A variety of sleeping pills are used for insomnia, including both over-the-counter (OTC) and prescription agents. Many of these sleep aids are not approved by the US Food and Drug Administration (FDA) for the treatment of insomnia.
Sleep medicine has made significant advances in the treatment of insomnia. More focused interventions on perpetuating factors of sleep problems are achieved with cognitive-behavioral therapy (CBT) and sleep medications.
A chronic symptom of insomnia can reflect a primary disorder or may be comorbid with medical, psychiatric and circadian rhythm disorders.
Transient insomnia results from acute stress, illness, jet lag or another life-style factors.
Sleeping pills from many different classes may be used as hypnotics, with the most common being:
- Benzodiazepines (alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, temazepam, triazolam) and nonbenzodiazepine gamma-aminobutyric acid (GABA) agonists (zolpidem, zaleplon, and eszopiclone)
- Other drugs
- Sedating antidepressants: Triciclic antidepressants, Trazodone and Nefazodone, Mirtazapine
- Melatonin and Melatonin receptor agonists (Ramelteon, Agomelatine)
- Gabapentin and Pregabalin
- Sedative Antipsychotics (Olanzapine, Quetiapine)
It is difficult to chose the best sleeping pills for treatment of insomnia due to the complexity of neurochemical regulation of sleep–wake stages and the complexity of insomnia itself, which is manifested by different symptoms and is likely to have multiple causes.
There are a number of alternative, effective nonpharmacologic therapies that can help patients who can’t sleep at night.
A patient seeking help for sleep disturbance may be suffering from unrecognized depression, and if it is present appropriate antidepressant therapy should be initiated.
Sleep deprivation is a major health problem. If insomnia can’t be treated using other therapeutic strategies, the use of sleeping pills might be beneficial.
A model of sleep wake regulation relevant to sleeping pills
Arousal states are generated by the ascending activity of:
- monoaminergic brainstem nuclei
- histaminergic nuclei in the posterior hypothalamus
- cholinergic nuclei of the pontine tegmentum and basal forebrain
Activity of these arousal systems is:
- promoted by input from orexin (hypocretin) neurons in the hypothalamus during wakefulness
- inhibited by gamma-aminobutyric acid (GABA) in the hypothalamus at the onset of sleep
Sleeping pills achieve their effects through different actions on different components of the sleep–wake regulatory systems:
- Benzodiazepine receptor agonists directly affect the sleep–wake state-switching system.
- Sedating antidepressant and antipsychotic medications affect the arousal systems through their activity on monoaminergic systems.
- Antihistamines antagonize histamine receptors in the hypothalamus and cortex
- Melatonin and melatonin receptor agonists influence the “wake signal” from the circadian timing system through their effects on MT 1 and MT 2 receptors.
Benzodiazepines, the only sleeping pills with a clearly defined risk and benefit
Benzodiazepine receptor agonists are categorized according to their common mechanism of action – enhancing the inhibitory effects of GABA – the neurotransmitter that is most important for promoting sleep. This is based on a stereospecific binding to a specific recognition site located on the benzodiazepine receptor (GABA A –benzodiazepine receptor complex).
The actual binding site for benzodiazepines is located at the junction of the alpha and gamma subunits. Each of the subunits has multiple isoforms. There are six alpha, three beta, and three gamma isoforms.
Alpha-1 subunit mediates both sedation and memory effects of agonists. Therefore it will be unlikely to develop a hypnotic that acts at this site and that will have sleep-promoting, but not amnesic, properties.
There are two particular combinations of isoforms that are noted Type-I (alpha 1, beta 2, gamma 2) and Type-II (alpha 3, beta 2, gamma 2) configurations.
Type-1 configuration is the most common type representing roughly 40% of GABA A receptors. Zolpidem and Zaleplon bind with relatively greater specificity to the Type-I receptor.
Most traditional benzodiazepine hypnotics bind to both types.
After the benzodiazepine agonist binds to its specific site, the flow of negatively charged chloride ions into the neuron is enhanced which changes the postsynaptic membrane potential and alters input resistance such that the postsynaptic neuron is less likely to achieve an action potential.
This inhibitory mechanism is a very potent one in the central nervous system (CNS) because the GABA A receptor is the most widespread receptor mechanism in inhibitory synapses.
Other substances with similar effects have a different mechanism of action:
- ethanol has profound effects on chloride channel function
- barbiturates bind to a distinct site and cause chloride channels to open for prolonged periods whereas benzodiazepines may increase the frequency of opening.
The receptor complex also mediates the anxiolytic, muscle relaxant and anticonvulsant effects of benzodiazepines.
Among their actions, hypnotics alter the perception of sleep and wakefulness.
Usually, good sleepers, when experimentally awakened early in stage 2 sleep report that they had been asleep, while insomniacs tend to report that they had been awake.
Studies show that after administration of benzodiazepines insomniacs were more likely to report that they had been asleep compared to when they were given placebo. Hypnotics may correct a misperception of sleep in some poor sleepers, such that their experience of whether they are awake or asleep becomes more like that of good sleepers.
Their own metabolism is inhibited by cimetidine and some steroids, and it may be accelerated in people who smoke.
The most clinically relevant differences among benzodiazepines are associated with duration of drug action, reflected by elimination half-life. Other factors that also influence duration of action are drug dose and formulation (e.g., extended release, sublingual absorption)
All of the benzodiazepines hypnotics reduce sleep latency, which reflects a rapid onset of the hypnotic effect. Most of them increase total sleep time. The exception is Zaleplon, which does not reliably increase total sleep time.
Investigations assessing number of awakenings or waking after sleep onset find that the longer the drug’s duration of action (i.e., the longer the half-life or the higher the dose, or both), the more likely it is that the drug will show efficacy on these measures.
At supratherapeutic doses sleep latency shows a relatively flat dose-response curve. Waking after sleep onset and total sleep time show more pronounced dose-response curves.
The longer-acting agents have mild respiratory depressant properties, which are much less evident in shorter-acting agents. Even for the longer-acting agents, however, respiratory depression is much milder than those of older nonbenzodiazepines such as the barbiturates.
In practical terms there is no significant effect in patients with normal ventilation. It may become evident when there is preexisting compromised respiration such as in patients with chronic obstructive pulmonary disease or persons with sleep-disordered breathing.
The newer nonbenzodiazepines (zaleplon, zolpidem, zopiclone) appear to have very few respiratory effects.
Zaleplon has few effects on measures of sleep-disturbed respiration in patients with mild-to-moderate obstructive sleep apnea on continuous positive air pressure.
Zolpidem has no respiratory depressant properties up to doses of 10 mg and exhibit very mild inhibition of mean inspiratory drive at 20 mg.
Zopiclone in therapeutic doses has no significant effect on sleep-disordered breathing in patients with chronic obstructive pulmonary disease.
Effects on sleep
Studies of benzodiazepines indicate that sleep latency and wake time after sleep onset are reduced, and total sleep time is increased. In contrast to the very potent REM suppression induced by barbiturates, REM sleep time is reduced mildly.
In contrast to the barbiturates, benzodiazepines are potent suppressors of slow-wave sleep.
Zolpidem has very mild effects on REM sleep and does not alter slow-wave sleep.
Studies indicate that following eszopiclone administration, there is a more rapid decline in metabolic activity in the midbrain and pontine reticular formation during the transition from waking to NREM sleep which can be translated as a decrease of the hyperarousal often seen in insomnia.
One of the few distinctions among the benzodiazepines is that the longer-acting agents such as flurazepam may not have as much effectiveness on sleep latency until the second night of administration.
The dependence potential of currently available hypnotics is minimal. Ramelteon has been found to have no dependence-producing properties in standard measures.
In general, adverse reactions to sleeping pills are relatively rare and mild.
The adverse events associated with benzodiazepines are related to:
- peak plasma concentration which is highly associated with dose (amnesia, ataxia)
- duration of action which is primarily determined by elimination half-life and dose (daytime hangover)
Unlike older hypnotics such as the barbiturates, the hypnotic benzodiazepines are relatively safe in overdose when taken alone by a medically healthy individual. They may become toxic when taken in combination with other central nervous system depressants such as alcohol.
Tolerance is defined as a reduction of a drug’s effect with repeated administration of a constant dose, or the need to increase the dose to sustain a specific level of effect.
In rigorous polysomnographic studies, zolpidem 10 mg and zaleplon 10 mg were shown to retain efficacy for 5 weeks of nightly use and also eszopiclone which showed continued hypnotic efficacy for 6 months of nightly use.
Residual sedation is merely a prolongation of the hypnotic effect of the drug into the wake period. The results are: sleepiness, drowsy feelings and impairment in driving and psychomotor performance. The likelihood of residual sedation is determined by the duration of drug activity, which in turn is determined by the elimination half-life and the dose of the drug.
Amnestic effect also known as anterograde amnesia is another side effect that is related to the sedative effects of hypnotics. Anterograde amnesia is memory failure for information presented after administration of the drug. It is associated with all sedatives, including all the benzodiazepines, alcohol, and barbiturates. Higher doses, drug taken in combination with another CNS depressant drug or alcohol, or drug taken during a period of sleep deprivation are associated with both a greater degree of amnesia and a higher prevalence of amnestic events. Sleep itself has amnestic effects. The promotion of rapid sleep onset as well as a direct drug effect combine to producen the risk of amnesia.
Rebound insomnia, the most commonly discontinuation effect of benzodiazepines hypnotics, is defined as a worsening of sleep relative to the patient’s status before starting treatment.
- it only lasts for 1 or 2 nights after the hypnotic is discontinued
- it can occur even after 1 nights’ hypnotic use
- it does not increase in severity with the number of repeated nights of use, at least within the time frame of a few weeks of nightly use
- it is more likely to occur after high doses of short- and intermediate-acting benzodiazepines
- it does not occur with long-acting drugs because of the gradual decline in plasma concentration that is inherent in the pharmacology of such drugs
- it can also be minimized with short- and intermediate-acting drugs by gradually tapering the dose over a few nights. A reduction of one clinical dose per week is usually recommended. Rebound can be avoided by using the lowest effective dose.
One must differentiate rebound insomnia from recrudescence.
Recrudescence is a return of symptoms to pretreatment level which should be expected because the benzodiazepines manage the symptoms, and hence drug discontinuation is associated with return of symptoms.
Also, there is a difference between rebound insomnia and withdrawal syndrome which is the appearance of new symptoms (not present before treatment) that are unpleasant and generally last a few days to a few weeks rather than 1 or 2 nights. Withdrawal syndrome is associated with long-term use and can occur with clinical doses.
Somnambulism is believed to be associated with incomplete arousal from sleep. It has been reported with zolpidem and zaleplon. These episodes of somnambulism have occurred in persons taking two to three times the clinical doses of the drug or in those who have a prior history of somnambulism or have experienced prior traumatic head injury.
Zolpidem-associated somnambulism has also been reported in combination with antidepressant medications and alcohol.
Alcohol and sleep deprivation also produce partial arousals and increase the likelihood of a somnambulistic event.
Sleep-related eating disorder might have a common pathophysiology with somnambulism.
This phenomena is caused by excessive sleep drive or hypnotic activity which can occur as a result of:
- high doses
- clinical doses in vulnerable persons (those who have a past history of sleep disorders or brain injury)
- the combination of clinical or high doses with the prior consumption of alcohol
- the combination of clinical or high doses with prior sleep deprivation caused by stress or illness,
Zolpidem was reported to exacerbate sleep-related eating disorder and in several cases to induce it de novo when doses greater than 10 mg were used, and in other cases when sedating antidepressants were administered simultaneously. Sleep-related eating disorder also has been reported with triazolam.
Hypnotic therapy should be considered for insomnia when the patient is significantly distressed by the presence or possibility of disturbed sleep.
The failure of insomnia to remit after 7–10 days of treatment may indicate the presence of a primary psychiatric or medical illness that should be evaluated. Long-term use of hypnotics is an irrational and dangerous medical practice.
Taking different benzodiazepines together is not indicated because they antagonize each other’s effect (competition for the receptor), the result being no effect at all.
Benzodiazepines are the only medications with a clearly defined risk and benefit by dose for use for insomnia. This fact is also sustained by The 2005 National Institutes of Health (NIH) state of the science report on the management of chronic insomnia. For most patients with insomnia, pharmacotherapy should be initiated with a benzodiazepine at the lowest effective dose for the shortest period of time.
Sleeping pills can be prescribed to be taken:
- on a predetermined intermittent schedule (e.g., every third night)
- as needed
- only when the patient has the opportunity to stay in bed 7 to 8 hours. Only zaleplon makes an exception to this rule. It has been evaluated in middle-of-the-night dosing protocols (medication is administered with 5 hours or less of time in bed remaining) and been found to improve sleep in the remaining time without residual effects the next morning. If nightly sleep medication use is not desirable, patients can be instructed to attempt sleep without it. If they don’t succeed, they may take the sleep aids later, provided there are 4 to 5 hours remaining before rising.
The primary contraindications are concomitant illnesses, such as:
- advanced liver disease
- obstructive sleep apnea because all sedative medications have the potential to worsen sleep apnea by blunting arousal from sleep
- substance abuse disorder
Pharmacotherapy for insomnia during pregnancy is contraindicated due to the teratogenic effects.
The “Z Drugs” (zolpidem, zaleplon, zopiclone, eszopiclone)
Their clinical effects are similar to those of benzodiazepines.
Zolpidem was the first of the “Z drugs”. It has a relative selectivity for the Type-I GABA A –benzodiazepine receptor and also a lower risk of dependence than the benzodiazepines due to less affinity for the alpha-2 subtype, which is related to abuse potential. It absorbs quickly after oral adminstration. Absorption is slightly decreased when taken on a full stomach. In the United States it is also marketed as a coated two-layer tablet, in which the inner layer has a more extended release time (Ambien CR).
Zopiclone, which is on the market in Europe and Asia but not the United States, acts at the GABA A –benzodiazepine receptor complex, but possibly at a different binding domain or by producing different conformational changes than the benzodiazepines.
Eszopiclone, the S-isomer of racemic zopiclone, is marketed in the United States as Lunesta. It has effectiveness without tolerance for at least 6 months and is the first drug in the United States that has no limitation on duration of administration by the FDA.
Zaleplon is recommended to be administered immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. In the latter case, it should be taken at least 4 hours before time of arising to avoid any possible memory difficulties.
Other drugs used as sleeping pills
Various sleeping pills other than benzodiazepine receptor agonists are used as hypnotics. These include drugs originally developed as antidepressants, anticonvulsants, and antipsychotics, hormones and other “natural” substances and newer drugs developed specifically to treat insomnia.
Clinical circumstances when non-benzodiazepines are preferred over benzodiazepines:
- nonresponse to BzRAs
- intolerance of BzRAs
- allergy-associated sleep disturbance
- the treatment of insomnia in substance abusers
- insomnia occurring with psychosis
- insomnia occurring with mania or hypomania
- insomnia occurring with depression where single-agent therapy is desired
- insomnia occurring with chronic pain where single-agent therapy is desired
Sedating antidepressants, the most commonly prescribed sleep aids
These include the tricyclic antidepressants doxepin, trimipramine, and amitriptyline as well as trazodone and mirtazapine.
Trazodone was the most commonly prescribed sleep aid to treat insomnia in 1996. Trazodone and other antidepressants continue to be either the first or second most commonly prescribed sleeping pills in the United States.
Tricyclic antidepressants used as sleeping pills
- at usual doses drug blood levels and metabolism are proportional to dose. At higher doses, metabolic enzymes can become saturated, leading to higher blood levels than predicted by dose alone.
- drugs that increase metabolic clearance and lead to reduced plasmatic TCA levels: barbiturates and tamoxifen
- drugs that reduce metabolic clearance and lead to increased plasmatic TCA levels: grapefruit juice, antipsychotic drugs, methylphenidate, fluoxetine, paroxetine, cimetidine, diltiazem
- age is associated with decreased metabolic clearance by CYP3A4, decreased renal clearance and altered hepatic blood flow
- they do not worsen sleep apnea and may have a small beneficial effect
- the acute effects of TCAs on sleep in depression are maintained during 1 to 3 years of maintenance treatment.
- peripheral alpha 1 – and alpha 2 -adrenergic receptors, which accounts for their cardiovascular effects
- M 1 muscarinic cholinergic receptors
- H 1 histamine receptors.
There are no data indicating that an antidepressant effect occurs with the dosages of these agents that are generally used to treat insomnia. A therapeutic effect on depression might be seen when they are combined with a nonsedating antidepressant (e.g., selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor).
Tricyclic antidepressants have been used in the treatment of anxiety and chronic pain and may be useful for treating sleep problems associated with these conditions. They are also a possible option for treating the sleep difficulties of substance abusers because they lack abuse potential.
Amitriptyline and doxepin inhibit both serotonin and norepinephrine reuptake transporters which results in an enhancement of these neurotransmitters effects in the CNS. Trimipramine has minimal reuptake effects.
Trimipramine dosed from 50 to 200 mg has been evaluated in primary insomnia. It improves sleep quality and sleep efficiency, though no effect on sleep-onset latency or sleep time was observed.
Doxepin has been evaluated at a dosage of 25 to 50 mg and found to improve sleep quality and reported daytime well-being, as well as polysomnographic indices of sleep onset and maintenance. Because doxepin’s predominant pharmacologic effect is the blockade of H 1 histamine receptors, as the dosage is decreased, doxepin becomes an agent with increasingly specific H 1 antagonist effects. Therefore it has also been evaluated in insomnia patients at dosages of 3 to 6 mg and approved by the FDA for the treatment of insomnia characterized by sleep maintenance difficulty in March, 2010. Other sedating antidepressants have not been approved for this indication.
The studies carried out with doxepin 1 to 6 mg have evidence of efficacy in indices of sleep onset and maintenance of sleep. Moreover, the therapeutic effects are largest in the last third of the night, and of particular note they are greatest in the last hour (hour 8) of the night.
A big advantage is that no daytime somnolence was noted as an adverse effect despite the relatively long half-life of this agent. The absence of daytime impairment with doxepin 1 to 6 mg suggests that an increase in wake-promoting neurotransmitter activity occurs after waking that counteracts the H 1 antagonism.
It also has a number of other effects, including antagonism at alpha 1 adrenoreceptors and muscarinic cholinergic receptors, and binding to serotonin 2a and 2c receptor subtypes.
Doxepin is a more potent antihistamine than many drugs marketed as antihistamines (e.g. diphenhydramine). It is relatively selective for H 1 antagonism relative to serotonergic, adrenergic, and cholinergic effects. Also, it may be useful in patients who have insomnia occurring in conjunction with allergies.
Amitriptyline is the most anticholinergic of all antidepressants.
The side effects of the tricyclic antidepressants derive from their blockade of H 1 histaminergic, M 1 muscarinic cholinergic, serotoninergic (5-HT 2 ) and α 1 and α 2 adrenergic receptors.
Anticholinergic side effects of doxepin and amitriptyline include dry mouth, increased perspiration, constipation, and urinary retention. More serious effects which are dose related include precipitation of ocular crises in patients with narrow-angle glaucoma, seizures, and anticholinergic delirium.
Side effects related to antihistaminic properties include sedation and weight gain.
In dosages of 1, 3 and 6 mg, doxepin is not associated with anticholinergic effects, significant weight gain, daytime impairment or sedation.
Side effects related to alpha 1 antagonism include orthostatic hypotension with attendant risks of lightheadedness, syncope, and falls. TCAs typically increase heart rate.
They also slow cardiac electrical conduction due to type I antiarrhythmic effects, which can lead to prolongation of the QRS duration and PR and QT intervals and heart block.
TCA overdose lethality is largely due to cardiovascular toxicity, which can occur at doses as low as 10 times the therapeutic antidepressant daily dose.
TCAs have no effect on cardiac contractility, and they can suppress atrial and ventricular ectopy.
Rebound insomnia, indicated by decreased sleep time and sleep efficiency, may occur on discontinuation of sedating TCAs.
Relative contraindications to the use of tricyclic antidepressants:
- risks of cardiac arrhythmias
- patients with a history of myocardial infarction or ischemia
- seizure disorder
- orthostatic hypotension
- significant liver disease
- closed-angle glaucoma
- decreased gastrointestinal motility
- urinary retention
- patients with bipolar disorder because of the increased risk of precipitating mania.
The risks and associated relative contraindications of these agents are dose related and might not be relevant in the lower dosages often used to treat insomnia.
Trazodone and Nefazodone as sleep medications
Trazodone is generally used at a dosage of 200 to 600 mg in the treatment of depression, but the dosage used to treat insomnia typically ranges from 25 to 150 mg.
With a T max of 1 to 2 hours and a T 1/2 of 7 to 15 hours, trazodone has therapeutic effects on initiating and maintaining sleep.
The major metabolic pathway for trazodone is N-dealkylation to produce m-chlorophenylpiperazine (mCPP), an active metabolite that possesses serotonergic activity.
Trazodone’s mechanism of action:
- it is a relatively weak but specific inhibitor of the serotonin reuptake transporter with minimal affinity for norepinephrine or dopamine reuptake
- it also inhibits serotonin 5-HT 1A , 5-HT 1C , and 5-HT 2 receptors
- it has essentially no affinity for M 1 receptors, but it does have moderate H 1 histamine receptor antagonism
- it is a relatively weak antagonist of alpha 2 -adrenergic receptors and a somewhat more potent antagonist of alpha 1 receptors.
Studies demonstrate that trazodone is safe and effective in patients with depression who had insomnia while being treated with fluoxetine or bupropion.
Trazodone is unlikely to have significant antidepressant effects when used as monotherapy in the dosing range generally used to treat insomnia (50 to 150 mg), though whether it has antidepressant effects when used in combination with other antidepressants is unknown.
Significant improvement in sleep efficiency and awakenings has also been found in abstinent alcoholics.
Side effects include: sedation, headache, dizziness, dry mouth, blurred vision and orthostatic hypotension.
It can also have antihistaminic effects such as weight gain.
Unlike TCAs, trazodone does not have anticholinergic side effects.
Case reports suggest a potential for ventricular tachyarrhythmias.
Some patients who take trazodone and have relatively diminished capacity to metabolize mCPP due to genetic or other factors are likely to experience anxiety or insomnia.
Priapism, a painful sustained erection, is a relatively uncommon side effect of trazodone that can require surgical intervention and can lead to impotence. The risk can occur even at low doses and appears to be greatest early in the course of treatment. Trazodone should be administered judiciously in men due to this risk. The incidence of abnormal erections during trazodone treatment is approximately 1 per 6000 male patients treated.
Individuals who are “poor metabolizers” through CYP2D6 or who are taking inhibitors of CYP2D6, such as fluoxetine can show increased side effects following treatment with trazodone.
Trazodone should be used with caution in those:
- at risk for falls because of the risk of orthostatic hypotension
- with bipolar disorder because of the increased risk of precipitating mania
A relative contraindication is significant liver or kidney disease.
The metabolite of trazodone (mCPP) can contribute to the development of the “serotonin syndrome” when this drug is used in combination with other serotonergic drugs.
The serotonin syndrome includes symptoms of confusion or delirium, restlessness similar to akathisia, muscle irritability, hyperreflexia, and autonomic instability including hypotension.
Nefazodone is not recommended for the treatment of insomnia because of potential hepatotoxicity. Unfortunately, in some cases can lead to fulminant hepatic failure and death. The reported rate of life-threatening liver failure is estimated at 1 case per 250,000 to 300,000 patient-years of exposure. This risk has led to withdrawal of nefazodone from the market in some countries. In overdose, nefazodone has not been associated with fatal toxicity.
Effects on Human Sleep
Sedation, reported by more than 40% of patients is a common effect of trazodone in the treatment of depression.
A study of sustained-release trazodone versus sertraline showed greater improvement in sleep disturbances with trazodone.
About half of the published studies show improvements in sleep latency, total sleep time, and sleep efficiency. Trazodone improved sleep in older controls, in patients with depression (including depressed patients concurrently treated with selective serotonin reuptake inhibitors) and in abstinent alcohol-dependent patients.
Unlike most TCAs, trazodone has little effect on the amount of REM sleep (studies show no significant change or a small decrease) and is also associated with increased stage 3/4 NREM sleep. Although no information has been published about its long-term effects on sleep, rebound insomnia has been noted on discontinuation after several weeks of use.
The magnitude of effects with trazodone (50 mg) in primary insomnia is similar to that for zolpidem (10 mg).
Nefazodone is less consistently sedating than trazodone. A series of studies in depressed patients comparing nefazodone and fluoxetine showed that both drugs improved subjective sleep disturbance, but nefazodone had a significantly greater effect.
Nefazodone shows no change in sleep latency and appears to have less potent effects on either sleep continuity or slow-wave sleep than trazodone has.
Mirtazapine – an effective medication for insomnia and depression
Mirtazapine is FDA approved for the treatment of major depression in dosages of 7.5 to 45 mg. The dosages generally used to treat insomnia are 7.5 to 30 mg.
The sedating effects diminish in dosages greater than 30 mg due to increasing adrenergic effects.
The T max of this agent is 15 minutes to 2 hours, and the T ½ is 20 to 40 hours.
Metabolic clearance is reduced in older adults, women and in those with liver disease. Mirtazapine blood levels are decreased by medications such as carbamazepine that increase metabolic clearance and increased by medications such as fluoxetine that decrease metabolic clearance.
The antidepressant, sleep enhancing and adverse effects of this agent derive from antagonism of:
- adrenergic (α 1 and α 2 )
- serotoninergic (5-HT 2 and 5-HT 3 )
- histaminergic (H 1 ) receptors
Mirtazapine is a very weak inhibitor of noradrenergic reuptake and has no effect on serotonin reuptake. It increases serotonergic and noradrenergic neurotransmission through blockade of alpha 2 autoreceptors and heteroreceptors.
Mirtazapine decreases sleep latency, awakenings, and stage 1 NREM sleep and increases stage ¾, sleep efficiency and sleep time. Although it is potentially promising, mirtazapine has not yet been adequately evaluated as a hypnotic.
Related to its antihistaminic properties, mirtazapine is associated with:
- increased appetite
- weight gain
- dry mouth
Clinical observations suggest that mirtazapine may be less sedating at doses above 30 mg per day than at lower doses. This is related to greater noradrenergic effects relative to antihistaminic and serotonergic effects at lower doses.
Mirtazapine is not associated with cardiac or sexual adverse effects. Also, it has not been associated with abuse potential, serious toxicity or death in overdose.
This agent should be considered in patients who have insomnia comorbid with sleep-disordered breathing because mirtazapine might decrease the apnea–hypopnea index in those with significant sleep-disordered breathing.
It should be used with caution in patients with bipolar disorder because of the risk of precipitating mania and in those with obesity, liver disease, and kidney disease.
Sleep-promoting medications -Melatonin and Melatonin Receptor Agonists
Melatonin is a hormone endogenously synthesized from serotonin and produced in the pineal gland, retina, and intestinal tract. The release of this hormone occurs during the period of darkness and has sleep-enhancing effect. Melatonin production is acutely suppressed by light acting on the retina. Administration of this hormone as a sleep aid has circadian rhythm modifying effects.
Pineal melatonin production is stimulated by the noradrenergic sympathetic nervous system. Specifically, beta 1 stimulation with alpha 1 amplification leads to increased availability of N-acetyltransferase, the rate-limiting enzyme in melatonin biosynthesis. Hence, beta- and alpha-adrenergic antagonists may affect melatonin synthesis (e.g. prazosin, doxazosin, tamsulosin, silodosin,alfuzosin, terazosin, and other agents used to reduce hypertension such as metoprolol, bisoprolol, nebivolol, atenolol etc.)
There are three subtypes of melatonin receptors. MT 1 and MT 2 receptor subtypes are most prevalent in the suprachiasmatic nucleus and retina and related to phase-shifting effects of melatonin. Melatonin receptors are also found in reproductive organs, immune cells, and vasculature, where they can mediate both vasoconstriction and vasodilation.
Mechanism of action: binding of agonists to the melatonin type I receptor decreases the waking signal from the suprachiasmatic nucleus.
Sleep-promoting effects of agonists at melatonin receptors are at least in part GABAergic. Studies show that melatonin administration raises GABA concentrations in the rat hypothalamus, as well as 3H-diazepam binding in the forebrain. Similarly, decreases in motor activity produced by melatonin in the hamster are prevented by the benzodiazepine receptor blocker flumazenil.
After oral administration, melatonin is rapidly absorbed, with peak levels occurring in about 20 to 30 minutes. It has a 40- to 60-minute elimination half-life. Therapeutic effects might not be manifest for as long as 3 hours after dosing despite achieving maximal serum concentration in approximately 30 minutes. When it is formulated with absorption-retarding binders, systemic availability can be prolonged to mimic the normal period of nocturnal secretion. Melatonin is secreted in breast milk.
Studies have shown that melatonin tends to have a therapeutic effect on sleep onset that is more consistent than its effects on the ability to stay asleep or on the duration of sleep. Therefore it has primary use in addressing problems of sleep onset.
Paradoxically, melatonin acts as a hypnotic in situations of low homeostatic drive for sleep (e.g., during the daytime period of low endogenous secretion).
It has not been well established if it is safe to administer melatonin to children, those with Alzheimer’s dementia, and children with neurodevelopmental disorders.
Studies suggest that melatonin regulates reproductive function in both males and females. Higher melatonin levels may be associated with reversible inhibition of spermatogenesis and ovulation. Those who are trying to conceive should avoid taking melatonin.
The risks of protracted melatonin consumption remain unknown. The most common side effect reported is headache. Acutely, increased sleepiness and fatigue might contribute to the loss of vigilance in critical work situations. Melatonin is nonaddicting.
Synthetic melatonin receptor agonists have been developed. These are Ramelteon and Agomelatine, a serotonergic-melatonergic antidepressant.
Ramelteon has no dependence-producing effects. In the United States, it is not a DEA-restricted drug. It is approved by the FDA with an indicated use of treatment of sleep-onset difficulty.
Ramelteon is rapidly absorbed, with time to maximal concentration of 0.75 to 1 hour and elimination half-life of 2.5 hours.
This agent is a selective, high-affinity MT 1 and MT 2 melatonin receptor agonist. It has negligible affinity for the GABA A , dopamine, serotonin, or muscarinic cholinergic receptors.
Ramelteon is associated with:
- reduced sleep latency
- increased sleep time
- reduced slow-wave sleep
- little effect on wakefulness after sleep onset or other sleep continuity measures.
Ramelteon, like melatonin, has no clear dose-response relationship. A therapeutic dosage of 8 mg and timing of dosing 30 minutes before bedtime has been established.
There is no evidence for tolerance developing with this medication in studies as long as 5 weeks. Elevations of prolactin have been noted with ramelteon in women receiving 6 months of nightly treatment with 16 mg. Although statistically significant, this fact is not clinically significant and is not a matter of concern.
Several studies show that ramelteon does not exacerbate breathing problems when used in patients with sleep apnea and mild to moderate chronic obstructive pulmonary disease.
Ramelteon is relatively free of contraindications. The only relative contraindication to use is severe liver failure.
The most common side effects reported with ramelteon include fatigue, somnolence, headache, dizziness, and nausea. Rebound insomnia has not been observed, and there is no evidence for abuse potential.
Agomelatine is an antidepressant with both melatonin MT 1 and MT 2 agonist and serotonin 5-HT 2C antagonist properties which also has effects on sleep and circadian rhythms.
A study of agomelatine administration in evening hours to healthy elderly men showed phase advances in circadian rhythms of body temperature and cortisol.
A 6-week study of depressed patients shows that agomelatine is associated with improved subjective measures of sleep latency and sleep quality, decreased wakefulness after sleep onset, and increased sleep efficiency and slow-wave sleep.
Antihistamines – the most frequently used over-the-counter sleeping pills
Most OTC sleeping pills are first-generation antihistamines that cross the blood–brain barrier. Of these, the agents most commonly used to treat insomnia are diphenhydramine (the prototype of this class) and doxylamine.
Their common quality is reversible inhibition of the histamine-1 receptor. They also possess to varying degrees other properties including anticholinergic effects similar to those of atropine.
Second-generation nonsedating antihistamine drugs are used for treatment of allergic reactions and are not used for the treatment of insomnia. The “nonsedating” H 1 antagonists have very little CNS effect because of their inability to penetrate the blood–brain barrier.
Tolerance to daytime sleepiness appears to develop rapidly, in about 4 days.
Antihistamines are divided clinically into two groups on the basis of their sedative potential. First-generation agents include:
Most first-generation antihistamines, including diphenhydramine, have 4- to 6-hour durations of action. Other specific agents, such as hydroxyzine and meclizine, may last for up to 24 hours. Diphenhydramine has an elimination half-life of 4 to 8 hours.
Mechanism of action
In the central nervous system, histamine serves as a neurotransmitter that promotes wakefulness through histaminergic neurons. Histaminergic neurons fire actively during wakefulness and are inhibited during sleep by the activity of GABAergic projections from the ventrolateral preoptic area.
H 1 receptor antagonists have central neurvous system effects including sedation, sleepiness, decreased alertness and decreased reaction times.
Paradoxically, a minority of patients respond with central nervous system activation, including anxiety, restlessness, and increased alertness.
Diphenhydramine increases serotonergic neurotransmission and antagonizes alpha-adrenergic receptors.
Effects on Human Sleep
Diphenhydramine is generally dosed at 25 to 50 mg for the treatment of insomnia. Clinical trials have shown subjective improvements in sleep latency, nocturnal awakenings, sleep duration, and sleep quality.
The effects on sleep maintenance appear to be more consistent than the effects on sleep onset.
Diphenhydramine can be used in the treatment of persons with sleep difficulty occurring in conjunction with allergy symptoms or upper respiratory infections.
Side effects include: sedation, dizziness, cognitive impairment (when used in the elderly), psychomotor impairment, blurred vision, tinnitus, dry mouth, constipation, urinary retention, decreased appetite, nausea, vomiting, diarrhea and weight gain.
The primary relative contraindications to diphenhydramine use are:
- closed-angle glaucoma
- urinary retention
- chronic obstructive pulmonary disease
- decreased gastrointestinal motility
- severe liver disease.
Doxylamine’s characteristics are very similar to those of diphenhydramine. It is generally used for insomnia in the same dose range (25 to 50 mg) and has a T ½ of 10 to 12 hours. Doxylamine has faster absorption, with a T max of 1.5 to 2.5 hours
The adverse-effects profile of doxylamine is essentially the same as for diphenhydramine. A number of case reports have documented potentially serious side effects such as coma, rhabdomyolysis, and resultant kidney failure.
Doxylamine can be used as a treatment for insomnia in those with associated allergy symptoms or upper respiratory infections. Relative contraindications to the use of doxylamine are the same as with diphenhydramine.
Gabapentin and Pregabalin developed as sleeping pills
Gabapentin and pregabalin were initially developed as anticonvulsant drugs but they are also used in treatment of neuropathic and fibromyalgia pain, periodic limb movement disorder, restless legs syndrome, bipolar mood disorder, and insomnia.
Gabapentin has a T max of 3 to 3.5 hours and a T ½ of 5 to 9 hours. It is generally used at a dosage of 100 to 900 mg for insomnia therapy, taken in divided doses with larger doses in the evening hours. Because of its slow absorption, it is less likely than other agents to improve sleep onset when taken at bedtime.
Doses of pregabalin are typically 150 to 600 mg. It is more rapidly absorbed, with a T max of 1 hour and T ½ of 4.5 to 7 hours.
Gabapentin and pregabalin have several mechanisms of action for their analgesic and sedative effects. They exert their primary central nervous system effects by binding to the alpha-2-delta subunit of N-type voltage-gated calcium channels, thereby diminishing the release of excitatory neurotransmitters such as glutamate and norepinephrine and is thought to be related to their analgesic effects.
Gabapentin and pregabalin are structural analogues of gamma-aminobutyric acid (GABA) but do not appear to interact with GABA A or GABA B receptors or to influence GABA reuptake. They may promote formation of GABA in the central nervous system.
Other mechanisms of action include antagonism of N-methyl-d-aspartate (NMDA) receptors and interaction with the l–amino acid transporter receptor.
Both drugs administration is associated with improved subjective sleep quality, reduced sleep latency and REM sleep and increased sleep efficiency, total sleep time, and slow-wave sleep.
Gabapentin and pregabalin are associated with improvement on self-reported sleep measures in patients with various pain conditions ( fibromyalgia, neuropathic pain, postherpetic neuralgia, postsurgical pain).
Studies also suggests that gabapentin might be useful in treating insomnia occurring in alcohol-dependent persons and those undergoing alcohol withdrawal.
Gabapentin: sedation, dizziness, ataxia, and diplopia.
Pregabalin: sedation, dizziness, cognitive impairment, dry mouth, and increased appetite.
Rarely, leukopenia has been noted with these agents.
Tiagabine – an anticonvulsant developed as sleep aid
Tiagabine is a GABA reuptake inhibitor that is FDA approved for treating partial seizures, being initially developed as an adjuvant anticonvulsant drug. Tiagabine has a T max of 1 to 1.5 hours and a T ½ of approximately 8 hours.
It’s mechanism of action consists of inhibiting the GABA transporter GAT1, thereby reducing GABA reuptake into presynaptic neurons and increasing the inhibitory actions of GABA in the central nervous system.
Tiagabine has been investigated in doses of 2 to 16 mg for the treatment of insomnia. These doses are much lower than those used in epilepsy.
This agent show increases in slow-wave sleep in a dose-dependent manner as well as reduced stage 1 NREM and REM sleep. It has small and inconsistent effects on total sleep time and wakefulness after sleep onset and no effect on sleep efficiency.
Side effects of tiagabine include dose-dependent somnolence, dizziness, nausea, sedation, and reduced objective measures of alertness. New-onset seizures have been observed in a small number of subjects, limiting its clinical utility.
Tiagabine should be used with caution in patients with significant liver disease.
Sedative antipsychotic drugs used as sleep medications
Although many different antipsychotic drugs have sedative effects, olanzapine and quetiapine are the most commonly used sleeping pills in nonpsychotic and non-bipolar patients for this purpose.
These sleep aids are used for insomnia in dosages that are lower than typically used in their FDA-approved indications, which include the treatment of psychotic disorders (schizophrenia and schizoaffective disorder), mania, and in some cases bipolar and unipolar major depression.
Olanzapine is structurally similar to benzodiazepines. It has a T max of 4 to 6 hours which makes it relatively unlikely to be effective on sleep-onset difficulty when taken near bedtime. However, having a T ½ of 20 to 54 hours it is likely to have a prolonged sleep-enhancing effect. It is administered in doses of 2.5 to 20 mg.
Olanzapine elimination is affected by factors that alter the liver enzymes CYP1A2 and CYP2D6 therefore is eliminated slower by female patients, tobacco smokers, and persons of Japanese descent.
Unlike older antipsychotic drugs that antagonize primarily dopamine receptors, olanzapine has a variety of receptor effects including antagonism of serotonin 5-HT 2A , muscarinic cholinergic, H 1 , and alpha 1 -adrenergic receptors as well as activity at serotonin 5-HT 2C , 5-HT 3 , and 5-HT 6 receptors.
Studies with healthy control subjects show that olanzapine is associated with decreased sleep latency, wakefulness, and stage 1 NREM sleep and increased sleep efficiency, stage 2, and stage 3/4 NREM sleep, with no consistent effect on REM. Clinical studies of patients with depression, mania, and schizophrenia have shown similar effects.
Quetiapine, with a T max of 1 to 2 hours has the potential to improve sleep onset. It has a T ½ of approximately 7 hours. Typically, quetiapine is administered in doses of 25 to 200 mg at bedtime.
Quetiapine, like olanzapine, is an antagonist of serotonin 5-HT 2A , H 1 , and alpha 1 receptors. It has somewhat more potent dopamine D 2 receptor antagonism than olanzapine does, but its dopamine binding is rapidly reversible.
The primary side effects of the antipsychotic agents used to treat insomnia include sedation, dizziness, orthostatic hypotension, blurred vision, dry mouth, constipation, urinary retention, increased appetite, and weight gain
Side effects caused by the antagonism of dopamine receptors (extrapyramidal side effects such as parkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia) are relatively uncommon in the newer antipsychotic agents, which include those most commonly used to treat insomnia.
Olanzapine has also been associated with cognitive impairment, glucose intolerance, and an elevated risk of mortality among patients with dementia.
Antipsychotic agents are best suited for treating insomnia occurring in persons with psychosis or bipolar disorder.
Second-generation antipsychotic drugs are clinically useful in the treatment of insomnia, particularly among patients with severe depression, bipolar disorder, and psychotic disorders.
Both of these antipsychotic drugs have a lower incidence of extrapyramidal side effects than that of traditional antipsychotic drugs such as haloperidol.
However, both can cause hypotension.
In addition, olanzapine has been associated with weight gain and glucose intolerance as well as with neurocognitive impairment at higher doses.
Quetiapine has been associated with prolongation of the Qtc interval on electrocardiography.
Both olanzapine and quetiapine are subjectively sedating.
Studies using these medications as primary or adjunctive treatments demonstrate improved subjective sleep quality and reduced sleepiness in patients with schizophrenia, unipolar depression, and bipolar depression.
Given their potentially significant neurologic and metabolic side effects, antipsychotic drugs are best reserved for treatment of individuals who have insomnia comorbid with major psychiatric disorders, particularly psychotic and bipolar disorders.
Because of their adverse effect profiles, antipsychotic agents commonly used to treat insomnia should be used with caution in those with a history of myocardial infarction, ischemia, conduction abnormalities, hypotension, closed-angle glaucoma, decreased gastrointestinal motility, urinary retention, liver disease or in whom weight gain would be of significant concern.
Olanzapine is also relatively contraindicated in patients with dementia because of a reported increase in risk of mortality in this population.
Treatment of Allergy-Associated Sleep Disturbance
A number of the non-benzodiazepines appear to have sleep-enhancing effects as well as significant antihistaminergic effects (H 1 antagonism). These agents include doxepin, diphenhydramine, doxlamine, amitriptyline, trimipramine, trazodone, mirtazapine, olanzapine, and quetiapine. No placebo-controlled trials of the treatment of insomnia occurring with allergic rhinitis have been carried out.
Single-Agent Therapy of Insomnia Occurring with Major Depression
Several benzodiazepines are effective and safe for the treatment of insomnia occurring with major depression. Studies have evaluated eszopiclone, zolpidem, zolpidem CR, and clonazepam as adjunctive therapy to antidepressant medications.
When single-agent therapy that addresses both the depression and the sleep disturbance is preferred, the most effective agents are: amitriptyline, trimipramine, doxepin, mirtazapine, trazodone, and quetiapine. Of these, only trimipramine and doxepin have been found to have efficacy in the treatment of insomnia in placebo-controlled trials.
For some agents, the antidepressant dosage is substantially higher than what is typically used to treat insomnia. Such a difference in dosage range precludes their utility for single-agent therapy of insomnia and depression. Agents where the dosing range for depression and insomnia are not substantially different and, as a result, could be considered for this purpose include trimipramine, doxepin, amitriptyline, mirtazapine, and quetiapine.
Single-Agent Therapy of Insomnia Occurring with Chronic Pain
The BzRAs eszopiclone and triazolam have been found to be safe and effective for the treatment of insomnia occurring with chronic pain. Agents with sleep-enhancing effects that have therapeutic effects on chronic pain include amitriptyline, doxepin, trimipramine, gabapentin, and pregabalin.