Sedatives

> 3 months or 500 to 600 mg/day for 1 month may induce a withdrawal syndrome when the drug is stopped.

Tolerance and tachyphylaxis develop irregularly and incompletely; thus, considerable behavioral, mood, and cognitive disturbances persist, even in regular users, depending on the dosage and the drug’s pharmacodynamic effects. Some cross-tolerance exists between alcohol and sedatives, especially drugs that act on GABA-A receptors. Barbiturates and alcohol are similar in the dependence, withdrawal symptoms, and chronic intoxication they cause. Physiologic dependence develops over weeks to months in chronic users.

Teratogenicity has been associated with benzodiazepine use during pregnancy, but the evidence is inconclusive. Prolonged use of barbiturates during pregnancy can cause barbiturate withdrawal in the neonate1

1. 1.Veroniki AA, Cogo E, Rios P, et al: Comparative safety of anti-epileptic drugs during pregnancy: A systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med 15 (1):95, 2017. doi: 10.1186/s12916-017-0845-1

The signs of sedative intoxication are depression of deep tendon reflexes, fine lateral-gaze nystagmus, slightly decreased alertness with coarse or rapid nystagmus, ataxia, slurred speech, and postural unsteadiness.

Increasing toxicity can cause nystagmus on forward gaze, miosis, somnolence, marked ataxia with falling, confusion, stupor, respiratory depression, and, ultimately, death. Overdose of a benzodiazepine rarely causes hypotension, and these drugs do not cause arrhythmias.

When intake of therapeutic doses of sedatives is stopped or reduced below a critical level, a self-limited mild withdrawal syndrome can ensue. After only a few weeks of use, attempts to stop using the drug can exacerbate insomnia and result in restlessness, disturbing dreams, frequent awakening, and feelings of tension in the early morning.

Withdrawal from benzodiazepinesalcohol withdrawal.

Withdrawal from barbiturates is also similar to alcohol withdrawal. In people who chronically take in large doses of barbiturates, as well as in those who stop or decrease the dosage abruptly, a potentially life-threatening withdrawal syndrome similar to delirium tremens may occur. Occasionally, even after properly managed withdrawal over 1 to 2 weeks, a seizure may occur. Without treatment, withdrawal of a short-acting barbiturate can cause the following:

• Within the first 12 to 20 hours: Increasing restlessness, tremulousness, and weakness

• By the 2nd day: More prominent tremulousness, sometimes increased deep tendon reflexes, and increased weakness

• During the 2nd and 3rd days: Seizures (in 75% of patients who were taking ≥ 800 mg/day), sometimes progressing to status epilepticus and death

• From the 2nd to the 5th day: Delirium, insomnia, confusion, frightening visual and auditory hallucinations, and often hyperpyrexia and dehydration

hemodialysis (1).

Urinary alkalinization

Severe acute withdrawal of sedatives requires hospitalization for close monitoring of withdrawal symptoms, preferably in an intensive care unit, and use of appropriate doses of IV benzodiazepines. Oral benzodiazepines may be used if withdrawal symptoms are mild.

One approach for managing sedative dependence is to withdraw the drug on a strict schedule while monitoring signs of withdrawal. Often, switching to a long-acting drug, which is easier to taper, is better. The timing of dose reduction depends on the presence and severity of withdrawal symptoms.

1. 1. Hoyland K, Hoy M, Austin R, et alBMJ Case Rep 2013: bcr2013010011, 2013. doi: 10.1136/bcr-2013-010011