NSAIDs have some mild GABA antagonistic properties and animal research indicate that some may even displace benzodiazepines from their binding site. However, NSAIDs taken in combination with fluoroquinolones cause a very significant increase in GABA antagonism, GABA toxicity, seizures, and other severe adverse effects. Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal. Imipramine was found to statistically increase the discontinuation success rate. Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia. Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred. In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper. Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms, and reduce the risk of relapse. Propranolol was not found to increase the discontinuation success rate. SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal. Trazodone was not found to increase the discontinuation success rate. Inpatient treatment
Inpatient drug detox or rehabilitation facilities may be inappropriate for those who have become tolerant or dependent while taking the drug as prescribed, as opposed to recreational use. Such inpatient referrals may be traumatic for these individuals. Prognosis
A 2006 meta-analysis found evidence for the efficacy of stepped care: minimal intervention (e.g.
The exact reason for the reduced responsiveness has not been elucidated but down-regulation of the number of receptors has only been observed at some receptor locations including in the pars reticulata of the substantia nigra; down-regulation of the number of receptors or internalization does not appear to be the main mechanism at other locations. Evidence exists for other hypotheses including changes in the receptor conformation, changes in turnover, recycling, or production rates, degree of phosphorylation and receptor gene expression, subunit composition, decreased coupling mechanisms between the GABA and benzodiazepine site, decrease in GABA production, and compensatory increased glutamatergic activity. A unified model hypothesis involves a combination of internalization of the receptor, followed by preferential degradation of certain receptor sub-units, which provides the nuclear activation for changes in receptor gene transcription.It has been postulated that when benzodiazepines are cleared from the brain, these neuroadaptations are "unmasked", leading to unopposed excitability of the neuron. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Increased glutamate excitatory activity during withdrawal may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse. Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around. Diagnosis
In severe cases, the withdrawal reaction or protracted withdrawal may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, agitated depression, panic disorder, generalised anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorders.