Clinical Pearls & Morning Reports
The first benzodiazepine to be approved and introduced into clinical practice was chlordiazepoxide, which was introduced to the market in 1960. Today, approximately 35 benzodiazepine derivatives exist, 21 of which have been approved internationally. They all bind to specific sites on the γ-aminobutyric acid (GABA) type A receptor, increasing the receptor’s affinity for GABA, an inhibitory neurotransmitter. A new Clinical Practice Review Article elaborates.
Q: What are the indications for benzodiazepines?
A: Benzodiazepines can be divided into anxiolytic agents and hypnotic agents on the basis of their clinical effects. In principle, however, all benzodiazepines have anxiolytic, hypnotic, muscle-relaxant, anticonvulsant, and amnesic effects. They are used as sedatives and to treat withdrawal symptoms, including alcohol withdrawal delirium.
Q: What side effects are associated with benzodiazepines?
A: The main disadvantages and dose-dependent side effects of benzodiazepines are drowsiness, lethargy, fatigue, excessive sedation, stupor, “hangover effects” the next day, disturbances of concentration and attention, development of dependence, symptom rebound (i.e., recurrence of the original disorder, most commonly a sleep disorder) after discontinuation, and hypotonia and ataxia. Benzodiazepines can seriously impair driving ability and are associated with increased risks of traffic accidents, as well as falls and fractures.
A: The mildest form of withdrawal is symptom rebound and is particularly common with withdrawal from benzodiazepines that are used for sleep disorders. The most common physical symptoms of withdrawal are muscle tension, weakness, spasms, pain, influenza-like symptoms (e.g., sweating and shivering), and “pins and needles.” The most common psychological withdrawal symptoms are anxiety and panic disorders, restlessness and agitation, depression and mood swings, psychovegetative symptoms (e.g., tremor), reduced concentration, and sleep disturbances and nightmares. Disorders of perception are relatively common and range from hyperacusis to photophobia to dysesthesia; these symptoms are not pathognomonic but are characteristic of benzodiazepine withdrawal. Seizures are quite common, especially if the agent is discontinued abruptly.
A: The overall consensus is that benzodiazepines should be discontinued gradually over a period of several weeks (e.g., 4 to 6 weeks or more for diazepam doses >30 mg per day), to prevent seizures and avoid severe withdrawal symptoms. The use of several benzodiazepines should be converted to the use of one, preferably diazepam. Withdrawal from short-acting benzodiazepines is associated with higher dropout rates than withdrawal from longer-acting agents, but switching from a drug with a short half-life to one with a longer half-life is not associated with a better outcome. Withdrawal is sometimes successful on an outpatient basis, but patients should be hospitalized for withdrawal from very high doses (a dose equivalent to ≥100 mg of diazepam daily). In patients receiving opioid maintenance therapy, the dose of the opioid (e.g., methadone) should be kept stable throughout the benzodiazepine-reduction period and high enough to prevent symptoms of opioid withdrawal. In general, the prognosis for patients who undergo withdrawal treatment for benzodiazepine dependence is fairly good.