With the long-term use of sedative-hypnotics, especially if doses are increased, a state of physiologic dependence can occur. This may develop to a degree unparalleled by any other drug group, including the opioids. Withdrawal from a sedative-hypnotic can have severe and life-threatening manifestations. Withdrawal symptoms range from restlessness, anxiety, weakness, and orthostatic hypotension to hyperactive reflexes and generalized seizures. Symptoms of withdrawal are usually more severe following discontinuance of sedative-hypnotics with shorter half-lives. However, eszopiclone, zolpidem, and zaleplon appear to be exceptions to this, because withdrawal symptoms are minimal following abrupt discontinuance of these newer short-acting agents. Symptoms are less pronounced with longer-acting drugs, which may partly accomplish their own “tapered” withdrawal by virtue of their slow elimination. Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked among sedative-hypnotics. This provides the rationale for therapeutic regimens in the management of withdrawal states: Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol.
The most common drug interactions involving sedative-hypnotics are interactions with other CNS depressant drugs, leading to additive effects. These interactions have some therapeutic usefulness when these drugs are used as adjuvants in anesthesia practice. However, if not anticipated, such interactions can lead to serious consequences, including enhanced depression with concomitant use of many other drugs. Additive effects can be predicted with concomitant use of alcoholic beverages, opioid analgesics, anticonvulsants, and phenothiazines. Less obvious but just as important is enhanced CNS depression with a variety of antihistamines, antihypertensive agents, and antidepressant drugs of the tricyclic class.
Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed (see also Chapters 4 and 66).
Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions •RamelteonActivates MT1 and MT2 receptors in suprachiasmatic nuclei in the CNS Rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms Sleep disorders, especially those characterized by difficulty in falling asleep •notacontrolledsubstanceOralactivity•formsactivemetaboliteviaCYP1A2•Toxicity:Dizziness•fatigue•endocrinechanges•Interactions:Fluvoxamine inhibits metabolism •Tasimelteon:OrallyactiveMT1 and MT2 agonist, recently approved for non-24-hour sleep disorder