly prescribed to improve sleep. All BzRAs and suvorexant have abuse potential and should be prescribed at the lowest effective dose. Next-day impairment is possible with zolpidem, eszopiclone, temazepam, suvorexant, and trazodone when taken at doses typically prescribed for insomnia. Driving simulation studies showed that 15% of women and 3% of men are too impaired to drive safely after taking 10 mg of zolpidem the previous night. In order to improve patient safety, in 2013, the FDA recommended a lower zolpidem starting dose of 5 mg for women.³² Similar testing with 3 mg of eszopiclone showed next-day impairment in both sexes and, in 2014, the FDA reduced the maximum starting dose of eszopiclone to 1 mg.³³ Similar pre-marketing driving simulation tests with suvorexant 20 mg, 40 mg, and 60 mg showed that doses above 20 mg were unsafe and 20 mg doses result in next-day impairment for approximately 10% to 20% of individuals.^27,28 Consequently, the FDA lowered the recommended starting dose of suvorexant to 10 mg, but a 5 mg strength is also available. Patients taking a cytochrome P450 (CYP) 3A4 inhibitor such as diltiazem should start at 5 mg of suvorexant instead of 10 mg to avoid excessive blood levels of suvorexant. Zolpidem, eszopiclone, and suvorexant act faster when given on an empty stomach than when given with food.⁵

Patients prescribed any BzRA or suvorexant should be cautioned about the consequences of escalating the dose without medical supervision or recommendation: hallucinations and amnesia may occur, and complex sleep behaviors, which is the phenomenon of being half-asleep while driving, cooking, or talking on the phone without remembering the activity the next day, are possible.^5,26

Non-prescription medications used for insomnia

Over-the counter remedies containing sedating antihistamines (e.g., diphenhydramine, doxylamine) are FDA approved for insomnia. However, these agents are not consistently effective and can result in next-day grogginess or impairment.^5,18

Melatonin 1 to 3 mg nightly may be effective for circadian rhythm sleep disorder and for children with insomnia associated with attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and in some elderly patients who have difficulty falling asleep. It has not been demonstrated to be effective for younger adults with insomnia.^5,19,21

Table 3: Benzodiazepine Receptor Agonists FDA Approved for Insomnia3,5,12,14,26
Drug (brand name)	Dose range (mg)	Onset (min)	Half-life (hours)	Type(s) of insomnia treated	Special considerations for counseling
Zaleplon	5-10	30	1.1	DFA	Rapid onset If middle-of-the-night awakening occurs, an extra dose can be taken without next-day impairment as long as at least 4 hours are left before wake time
Zolpidem tablet, sublingual tablet, oral spray Zolpidem CR Zolpidem sublingual tablet	5-10 6.25,  12.5 1.75, 3.5	30	2.5 2.8	DFA, DMS	Take on empty stomach for rapid onset Next-day impairment possible Women achieve higher blood levels than men If middle-of-the-night awakening occurs, a 1.75 or 3.5 mg dose can be taken without next-day impairment as long as at least 4 hours are left before wake time Oral spray delivers 5 mg/actuation
Eszopiclone	1-3	45	6	DFA, DMS	Effective at inducing sleep and maintaining sleep Unpleasant taste possible
Triazolam	0.125-0.25	20	2.5	DFA	Rebound insomnia possible; do not take longer than 7-10 days to minimize risk of rebound insomnia High rate of anterograde amnesia
Temazepam	7.5-30	60-120	10	DMS	Additional anti-anxiety effect Long onset of action Does not undergo hepatic metabolism; no accumulation in liver impairment
Notes: Estazolam and flurazepam are FDA approved for insomnia, but they were omitted from this table, since the disadvantages associated with treatment outweigh the advantages and neither can be recommended as a safe and effective treatment of insomnia; all of the agents listed in the table have abuse potential and are classified as C-IV controlled substances. CR: controlled release; DFA: difficulty falling asleep; DMS: difficulty maintaining sleep.

Table 4. Non-Benzodiazepine Receptor Agonists for Insomnia 3,5,12,14,23,27-29
Drug (brand name)	Dose range (mg)	Onset (min)	Half-life (hours)	Type(s) of insomnia treated	Special considerations for counseling
Suvorexant* (classified as a C-IV controlled substance)	5-20	30-60	9-13	DFA, DMS	Increased bioavailability in patients with obesity, so lower dose is needed in these patients Has not been studied in comorbid psychiatric illness Avoid use with narcolepsy and with suicide risk Next-day impairment possible
Doxepin*	3-6	60-180	12-30	DMS	Slow onset Well tolerated in elderly at recommended doses Higher doses (10-25 mg) are used off label High histamine blockade
Trazodone	50-200	30-60	7-15	DFA, DMS	Dizziness and next-day impairment possible; priapism rare Next-day irritability and aggression possible, particularly when coadministered with CYP 2D6 inhibitor due to formation of active metabolite Caution in elderly and in patients with cardiac disease due to hypotension and fall risk
Amitriptyline	10-100	60-180	15-25	DFA, DMS	Dizziness, anticholinergic effects, and next-day impairment possible Caution in elderly with cardiac disease due to hypotension, arrhythmia, and fall risks High lethality in overdose
Ramelteon*	4-8	15-30	1-3	DFA	Do not co-administer with CYP 1A2 inhibitors (e.g., fluvoxamine) Mild increase in prolactin level and decrease in testosterone level with chronic use
Melatonin	1-6	60-120	< 1	DFA	Recommended for  youth, elderly, and people with jet lag Recommend United States Pharmacopeia labeling for purity
Diphenhydramine*	12.5-50	30	4-8	DFA, DMS	Tolerance develops over 1-2 weeks of regular use Next-day impairment and anticholinergic side effects possible
Doxylamine*	12.5-25	30	10	DFA, DMS	Tolerance develops over 1-2 weeks of regular use Next-day impairment and anticholinergic side effects possible
*FDA-approved for insomnia CYP: cytochrome P450; DFA: difficulty falling asleep; DMS: difficulty maintaining sleep.

Patient education and counseling

Pharmacists are well-positioned to interact with patients who experience insomnia. The pharmacist should: 1) educate the patient on the importance of good sleep for overall health and well-being; 2) encourage patients to implement multimodal cognitive behavioral interventions; and 3) provide counseling on the safe and effective use of hypnotics for the shortest duration of time at the lowest effective dose to improve sleep while minimizing adverse effects. Patients should be informed that alcohol and other CNS depressants, such as opioids, should not be mixed with hypnotics.⁵ Patients should also be cautioned not to drive the day after taking medications associated with a risk of next-day impairment; the risk of accidents is greatest for patients with new prescriptions of hypnotics.⁷

SUMMARY

Persistent insomnia increases a person’s risk for obesity, diabetes, stroke, and cancer, and it can be a sign of an untreated psychiatric disorder. All comorbid conditions must be treated concurrently in order to achieve the best outcomes. Multimodal CBT is the most effective non-pharmacologic treatment of insomnia for adults, but it can take up to 3 to 6 weeks to implement and realize improvement in sleep. Analyses of clinical studies show that zolpidem, eszopiclone, and suvorexant are the most effective hypnotic agents for insomnia for decreasing time to fall asleep and for increasing total sleep time. Hypnotics are best used on an as-needed or short-term (1-3 months) basis and while non-pharmacologic treatment is implemented. The lowest effective dose for the shortest duration of time should be used in order to minimize adverse events. Chronic or long-term hypnotic use is associated with negative health outcomes including cognitive impairment, falls, and dementia. Melatonin is considered safe and likely effective for insomnia associated with circadian rhythm sleep disorders, for youth with ASD or ADHD, and for insomnia in the elderly. Pharmacists can assist patients with insomnia through effective education and counseling.

References

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