Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, however, the continued use seems to be associated with the avoidance of unpleasant withdrawal reaction rather than from the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, without the described dependence behavior.Addiction consists of people misusing or craving the drug not to relieve withdrawal symptoms, but to experience its euphoric or intoxicating effects. It is necessary to distinguish between addiction to and abuse of benzodiazepines and physical dependence on them. The increased GABA inhibition on the neural systems caused by benzodiazepines is counteracted by the bodys development of tolerance to the drugs effects; the development of tolerance occurs as a result of neuroadaptations, which result in decreased GABA activity and increased excitability of the glutamate system; these adaptations occur as a result of the body trying to overcome the central nervous system depressant effects of the drug to restore homeostasis. When benzodiazepines are stopped, these neuroadaptations are "unmasked" leading to hyper-excitability of the nervous system and the appearance of withdrawal symptoms.Therapeutic dose dependence is the largest category of people dependent on benzodiazepines. These individuals typically do not escalate their doses to high levels and generally use their medication as intended by their prescriber.
The active metabolite of progesterone has been found to enhance the binding of benzodiazepines to the benzodiazepine binding sites on the GABAA receptor. The cross-tolerance between GABAA receptor positive modulators, including benzodiazepines, occurs because of the similar mechanism of action and the subunit changes that occur from chronic use from one or more of these compounds in expressed receptor isoforms. Abrupt withdrawal from any of these compounds, e.g., barbiturates, benzodiazepines, alcohol, corticosteroids, neuroactive steroids, and nonbenzodiazepines, precipitate similar withdrawal effects characterized by central nervous system hyper-excitability, resulting in symptoms such as increased seizure susceptibility and anxiety. While many of the neuroactive steroids do not produce full tolerance to their therapeutic effects, cross-tolerance to benzodiazepines still occurs as had been demonstrated between the neuroactive steroid ganaxolone and diazepam. Alterations of levels of neuroactive steroids in the body during the menstrual cycle, menopause, pregnancy, and stressful circumstances can lead to a reduction in the effectiveness of benzodiazepines and a reduced therapeutic effect. During withdrawal of neuroactive steroids, benzodiazepines become less effective. Physiology of withdrawal
Withdrawal symptoms are a normal response in individuals having chronically used benzodiazepines, and an adverse effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABA is the second-most-common neurotransmitter in the central nervous system (the most common being glutamate) and by far the most abundant inhibitory neurotransmitter; roughly one-quarter to one-third of synapses use GABA.