Episode 124: Commonly Prescribed Sleep Medications and Treatment for Insomnia
Shizuka Tomatsu MD, Shilpa Krishnan DO, David Puder, MD
*Both Dr. Tomatsu and Dr. Krishnan are first authors for different sections of this handout.
Dr. Tomatsu, Dr. Krishnan, and Dr. Puder don’t have any conflicts of interest to report.
Table of Contents
I. Intro to insomnia (Dr. Tomatsu and Dr. Krishnan)
II. Dr. Krishnan (primary author)
Barbiturates
Benzodiazepine
Z-drugs
III. Dr. Tomatsu (primary author)
Orexin antagonists
Melatonin receptors
Heterocyclics
Over the counter / Off-Label
INSOMNIA: INTRODUCTION
A fairly common problem; it is likely that almost all individuals suffer from at least transient insomnia.
Insomnia Criteria: American Academy of Sleep Medicine (AASM Practice Guidelines)
Sleep symptoms:
difficulty initiating sleep
difficulty maintaining sleep
waking up earlier than desired
resistance to going to bed on an appropriate schedule
difficulty sleeping without caregiver intervention
Daytime symptoms:
fatigue/malaise
attention, concentration, or memory impairment
Impaired social, family, vocational, or academic performance
Mood disturbance or irritability
Daytime sleepiness
Behavioral problems
Reduced motivation/energy/initiative
Proneness for errors/accidents
Concerns about or dissatisfaction with sleep
Short-term insomnia: at least one of the sleep symptoms and at least one of the daytime symptoms have been experienced for fewer than 3 months
Chronic insomnia: at least one of the sleep symptoms and at least one of the daytime symptoms have been experienced for more than 3 months
The International Classification of Sleep Disorders, Third Edition also includes frequency of at least 3 times per week for at least 3 months (Sateia, 2014)
DSM-V Definition: The inability to fall asleep or maintain sleep for at least 3x/week for at least 3 months
Insomnia architecture:
Initial insomnia: Difficulty going to sleep
Middle insomnia: Difficulty maintaining sleep, waking up in the middle of the night
Terminal insomnia: early awakening
Sleep Architecture:
NREM sleep is essential for the following functions: repair and regenerate body tissues, flush out toxic waste
REM sleep (atonic, vivid dreams) is essential for memory consolidation and improves depression and anxiety
No single medication has strong evidence for long-term use in insomnia. The primary purpose of medications in insomnia is as short-term adjunctive therapy while the patient works on CBTi (including sleep hygiene)
Medications may physically knock you out but may not enhance the quality of sleep. Medications mask the underlying cause of insomnia
Clinicians should attempt to identify the underlying cause of insomnia and treat accordingly
Common problems that impair proper sleep:
Screen time prior to bed: phase delays sleep-wake cycle
Particular issue with emission of blue light, which has the shortest wavelength and therefore produces the highest energy, is suppression of melatonin production
Of note, there is a lack of high quality evidence demonstrating that blue light blocking glasses improve insomnia. They likely don’t help enough and screens should be turned off 2 hours before bed
Maladaptive sleep associations, i.e., watching television
Per Dr. Cummings: make sure to dim the light emanating from the screen if watching television before bed
Exercise prior to bed
Per Dr. Cummings: Exercise, in general, is helpful for insomnia. However, doing so immediately prior to going to sleep at night increases sympathetic activity, promotes energy, and negatively impacts the ability to fall asleep
Of note, exercise earlier in the day is helpful for sleep
Non-pharmaceutical options to promote sleep in the inpatient psychiatric setting:
Discontinue nocturnal or early morning vitals measurements if they are not necessary for treatment
Schedule HS medications prior to going to bed
Work with administration and nursing staff to change lighting and noise levels during the evening and overnight, as appropriate
CBTi BRIEF OVERVIEW (Bootzin, 1972, Morin, 2004, Lichstein, 2001)
Gold standard treatment for insomnia
Performed primarily by a sleep psychologist or CBTi trained psychiatrist
Time intensive treatment requires maintenance of sleep log prior to intervention as well. This can be a barrier for many individuals
Main components
Sleep restriction/sleep consolidation
Stimulus control
CBT
Sleep habits (rarely effective by itself in treating chronic insomnia)
Relaxation Technique
PHARMACOTHERAPY : SEDATIVE-HYPNOTICS
Benzodiazepines/Barbiturates
History: (APA Publishing Textbook of Substance Use Disorders)
Barbituric acid was synthesized in 1864 by Adolf von Baeyer of Bayer Chemical Company. In 1904, barbital (diethylbarbituric acid) was marketed and began to be used clinically. During the 1st and 2nd world wars, barbiturates were widely used for induction of anesthesia, refractory psychiatric conditions, insomnia, and epilepsy. By the late 1960s, concern grew for overdose potential of barbiturates (namely respiratory depression) and addictive properties.
In 1955, chemist Leo Sternbach identified chlordiazepoxide (Librium) which soon became widely marketed and used in a clinical setting. This was soon followed with diazepam (Valium). These medications initially appeared safer, less toxic in overdose and there was apparently less potential for abuse. Widely began to be used, peaking in 1970s for insomnia and anxiety.
The first benzodiazepine that was approved/indicated for sleep was Flurazepam in 1970
Increase awareness in the 1980s and 1990s for overdose risk potential, especially in combination with other sedatives, and concern for the dangers of using benzodiazepines in the elderly population
Mechanism of Action: Barbiturates (Scatzberg's Manual of Clinical Psychopharmacology)
Increase duration of GABAA receptors
Capable of activating the GABAA complex even in absence of GABA so they carry increased risk of toxicity in overdose
Mechanism of Action: Benzodiazepines (Scatzberg's Manual of Clinical Psychopharmacology)
Increase frequency of channel opening
Benzodiazepines have anxiolytic and sedative-hypnotic properties ***Exception: Quazepam, strictly a hypnotic***
Binds to type 1 and type 2 GABAA receptors, broad subunits both centrally and peripherally that have anxiolytic, hypnotic, and muscle relaxant properties
Quazepam: binds only to GABAA receptors that contain the α1 subunit responsible for the hypnotic effect, similar to the Z-drugs
Current medical uses: anxiety disorders, sleep disorders, seizure disorders, muscle spasticity, movement disorders, management of acute intoxication (cocaine, meth) and acute withdrawal (alcohol), catatonia
Barbiturates: tx of seizures (phenoba\rbital, primidone), general anesthesia (sodium thiopental), migraine headaches (Butalbital)
Prevalence of Benzodiazepine use:
Using data from the 2015 and 2016 National Survey on Drug Use and Health (Maust, 2019)
In the United States, 12.6% of adults reported past-year benzodiazepine use
Misuse accounted for nearly 20% of overall use, highest in ages 18-25yo (5.2%) and lowest in the elderly (0.6%)
However, use as-prescribed was highest among adults aged 50-64yo. The second highest subgroup that used benzodiazepines as prescribed were ages greater than 65yo
Class adverse effects:
Acute: (Lader, 2014), (The APA Publishing Textbook of Psychopharmacology)
Sedation and daytime sleepiness can develop tolerance over time
Ataxia
Slurred speech, disorientation
Memory dysfunction, particularly anterograde amnesia
Psychomotor impairment
Chronic: evidence of cognitive impairment with long term use
A meta-analysis on the effects of benzodiazepine use on cognitive functioning, published in 2017 in Archives of Clinical Neuropsychology, demonstrated significant cognitive impairments in the domains listed below. Includes current users as well as those who have recently withdrawn and abstained from use -up to 42 months post-withdrawal. (Crowe, 2017)
Working memory
Processing speed
Divided and sustained attention
Visuoconstruction
Expressive language (deficit only found in current users, not seen in those who have successfully abstained)
Executive function (deficit only found in current users, not seen in those who have successfully abstained)
Cognitive deficits in the elderly: Liu, 2020
A meta-analysis from 2020, published in Frontiers in Psychiatry, looked at benzodiazepine use and abuse in the elderly population
Found significant impairment in processing speed (digital symbol test scores), both with long term use and abuse
Global cognition, assessed with Mini-Mental State Examination, was found to be significantly impaired only with long term abuse
Studies included in this meta-analysis had large heterogeneity regarding tests for memory (auditory and verbal recall) and executive function (planning/reasoning, inhibitory control). However, most studies did find significant impairments in the above cognitive domains with benzodiazepine use and abuse
Association with dementia:
A 2018 meta-analysis included six case-control studies, four prospective cohort studies, and one retrospective cohort study. Most studies adjusted for depression, anxiety, and/or insomnia (Lucchetta, 2018).
Found that benzodiazepine ever-users were 1.38 times more likely to develop dementia as compared to non-users (OR 1.38, 95% CI 1.07–1.77) and that benzodiazepine users have a 28% higher risk of developing dementia (RR 1.28, 95% CI 1.06–1.55)
Large heterogeneity in the studies, lack of consistent adjustment of confounding variables, and inability to differentiate between short-term and long-term use or dose relationship provided significant limitations to this meta-analysis
A 2020 study done in Denmark attempted to mitigate the above limitations. They analyzed prescription registry data for benzodiazepines and Z-drugs in patients with affective disorders (ICD-10 codes F30-F30.9) from 1969 to 2016, and looked for diagnosis of dementia or prescriptions for dementia medication during the 6 year follow up period. The authors then compared members of the population that remained dementia-free (control) and matched them with subjects who developed dementia (Osler, 2020)
Explored rates of dementia with regards to drug type (benzodiazepines, Z-drugs, long or short-acting drugs) and timing of exposure and duration of treatment.
They found no association between the use of any benzodiazepines or Z-drugs and subsequent diagnosis of dementia. No association with the timing of exposure, between long and short-acting drugs, and no dose-response effect was observed
Possible protective effect?
The same 2020 Denmark study above demonstrated that continued and new users of benzodiazepines had lower rates of dementia than patients with no lifetime use or patients with former use (Osler, 2020)
Adjusted hazard ratio: as compared to control (never users)
Continuing use: 0.78 (CI 0.70-0.88)
New use: 0.83 (CI 0.76-0.89)
Former use: 1.05 (CI 0.96-1.16)
The odds of developing dementia were slightly higher among individuals with the lowest rates of benzodiazepine use
OR: 1.08 (CI 1.01-1.15)
It is well known that benzodiazepines impair cognition, especially in the elderly. However, the use of short-acting benzodiazepines in low doses can reduce stress and, some argue, promote sleep.
Affective disorders are associated with the risk of developing dementia later in life; perhaps the calming effect of benzodiazepines in reducing the pathological effects of stress on the brain is protective and thereby decreases the risk of developing dementia (Salzman, 2020)
Dr. Cummings commented that “Taking Benzodiazepines chronically is statistically associated with an increased rate of dementia. It’s not clear that the benzodiazepine is causing the dementia. It may well be that people who suffer from chronic anxiety, insomnia, and other issues for which they are taking the benzodiazepine - these people may also have a greater burden of general physical illness which may also be risk factors for dementia”.
Dr. Cummings further noted that “Benzodiazepines are good, short term rescue medications, either for sleep or for anxiety. They are generally dangerous long term medications because of the increased mortality risk and increased cognitive impairment”.
Tapering Benzodiazepines:
Very gradual. If an individual has been taking benzodiazepines chronically, the taper needs to be slow; as long as 6 months to more than 1 year
Benzodiazepines as drugs of abuse:
Using data from the 2015 and 2016 National Survey on Drug Use and Health (Blanco, 2018)
17.1% of benzodiazepine users reported misuse; however, only 1.5% had a diagnosis of benzodiazepine use disorder
The same data showed that benzodiazepine use was associated with emergency room visits, suicidal ideation, use of other illicit substances, and mental illness
Benzodiazepines have played a major role in opiate overdose and deaths in the United States (Bachhuber, 2016)
2018 data from National Institute on Drug Abuse showed benzodiazepine involvement one third of fatal overdoses (National Institute on Drug Abuse)
Risk of respiratory depression when combined with opiates and/or alcohol (Blanco, 2018)
Benzodiazepines and Mortality:
A large retrospective, matched cohort study done in the United Kingdom, spanning the years 1998-2011, studied the association between prescriptions for anxiolytics and hypnotics, including benzodiazepines and Z drugs, with mortality. (Weich, 2014)
For the benzodiazepines, the hazard ratio for mortality averaged 3.68 compared to matched controls, with a significant dose-response pattern observed. This was after adjusting for confounders, including physical comorbidities, psychiatric diagnoses, sleep disorders, and prescriptions for non-study drugs
Benzodiazepine use is common in patients who complete suicide
A study done in 2013 pulled data from the National Violent Death Reporting System to compare factors that led to suicide between physician and non-physician victims (Gold, 2013).
27% of all suicides had one or more illicit drug or alcohol levels above 0.8%
Compared to non-physicians, physicians were at significantly higher odds of having benzodiazepines or barbiturates, as well as antipsychotics, in their system (measured via toxicology testing).
Benzodiazepines: OR 21.0, CI 11.4-38.6, p <0.0005
Barbiturates: OR 39.5, CI 15.8-99.0, p <0.0005
This study also showed no significant difference in the presence of antidepressants, opiates, amphetamines, or cocaine between physicians and non-physicians
FDA-approved indication for insomnia (only 5): Flurazepam, Temazepam, Estazolam, Quazepam, and Triazolam
A. Flurazepam:
Oxidized in the liver and has a long half-life (40 hours). It also forms a long acting metabolite (desalkylflurazepam) that has a half-life of 100 hours
Efficacy/Uses:
15 and 30mg doses were studied for sleep onset and maintenance insomnia
American Academy of Sleep Medicine makes no recommendations for or against Flurazepam, given numerous inconsistencies in studies and high variability across studies
In their meta-analysis, the American Academy of Sleep Medicine found mixed data for sleep latency:
Increases in Total Sleep Time with 30mg dosing
Moderate improvement in Wake After Sleep Onset at 30mg
Increase in sleep quality subjectively reported at both 15 and 30mg doses (ASM, 2017)
Limited studies reporting moderate to large effect sizes on subjective measurements of sleep latency, total sleep time, and number of awakenings with 30mg dosing (Nowell, 1997)
Effect size 0.43 for sleep latency; 0.60 for Total Sleep Time; 0.99 for Number of Awakenings (Elie 1990)
Effect size 0.49 for sleep latency; 1.00 for TST; 0.64 for Number of Awakenings (Scharf, 1990)
Effect size 0.40 for sleep latency; 0.97 for Total Sleep Time; 1.00 for Number of Awakenings (Dominguez 1986)
Studies ranging from 4 weeks to 12 weeks have been done to study the efficacy of Flurazepam 15 and 30mg and have not demonstrated significant tolerance development over this period of time (Reeves 1977), (Leibowitz, 1979)
Adverse effects:
Dose-dependent relationship
Reports of significant daytime somnolence, drowsiness, and fatigue (Dominguez, 1986)
Impairments in daytime psychomotor functioning (reaction time, pursuit rotor, tapping speed) with 30mg dosing (Salkind, 1975)
Carryover effectiveness of Flurazepam 2-3 days after abrupt discontinuation without rebound insomnia (Kales, 1982)
B. Quazepam: Benzodiazepine hypnotic
Pharmacokinetics is similar to Flurazepam. Uniquely, Quazepam is selective for type 1 GABAA receptors containing the α1 subunit, similar to the Z-drugs; therefore, little to no anxiolytic or muscle relaxant properties. However, the long-acting metabolite (desalkylflurazepam) binds selectively to type 1 and type 2 GABAA receptors
Efficacy/Uses:
Doses: 7.5 to 15mg
Academy of Sleep Medicine makes no recommendations for or against Quazepam
Subjective reports indicated a small reduction in sleep latency and modest improvement in quality of sleep (ASM, 2017)
Data on effect sizes were not published for Quazepam and only a few studies exist that have adequate data and utilize randomization, placebo control, and double-blind assessments
Measurement of sleep latency, total sleep time, number of awakenings, and sleep quality using Quazepam 30mg: significantly better (p-value 0.05) subjective reports in all categories measured compared to placebo (Aden, 1983)
Subjective rating scale measurements of short-term use of 15mg Quazepam. Significant improvements with sleep latency (p-value 0.01), total sleep time (p-value 0.05), and sleep quality (p-value 0.03). (Hernandez, 1983)
Adverse effects:
Daytime drowsiness, fatigue, lethargy, and hypokinesia (Aden, 1983)
Carryover effectiveness of Quazepam 2-3 days after abrupt discontinuation without rebound insomnia (Kales, 1982)
C. Temazepam
Conjugated in the liver and with a much shorter half-life of 8 hours, no active metabolites
Efficacy/Uses:
Doses: usually 15mg. Can start at 7.5, highest dose is 30mg
Academy of Sleep Medicine recommends use for sleep onset and sleep maintenance insomnia
From their meta-analysis:
Mean reduction in Sleep Latency of 37min greater than placebo (CI 21 - 53min reduction)
Total Sleep Time - mean 99min longer compared to placebo (CI 18 to 76min improvement)
Small improvement in quality of sleep (ASM, 2017)
Limited studies have shown moderate to large effect size on subjective reports on sleep latency, total sleep time, number of awakenings, and sleep quality
Temazepam 20mg - Effect size 0.80 for Sleep Latency; 0.89 for Total Sleep Time (Cuanang, 1982)
Temazepam 30mg - Effect size 0.76 for Sleep Latency; 0.57 for Total Sleep Time; 0.76 for Number of Awakenings; 0.76 for Sleep Quality (Fillingim 1979)
Studies over the course of 1-3 months have not shown significant development of tolerance with 15 or 30mg dosing; subjective reports of efficacy were maintained over this period of time (Allen, 1987), (Mitler, 1979)
CBTI vs. Temazepam: A 2006 RCT compared CBTI with combination CBTI + Temazepam, Temazepam alone, and placebo; treatment duration of 8 weeks. Follow-ups were conducted at 3 and 8 months (Wu, 2006).
Initially (within the 8 weeks), measurements of sleep latency, sleep efficacy, and total sleep time were significantly better in the Temazepam alone group than in CBTI group
At the 3 and 8 month follow-ups, however, sustained improvements in sleep latency, sleep efficacy, and total sleep time were observed only with the CBTI group; Temazepam alone group were gradually returning to pretreatment baseline and combination therapy yielded variable results.
The combined group yielded the greatest reduction in sleep latency and the highest increase in sleep efficiency immediately after the 8-week treatment duration; however, this was not sustained at the 3 and 8 month follow ups, with sleep latency and sleep efficiency returning to baseline, similar to the temazepam alone group.
Psychological tests: using the Pre-Sleep Arousal Scale (PSAS), Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS), and Daytime Dysfunction Questionnaire (Pittsburgh Sleep Quality Index)
All three measures for sleep quality improved over time and was significantly better with the CBTI group alone as compared to temazepam and combination therapy
Adverse effects:
A 2-week trial done on elderly patients with insomnia demonstrated no increase in overall adverse effects with 15mg dosing though there was one reported fall (Glass, 2008)
Higher doses (20 and 30mg) were associated with headache, blurred vision, depression, lethargy, vertigo and confusion (Cuanang, 1982) (Heffron, 1979)
D. Triazolam
Oxidized in the liver. Extremely short half-life of 3-6 hours. No active metabolites.
Efficacy/Uses:
Dosing: 0.125, 0.25, 0.5mg
Academy of Sleep Medicine recommends for sleep-onset insomnia
From their meta-analysis: Mean reduction in Sleep Latency 9 min greater compared to placebo (CI 4 to 22 min reduction).
Quality of sleep: moderate improvement compared to placebo (ASM, 2017)
Objective measurements of sleep using polysomnography demonstrated short-term improvements in sleep onset and maintenance; however, tolerance developed with loss of effectiveness over the course of 2 weeks, as well as a significant rebound insomnia following discontinuation (Kales, 1976)
A study looked at behavioral therapy vs. triazolam treatment for the management of sleep-onset insomnia. Found Triazolam treatment was initially superior to behavioral therapy with greater initial reductions in sleep latency; however, the effect quickly weaned and returned to baseline during follow-up measurements (McCulsky, 1991)
No data measuring effect sizes could be found in literature review; however, randomized control trials looking at subjective measurements of sleep reported significant p-values
Sleep Latency (p-value 0.01), Total Sleep Time (p-value 0.05), Sleep Quality (p-value 0.002). (Hajak, 1994)
P-value of 0.01 measured in all categories (Sleep Latency, Total Sleep Time, Number of Awakenings, Sleep Quality). (Cohn, 1984)
Studies have shown significant development of tolerance in as little as 2 weeks of administration (Kales, 1978), (McCulsky, 1991). A meta-analysis looking at sleep laboratory studies from 1966 to 1997 found the development of tolerance with intermediate and long-term use of triazolam (Soldatos, 1999)
Adverse effects: (Institute of Medicine Committee Reports)
Increased incidence of nervousness/anxiety with 0.25 and 0.5mg dosing
Increased evidence of memory impairment with longer duration of use rather than dose-related effects
Impaired coordination: higher risk with 0.25mg and 0.5mg
Rebound insomnia has been demonstrated in the first 1-2 nights following withdrawal (Soldatos, 1999), (Gillin, 1989)
CBTI vs. Triazolam:
A 1991 RCT compared behavioral therapy (stimulus control/relaxation training) with triazolam; treatment duration of 4 weeks, with follow-up conducted 5 weeks later (McClusky, 1991)
Triazolam was initially superior to behavioral therapy in measures of sleep latency (with effects even seen on the first night of administration); however, its effectiveness decreased after discontinuation and gradually returned to pretreatment baseline.
Behavioral therapy decreased sleep latency over the course of treatment duration, with sustained effects seen on follow-up.
E. Estazolam
Oxidized in the liver. Similar half-life to Temazepam (approximately 8 hours). No active metabolites.
Efficacy/Uses:
Dosing: 1-2mg
Academy of Sleep Medicine makes no recommendations for or against use, given limited data
Statistically significant improvement in Sleep Latency with Estazolam 2mg, improvements in sleep duration with 2mg, sleep quality improved with 1 and 2mg (Cohn 1991), (Dominguez, 1986), (Scharf, 1990)
Only one study found which reported moderate effect size with Estazolam 2mg in measurements of sleep latency, total sleep time, number of awakenings, and sleep quality (Walsh, 1984)
Effect size 0.56 for Sleep Latency; 0.67 for Total Sleep Time; 0.57 for Number of Awakenings; 0.63 for Sleep Quality
Limited data looking at long-term efficacy. Sleep laboratory studies over the course of 4 to 6 weeks have found no significant development of tolerance (Pierce, 1990), (Vogel, 1992)
Adverse effects:
Limited data on rebound insomnia, significant only one night after discontinuation (Vogel, 1992)
Somnolence, hypokinesia, residual daytime fatigue and sleepiness were reported with Estazolam in a dose-related fashion (Dominguez, 1986), (Scharf, 1990)
Non-benzodiazepine hypnotics: Zolpidem, Zaleplon, Eszopiclone
History: (The Big Sleep, 2013)
Zopiclone was the first non-benzodiazepine, developed in the 1970s in France. The first in the new category, “z-drugs.” It has a similar broad receptor profile to the benzodiazepines, with muscle relaxing, anticonvulsant, hypnotic and anxiolytic properties.
Zolpidem was introduced to the market in 1988 and launched by the French pharmaceutical company Synthélabo. It was brought to the United States as Ambien in 1992. Unique selectiveness of Zolpidem’s mechanism of action made it more appealing; theoretically, the selectivity was thought to lead to fewer adverse effects as compared to the benzodiazepines.
Development of Zaleplon and Eszopiclone followed (Eszopiclone is the active stereoisomer of Zopiclone. Approved by FDA in 2004).
Mechanism of Action: Act on the benzo α1 sites on the GABAA receptor. Lack of activity at α2 and peripheral benzodiazepine sites, therefore little to no muscle relaxing, anticonvulsant, or anxiolytic effects (Scatzberg's Manual of Clinical Psychopharmacology)
Current Medical Uses: Used only in the treatment of insomnia
Use in Obstructive Sleep Apnea is being studied:
Obstructive Sleep Apnea is associated with low respiratory arousal threshold (LAT), meaning low levels of respiratory effort leads to frequent awakening, greater ease of arousal.
Prior studies have shown a slight increase in the respiratory arousal threshold with the use of sedative hypnotics, Eszopiclone and Zolpidem specifically (Eckert, 2011).
However, a recent large retrospective study did not demonstrate a significant reduction in the low arousal threshold with either Eszopiclone or Zolpidem in individuals with mild to moderate disease; these participants still met the criteria for low arousal threshold, leading to frequent awakenings (Smith, 2017).
Per Dr. Cummings: melatonin is a safe option for individuals with OSA as it doesn’t directly affect respiration.
Z drugs dependence, misuse, and abuse:
Z drugs have been associated with the following adverse drug effects:
Withdrawal effects including insomnia, anxiety, tremor, restlessness, disorientation, and even case reports of tonic-clonic seizures with Zopiclone and Zolpidem (Flynn, 2006), (Aranko, 1991) (Pitchot, 2009), (Russo, 2021)
Paradoxical effects of euphoria, excitability, and hyperactivity that may drive misuse and abuse with high doses of Zolpidem (Victorri-Vigneau, 2007)
Increased likelihood of dependence with history of psychiatric disorder and previous history of substance abuse. Doses up to 300mg were reported.
Risks of misuse and abuse:
A study published in the International Journal of Neuropsychopharmacology in 2019 looked at reports made to the European Medicines Agency database of adverse drug effects in relation to the Z drugs, spanned between 2003 and 2017. This study found that among the Z drugs, Zolpidem had the highest rate of misuse/abuse and rates of the following adverse effects (Schifano, 2019)
A total of 23,420 adverse drug reactions related to misuse/abuse/dependence/withdrawal of Zolpidem
Intentional overdose involving Zolpidem 16.7%, suicide attempt 13.2%, intentional self injuiry 0.5%
Use alongside other recreational illicit drugs including cocaine, alcohol, cannabis, and amphetamines
Atypical use including intravenous, nasal, and sublingual modalities
The same study above (Schifano, 2019) had data for Zaleplon as well. Zaleplon was associated with the following (though much less frequent as compared to Zolpidem):
A total of 537 adverse drug reactions related to misuse/abuse/dependence/withdrawal of Zaleplon
Intentional overdose involving Zaleplon 51.9%, suicide attempt 13.6%, suicidal ideation 5.21%
A few case reports of atypical nasal use modality
With Eszopiclone, no evidence of misuse or abuse could be found in individuals without an already established history of drug abuse
One study, unpublished, shows that Eszopiclone at 6mg and 12mg doses (not dosages approved for insomnia) produce euphoric effects similar to diazepam 20mg (Scharf, 2006)
Z drugs and Mortality:
A large retrospective, matched cohort study done in the United Kingdom, spanning the years 1998-2011, studied the association between prescriptions for anxiolytics and hypnotics, including benzodiazepines and Z drugs, with mortality. (Weich, 2014)
For the Z drugs, the hazard ratio for mortality averaged 3.19 compared to matched controls, with a significant dose-response pattern observed. This was after adjusting for confounders including physical comorbidities, psychiatric diagnoses, sleep disorders, and prescriptions for non-study drugs.
A. Zolpidem (Ambien)
Half-life of 2-4 hours. Zolpidem ER has a similar half-life but is absorbed over a longer period of time.
Efficacy/Uses:
Dosing: 5 or 10mg
Academy of Sleep Medicine recommends for sleep onset and sleep maintenance insomnia
From their meta-analysis:
Sleep Latency mean reduction was 5–12 minutes greater compared to placebo
Total Sleep Time mean improvement was 29 minutes longer compared to placebo
Wake After Sleep Onset mean reduction was 25 minutes greater compared to placebo
Moderate improvement in quality of sleep (ASM, 2017)
A 2012 prospective 8 month placebo-controlled study, in adults ages 23-70, showed a significant increase in Total Sleep Time compared to baseline and placebo, as well as decreases in Sleep Latency and Wake After Sleep Onset, that was sustained over the course of 8 months. (Randall, 2012)
Subjective questionnaires and objective polysomnography measures were correlated
Using polysomnography, limited studies have shown moderate to large effect size for sleep latency, however variable effect sizes for total sleep time and small effect size for the number of awakenings. Zolpidem 10mg was used for evaluation.
Effect size 1.00 for Sleep Latency; 0.81 for Total Sleep Time; 0.38 for Number of Awakenings (Herrmann, 1993)
Effect size 0.68 for Sleep Latency; 0.22 for Total Sleep Time (Scharf, 1994)
Also studied Zolpidem 15mg, however, found no significant advantage compared to 10mg.
A 2008 randomized placebo-controlled study, using polysomnography and studying Zolpidem 10mg dosing, demonstrated similar efficacy with regards to sleep latency (significant reduction in latency to persistent sleep measurements); however, reductions in night time awakenings and wake after sleep onset were not statistically significant compared to placebo. (Erman, 2008)
CBTI vs. Zolpidem:
A 2004 RCT compared CBTI alone with combination CBTI + Zolpidem and Zolpidem use alone, along with placebo, in adults with sleep-onset insomnia; treatment phase was 8 weeks. The primary outcome measure was sleep latency, with sleep efficiency and total sleep time measured as secondary outcomes (Jacobs, 2004). Their findings are as follows:
With regards to sleep latency and sleep efficiency mid and post treatment:
CBTI, alone or in combination with Zolpidem, is more effective than pharmacotherapy alone
CBTI was equal to or superior to combination therapy
CBTI was significantly superior to Zolpidem alone mid and post-treatment
Effect sizes were only reported for sleep latency:
Mid treatment: CBTI effect size 1.17, combined treatment effect size 1.08, Zolpidem alone effect size 0.51
Post treatment: CBTI effect size 1.22, combined treatment effect size 1.12, Zolpidem alone effect size -0.1
No significant differences among all groups on total sleep time, including placebo
A 2009 RCT compared CBTI alone to the combination CBTI + Zolpidem for acute insomnia treatment (6 weeks duration) and maintenance treatment (6 months duration) in adults with persistent insomnia. Participants in the combined group during the acute phase were subsequently randomized to CBT alone or CBT + Zolpidem in the maintenance phase (Morin, 2011).
During the acute phase of treatment:
CBTI + Zolpidem showed a modest, but significant increase in Total Sleep Time relative to those treated with CBTI alone
Significant reductions in sleep latency and wake after sleep onset for CBTI alone and in combination with Zolpidem, without substantial differences
Maintenance treatment:
The best outcome, defined as the highest rate of remission measured by the insomnia Severity Index, was achieved in participants who were initially treated by combination therapy (CBTI + Zolpidem) and then maintained by CBTI alone rather than continuing with combination therapy.
Those maintained by CBTI alone had significant, sustained increases in Total Sleep Time
Adverse effects:
Rebound insomnia: very little evidence to support this happens. Only one study found in literature review showed possible rebound insomnia day one after discontinuation but didn’t extend further (Ware, 1997)
Withdrawal:
In a 2012 RCT, no evidence of clinically significant withdrawal symptoms were found (Roehrs, 2012)
However, numerous case reports have been published demonstrating clinically significant withdrawal from Zolpidem (Victorri-Vigneau, 2007) as well as case reports linking Zolpidem withdrawal to delirium ((Mattoo, 2011) and seizure-like activity (Gilbert, 1997), (Aragona, 2000)
Global impairments were reported in psychomotor function, attention, memory, cognition. Most prominent in the middle of the night, a few hours after administration. (Kleykamp, 2012)
Anterograde Amnesia: dose-dependent effect
Significant memory and cognitive impairments 6 hours after administration with 20mg dosing (Verster, 2002)
Psychomotor performance: dizziness, postural instability, ataxia, falls
Increased odds of fracture in elderly population associated with Zolpidem use, by at least two-fold: (Kang, 2012), (Wang, 2001)
Profound dose-dependent impairments with body balance and standing steadiness, even after a single administration (Mets, 2010)
Next day performance:
Driving:
2016 literature review found an association with Zolpidem use and motor vehicle collisions (Rudisill, 2016)
Studies have reported a relationship between early or middle of the night administration of Zolpidem and residual next-day driving impairments in healthy and elderly participants (Leufkens, 2009), (Bocca, 2011), (Otmani, 2008)
Complex sleep-related behaviors:
Parasomnia behaviors: nightmares/terrors, somnambulism, sleep-driving
These neuropsychiatric effects, including hallucinations, were extensively reported in association with Zolpidem in a systematic review of the drug database in Australia from 2001-2008. (Ben-Hamou, 2011)
A study in Taiwan published in the Journal of Clinical Psychiatry in 2010 reported an incidence of 15.2% of complex sleep-related behaviors associated with Zolpidem use in patients with depressive and anxiety disorders (matched controls). (Hwang, 2010)
Somnambulance, sleep-talking, sleep-related eating disorders, hallucinations, and one instance of sleep-driving.
Increased risk with doses greater than 10mg of Zolpidem, younger age, and it affected females more than males
In Australia, by 2007, the Adverse Drug Reactions Advisory Committee had received 104 reports of hallucinations, 62 of amnesia, and 16 of “unusual or inappropriate behavior” linked to Zolpidem (Olson, 2008)
Sleep-eating, sleep-cleaning, and sleep-shopping have been reported (Tsai, 2007)
Confusional arousal vs. sleepwalking
Perhaps the unusual behaviors described above are related to amnesia and disorientation that is indicative of confusional arousal (a side effect of any sedative) rather than sleepwalking. Sleepwalking is constricted to what can be done without cortical input, as the cortex is asleep, rather than the complex behaviors described above (Olson, 2008)
Sleep-Driving:
Prior to 2006, 14 post-marketing cases of sleep-driving was reported to the FDA, 13 associated with Zolpidem (Southworth, 2008)
Case reports of sleep-driving in association with Zolpidem:
B. Zaleplon (Sonata)
Extremely short half-life of 1-2 hours.
Efficacy/Uses:
Dosing: 5 or 10mg, max 20mg
Academy of Sleep Medicine recommends only for sleep-onset insomnia. In their meta-analysis, Sleep Latency mean reduction was 10 minutes greater compared to placebo (ASM, 2017)
A double-blind placebo-controlled RCT (published in 2000) assessed the efficacy of Zaleplon 10mg dose using polysomnography over a course of 5 weeks. Found significant reduction in Sleep Latency without effect on Total Sleep Time or the number of awakenings (Walsh, 2000).
A Multi-center, double-blind RCT in 2000 that lasted for 2 weeks assessed Zaleplon efficacy in elderly population greater than 65 years old. Subjective sleep latency was significantly reduced at both 5 and 10mg doses and subjective sleep quality was significantly improved with the 10mg dose (Hedner, 2000)
A 2014 meta-analysis of polysomnographic randomized placebo-controlled trials calculated effect size using data from the above study (Winkler, 2014). Found small effect sizes for sleep latency and total sleep time.
Effect size 0.35 for Sleep Latency; 0.12 for Total Sleep Time (Walsh, 2000)
No evidence of tolerance development/decrease in efficacy in studies from 4 weeks up to 12 months (Heesch, 2014), (Fry, 2000)
Adverse effects:
No evidence of rebound insomnia in literature review (Fry, 2000), (Dooley, 2000), (Israel, 2002)
Headache, dizziness, and somnolence are the most reported symptoms; however, there is no significant difference from placebo (Walsh, 2000).
No impairments found with driving ability, psychomotor performance, or memory 4 hours and 6 hours after administration of 10mg or 20mg doses (Verster, 2002)
One case of sleep-driving associated with zaleplon use that was reported to the FDA prior to 2006 (Southworth, 2008)
Next day performance:
No studies were found that demonstrated significant impairments in next-day performance specifically
C. Eszopiclone (Lunesta)
Half-life of 4-5 hours.
Per Dr. Cummings: For individuals with terminal insomnia, of all the Z-drugs, Eszopiclone has been shown to have the most benefit given its longer half-life.
Efficacy/Uses:
Dosing: 1-3mg
Academy of Sleep Medicine recommends for sleep onset and sleep maintenance insomnia
From their meta-analysis:
Sleep Latency mean reduction was 14 min greater compared to placebo.
Total Sleep Time mean improvement was 28–57 min longer compared to placebo
Wake After Sleep Onset mean reduction was 10–14 min greater compared to placebo
Moderate-to-Large improvement in quality of sleep (ASM, 2017)
Significant reductions in subjective reports of Sleep Latency, Wake After Sleep Onset, and Number of Awakenings along with a significant increase in subjective reports of Total Sleep Time over a course of 6 months in adults with chronic insomnia (Krystal, 2003)
Polysomnography measurements over 2 nights demonstrated decreases in Sleep Latency with all doses (1-3mg). Nighttime awakenings and Wake After Sleep Onset improved with only 2.5 and 3mg doses (Erman, 2008)
2014 meta-analysis of polysomnographic randomized placebo-controlled trials found two studies that assessed Eszopiclone and had adequate data to calculate effect size (Winkler, 2014). At 2mg dosing, the effect size was moderate for total sleep time but small for measures of sleep latency and variable (small-moderate) for sleep efficiency. At 3mg dosing, the effect size was moderate for all three categories: total sleep time, sleep latency, and sleep efficiency. This suggests a clinical advantage with higher Eszopiclone dosing.
(McCall, 2006) Eszopiclone 2mg: effect size 0.52 for Total Sleep Time, 0.40 for Sleep Latency, 0.51 for Sleep Efficiency
Eszopiclone 2mg: effect size 0.23 for Sleep Latency, 0.32 for Sleep Efficiency
Eszopiclone 3mg: effect size 0.61 for Sleep Latency, 0.54 for Sleep Efficiency
Insomnia in conjunction with depression:
2 large multi-center trials have demonstrated that 1-3mg of Eszopiclone can help improve symptoms of insomnia (sleep onset and maintenance) in individuals diagnosed with depressive disorders (Fava, 2006), (Joffe, 2010)
No evidence of rebound insomnia or development of tolerance in studies ranging from 3 to 12 months (Heesch, 2014), (Ancoli-Israel, 2010), (Roth, 2005), (Walsh, 2007)
Bipolar disorder:
It is well known that insomnia in these individuals can precipitate manic episodes. Per Dr. Cummings: Eszopiclone can be used for individuals with bipolar disorder and insomnia.
During acute mania, sometimes Eszopiclone has been used in doses up to 8mg.
Adverse effects:
In both non-elderly patients (2-3mg of Eszopiclone) and elderly patients (1-2mg of Eszopiclone), only dry mouth and unpleasant taste were found to be statistically significant compared to placebo (Zammit, 2004), (Scharf, 2005)
Adverse effects of headache, dizziness, residual somnolence, dyspepsia were reported by both groups; however, incidence was not significantly different from placebo
Next day performance:
No studies were found that demonstrated significant impairments in next-day performance specifically.
Non-benzodiazepine hypnotics: Orexin Receptor Antagonists
History: 1998 gene encoding hypothalamic orexin neuropeptides, OX-1 and OX-2 were described. There are 50,000-80,000 orexin neurons originating in the lateral hypothalamus (Winrow, 2014, Janto, 2018).
Mechanism of Action: Competitive antagonist of OX1 and 2 receptors. Prevents Orexin A and B from binding. Blocks orexin-mediated wake signaling, allowing maintenance of sleep.
A. Almorexant
GlaxoSmithKline and Actelion abandoned the project in 2011 due to undisclosed reasons relating to its safety profile despite concluding Phase III clinical trial, RESTORA 1 (Press release, 2011).
B. Suvorexant (Belsomra)
2014 (Merck), Suvorexant became the first FDA approved therapeutic agent for the treatment of insomnia. Two trials were conducted consisting of two weeks of placebo for everybody followed by a 3m double-blinded placebo-controlled 3 arm phase (Suvorexant 40/30, Suvorexant 20/15, or placebo). Trial 1: ratio of 3:2:3, Trial 2: ratio of 1:1:1 in Q cohort, 2:1:2 in PQ cohort (Herring, 2016).
Efficacy/Uses:
Recommended for sleep maintenance insomnia.
10 mg starting dose, 20 mg max dose.
If using another CNS depressant drug or moderate CYP3A inhibitors, half the dosing range (5-10 mg).
Take 30 min before bed, with or without a meal. Don’t take with alcohol (Belsomra info packet)
Clinically significant reduction in wake after sleep onset (16-28m) for both 10 and 20 mg doses.
EFFECT SIZE (difference in the least square mean): Suvorexant 20/15 vs. Placebo
Trial 1: Night 1 -32.5 min; Month 1 -26.4 min; Month 3 -16.6 min
Trial 2: Night 1 -37.0 min; Month 1 -24.1 min; Month 3 -31.1 min
Clinically significant reduction in sleep onset at 20 mg dose, suggesting higher doses may help with sleep onset (Herring, 2016).
EFFECT SIZE (difference in the least square mean): Suvorexant 20/15 vs. Placebo
Trial 1: Night 1 -9.6 min; Month 1 -10.3 min; Month 3 -8.1 min
Trial 2: Night 1 -12.4 min; Month 1 -7.8 min; Month 3 -0.3 min (crosses 0 CI for months 1 and 3).
Adverse effects/potential for abuse
Twice the rate of somnolence compared with placebo, but overall placebo had more discontinuation rate due to adverse events (Herring, 2016).
No plasma concentration difference in moderate hepatic or renal dysfunction (Bennett, 2014)
Contraindicated if on a strong CYP3A inhibitor
Addiction liability is lower than Zolpidem (Schoedel, 2016)
Next day performance
No data on subjective sleep quality or next day performance (limitation of trial) (AASM, 2017)
C. Lembroexant (Dayvigo)
In June 2016, Eisai pharmaceuticals initiated a pair of phase III clinical trials in the US, France, Germany, Italy, Japan, Poland, Spain, and the UK. Three years later, in December 2019, at the completion of these industry-sponsored trials (SUNRISE I and II), Lemborexant was approved for use in the US by the FDA.
o SUNRISE I (Rosenburg, 2019)
o SUNRISE II (Yardley, 2020)
Efficacy/Uses:
FDA approval: Recommended for sleep onset and sleep maintenance insomnia
2.5mg – 10mg efficacious while minimizing next-morning residual sleepiness.
Statistically significant improvements in sleep onset compared to placebo.
EFFECT SIZE (difference in raw mean change from baseline)
Lemborexant 5mg: Night 1&2 was -10.1 min; Night 29&30 was -11.6 min.
Lemborexant 10mg: Night 1&2 was -13 min; Night 29&30 was -13.6 min.
Statistically significant improvements in wake after sleep onset compared to placebo.
EFFECT SIZE (difference in raw mean change from baseline)
Lemborexant 5mg: Night 1&2 was -34.9 min; Night 29&30 was -25.3 min.
Lemborexant 10mg: Night 1&2 was -44.5 min; Night 29&30 was -27.8 min
Adverse effects/potential for abuse
Headache and somnolence (SUNRISE I)
Somnolence, nasopharyngitis, and headache (SUNRISE II)
Similar to suvorexant, limited abuse potential. Doses up to 7 times the recommended dose only caused an increase in somnolence (Murphy, 2017, Ardeljan, 2021)
No dependence or withdrawal symptoms were noted (Murphy, 2017, Ardeljan, 2021)
Next day performance
Statistically significant improvements in insomnia Severity Index (ISI) compared to placebo (Yardley, 2020).
EFFECT SIZE (difference in raw mean change from baseline score)
Lemborexant 5mg: Month 1 was -1.0; Month 3 was -1.5; Month 6 was -1.7.
Lemborexant 10mg: Month 1 was -1.1; Month 3 was -1.5; Month 6 was -1.4.
Statistically significant improvements in Fatigue Severity Scale (FSS) compared to placebo (Yardley, 2020).
EFFECT SIZE (difference in raw mean change from baseline score)
Lemborexant 5mg: Month 1 was -2.7; Month 3 was -3.4; Month 6 was -3.8.
Lemborexant 10mg: Month 1 was -2.5; Month 3 was -3.6; Month 6 was -2.6.
D. Daridorexant
Phase III, 04/2020 (Press Release, 2020)
Efficacy/Uses:
Not yet FDA approved: Maybe early 2022?
Requesting recommendation for sleep onset and sleep maintenance insomnia
Adverse effects/potential for abuse
Nasopharyngitis, headache, somnolence, and fatigue
Next day performance
No next day somnolence, no final data.
Non-benzodiazepine hypnotics: Melatonin Receptor Agonists
History: Researchers investigated the modulation of the core structure of melatonin to develop a better agonist. Things that were more potent and better pharmacokinetic and had a longer half-life by changing the structure of melatonin. (Zammit, 2007)
Mechanism of action: Acts on MT1 and MT2 receptors to promote sleep and exert an effect on circadian rhythms.
A. Ramelteon (Rozarem)
Efficacy/Uses:
Recommended for sleep-onset insomnia
Reduced sleep onset over 5 weeks with no clinically significant changes to sleep architecture (Zammit, 2007)
Sleep onset latency @ 1 week: Placebo (47.9 min), Ramelteon 8mg (32.2 min), Ramelteon 16mg (28.9 min)
Effect size via raw mean difference: 15.7 min Placebo vs. Ramelteon 8mg
Effect size via raw mean difference: 19 min Placebo vs. Ramelteon 16mg
No improvement in quality of sleep (Zammit, 2007)
Take 8mg 30 minutes before bedtime
Adverse effects/potential for abuse
No next morning drowsiness (Zammit, 2007)
No rebound insomnia, no withdrawal due to no affinity to CNS receptors associated with sedation (Zammit, 2007)
Next day performance
Limited data.
Cummings: good for sleep-onset
B. Agomelatine (Valdoxan, Melitor, Thymanax)
Approved in Europe and Australia but was discontinued in the US due to the negative outcome of phase III clinical trials (Parkinson Disease and MDD) and side effects included severe liver toxicity. (Zajecka, 2010, Clinical Trial, 2019, Press Release, 2019).
C. Tasimelteon (Hetlioz) Not used for insomnia
FDA approved for non-24 hour sleep wake disorder (Lockley, 2015).
Non-benzodiazepine hypnotics: Heterocyclics
Mechanism of action: Low dose doxepin blocks H1 receptors to treat insomnia. Has a binding affinity 100 times more towards H1 receptors than any other receptors, which then inhibits the arousal pathway and produces the hypnotic action. Increases concentration of serotonin and norepinephrine at higher doses.
A. Doxepin (Silenor )
Efficacy/Uses
FDA approved for short and long-term insomnia
AASM recommended for sleep maintenance insomnia
3-6mg for insomnia
Lower doses (less than 25mg) produce anti-anxiety and sedative effects
Higher doses (greater than 25mg) produce anti-depressant effects
Sleep onset latency is not clinically significant from placebo (Katwala, 2013)
Total sleep time 26-32 minutes longer compared to placebo (Katwala, 2013)
Statistically significant improvements in wake after sleep onset compared to placebo (Krystal, 2010)
Dr. Puder and Dr. Tomatsu’s recommended first-line medication for many patients due to the lower side effect profile at the 3-6mg dosage
EFFECT SIZE (difference in raw mean from baseline)
Doxepin 1mg Night 1 was -17.1 min; Night 29 was -8.2 min; Night 85 was -12.2 min.
Doxepin 3mg: Night 1 was -34.4 min; Night 29 was -20.3 min; Night 85 was -33.5 min.
Statistically significant improvements in WASO compared to placebo (Krystal, 2011)
EFFECT SIZE (difference in raw mean from baseline)
Doxepin 3mg: Night 1 was -25.4 min; Night 15 was -15.8 min; Night 29 was -13.3 min.
Doxepin 6mg: Night 1 was -30.5 min; Night 15 was -18.8 min; Night 29 was -19.8 min.
Adverse effects/potential for abuse
No physical dependence, withdrawal (Katwala, 2013)
Headache, somnolence/sedation, and nausea (Krystal, 2011)
When doxepin is greater than or equal to 25mg non-selective and are anticholinergic, anti-adrenergic, and potentiate cardiac conduction abnormalities (Katwala, 2013)
Next day performance
Next day severe somnolence and grogginess (Katwala, 2013)
No statistical difference in Digit symbol substitution test (DSST), Symbol copying test (SCT), Subjective alertness and drowsiness (Krystal, 2010)
Off-Label / Over the counter
A. Diphenhydramine
History
Not FDA-approved for insomnia. However, it was included by the FDA as a safe and effective nighttime sleep aid as part of the FDA’s Final Drug Monograph for OTC use
AASM recommends AGAINST using diphenhydramine for the treatment of chronic sleep onset or sleep maintenance insomnia
Two RCTs – significant risk of imprecision and publication bias
Mechanism of action
First generation H1 antagonist with non-specific anticholinergic and sedative effects
Efficacy/Uses
Do not use, but typically 25-50 mg over the counter
Sleep onset latency reduction of 8 min, total sleep time 12 min, No improvement in sleep quality. All were below the threshold of clinical significance thresholds
Not clinically significant difference in the number of awakenings with diphenhydramine vs placebo (Glass, 2008)
Adverse effects/potential for abuse
No rebound effects (Morin, 2005)
Next day performance
No difference in morning-after DSST or MTT from placebo
Sleep diaries, morning-after psychomotor impairment, morning-after memory impairment: Temazepam worse than Diphenhydramine (Glass, 2008)
Diphenhydramine > Placebo for awakenings 1.7 vs. 2.0 (Glass, 2008)
Diphenhydramine better sleep efficiency (total sleep time/total time in bed) and total sleep time but by day 28 no different from placebo (Morin, 2005)
B. Valerian
History
Not FDA-approved for the treatment of insomnia
Not recommended by the AASM
Only one study evaluating valerian for chronic insomnia
Mechanism of action: Binds to the beta subunit of GABA-A receptor (allosterically modulates the receptor)
Efficacy/Uses (Morin, 2005) **Not blinded study**
Typically 2 mg (no more than 3 mg)
Valerian better sleep onset latency compared to placebo (not stat sig) (Morin, 2005)
Subjectively rated that quality of life and insomnia improved at the end of 28 days (Morin, 2005)
Per Dr. Cummings: It is a sedative but due to the lack of control and variation depending on the product, efficacy is unknown
Adverse effects/potential for abuse (Morin, 2005)
No adverse events compared to placebo group, even at high doses
Overall safe with no rebound insomnia (Morin, 2005)
Next day performance
Limited data
C. Melatonin
Biological Melatonin: pineal gland, action on the sleep/wake cycle
Can cross placenta, synchronize fetal biological clock
Synthesis affected by ambient light
Complex interplay between physiological need and environmental cues
Mechanism of Action
Melatonin is a tryptophan derivative that binds to MT1A receptors
Efficacy/Uses
Not FDA-approved for the treatment of insomnia
Not recommended by the AASM
First line recommendation by the AAFP
Multiple RCTs but no meta-analyses were conducted for melatonin in insomnia, except for sleep quality which was clinically insignificant
Not recommended, but studies looked at 2mg nightly
Effect size: Sleep onset was -8.9min for melatonin compared with placebo (Luthringer, 2009).
Total sleep time increased by 2 min for melatonin compared to placebo. Wake after sleep onset was 8.5 min better for placebo compared to melatonin. The confidence interval crossed for all data (Luthringer, 2009).
Per Dr. Cummings: Recommends for patients with OSA due to low side effect profile.
Adverse effects/potential for abuse
No harms reported
Next day performance
Limited data
D. L-tryptophan
Mechanism of action: Tryptophan is hydroxylated to 5-HTP and decarboxylated to 5-HT and melatonin. Increasing blood levels of tryptophan directly increases serotonin and melatonin levels (Hajak, 1991)
Efficacy/Uses
Not FDA-approved for the treatment of insomnia
Not recommended by the AASM
Limited data
Modest decline in TST, decrease in WASO, increase in sleep quality. None met thresholds for clinical significance (Hudson, 2005)
Adverse effects/potential for abuse
Limited and subjective data
Next day performance
Limited and subjective data
E. L-theanine
History
Discovered in 1949 in tea, isolated in 1950 in Kyoto, Japan
Marketed as a “natural alternative to prescription sleep aids”
Mechanism of Action: AMPA receptor antagonist and NMDA receptor agonist. Blocks the reuptake of glutamine and glutamate
Efficacy/Uses
May show some benefit in mice and rat models (Kim, 2018)
Adverse effects/potential for abuse
Found in tea such as green tea→ has caffeine which would potentially counteract effect
Next day performance
Limited data
F. Trazodone
History: Due to concerns with tolerance and dependency with benzos, physicians increasingly began prescribing sedating antidepressants “off-label,” especially trazodone, despite the absence of efficacy. A survey of office-based physician prescribing practices from 1987-1996 revealed a 50% decline in benzo hypnotic prescriptions coinciding with a 150% increase in trazodone prescriptions (Roehrs, 2004).
Mechanism of action
Serotonin (5HT2) antagonist and reuptake inhibitor (SARI)
Has effects on serotonin, noradrenaline, dopamine, acetylcholine, and histamine
Efficacy/Uses
Not FDA-approved for insomnia. Used off-label
AASM recommends physicians DO NOT use this medication, as the potential harms outweigh any perceived benefits
Do not use, but typically 50 mg – 100 mg qHS
Only one study-- compared with placebo, at week 1, a modest reduction in sleep onset latency (10.2 min), a modest increase in total sleep time (21.8 min), and a small reduction in wake after sleep onset (7.7 min). By week 2, effects were not sustained. Subjective sleep quality and the number of awakenings were slightly improved. However, every single one of these measures fell below the clinical significance threshold (Walsh, 1998)
Per Dr. Cummings: Has not found it very helpful. Don’t give it to bipolar patients because it can induce mania/hypomania. It also has alpha antagonist properties that may be dangerous for older adults.
Adverse effects/potential for abuse
Significantly more side effects than the placebo group, with the primary side effects being headache (30% vs 19%) and somnolence (23% vs 8%) (Walsh, 1998)
Not habit forming (Jaffer, 2017)
Side effects: withdrawal--anxiety, agitation, insomnia (Jaffer, 2017)
Next day performance
Not clinically significant short term memory performance, recall, attention, balance, and muscle endurance (Roth, 2012)
G. Mirtazapine
Mechanism of action: Noradrenergic and specific serotonergic antagonist. Blocks a2, 5-HT2, and 5-HT3 receptors. Also has histamine 1 antagonism.
Efficacy/Uses
Not FDA-approved for the treatment of insomnia
Not recommended by the AASM15 mg once daily (up to 45 mg/day)
Statistically significant improvement in sleep onset latency compared to SSRIs/SNRIs in MDD
EFFECT SIZE (difference in raw mean from baseline)
Mirtazapine 15mg-45mg overall had -10.1 minutes compared to SSRIs/SNRIs (Wang, 2013)
Adverse effects/potential for abuse
Contraindicated in those using MAOi
Withdrawal causes insomnia
Overdose can lead to QT prolongation and torsades
Major side effects: discontinuation syndromes, somnolence, appetite increase
Per Dr. Cummings: less likely with lower doses; can stop at 7.5mg without issues
Next day performance
Limited data
H. Hydroxyzine
Mechanism of action: potent and selective H1-receptor inverse agonist
Efficacy/Uses
Not FDA-approved for the treatment of insomnia
Not listed on the AASM guidelines
See diphenhydramine for general antihistamine efficacy in insomnia
Per Dr. Cummings: His personal favorite because it does not have alpha antagonist or anticholinergic properties that trazodone or diphenhydramine may have, respectively.
Often dosed at 25-50mg qHS.
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Acknowledgements:
This article was supported by “Mental Health Education & Research”.