Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal or BZD withdrawal —is the cluster of signs and symptoms that emerge when a person who has been taking benzodiazepines, either medically or recreationally, and has developed a physical dependence, undergoes dosage reduction or discontinuation. Development of physical dependence and the resulting withdrawal symptoms, some of which may last for years, may result from taking the medication as prescribed. Benzodiazepine withdrawal is characterized by sleep disturbance, irritability, mast cell activation, increased tension and anxiety, panic attacks, hand tremor, shaking, sweating, difficulty with concentration, confusion and cognitive difficulty, memory problems, dry retching and nausea, weight loss, palpitations, headache, muscular pain and stiffness, a host of perceptual changes, hallucinations, seizures, psychosis, and increased risk of suicide (see "signs and symptoms" section below for full list). Further, these symptoms are notable for the manner in which they wax and wane and vary in severity from day to day or week by week instead of steadily decreasing in a straightforward monotonic manner. This phenomenon is often referred to as "waves" and "windows". It is a potentially serious condition, and is complex and often protracted in its course. Long-term benzodiazepine use, defined as daily use for at least three months, is not desirable because of the associated increased risk of dependence, dose escalation, loss of efficacy, increased risk of accidents and falls, particularly for the elderly, as well as cognitive, neurological, and intellectual impairments.
Ethanol, the primary alcohol in alcoholic beverages, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines. Flumazenil has been found to stimulate the reversal of tolerance and the normalization of receptor function. However, further research is needed in the form of randomised trials to demonstrate its role in the treatment of benzodiazepine withdrawal. Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABAA receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates. Because of limited research and experience compared to the possible risks involved, the flumazenil detoxification method is controversial and can only be done as an inpatient procedure under medical supervision.Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles feeling, burning skin, pain and subjective sensations of bodily distortion.