Central Nervous System Depression

When taken to promote sleep, benzodiazepines cause drowsiness, lightheadedness, incoordination, and difficulty concentrating. When these effects occur at bedtime, they are generally inconsequential. However, if sedation and other manifestations of CNS depression persist beyond waking, interference with daytime activities can result.

Anterograde Amnesia

Benzodiazepines can cause anterograde amnesia (impaired recall of events that take place after dosing). Anterograde amnesia has been especially troublesome with triazolam [Halcion]. If patients complain of forgetfulness, the possibility of drug-induced amnesia should be evaluated.

Sleep Driving and Other Complex Sleep-Related Behaviors

Patients taking benzodiazepines in sleep-inducing doses may carry out complex behaviors and then have no memory of their actions. Reported behaviors include sleep driving, preparing and eating meals, and making phone calls. Although these events can occur with normal doses, they are more likely when doses are excessive and when benzodiazepines are combined with alcohol and other CNS depressants. Because of the potential for harm, benzodiazepines should be withdrawn if sleep driving is reported. To minimize withdrawal symptoms, dosing should be tapered slowly, rather than discontinued abruptly.

Paradoxical Effects

When employed to treat anxiety, benzodiazepines sometimes cause paradoxical responses, including insomnia, excitation, euphoria, heightened anxiety, and rage. If these occur, the benzodiazepine should be withdrawn.

Respiratory Depression

Benzodiazepines are weak respiratory depressants. Death from overdose with oral benzodiazepines alone has never been documented. Hence, in contrast to the barbiturates, benzodiazepines present little risk as vehicles for suicide. It must be emphasized, however, that although respiratory depression with oral therapy is rare, benzodiazepines can cause severe respiratory depression when administered intravenously. In addition, substantial respiratory depression can result from combining oral benzodiazepines with other CNS depressants (e.g., alcohol, barbiturates, opioids).

Abuse

Benzodiazepines have a lower abuse potential than barbiturates and most other general CNS depressants. The behavior pattern that constitutes “addiction” is uncommon among people who take benzodiazepines for therapeutic purposes. When asked about their drug use, individuals who regularly abuse drugs rarely express a preference for benzodiazepines over barbiturates. Because their potential for abuse is low, the benzodiazepines are classified under Schedule IV of the Controlled Substances Act. This contrasts with the barbiturates, most of which are classified under Schedule III.

Use in Pregnancy and Lactation

Benzodiazepines are highly lipid soluble and can readily cross the placental barrier. Use of benzodiazepines during the first trimester of pregnancy is associated with an increased risk for congenital malformations, such as cleft lip, inguinal hernia, and cardiac anomalies. Use near term can cause CNS depression in the neonate. Because they may represent a risk to the fetus, most benzodiazepines are classified in U.S. Food and Drug Administration (FDA) Pregnancy Risk Category D. Four of these drugs—estazolam, flurazepam, temazepam, and triazolam—are in Category X. Women of childbearing age should be warned about the potential for fetal harm and instructed to discontinue benzodiazepines if pregnancy occurs.

Benzodiazepines enter breast milk with ease and may accumulate to toxic levels in the breastfed infant. Accordingly, these drugs should be avoided by nursing mothers.

Other Adverse Effects

Occasional reactions include weakness, headache, blurred vision, vertigo, nausea, vomiting, epigastric distress, and diarrhea. Neutropenia and jaundice occur rarely. Rarely, benzodiazepines may cause severe allergic reactions, including angioedema and anaphylaxis.

Central Nervous System Depressants

The CNS-depressant actions of benzodiazepines add to those of other CNS depressants (e.g., alcohol, barbiturates, opioids). Hence, although benzodiazepines are very safe when used alone, they can be extremely hazardous in combination with other depressants. Combined overdose with a benzodiazepine plus another CNS depressant can cause profound respiratory depression, coma, and death. Patients should be warned against use of alcohol and all other CNS depressants.

Physical Dependence

Benzodiazepines can cause physical dependence—but the incidence of substantial dependence is low. When benzodiazepines are discontinued after short-term use at therapeutic doses, the resulting withdrawal syndrome is generally mild and often goes unrecognized. Symptoms include anxiety, insomnia, sweating, tremors, and dizziness. Withdrawal from long-term, high-dose therapy can cause more serious reactions, such as panic, paranoia, delirium, hypertension, muscle twitches, and seizures. Symptoms of withdrawal are usually more intense with benzodiazepines that have a short duration of action. With one agent—alprazolam [Xanax, Xanax XR, Niravam]—dependence may be a greater problem than with other benzodiazepines. Because the benzodiazepine withdrawal syndrome can resemble an anxiety disorder, it is important to differentiate withdrawal symptoms from the return of the original symptoms of anxiety.

The intensity of withdrawal symptoms can be minimized by discontinuing treatment gradually. Doses should be slowly tapered over several weeks or months. Substituting a benzodiazepine with a long half-life for one with a short half-life is also helpful. Patients should be warned against abrupt cessation of treatment. After discontinuation of treatment, patients should be monitored for 3 weeks for indications of withdrawal or recurrence of original symptoms.

Routes

All benzodiazepines can be administered orally. When used for sedation or induction of sleep, benzodiazepines are almost always administered by mouth.

Oral

Patients should be advised to take oral benzodiazepines with food if gastric upset occurs. Also, they should be instructed to swallow sustained-release formulations intact, without crushing or chewing. Patients should be warned not to increase the dosage or discontinue therapy without consulting the prescriber.

For treatment of insomnia, benzodiazepines should be given on an intermittent schedule (e.g., 3 or 4 days a week) in the lowest effective dosage for the shortest duration required. This will minimize physical dependence and associated drug-dependency insomnia.

Zolpidem

Zolpidem [Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist], our most widely used hypnotic, is approved only for short-term management of insomnia. However, although approval is limited to short-term use, many patients have taken the drug long term with no apparent tolerance or increase in adverse effects. All zolpidem formulations have a rapid onset and hence can help people who have difficulty falling asleep. In addition, the extended-release formulation—Ambien CR—can help people who have difficulty maintaining sleep.

Although structurally unrelated to the benzodiazepines, zolpidem binds to the benzodiazepine receptor site on the GABA receptor–chloride channel complex and shares some properties of the benzodiazepines. Like the benzodiazepines, zolpidem can reduce sleep latency and awakenings and can prolong sleep duration. The drug does not significantly reduce time in rapid eye movement (REM) sleep and causes little or no rebound insomnia when therapy is discontinued. In contrast to the benzodiazepines, zolpidem lacks anxiolytic, muscle relaxant, and anticonvulsant actions because zolpidem doesn’t bind with all benzodiazepine receptors. Rather, binding is limited to the benzodiazepine-1 subtype of benzodiazepine receptors.

Zolpidem is rapidly absorbed after oral dosing. Plasma levels peak in 2 hours. The drug is widely distributed, although levels in the brain remain low. Zolpidem is extensively metabolized to inactive compounds that are excreted in the bile, urine, and feces. The elimination half-life is 2.4 hours.

Zolpidem has a side-effect profile like that of the benzodiazepines. Daytime drowsiness and dizziness are most common, and these occur in only 1% to 2% of patients. Like the benzodiazepines, zolpidem has been associated with sleep driving and other sleep-related complex behaviors. At therapeutic doses, zolpidem causes little or no respiratory depression. Safety in pregnancy has not been established. According to the FDA, zolpidem may pose a small risk for anaphylaxis and angioedema.

Short-term treatment is not associated with significant tolerance or physical dependence. Withdrawal symptoms are minimum or absent. Similarly, the abuse liability of zolpidem is low. Accordingly, the drug is classified under Schedule IV of the Controlled Substances Act.

Like other sedative-hypnotics, zolpidem can intensify the effects of other CNS depressants. Patients should be warned against combining zolpidem with alcohol and all other drugs that depress CNS function.

Zaleplon

Zaleplon [Sonata] is the first representative of a new class of hypnotics, the pyrazolopyrimidines. The drug is approved only for short-term management of insomnia, but prolonged use does not appear to cause tolerance. Like zolpidem, zaleplon binds to the benzodiazepine-1 receptor site on the GABA receptor–chloride channel complex, enhancing the depressant actions of endogenous GABA. In contrast to zolpidem, zaleplon has a very rapid onset and short duration of action and hence is good for helping patients fall asleep, but not for maintaining sleep.

Zaleplon is rapidly and completely absorbed after oral dosing. However, because of extensive first-pass metabolism, bioavailability is only 30%. A large or high-fat meal can delay absorption substantially. Plasma levels peak about 1 hour after administration and then rapidly decline, returning to baseline in 4 to 5 hours. Zaleplon is metabolized by hepatic aldehyde oxidase before excretion in the urine. Its half-life is just 1 hour.

Because of its kinetic profile, zaleplon is well suited for people who have trouble falling asleep, but not for people who can’t maintain sleep. The drug can also help people who need a sedative-hypnotic in the middle of the night: because of its short duration, zaleplon can be taken at 3:00 AM without causing residual daytime sedation.

Zaleplon is well tolerated. The most common side effects are headache, nausea, drowsiness, dizziness, myalgia, and abdominal pain. Like the benzodiazepines, zaleplon has been associated with rare cases of sleep driving and other complex sleep-related behaviors. Respiratory depression has not been observed. Physical dependence is minimum, the only sign being mild rebound insomnia the first night after drug withdrawal. Next-day sedation and hangover have not been reported. Like the benzodiazepines, zaleplon has a low potential for abuse and hence is classified as a Schedule IV drug.

Eszopiclone

Eszopiclone [Lunesta], like zaleplon and zolpidem, binds selectively with the benzodiazepine-1 receptor on the GABA receptor–chloride channel complex and thereby enhances the depressant actions of endogenous GABA.

Eszopiclone is approved for treating insomnia, with no limitation on how long it can be used. This contrasts with zaleplon and zolpidem, which are approved for short-term use only. Does this mean that eszopiclone is safer than the other two drugs, or less likely to promote tolerance? Not necessarily. It only means that the manufacturer of eszopiclone conducted a prolonged (6-month) study, whereas the manufacturers of the other two drugs did not. In that prolonged study, eszopiclone reduced sleep latency and nighttime awakening, increased total sleep time and sleep quality, had no significant effect on sleep architecture, and showed no indication of tolerance.

Eszopiclone is rapidly absorbed after oral dosing, reaching peak blood levels in 1 to 2 hours. The drug undergoes extensive hepatic metabolism, primarily by CYP3A4 (the 3A4 isoenzyme of cytochrome P450). The resulting inactive (or weakly active) metabolites are excreted in the urine. The elimination half-life is 6 hours.

Eszopiclone is generally well tolerated. The most common adverse effect is a bitter aftertaste, reported by 17% of patients dosed with 2 mg and 34% of those dosed with 3 mg. Other common effects are headache, somnolence, dizziness, and dry mouth. Rebound insomnia may occur on the first night after discontinuing the drug. Like the benzodiazepines and the other benzodiazepine-like drugs, eszopiclone has been associated with cases of sleep driving and other sleep-related complex behaviors. Rarely, eszopiclone may cause anaphylaxis or angioedema. Eszopiclone has a low potential for abuse and hence is classified as a Schedule IV drug.