Prolonged regular use of benzodiaze-pines can lead to physical dependence. With the long-acting substances marketed initially, this problem was less obvious in comparison with other dependence-producing drugs because of the delayed appearance of withdrawal symptoms. The severity of the abstinence syndrome is inversely related to the elimination t1/2, ranging from mild to moderate (restlessness, irritability, sensitivity to sound and light, insomnia, and tremulousness) to dramatic (depression, panic, delirium, grand mal seizures). Some of these symptoms pose diagnostic difficulties, being indistinguishable from the ones originally treated. Administration of a benzodiazepine antagonist would abruptly provoke abstinence signs. There are indications that substances with intermediate elimination half-lives are most frequently abused (violet area in B).
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