The pharmacologic treatment of insomnia has made great advances in the last two decades. In the early 19th century, alcohol and opioids were used as sleeping medications. In the late 19th century, chloral hydrate was used (and misused, in combination with alcohol, as “knockout drops” or a “Mickey Finn”). Barbiturates were used from the early 20th century until the early 1960s, when benzodiazepines (ie, flurazepam and quazepam) were first approved by the US Food and Drug Administration (FDA) for the treatment of insomnia. In 2017, the American Academy of Sleep Medicine (AASM) released an updated guideline for the pharmacologic treatment of chronic insomnia in adults. [7] Benzodiazepines include long-acting forms (eg, flurazepam, quazepam), intermediate-acting forms (eg, temazepam, estazolam), and short-acting forms (triazolam). The long-acting agents are rarely used today for insomnia because of daytime sedation, cognitive impairment, and increased risk of falls in elderly patients. Benzodiazepines were commonly used until the 1980s, when tolerance, dependence, and daytime side effects were recognized as major limitations of these agents, particularly those with long elimination half-lives. Temazepam is still used for a short-term course (ie, from days to 1-2 weeks), at a dose of 15-30 mg at bedtime. In the 1990s, antidepressants were widely used for primary insomnia, and they continue to be widely used, despite the fact that few randomized, controlled trials have demonstrated their efficacy in treating primary insomnia. At present, sedative-hypnotics remain the most commonly prescribed sleep medications. Sedative-hypnotic medications do not usually cure insomnia, but they can provide symptomatic relief as sole therapy or as an adjunct with CBT. Furthermore, some patients cannot adhere to or do not respond to CBT and are candidates for these agents. The nonbenzodiazepine receptor agonists (eg, eszopiclone, zolpidem, zaleplon) are believed to be less habit-forming than benzodiazepines and, therefore, represent important advances in the long-term treatment of chronic insomnia. The most appropriate use of nonbenzodiazepine receptor agonists is for transient and short-term insomnia in combination with nonpharmacologic treatment. Most authorities now agree that they should infrequently be the only therapy for chronic insomnia. In the past, most studies of the efficacy of sedative-hypnotics had been short-term trials, generally less than 4 weeks. Use for longer than 4 weeks was thought to result in tolerance and decreased efficacy, although supportive findings are scarce, and the epidemiologic literature suggests that patients report continued efficacy with continued use. Nevertheless, because of the addictive nature of benzodiazepines, most authorities believe that the duration of use of these drugs should be limited. Studies have indicated, however, that nonbenzodiazepine receptor agonists can have long-term efficacy for 6-12 months without the development of tolerance. Eszopiclone, the first sedative-hypnotic to be tested over a 6-month period, showed continued efficacy with nightly use over that period, with improved quality of life, reduced work limitations, and reduced global insomnia severity. [78, 79] Another study demonstrated continued efficacy at 12 months. [80] Krystal et al showed long-term efficacy and safety of sustained-release zolpidem (Ambien-CR) for 6 months in a double-blind, placebo-controlled trial. [81] Zolpidem can be used at a dose of 5 or 10 mg at bedtime for sleep-onset insomnia; zolpidem-controlled release can be used at doses of 6.25 or 12.5 mg for patients with sleep-maintenance insomnia or patients with both sleep-onset and sleep-maintenance insomnia. Lower zolpidem doses were recommended by the FDA in January 2013, owing to the risk of next-morning mental impairment. [82, 83] Data show that zolpidem blood levels may remain high enough the morning after nighttime usage to impair activities that require alertness, including driving. This next-morning impairment is highest for the controlled-release dosage form and is more prevalent in women because of their slower elimination compared with men. The revised labeling for zolpidem recommends that the initial dose for immediate-release zolpidem products (Ambien and Edluar) be 5 mg for women and either 5 mg or 10 mg for men. The recommended initial dose for extended-release zolpidem (Ambien CR) is 6.25 mg for women and either 6.25 or 12.5 mg for men. The FDA also added a warning against driving or other activities requiring mental alertness the day after taking extended-release zolpidem at the 6.25-mg or 12.5-mg dose, because drug levels can remain high enough to impair these activities. [84, 83] Eszopiclone has a half-life of 5-7 hours and can be used for sleep-maintenance insomnia. The starting dose is 1 mg immediately before bedtime, with at least 7-8 hours remaining before the planned time of awakening. The dose may be increased if clinically warranted to 2-3 mg HS in nonelderly adults, and 2 mg in elderly or debilitated patients. Next-day impairment can occur after taking after a starting dose of 2 mg. FDA findings from observing 91 healthy adults showed that individuals who took a 3 mg dose of eszopiclone displayed severe psychomotor and memory impairment 7.5 hours later and that driving skills, memory, and coordination could remain impaired up to 11 hours later. [12] In a comprehensive comparative-effectiveness analysis, eszopiclone and lemborexant showed the best efficacy, acceptability, and tolerability for acute and long-term insomnia treatment. However, eszopiclone may cause substantial side effects. [85] Zaleplon has a very short half-life (1 hr) and is indicated for sleep-onset insomnia at doses ranging from 5-20 mg. It can also be used for sleep-maintenance insomnia if taken at the time of awakening during the night. However, the patient should allow at least 4 hours for remaining sleep to avoid possible daytime sedation. The following general precautions should be taken when using sedative-hypnotics:
Long-term hypnotic pharmacotherapy may be necessary in patients with severe or treatment-resistant insomnia or chronic comorbid disorders, but follow-up must include regular assessment of necessity, efficacy, and adverse effects. [1] Long-term administration of hypnotics may be intermittent, as needed, or nightly. [1] If possible, during long-term therapy, patients should receive an adequate trial of CBT. [1] These agents should be used with caution in patients with a history of insufficient sleep syndrome, particularly in patients prone to alcohol use, since this group can be predisposed to the development of parasomnias (eg, sleep-walking or sleep-related eating disorder [86, 87] ) In most patients, the risk of dependency is low. Few patients escalate the dose or use the drug more frequently than prescribed. Roehrs et al found no dose escalation after 12 months of nightly use of zolpidem by patients with primary insomnia. [88] Nevertheless, sedative-hypnotics should be avoided in patients with a history of substance abuse. Rebound insomnia may develop when a sedative-hypnotic is abruptly withdrawn. This is more likely to occur with larger doses and with the short-acting agents. Using smaller doses and tapering the drug can avoid rebound insomnia. The AASM guideline states that these measures are aided by concurrent CBT for insomnia (CBT-I). [1, 7] Suvorexant (Belsomra) was approved by the FDA in August 2014 and is the first orexin receptor antagonist for insomnia. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. Approval was based on three clinical trials involving more than 500 participants. The recommended dose is 10 mg for most patients. After taking 20 mg, impairment of next-day driving was observed. The American Academy of Sleep Medicine (AASM) recommends that suvorexant be used as a treatment for sleep maintenance insomnia as opposed to no treatment. [7] A second orexin inhibitor, lemborexant (Dayvigo), was approved by the FDA in December 2019. A major metabolite of lemborexant, M10, binds with comparable affinity as the parent drug to orexin receptors OX1R and OX2R. It is indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Approval of lemborexant was based on results from the phase 3 studies, SUNRISE 1 and SUNRISE 2, that included nearly 2000 patients. Sleep onset and maintenance was improved compared with placebo. Middle-of-the-night safety (including wakening to sound) and next-day postural stability and memory studies over 12 months were also conducted. There were no meaningful differences between lemborexant 5 mg, 10 mg, or placebo with ability to wake to sound in the middle of the night; however, balance impairment at 4 hours postdose was evident with lemborexant compared with placebo. [89] A large-scale systematic review and network meta-analysis analyzed data from 154 double-blind, randomized controlled trials of medications (licensed or not) used for acute and long-term treatment of insomnia in 44,089 adults (mean age, 51.7 years; 63% women). Results showed that benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more effective than placebo for the acute treatment of insomnia. [85] Daridorexant (Quviviq) is a dual orexin receptor antagonist that blocks the binding of neuropeptide orexins, OX1R and OX2R, and is believed to decrease overactive wakefulness. In January 2022, the FDA approved daridorexant for insomnia in adults. Approval was based on the Phase 3 extensive clinical program that had 1854 adults with insomnia at more than160 clinical trial sites in multiple different countries. Two clinical trials studied the efficacy of daridorexant in adults with insomnia who were randomized to receive either daridorexant or placebo over 3 months. The primary endpoints for both studies were the changes from baseline to month 1 and month 3 in Latency to Persistent Sleep and Wake After Sleep Onset (WASO) objectively by polysomnography. The secondary endpoints included in the statistical testing hierarchy with type I error control were patient-reported Total Sleep Time (sTST), evaluated every morning at home using a validated sleep diary questionnaire. In study 1, the daridorexant 25-mg and 50-mg doses showed a statistically significant improvement in all endpoints against placebo, at both months 1 and 3. In study 2, the daridorexant 25-mg dose showed statistically significant improvement on WASO and sTST at months 1 and 3 when compared to the placebo. The 10-mg dose did not show significant improvement on the 3 measurements. [90] Ramelteon (Rozerem), a melatonin receptor agonist, is approved by the FDA for use in persons with insomnia. It has been shown to have no potential for abuse and, as such, is the first nonscheduled prescription drug available in the United States for the treatment of insomnia. Ramelteon is a specific melatonin receptor agonist that binds to the melatonin MT1 and MT2 receptors. It has a half-life of 1-3 hours. The MT1 receptor attenuates the alerting signal of the suprachiasmatic nucleus (SCN) clock, and the MT2 receptor phase shifts (advances) the SCN clock to promote sleep. Controlled trials have shown a decrease in sleep latency but no change in wake time after sleep onset and no next-morning residual effects. Additionally, studies thus far on elderly patients have shown no impairment in night balance, mobility, or memory. [91, 92, 93] This medication is suited for patients with sleep-onset insomnia, particularly for elderly patients with gait disorders who have an increased risk of falls and in patients with a history of substance abuse. The typical starting dose is 8 mg before bedtime. Ramelteon is not effective for sleep-maintenance insomnia. The AASM recommends ramelteon for the treatment of sleep onset insomnia (versus no treatment). [7] Although there is a paucity of clinical data on the use of sedating antidepressants for the treatment of primary insomnia without mood disorders, these agents are still sometimes used. Sedating tricyclic antidepressants, such as amitriptyline, nortriptyline, and doxepin, and the tetracyclic drug mirtazapine have been used. Many clinicians believe that sedating antidepressants have fewer adverse effects than nonbenzodiazepine receptor agonists; however, this is not the case. Tricyclic drugs and mirtazapine can cause daytime sedation, weight gain, dry mouth, postural hypotension, and cardiac arrhythmias. Trazodone can cause priapism in men, daytime sedation, and hypotension. The efficacy and safety of low-dose doxepin have been demonstrated in 2 randomized, double-blind, parallel-group, placebo-controlled trials. Low-dose doxepin is thought to be a hypnotic that primarily works through an antihistaminic effect. Roth et al reported that low-dose doxepin (6 mg) provided significant improvements in sleep onset, maintenance, duration, and quality, as well as appearing to reduce early morning awakenings. These researchers used a first-night effect combined with a 3-hour phase advance to induce transient insomnia in healthy adults. The incidence of adverse events was comparable to placebo. [94] . In a 12-week study of elderly patients with chronic primary insomnia, Krystal et al reported that a nightly 1-mg or 3-mg dose of doxepin resulted in significant and sustained improvements in most insomnia endpoints, including sleep maintenance and early morning awakenings. There was no evidence of next-day residual sedation or other significant adverse effects. Efficacy was assessed using polysomnography, patient reports, and clinician ratings. [95] Antihistamines are the major ingredient of over-the-counter (OTC) sleep aids and are the ingredient in cold and sinus formulas sold as bedtime-use medications. Nevertheless, common antihistamines (ie, first-generation H1-receptor antagonists such as diphenhydramine, hydroxyzine, and doxylamine) are not indicated for the treatment of sleeplessness. Zhang et al reported that a nighttime dose of 50 mg diphenhydramine resulted in a next-day residual sedative effect. This double-blind, placebo-controlled, crossover study used positron emission tomography (PET) for an objective measurement of residual effect. [96] While H1 antihistamines have sedative effects in healthy individuals, no study has established an effective dose range for these agents’ hypnotic effect in patients with insomnia. These agents may have some subjective benefit, but long-term efficacy and safety have not been demonstrated. Thus, their regular use in individuals with insomnia is not advised. [7] Melatonin has also become a popular OTC sleep aid. Melatonin is a naturally occurring hormone secreted by the pineal gland. The concentration of melatonin is highest in the blood during normal times of sleep and lowest during normal times of wakefulness. The general consensus is that melatonin given during normal waking hours has hypnotic properties. However, the timing of evening administration is critical as to whether a hypnotic or chronobiologic effect occurs. Melatonin given early in the evening appears to increase sleep time; however, administration 30 minutes before a normal bedtime has not resulted in a decreased sleep latency or an increase in sleep time. Most studies of melatonin have been small and of limited duration, and the results have conflicted somewhat, with several studies showing limited or no effect. [19] Most of the data, however, seem to suggest that melatonin taken before bedtime decreases sleep latency, may increase total sleep time, [97, 98] and may entrain irregular circadian rhythms. Studies of melatonin in individuals with chronic insomnia have not demonstrated objective changes in patient sleep habits or changes in mood or alertness the day after treatment. In addition, a dose-response relationship has not been determined. OTC melatonin is also sold at doses much higher than those that naturally occur in the blood. The 2008 AASM guideline notes a relative lack of safety data and efficacy data and, therefore, states that melatonin is not recommended for the treatment of chronic insomnia. [1] Some studies, however, suggest a possible role for melatonin in the elderly. In a 2010 study, Wade et al determined that prolonged-release melatonin (2 mg) improved sleep latency and additional sleep and daytime parameters in patients 65 years of age and older. These improvements were maintained or enhanced over a 6-month period, with no signs of tolerance. [99] A double-blind, placebo-controlled clinical trial by Rondanelli et al in residents of a long-term care facility found that a nighttime dose of melatonin, combined with magnesium and zinc, appeared to improve residents’ quality of sleep and quality of life. The supplement, containing 5 mg melatonin, 225 mg magnesium, and 11.25 mg zinc, was administered 1 hour before bedtime. [100] Melatonin is not recommended by the AASM for sleep onset or sleep maintenance insomnia. [7] Alternative and herbal medications have also been tried in the treatment of insomnia. Valerian root extract is the most widely used and studied of these agents. A 2006 meta-analysis of 16 randomized, controlled trials of valerian for the treatment of insomnia had conflicting results. [101] The pooled data did seem to show evidence of improved sleep; however, the authors noted a possible publication bias that may have contributed to this result. A 2010 met-analysis of 18 randomized, controlled trials of valerian for the treatment of insomnia detected no publication bias. However, although the results suggested that valerian may be effective for subjective improvement of insomnia, its effectiveness has not been demonstrated with quantitative or objective measurements. [102] A randomized, placebo-controlled trial by Taavoni et al found that valerian improves the quality of sleep in women with menopause who are experiencing insomnia. Patients in the treatment arm received 530 mg of concentrated valerian extract twice a day for 4 weeks. [103] Other herbal remedies such as chamomile and St. Johns wort have not shown efficacy for insomnia. Furthermore, potential risks have been associated with the use of some OTC remedies, such as dogwood, kava kava, alcohol, and L-tryptophan. [104] For these reasons, the 2017 AASM guideline states that valerian and other alternative or herbal medications are not recommended for treatment of chronic insomnia. [7] |
A nurse is caring for a client who is taking diphenhydramine for insomnia and reports drowsiness
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