Sleep Drugs

Nonbenzodiazepine GABA Agonists

• Benzodiazepines commonly used for sleep include flurazepam, temazepam, quazepam, estazolam, and triazolam.

• Nonbenzodiazepine agonists (Z drugs):

  • Zolpidem (Ambien)

  • Zaleplon (Sonata)

  • Eszopiclone (Lunesta)

• Bind at a location close to the benzodiazepine receptor.

Pharmacologic Action

• Zaleplon, zolpidem, and eszopiclone are structurally distinct and vary in their binding to the GABA receptor subunits.

• Benzodiazepines activate all three specific GABA–benzodiazepine (GABA–BZ) binding sites of the GABAA- receptor:

  • Opens chloride channels

  • Reduces the rate of neuronal and muscle firing.

• Zolpidem, zaleplon, and eszopiclone:

  • Have selectivity for specific subunits of the GABA receptor.

  • Specificity may account for their selective sedative effects and relative lack of muscle relaxant and anticonvulsant effects.

• Absorption:

  • Rapidly and well absorbed after oral administration.

  • Absorption can be delayed by as long as 1 hour if taken with food.

• Zolpidem:

  • Reaches peak plasma concentrations in 1.6 hours.

  • Half-life of 2.6 hours.

• Zaleplon:

  • Reaches peak plasma concentrations in 1 hour.

  • Half-life of 1 hour.

• Eszopiclone:

  • Reaches peak plasma concentrations in 1 hour.

  • If taken immediately after a high-fat or heavy meal, the peak is delayed by approximately 1 hour, reducing the effects of eszopiclone on sleep onset.

  • The terminal-phase elimination half-life is approximately 6 hours in healthy adults.

  • Weakly bound to plasma protein (52 to 59 percent).

• The rapid metabolism and lack of active metabolites of zolpidem, zaleplon, and eszopiclone avoid the accumulation of plasma concentrations compared with the long-term use of benzodiazepines such as flurazepam or diazepam.

• Flumazenil can reverse the adverse psychomotor, amnestic, and sedative effects of zolpidem and zaleplon.

Therapeutic Indications

• Insomnia: Zolpidem, zaleplon, and eszopiclone are indicated only for insomnia.

• “Z drugs” are not usually associated with rebound insomnia after the discontinuation of their use for short periods, some patients experience increased sleep difficulties the first few nights after discontinuing their use.

• The use of zolpidem, zaleplon, and eszopiclone for periods more extended than 1 month is not associated with the delayed emergence of adverse effects.

• No development of tolerance to any parameter of sleep measurement was observed over 6 months in clinical trials of eszopiclone.

• γ-Hydroxybutyrate (GHB, Xyrem):

  • Approved for the treatment of narcolepsy and improves slow-wave sleep

  • Agonist at the GABAA receptor, where it binds to specific GHB receptors.

  • Has the capacity both to reduce drug craving and to induce dependence, abuse, and absence seizures as a result of complex actions on tegmental dopaminergic systems.

• Parkinson Disease

  • A small number of persons with idiopathic Parkinson disease respond to long-term use of zolpidem with reduced bradykinesia and rigidity.

  • Zolpidem dosages of 10 mg four times daily may be tolerated without sedation for several years.

Precautions and Adverse Reactions

• Zolpidem and zaleplon are generally well tolerated.

• At zolpidem dosages of 10 mg/day and zaleplon dosages above 10 mg/day, a small number of persons will experience dizziness, drowsiness, dyspepsia, or diarrhea.

• Zolpidem and zaleplon are secreted in breast milk and are therefore contraindicated for use by nursing mothers.

• The dosage of zolpidem and zaleplon should be reduced in elderly persons and persons with hepatic impairment.

• Zolpidem (Ambien) has been associated with automatic behavior and amnesia.

• In rare cases, zolpidem may cause hallucinations and behavioral changes.

• The coadministration of zolpidem and SSRIs may extend the duration of hallucinations in susceptible patients.

• Eszopiclone exhibits a dose–response relationship in elderly adults for the side effects of pain, dry mouth, and unpleasant taste.

• Zolpidem and zaleplon can produce a mild withdrawal syndrome lasting 1 day after prolonged use at higher therapeutic dosages.

• Rarely, a person taking zolpidem has self-titrated up the daily dosage to 30 to 40 mg a day. Abrupt discontinuation of such a high dosage of zolpidem may cause withdrawal symptoms for 4 or more days.

• Tolerance does not develop to the sedative effects of zolpidem and zaleplon.

Drug Interactions

• These agents are most dangerous when used with other CNS depressants, such as alcohol, barbituates, opioids, and similar drugs.

• Cimetidine increases the plasma concentrations of zaleplon.

• Rifampin (Rifadin), phenytoin (Dilantin), carbamazepine, and phenobarbital (Solfoton, Luminal) significantly increase the metabolism of zaleplon.

• The CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone.

• Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.

Laboratory Interferences

• No known laboratory interferences are associated with the use of zolpidem and zaleplon.

Dosage and Clinical Guidelines

• Zaleplon is available in 5- and 10-mg capsules.

  • A single 10-mg dose is the usual adult dose.

  • The dose can be increased to a maximum of 20 mg as tolerated.

  • A single dose of zaleplon can be expected to provide 4 hours of sleep with minimal residual impairment.

  • For persons older than age 65 years or persons with hepatic impairment, an initial dose of 5 mg is advised.

• Eszopiclone is available in 1-, 2-, and 3-mg tablets.

  • The starting dose should not exceed 1 mg in patients with severe hepatic impairment or those taking potent CYP3A4 inhibitors.

  • The recommended dosing to improve sleep onset or maintenance is 2 or 3 mg for adult patients (ages 18 to 64 years) and 2 mg for older adult patients (ages 65 years and older).

  • The 1-mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep.

• Zolpidem

  • Available in 5- and 10-mg capsules, and 6.25- and 12.5-mg capsules for the controlled-release capsules

  • There is also a sublingual tablet and an oropharyngeal spray.

  • The controlled-release form is usually for problems with sleep maintenance.

  • The sublingual and oropharyngeal forms are for difficulties with taking the pill, or in particular circumstances. For example, the sublingual can be used for middle of the night awakening.

  • With the oral capsule, the starting dose is 5 mg for females and 5 to 10 mg for males before bedtime.

  • A single 10-mg dose is the usual adult dose (6.25- or 12.5-mg of the controlled release).

  • The capsule should only be taken at the beginning of the night, as the drug can impair a person if they attempt activity within 7 to 8 hours of using the drug.

  • For persons older than age 65 years or persons who are medically frail, 5 mg is the recommended dose.

Melatonin Agonists: Ramelteon and Melatonin

• Two melatonin receptor agonists commercially available in the United States:

  • Melatonin: dietary supplement available in various preparations in health food stores, and not under FDA regulations

  • Ramelteon (Rozerem): an FDA-approved drug for the treatment of insomnia characterized by difficulties with sleep onset.

• Both exogenous melatonin and ramelteon are thought to exert their effects by interaction with central melatonin receptors.

Ramelteon

• Ramelteon (Rozerem) is a melatonin receptor agonist used to treat sleep- onset insomnia.

• Unlike the benzodiazepines, ramelteon has no appreciable affinity for the GABA receptor complex.

Pharmacologic Actions

• Ramelteon essentially mimics melatonin’s sleep-promoting properties and has a high affinity for melatonin MT1 and MT2 receptors in the brain.

• These receptors are thought to be critical in the regulation of the body’s sleep–wake cycle.

• Ramelteon is rapidly absorbed and eliminated over a dose range of 4 to 64 mg.

• Maximum plasma concentration (Cmax) is reached approximately 45 minutes after administration, and the elimination half-life is 1 to 2.6 hours.

• The total absorption of ramelteon is at least 84 percent, but extensive first- pass metabolism results in a bioavailability of approximately 2 percent.

• Ramelteon is metabolized primarily through the CYP1A2 pathway and eliminated principally in urine.

• Repeated once-daily dosing does not appear to result in accumulation, likely because of the compound’s short half-life.

Therapeutic Indications

• The FDA-approved ramelteon for the treatment of insomnia characterized by difficulty with sleep onset.

• Potential off-label use is centered on the application in circadian rhythm disorders, predominantly jet lag, delayed sleep phase syndrome, and shift work sleep disorder.

• Clinical trials and animal studies have failed to demonstrate evidence of rebound insomnia or withdrawal effects.

Precautions and Adverse Events

• Headache is the most common side effect of ramelteon.

• Other adverse effects may include somnolence, fatigue, dizziness, worsening insomnia, depression, nausea, and diarrhea.

• We should not use the drug in patients with severe hepatic impairment.

• It is also not recommended in patients with severe sleep apnea or severe chronic obstructive pulmonary disease.

• Prolactin levels may be increased in women.

• The drug should be used with caution, if at all, in nursing mothers and pregnant women.

• Ramelteon has been found sometimes to decrease blood cortisol and testosterone and to increase prolactin.

• Female patients should be monitored for the cessation of menses and galactorrhea, decreased libido, and fertility problems.

• The safety and effectiveness of ramelteon in children has not been established.

Drug Interactions

• CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon. Accordingly, fluvoxamine (Luvox) and other CYP1A2 inhibitors may increase the side effects of ramelteon.

• Ramelteon should be administered with caution in patients taking CYP1A2 inhibitors, potent CYP3A4 inhibitors such as ketoconazole, and strong CYP2C inhibitors such as fluconazole (Diflucan).

• No clinically meaningful interactions were found when ramelteon was coadministered with omeprazole, theophylline, dextromethorphan, midazolam, digoxin, and warfarin.

Dosing and Clinical Guidelines

• The usual dose of ramelteon is 8 mg within 30 minutes of going to bed.

• It should not be taken with or immediately after high-fat meals.

Melatonin

• Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced mainly at night in the pineal gland.

• Ingested melatonin can reach and bind to melatonin-binding sites in the brains of mammals and produce somnolence when used at high doses.

• Melatonin is available as a dietary supplement and is not a medication.

• Few well-controlled clinical trials have been conducted to determine its effectiveness in treating such conditions as insomnia, jet lag, and sleep disturbances related to shift work.

Pharmacologic Actions

• Melatonin’s secretion is stimulated by the dark and inhibited by the light.

• It is naturally synthesized from the amino acid tryptophan, which is converted to serotonin and finally converted to melatonin.

• The suprachiasmatic nuclei (SCN) of the hypothalamus have melatonin receptors, and melatonin may have a direct action on SCN to influence circadian rhythms, which are relevant for jet lag and sleep disturbances.

• In addition to the pineal gland, melatonin is also produced in the retina and GI tract.

• Melatonin has a very short half-life of 0.5 to 6 minutes.

• Plasma concentrations are a function of the dose administered and the endogenous rhythm.

• Approximately 90 percent of melatonin is cleared through the first- pass metabolism by way of the CYP1A1 and CYP1A2 pathways.

• Elimination occurs principally in urine.

• Exogenous melatonin interacts with the melatonin receptors that suppress neuronal firing and promote sleep.

• There does not appear to be a dose– response relationship between exogenous melatonin administrations and sleep effects.

Therapeutic Indications

• Melatonin is approved for insomnia in the European Union and several other countries, however, it is not approved by the FDA for any medical use.

• It is sold over the counter in the United States and Canada but requires a prescription in some other countries such as the United Kingdom.

• Individuals have used exogenous melatonin to address sleep difficulties (insomnia, circadian rhythm disorders), cancer (breast, prostate, colorectal), seizures, depression, anxiety, and seasonal affective disorder.

• Some studies suggest that exogenous melatonin may have some antioxidant effects and antiaging properties.

Precautions and Adverse Reactions

• Adverse events associated with melatonin include fatigue, dizziness, headache, irritability, and somnolence.

• Disorientation, confusion, sleepwalking, vivid dreams, and nightmares have also been observed, often with effects resolving after melatonin administration was suspended.

• Melatonin may reduce fertility in both men and women.

• In men, exogenous melatonin reduces sperm motility, and long-term administration has been shown to inhibit testicular aromatase levels.

• In women, exogenous melatonin may inhibit ovarian function, and for that reason, it has been evaluated as a contraceptive, but with inconclusive results.

Drug Interactions

• As a dietary supplement preparation, exogenous melatonin is not regulated by the FDA and has not been subjected to the same type of drug interaction studies that were performed for ramelteon.

• Caution is suggested in coadministering melatonin with blood thinners (e.g., warfarin [Coumadin], aspirin, and heparin), antiseizure medications, and medications that lower BP.

Laboratory Interference

• Melatonin is not known to interfere with any commonly used clinical laboratory tests.

Dosage and Administration

• Over-the-counter melatonin is available in the following formulations:

  • 1-, 2.5-, 3-, and 5-mg capsules

  • 1-mg/4-mL liquid

  • 0.5- and 3-mg lozenges

  • 2.5-mg sublingual tablets

  • 1-, 2-, and 3- mg timed-release tablets

• Standard recommendations are to take the desired melatonin dose at bedtime, but some evidence from clinical trials suggests that dosing up to 2 hours before habitual bedtime may produce a more significant improvement in sleep onset.

Agomelatine (Valdoxan)

• Agomelatine is structurally related to melatonin and is used in Europe as a treatment for MDD.

• It acts as an agonist at melatonin (MT1 and MT2) receptors.

• It also acts as a serotonin antagonist.

• Analysis of agomelatine clinical trial data raised serious questions about the efficacy and safety of the drug.

• The drug is not being marketed in the United States.

Prazosin

• Prazosin (Minipress) is a quinazoline derivative and one of a new chemical class of antihypertensives.

• It is an α1-adrenergic receptor antagonist as opposed to the drugs mentioned above, which are α2-blockers.

Pharmacologic Actions

• The exact mechanism of the hypotensive action of prazosin, and how it suppresses nightmares, is unknown.

• Prazosin causes a decrease in total peripheral resistance that is related to its action as an α1-adrenergic receptor antagonist.

• BP is lowered in both the supine and standing positions.

• This effect is most pronounced on the diastolic BP.

• After oral administration, human plasma concentrations reach a peak at about 3 hours with a plasma half-life of 2 to 3 hours.

• The drug is highly bound to plasma protein.

• Tolerance has not been observed to develop with long-term therapy.

Therapeutic Action

• Prazosin is used in psychiatry to suppress nightmares, particularly those associated with PTSD.

Precautions and Adverse Reactions

• During clinical trials and subsequent marketing experience, the most frequent reactions were dizziness (10.3 percent); headache (7.8 percent); drowsiness (7.6 percent); lack of energy (6.9 percent); weakness (6.5 percent); palpitations (5.3 percent); and nausea (4.9 percent).

• In most instances, side effects disappeared with continued therapy or have been tolerated with no decrease in the dose of the drug.

• Prazosin should not be used in nursing mothers or during pregnancy.

Drug Interactions

• No adverse drug interactions have been reported.

Laboratory Interferences

• No laboratory interferences have been reported.

Dosage and Clinical Guidelines

• The drug is supplied in 1-, 2-, and 5-mg capsules and a nasal spray.

• The therapeutic dosages most commonly used have ranged from 6 to 15 mg daily given in divided doses.

• Doses higher than 20 mg do not increase efficacy.

• When adding a diuretic or other antihypertensive agent, the dose should be reduced to 1 or 2 mg three times a day, and retitration then carried out.