Dependence and abuse
Benzodiazepines taken regularly at therapeutic levels can produce physical dependence and withdrawal symptoms when abruptly discontinued. Symptoms such as rebound anxiety, agitation, insomnia, sensory disturbances, and even seizures may result if the medication is not gradually tapered.
In 1990, the APA Task Force on Benzodiazepines concluded that benzodiazepines are not drugs of abuse, although benzodiazepine abuse is common among people who are actively abusing alcohol, opiates, cocaine, or sedative hypnotics.29 Particularly, there is little empirical evidence to guide the rational use of benzodiazepines in the common clinical situation of comorbid anxiety and alcohol use disorders.30 There are advocates on both sides of this issue; extremely careful monitoring is a possible compromise in patients who are abstinent from alcohol.
As Salzman31 pointed out, "dependence" is not necessarily "addiction." Developing dependence is a predictable phenomenon, influenced by dosage, duration of treatment, and other patient factors. Most often, dependence is a normal consequence of long-term pharmacological receptor-site activity. Addiction implies not only dependence, but also nonmedical use, pleasure-seeking use, and often polysubstance abuse. Most benzodiazepine use is not addictive, but appropriate use can sometimes result in dependence.
Whatever the reason for starting benzodiazepines, long-term use takes over many of the functions of the body's GABA neurotransmitter system, leaving a state of GABA underactivity when benzodiazepines are stopped, resulting in hyperexcitability of the nervous system.32 The key point is that it takes time to establish dependency. For example, in a 1983 study of 180 chronically anxious patients taking 15 to 40 mg/d of diazepam, only 3% experienced any symptoms of withdrawal when abruptly switched to placebo after 6 weeks of treatment. Even patients taking diazepam for 14 to 22 weeks had withdrawal symptoms at a rate of only 18%. However, 43% of patients taking diazepam for 8 months or more experienced withdrawal.33 Clearly, patients who have taken a benzodiazepine regularly for many months or years will need very gradual tapering of the drug.
The dosage of a medication also affects withdrawal, but it does so in combination with the duration of treatment and half-life of the benzodiazepine involved. Withdrawal symptoms tend to be more severe and have a quicker onset in patients taking higher doses of benzodiazepines with shorter half-lives. For example, 2 to 10 mg/d of alprazolam for 8 weeks produced withdrawal symptoms in 35% of patients.34 Shorter-acting drugs produce a briefer and more intense reaction that begins within 24 hours of discontinuation. Longer-acting benzodiazepines, in contrast, show a slower development of withdrawal symptoms, beginning several days after discontinuation, with peak effects in about 7 days.
The most common withdrawal symptoms are restlessness, irritability, insomnia, muscle tension, weakness, aches and pains, blurred vision, and a racing heart (in that order). Rarely, after long-term use of high doses or abrupt withdrawal of a short-acting benzodiazepine, a patient may have seizures or experience hallucinations.
Traditional advice for discontinuing benzodiazepines is to reduce the dosage by no more than a quarter of the usual daily dose per week, resulting in a minimum taper time from full dosage to discontinuation of 4 weeks.35 Others recommend even slower tapers, with progressive withdrawal over 10 weeks.36
Benzodiazepines still have a major role in the treatment of acute anxiety symptoms and other psychiatric and medical conditions that are accompanied by anxiety. Benzodiazepines continue to be widely used because, despite their risks and adverse effects, they work quickly, are quite safe when used properly, and have good patient tolerance. Clearly, benzodiazepine abusability and negative effects on wakefulness, attention, memory, and cognition are problems. The possibility of mild cognitive decline with long-term exposure needs further investigation.
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