Sedatives are drugs that produce sleep or drowsiness by depressing central nervous system (CNS) function. There are a number of drugs and drug classes that can produce drowsiness, but for which sedation is not the primary effect or use. Drugs that are used therapeutically as sedatives generally fall into one of three categories: positive GABAA receptor modulators (e.g., barbiturates, benzodiazepines); antihistamines (e.g., diphenhydramine, trade name Benadryl; doxylamine, trade name Unisom); and melatonin or melatonin receptor agonists (e.g., ramelteon, trade name Rozerem).
Prior to the development of benzodiazepines, barbiturates were the most commonly used sedative/hypnotic drugs in medical practice. Barbiturates such as butabarbital, pentobarbital, phenobarbital, and secobarbital were commonly used to induce sedation and to treat insomnia. Barbiturates bind to GABAA receptors and activate the receptors (i.e., promote chloride flux through the membrane channel) through direct binding and through the facilitation of GABA binding to the receptor. Barbiturates are still used in medical practice to produce sedation prior to procedures that require anesthesia; however, the use of barbiturates for the outpatient treatment of insomnia has become uncommon as a result of the availability of drugs with better safety profiles such as the benzodiazepines.
Like barbiturates, benzodiazepines also bind to GABAA receptors, but they bind at a different site than do the barbiturates. Benzodiazepines facilitate the binding of GABA to GABAA receptors, but unlike barbiturates, they do not activate the receptor directly. This difference is thought to account for the greater safety profile of the benzodiazepines as compared to the barbiturates. For example, benzodiazepine overdose is not usually fatal unless another drug such as a barbiturate, opioid, or alcohol has been taken together with the benzodiazepine. As a result of the improvement in safety profile over the barbiturates, benzodiazepines are currently the most widely prescribed sedative/hypnotic drugs in the United States.
The same pharmacological mechanism of action (facilitation of GABA binding to GABAA receptors) and sedative effects appear to be shared by all of the benzodiazepines. However, only some of the benzodiazepines are U.S. Food and Drug Administration (FDA)-approved for the treatment of insomnia (e.g., estazolam, trade name ProSom; flurazepam, trade name Dalmane; quazepam, trade name Doral; temazepam, trade name Restoril; and triazolam, trade name Halcion). The most important clinical differences between different benzodiazepines appear to involve differences in pharmacokinetic effects such as the duration of action of individual drugs.
Another class or subclass of drugs that also bind to the benzodiazepine site on GABAA receptors (or a site nearby in the case of eszopiclone) and facilitate the binding of GABA, but do not have benzodiazepine chemical structures are the “Z-drugs,” which include zolpidem (trade name Ambien), eszopiclone (trade name Lunesta), and zaleplon (trade name Sonata). In addition to differences in chemical structure, the Z-drugs also differ from the traditional benzodiazepines in that they bind preferentially to a subset of GABAA receptors that contain an a1 subunit (as compared to most of the benzodiazepines that bind non-selectively to GABAA receptors that contain a1, a2, a3, or a5 subunits). The preferential binding of the Z-drugs to a1 subunit-containing GABAA receptors have been purported to result in greater sedative/hypnotic effects and lesser anxiolytic (i.e., anxiety decreasing) effects of these drugs compared to the benzodiazepines; however, the effects of the Z-drugs are very similar and often indistinguishable from the traditional benzodiazepines. The relatively short half-lives of the Z-drugs (one to six hours) might be one of the most clinically relevant differences between these non-benzodiazepine positive GABAA receptor modulators and the more traditional benzodiazepines for their use in the treatment of insomnia.
There are a number of other sedative drugs that directly or indirectly act at GABAA receptors, but that do not fit into one of the classes described above. These drugs include, for example, ethanol (alcohol), chloral hydrate (perhaps best known for being added to alcoholic drinks to create a “Mickey Finn” to render victims unconscious), and methaqualone (trade name Quaalude). Each of these drugs has sedative effects, but are no longer commonly used in medical practice.
Antihistamines are drugs that are antagonists at histamine receptors and block the effects of the histamine that is released by the body. Perhaps the most commonly used antihistamine in the United States is diphenhydramine (trade name Benadryl), which is known to produce drowsiness and sedation and is included at doses of 25-50 milligrams as a sedative in over-the-counter (OTC) medicines such as Tylenol PM. Another antihistamine found in OTC sleep aids is doxylamine, which can be found in products under the trade name Unisom. More recently, a prescription antihistamine by the name of doxepin (trade name Silenor) has been developed and subsequently approved by the FDA in March of 2010 for the treatment of insomnia characterized by difficulty with sleep maintenance.
Melatonin is a naturally occurring neurohormone that is released by the pineal gland in the brain. Melatonin (N-acetyl-5-methoxytryptamine) is chemically similar to the neurotransmitter serotonin (5-hydroxytryptamine) and is thought to regulate sleep, body temperature, and the entrainment of circadian rhythms. Melatonin binds to melatonin 1 and 2 receptors (MT1 and MT2, respectively) in human brain, which are thought to be responsible for the sedative effects of melatonin. The effectiveness of melatonin to produce sedation or to treat insomnia has been questioned by some, with some studies showing therapeutic benefit and others failing to do so. Melatonin is currently sold as a dietary supplement in the United States, which means that it is not regulated as a medication by the FDA. There also do not appear to be any widely agreed upon guidelines for the use of melatonin (e.g., dose and timing of administration) for the treatment of insomnia.
Ramelteon (trade name Rozerem) is a synthetic melatonin receptor agonist that was developed and subsequently approved by the FDA as a prescription medication for the treatment of insomnia characterized by difficulty with sleep onset. Ramelteon, like melatonin, is an agonist at MT1 and MT2 receptors and has been shown to promote sleep in human and non-human studies.
Positive GABAA receptors modulators such as the barbiturates, benzodiazepines, Z-drugs, and ethanol have abuse liability. These drugs are self-administered by animals in the laboratory and are reported as being liked by individuals who abuse sedative drugs. Ratings of liking in human laboratory assessments of abuse liability tend to be higher for the barbiturates as compared to the benzodiazepines and the Z-drugs, suggesting that barbiturates have greater liability for abuse as compared to benzodiazepines. Together with a greater potential for adverse effects (e.g., respiratory depression) with the barbiturates as compared to the benzodiazepines and the Z-drugs (suggesting greater liability of abuse), the barbiturates are generally considered to have greater relative abuse liability than the benzodiazepines and the Z-drugs. Antihistamines are generally considered to have low abuse liability. However, the antihistamine diphenhydramine has been shown to be self-administered by animals in the laboratory and has been reported as being liked by individuals who abuse sedative drugs. It should be noted, however, that liking in the human abuse liability study occurred at a dose that was eight to 16 times larger than the therapeutic dose. The actual abuse of antihistamines might be limited by the adverse effects (e.g., headache, dizziness, nausea, dry mouth) of these drugs at large doses or by the licit or illicit availability of other preferred sedative drugs (e.g., benzodiazepines). Nonetheless, the real-world abuse of antihistamines has been low in spite of their widespread availability without a prescription.
The abuse liability of the melatonin receptor agonist ramelteon has been studied in human participants with histories of sedative drug abuse. Remarkably, almost 80 percent of the participants in that study reported that the largest dose of ramelteon that was studied felt like placebo. Thus, up to a dose 20 times larger than the therapeutic dose, ramelteon did not have appreciable subjective, psychomotor, or cognitive effects. These data suggest that ramelteon has low potential for abuse.
Sedatives are among the most widely used illegal drugs by American youths. Based on recent Monitoring the Future data only marijuana, inhalants, narcotics other than heroin, amphetamine, and tranquilizers were used by more high school seniors than were sedatives. Rates of sedative use have recently decreased, from 11.0 percent of high school seniors in 2005 to 8.4 percent of seniors in 2009.
Repeated administration of GABAA receptor positive modulators such as the barbiturates and benzodiazepines can result in the development of physical dependence that is evidenced by a withdrawal syndrome upon discontinuation of the drug. The severity of withdrawal from a barbiturate or benzodiazepine is likely to depend upon the duration of treatment with the drug prior to discontinuation, the dose and frequency by which the drug was administered, and the half-life of the drug and any of its active metabolites. In general, the administration of larger and more frequent doses will result in greater physical dependence. Treatment with long-acting drugs or drugs with long-acting metabolites might produce greater levels of physical dependence due to a more continuous activation of the receptors; however, long-acting drugs might also result in a less severe withdrawal syndrome upon discontinuation as compared to shorter-acting drugs due to a more gradual discontinuation or “built-in” taper associated with their long duration of action. Barbiturate and benzodiazepine withdrawal signs and symptoms have been reported to include the possible return of clinical symptoms being treated such as anxiety and insomnia in addition to agitation, depression, panic, paranoia, delirium, muscle pain, muscle spasm, seizure, and death.
Physical dependence and withdrawal have not been commonly reported following the discontinuation of the use of antihistamines or melatonin receptor agonists.
The sedative drugs that act through GABAA receptors have typically been scheduled under the U.S. Controlled Substance Act, whereas the antihistamines and melatonin receptor agonists are not Federally Scheduled drugs. Barbiturates have accepted medical use and have been placed in schedules ranging from II to IV. Perhaps reflecting the general sentiment that the benzodiazepines and Z-drugs have lower abuse liability as compared to the barbiturates, all of the benzodiazepines and Z-drugs are listed in schedule IV. Other GABA drugs described above include ethanol, which is not regulated as a drug by the FDA and is not scheduled under the U.S. Controlled Substance Act; chloral hydrate, which has accepted medical use (for sedation) and is listed in schedule IV; and methaqualone, which is no longer available for medical use and is listed in schedule I (for drugs with high abuse liability and no accepted medical use).
Alcohol, Barbiturates, Inhalants
Abstract The sedatives outlined in this article represent a group of drugs which were largely marketed in response to growing concerns regarding the
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