Abstract

Description

Benzodiazepines (BZDs), a form of gamma-aminobutyric acid-A (GABA-A) agonists, belong to a major class of sedative and hypnotic drugs that slow brain and bodily functions by binding to a specific allosteric site (BZD receptor) in the GABA-A receptor complex, increasing GABA’s inhibitory activity in the central nervous system (CNS).⁵ In short, BZDs binding to GABA-A receptors allow for a chloride ion influx that reaches the postsynaptic neuron, creating a slowing of nerve impulses.⁵ This class treats insomnia effectively because BZDs create amnesic and anxiolytic effects, allowing patients to experience shorter times for sleep onset and better sleep maintenance overall.⁵ Of the 3 guidelines, only the 2017 AASM recommends the use of BZDs, namely, triazolam and temazepam. The 2019 VA/DoD guideline weakly recommends against the use of BZD due to the AEs, risk of diversion, and interactions with alcohol or CNS depressants.⁴ The ACP guideline does not fully address the use of BZDs for sleep as many of the studies do not meet the inclusion criteria for review.¹ Although not individually discussed in any of the 3 guidelines, flurazepam, quazepam, and estazolam are additional FDA-approved BZDs for the treatment of insomnia.⁶

Adverse Effects

Commonly reported AEs of BZDs include disinhibition, delirium, fatigue, anterograde amnesia, and depression, especially over long-time use.^5–7 For example, temazepam has a reported incidence rate of 1.3%, 4.8%, and 1.7% for delirium, fatigue, and depression, respectively.⁸ Long-acting BZDs report a larger propensity for daytime sedation and impairment, demonstrating a lower potential for rebound insomnia or tolerance.⁵ In contrast, short-acting agents have less reported daytime sedation and overall incidence of side effects. However, rebound insomnia and tolerance appears to be more frequently reported.

The 2019 American Geriatrics Society (AGS) Beers criteria suggest avoiding BZDs in elderly patients with dementia or cognitive impairment or those at increased risk of falls and fractures as this population has an increased sensitivity to CNS depressants.⁹ Similarly, the 2019 VA/DoD guideline has a weak recommendation against this medication class due to side effects, including impaired daytime function, risks of dependency especially in elderly patients, and possible stigma.⁴ Additionally, in 2016, a large retrospective cohort study conducted in Japan finds that elderly patients who receive at least 180 days of triazolam have an increased risk of developing pneumonia, injuries from falls, and pressure ulcers by 40% (number needed to harm [NNH] = 25), 30% (NNH = 17), and 29% (NNH = 90), respectively.¹⁰ The authors attribute the increased risk of pneumonia to potential impairment of swallowing and immune system functioning. Increased pressure ulcers are attributed to more significant sedation and psychomotor impairment, leading to extended bed confinement.

Description

Zolpidem, eszopiclone, and zaleplon are BZD receptor agonistic modulators or GABA-A agonists also known as “Z-drugs.”¹¹ These agents work by positively modulating the GABA-A receptor complex similar to BZDs but differ in their chemical structure and display minimal anxiolytic effects.¹¹ Moreover, Z-drugs are more selective than BZDs, which affect all BZD receptor subtypes. For example, zolpidem, in contrast to BZDs, displays selective binding to the BZD₁ receptor, which is speculated to be related to the maintenance of sleep stages 3 and 4.¹¹ Zolpidem and eszopiclone share similar pharmacodynamic and pharmacokinetic properties. Zaleplon has a shorter duration of action than zolpidem and eszopiclone, hence, its use for sleep onset insomnia only.¹¹ Z-drugs are found to have a lower risk of tolerance, abuse, dependence, and residual effects when compared with BZDs, displaying similar efficacy in the promotion of sleep.¹¹ All 3 guidelines generally recommended the use of Z-drugs for short-term treatment of chronic insomnia.^1,3,4

Adverse Effects

Despite their increased selectivity and ability to induce normal physiological sleep, Z-drugs still share several AEs common to BZDs.¹¹ The most prominent are daytime drowsiness, headache, dizziness, impaired concentration, confusion, and falls.¹¹ Individually, zolpidem uncommonly causes visual disturbances, whereas eszopiclone use is associated with taste disturbances and xerostomia.^6,11 The 2019 AGS Beers criteria recommends avoiding Z-drug use for more than 3 months in older adults because Z-drugs have similar effects on CNS in older adults as BZDs.⁸ A recent 2019 study by Borchert et al¹² compares 1407 online patient reviews with 5916 cases reported in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). This study finds that amnesia is among the top 10 most reported side effects of Z-drugs with zolpidem particularly standing out.¹² Importantly, in 2019, the US FDA issued a new boxed warning on all Z-drugs about rare but serious instances of complex sleep behaviors, such as sleepwalking and sleep driving that result in serious injury or death.¹³

Description

Approved by the FDA in 2014, suvorexant is the first member of a new class of hypnotic drugs known as dual orexin receptor antagonists (DORAs).¹⁴ A second drug, lemborexant, was FDA approved in 2019 for the treatment of sleep onset and maintenance.¹⁵ The newest member of this class is daridorexant, approved in 2022.⁶ DORA agents act by preventing orexin receptors OX1R and OX2R from being activated by orexins A and B. In patients with narcolepsy, these neuropeptides are found to play a critical role in arousal and promoting wakefulness.¹⁵ This alternative MOA is believed to result in a more favorable side-effect profile compared with GABA-A agonists or BZDs. For example, DORAs appear to promote both rapid eye movement (REM) and non-REM sleep, whereas GABA-A agonists, such as BZDs and Z-drugs, promote only non-REM sleep.^16,17 Of the 3 guidelines, only the 2016 ACP and 2017 AASM recommend suvorexant (Table 2), whereas the 2019 VA/DoD guideline recommends neither for nor against its use.^1,3,4

Adverse Effects

All the dual orexin receptor antagonists carry a warning for use in compromised respiratory function (eg, sleep apnea). Additionally, there is a warning for worsening of depression or suicide, sleep paralysis, hypnagogic or hypnopompic hallucinations, and cataplexy-like symptoms.⁶ Although the side-effect profile of DORAs is still being studied, they display less risk for falls, next-day sedation, and dependence than observed in GABA-A agonists.¹⁷ All DORAs appear to be well-tolerated, but it should be noted that suvorexant, lemborexant, and daridodexant are classified as schedule IV controlled substances with an abuse potential comparable to zolpidem.^18,19 However, in a 2016 crossover study, although the results from the visual analog scale peak effect were generally similar between suvorexant and zolpidem, the overall incidence of the AE of abuse potential was lower with suvorexant (30.6% vs 58.3%). Similarly, incidences of euphoric mood (11.1% vs 19.4%) and visual hallucination (2.8% vs 11.1%) were lower with suvorexant compared with zolpidem, respectively.²⁰

The most common side effects of suvorexant include dose-related somnolence (7%), headache (4%), and dizziness (3%).²¹ Additionally, rare AEs, namely, suicidal ideation, sleep paralysis, and cataplexy, have been reported. Underreported side effects, such as nightmares, have also been observed though the package insert only lists abnormal dreams occurring in 1% of tested patients.²¹ A 2017 case report by Tabata et al²² describes a 72-year-old man with Parkinson disease that experienced vivid, disruptive nightmares after taking suvorexant for 7 weeks.²² His described behavior included yelling, kicking, and pulling his wife’s hair. The vocalizations and abnormal behaviors promptly disappeared after suvorexant cessation.²² Whereas this was the only detailed case report found, it should be noted that the previously described study by Borchert notes that nightmares were the most frequently reported side effects of suvorexant by patients in both online reviews and the FAERS report.¹²

Description

Ramelteon, a melatonin receptor agonist, was approved in 2005 for sleep-onset insomnia.²³ This agent has a selective affinity for melatonin receptors MT1 and MT2 located in the suprachiasmatic nucleus, and they are associated with the regulation of endogenous melatonin. Melatonin activity is found to correlate with the onset of nocturnal sleepiness in the sleep–wake cycle. Compared with exogenous melatonin, ramelteon displays 3 to 5 times the affinity to bind and activate the MT1 and MT2 receptors and has a half-life of 1 to 2.6 hours.²⁴ Ramelteon shows negligible activity at GABA, serotonin (5HT), histamine, and other CNS receptors, resulting in a lack of observed tolerance, dependence, withdrawal, or residual effects.²⁵ Despite notable advantages, the aforementioned Borchert study finds that, in patient reviews, ineffectiveness was the top complaint from those prescribed ramelteon.¹¹ The 3 guidelines have inconsistent recommendations for using ramelteon.^1,3,4

Adverse Effects

Ramelteon is well tolerated with only mild to moderate AEs. The most significant and frequently reported side effects of ramelteon are dizziness (4%), fatigue (3%), and somnolence (3%).²⁵ Only a few case reports were found reporting notable AEs not reported by the manufacturer. A 2013 case report describes a 50-year-old man with a history of chronic alcohol consumption who developed autoimmune hepatitis (AIH) after taking ramelteon 8 mg for 7 weeks. The patient is then reported to have died due to sepsis with autopsy confirmation that the underlying cause was AIH. Due to the temporal relationship between ramelteon initiation and AIH development, authors of the case report propose ramelteon as a possible cause. Alcoholic hepatitis is deemed unlikely based on histologic and laboratory data, and the authors note that more than 4 decades of research suggests melatonin plays a role in the modulation of the immune system.²⁶ Another 2015 case report presents the first instance of nightmares occurring in a patient shortly after initiating ramelteon therapy. It should be noted that both case reports appear to be isolated events, and no other instances are found in the literature searched in this review.²⁷

Description

In the past 30 years, antidepressant use has increased for the treatment of insomnia despite a paucity of efficacy data for many agents.³ Doxepin is a tricyclic antidepressant that strongly binds to histamine-1 (H1) receptors in the CNS, preventing histamine arousal and promoting sedation. Doxepin is selective for H1 at low doses (< 6 mg) and does not inhibit serotonin or norepinephrine reuptake, thus avoiding undesirable AEs, namely, cardiac arrhythmias, hypotension, and seizures seen at higher doses (25 to 150 mg).²⁸

Trazodone, an atypical antidepressant, is widely used off-label for the treatment of insomnia. Its MOA is not fully understood; however, it is known to inhibit serotonin 5-HT2A, H1, and α1 receptors at low doses (< 100 mg). This combined antagonism with different receptors is expected to produce hypnotic effects without triggering the antidepressant effect observed with the simultaneous inhibition of the serotonin transporter and 5-HT2A seen at higher doses (150 to 600 mg).²⁹ Although trazodone is widely used in clinical practice, none of the guidelines recommends its use. This is mainly due to limited evidence supporting its efficacy and lack of data on its AEs. Therefore, trazodone is weakly recommended against use as the harm may outweigh the benefits.^1,3,4

Last, mirtazapine, an atypical antidepressant, works by enhancing the release of norepinephrine and 5‐HT_1A‐mediated serotonergic transmission. It antagonizes adrenergic α₂‐autoreceptors and α₂‐heteroreceptors and blocks 5‐HT₂ and 5‐HT₃ receptors. Low-dose mirtazapine is associated with sedation owing to its H₁ receptor blocking effect. However, in some clinical studies, the sedation was diminished despite dose increases.³⁰ Although it is speculated that there is an inverse dose relationship for sedation associated with mirtazapine, an exploratory analysis from 2019 does not support this theory.³¹ Therefore, more studies are needed in this area. Although mirtazapine is widely used in clinical practice in patients with insomnia, none of the three guidelines address this medication.

Adverse Effects

At low doses indicated for the treatment of insomnia, doxepin is shown to be well-tolerated. AEs reported to occur for more than 2% of patients are somnolence (5%), nausea (4%), and upper respiratory tract infections (2%).³² To date, this review has found no evidence of new or uncommon AEs regarding doxepin use at low doses. Low-dose doxepin is recommended by all 3 guidelines, especially for sleep maintenance.^1,3,4

In contrast, trazodone appears to exhibit more significant side effects, such as somnolence, headaches, orthostatic hypotension, and impaired memory, even at low doses and rare cases of priapism.^33,34 Additionally, trazodone can cause an increase in residual morning sedation and suicidal thoughts, explaining its assignment to the “weak against” category in the VA/DoD guideline and its lack of recommendations in both the 2016 ACP and 2017 AASM guidelines.⁴ A 2017 case report from Santos et al³⁵ describes a 60-year-old man developing distressing visual hallucinations 2 days after starting trazodone 100 mg, which promptly resolved after discontinuation. In 2018, Sarwar et al³⁶ report a case of an elderly patient developing bradykinetic parkinsonism after taking trazodone 100 mg with symptoms completely reversing after withdrawal. Last, in 2020, Pereira et al³⁷ describe the case of a 44-year-old female patient who presented with delirium to the ER after being prescribed trazodone 100 mg. Although the patient was hospitalized, discontinuation of trazodone led to the resolution of symptoms without antipsychotic medication use.

Common side effects of mirtazapine include drowsiness (54%), xerostomia (25%), increased serum cholesterol (15%), increased appetite (17%), constipation (13%), and potential weight gain (12%).^30,38,39 Furthermore, a 2017 case report from Menon et al³⁹ describes an experience of a 21-year-old female taking a 7.5-mg dose of mirtazapine for insomnia. The patient initially took 20 mg of escitalopram but was tapered off over 6 weeks and put on mirtazapine.⁴⁰ While participating in this treatment over a week, the patient developed distressing nightmares after 4 days, and they subsided once she stopped taking mirtazapine and switched to a 50-mg dose of sertraline.⁴⁰ Researchers conclude that the association between the drug and AEs was probable based on the Naranjo adverse drug scale. This finding agrees with the results of the pharmacovigilance report published in 2003 that describes 50 cases of nightmares associated with mirtazapine.⁴¹ Additionally, 2 other case studies by Mathews et al in 2006 and Dang et al in 2009 report this AE.^41–43

Description

Quetiapine is an antipsychotic used at low doses (25 to 100 mg) off-label for insomnia.⁴⁴ This drug affects H1 receptors and α-1 and α-2 receptors causing sedative effects and is known for having the shortest half-life among the second generation antipsychotics.⁴⁴ Similar to trazodone, low-dose quetiapine is not recommended by the 2019 VA/DoD guideline. This is mainly because of the lack of efficacy data and the known harms associated with antipsychotics.⁴ The other 2 guidelines do not address quetiapine.

Adverse Effects

Common AEs of quetiapine include weight gain, increased blood sugar levels, and an increase in low-density lipoprotein cholesterol.^6,44 Notably, extreme AEs can be observed in elderly patients as seen in the 2016 case study by Desforges et al.⁴⁵ In this case study, an 80-year-old man was prescribed 12.5 mg of quetiapine when hospitalized to aid in sleep onset when being treated for E. coli and pyelonephritis.⁴⁵ The patient took the prescribed medication and fell into a comatose state for a 2 and a half days before returning to his precognitive state.⁴⁵ Overall, researchers in the study suggest against quetiapine use and recommend alternative methods/medications for treating insomnia falling in line with the 2017 AASM and 2019 VA/DoD guidelines.^3,4,45

Description

Tiagabine, uncommonly used off-label for treatment of insomnia, is a selective GABA reuptake inhibitor. It increases the GABA availability in the synapses by inhibiting the GAT-1 GABA transporter.⁴⁶ The 2017 AASM guideline recommends against tiagabine use due to lack of evidence and limited information on its AE.³

Adverse Effects

Tiagabine’s side effects include nausea, dizziness, asthenia, tremors, headache, anxiety, and lack of concentration.⁶ In the randomized controlled trial conducted by Walsh et al,⁴⁶ the tolerability of tiagabine 4 and 6 mg was comparable to placebo with the exception of headache.

Description

This section covers medications or supplements that are available without a prescription for sleep promotion although they generally lack robust clinical evidence supporting their efficacy. The most studied of these medications or supplements is exogenous melatonin.⁴⁷ As previously noted when discussing the drug ramelteon, exogenous melatonin acts by activating MT1 and MT2 receptors but with less affinity and a shorter half-life (30 minutes).²³ It is essential to administer melatonin based on an individual’s circadian timing. If not, it may fail to produce the desired effect or may even produce the opposite effect by causing a phase shift in the circadian clock.⁴ The benefits of using melatonin approximately equal its harm.³ However, melatonin use is weakly recommended against by all the 3 guidelines. This is mainly due to insufficient evidence for its efficacy, lack of adequate data on its AEs, poor study design, concerns about purity or contaminants of OTC medications and undesirable circadian consequences if not administered correctly.^1,3,4 Melatonin is well-tolerated with the most commonly reported side effects being headaches (< 1%), somnolence (< 1%), dizziness (< 1%), and nausea (< 1%).^6,48

The FDA-approved OTC antihistamines for short-term treatment of insomnia include diphenhydramine and doxylamine.^6,49 These agents work by binding or blocking the action of histamine in centrally located H1 receptors, causing sedation and sleepiness. Few studies have been conducted to evaluate the efficacy and safety of these agents for insomnia treatment, especially doxylamine.⁴⁷ Diphenhydramine is well-known for its daytime sedation, dizziness, xerostomia, nausea, and nervousness. It has a Beers criteria warning for its use in elderly patients due to increased sensitivity to anticholinergic side effects.⁵⁰ Another factor limiting diphenhydramine’s usefulness for insomnia is quick development of tolerance to its sedating effects (after 3 to 4 days of use). This is consistent with results of a randomized, double-blind crossover study by Richardson et al,⁵¹ in which 15 men received either diphenhydramine 50 mg or a placebo twice a day for 4 days. By the third day, both objective and subjective measures of sleepiness were almost identical between diphenhydramine and the placebo.⁵¹ None of the 3 guidelines recommends the use of diphenhydramine for insomnia even though benefits approximately equal its harm. The main reason behind the recommendation is lack of evidence for its benefit.^1,3,4 Patients can expect anticholinergic side effects, such as dry eyes, dry mouth, constipation, and confusion.^3,6

L-tryptophan is an essential amino acid and serotonin precursor in many proteins, including red meat, poultry, eggs, and dairy products.⁵² L-tryptophan penetrates the blood-brain barrier and is converted into serotonin, which accounts for its ability to cause sedation with minimal impairment in performance.⁵³ Few studies have analyzed L-tryptophan’s efficacy and safety for insomnia treatment, and no significant side effects have been reported.⁵⁴ However, L-tryptophan can increase the risk of serotonin syndrome when used with selective serotonin reuptake inhibitors and other serotonergic drugs.^55,56 L-tryptophan was only addressed in the 2017 AASM guideline and was not recommended for general use.³

Valerian (valerian officinalis) is an herbal product often used for insomnia treatment. Valerian root has sedative properties believed to stimulate GABA release from nerve endings and prevent GABA reuptake back into nerve cells.⁵⁷ Furthermore, valeric acid, a constituent of valerian oil, inhibits GABA breakdown from taking place.⁵⁸ Overall, the data regarding valerian is conflicting with some studies showing efficacy, whereas others found no significant effect.⁵⁸ Notable side effects of valerian include headache, mental dullness, dizziness, and depression.⁵⁹ Valerian is implicated in a few cases of mild to moderate, reversible hepatotoxicity with typical onset of 3 to 12 weeks within 2 to 4 weeks postdiscontinuation.^60–62 Of note, usually the case reports associated with valerian involve other botanical products, such as skullcap and black cohosh, which can serve as confounders.⁶⁰ The recent 2019 VA/DoD guideline has a weak recommendation against the use of valerian, mainly due to lack of evidence to support its efficacy, concerns about the purity of herbal products, and rare cases of hepatotoxicity.⁴

Chamomile (Matricaria recutita) and kava (Piper methysticum) are both herbal products used for insomnia. Their MOA is unknown; however, they are both speculated to work on the GABA receptors.^63,64 Chamomile and kava were only addressed in the 2019 VA/DoD guideline. Although it has no known AE, chamomile use is weakly recommended against due to concerns about purity in herbal supplements, low-quality evidence, and no proven clinical efficacy. On the contrary, kava use is strongly recommended against mainly due to its lack of efficacy, low-quality studies, and potential risk of fatal liver toxicity.⁴