Sedative hypnotics, such as benzodiazepines, barbiturates and alcohol cause the most serious medical complications during withdrawal. They are considered more clinically hazardous to withdraw from than opiates.[12Due to tolerance and physical and psychological dependence, benzodiazepines are generally recommended only for short-term use, several weeks, followed by a dose titration off of the medication.[13.

Withdrawal symptoms can occur while on a stable dose of benzodiazepines due to the "tolerance withdrawal" phenomenon, where the body experiences "withdrawal effects" and craves increasing doses to feel normal which can lead to dosage escalation, but most often withdrawal symptoms occur during dosage reduction. It is difficult to say who will suffer withdrawal symptoms. Some estimates say anything from 15% of people who have taken benzodiazepines for a year will suffer from clinically significant withdrawal symptoms. Onset of the withdrawal syndrome from long half-life benzodiazepines might be delayed for up to 3 weeks, although withdrawal symptoms from short-acting benzodiazepines often presents early, usually within 24–48 hours.Withdrawal symptoms from low dose dependence typically last 6–12 months and gradually improve over that time period. Symptoms may lack a psychological cause and can fluctuate in intensity with periods of good and bad days until eventual recovery.[17][18][19] For this reason, many experts agree that after withdrawal from long term or even fairly short term use of benzodiazepine drugs, at least six months should have elapsed prior to re-evaluating the symptoms and updating a diagnosis. The acute benzodiazepine withdrawal syndrome generally lasts for about 2 months but clinically significant withdrawal symptoms may persist, although gradually declining, for many months or even several years. The severity and length of the withdrawal syndrome is likely determined by various factors including rate of tapering, length of use of benzodiazepines and dosage size and possibly genetic factors.[3][22]

Symptoms such as rebound insomnia and rebound anxiety may occur after only 7 days administration of benzodiazepines.After only 8–9 weeks of alprazolam (Xanax) taken at a fixed prescribed dose, the following symptoms have been found to occur during abrupt discontinuation: dysphoria, fatigue, low energy, confusion, and elevated systolic blood pressure, severe anxiety.[35]

Benzodiazepines cause enhanced GABA inhibition; when this inhibition is sustained, i.e. long-term use, this increased central nervous system depression is balanced by neuroadaptations which result in decreased GABA inhibition and increased excitability of the glutamate system. When benzodiazepines are stopped, these neuroadaptations are "unmasked" leading to excitability of the nervous system and the appearance of withdrawal symptoms. Increased glutamate excitatory

activity during withdrawal is believed to result in kindling phenomena.Repeated benzodiazepines withdrawals, like with alcohol withdrawal, may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse.[84Detoxification of a benzodiazepine dependent individual is often carried out using an equivalent dose of either diazepam or chlordiazepoxide to the benzodiazepine the individual is dependent on and by reducing in steps of 10% every 2–4 weeks depending on the severity of the dependency and the patient's response to reductions. However, if withdrawal is carried out slow enough and preferably using an equivalent dose of diazepam or chlordiazepoxide to withdraw, many benzodiazepine dependent patients find that they experience little or sometimes no withdrawal when it comes time to come off the last 0.5 mg dose of diazepam or 5 mg dose of chlordiazepoxide. Those who have withdrawn slow enough but still experience withdrawal effects typically find that their withdrawal symptoms have largely disappeared after a few months.[3] It is important to note that the elimination half-life of diazepam and chlordiazepoxide as well as other long half-life benzodiazepines is twice as long in the elderly compared to younger individuals. Many doctors do not adjust benzodiazepine dosage according to age in elderly patients.[110]

It is strongly recommended that during benzodiazepine withdrawal that the drug used is diazepam (Valium) or chlordiazepoxide (Librium) as they are available in low potency doses in addition to having a longer half-life than most other benzodiazepines such as lorazepam (Ativan) or alprazolam (Xanax

Detoxification of a benzodiazepine dependent individual is often carried out using an equivalent dose of either diazepam or chlordiazepoxide to the benzodiazepine the individual is dependent on and by reducing in steps of 10% every 2–4 weeks depending on the severity of the dependency and the patient's response to reductions. However, if withdrawal is carried out slow enough and preferably using an equivalent dose of diazepam or chlordiazepoxide to withdraw, many benzodiazepine dependent patients find that they experience little or sometimes no withdrawal when it comes time to come off the last 0.5 mg dose of diazepam or 5 mg dose of chlordiazepoxide. Those who have withdrawn slow enough but still experience withdrawal effects typically find that their withdrawal symptoms have largely disappeared after a few months.[3] It is important to note that the elimination half-life of diazepam and chlordiazepoxide as well as other long half-life benzodiazepines is twice as long in the elderly compared to younger individuals. Many doctors do not adjust benzodiazepine dosage according to age in elderly patients.[110]

It is strongly recommended that during benzodiazepine withdrawal that the drug used is diazepam (Valium) or chlordiazepoxide (Librium) as they are available in low potency doses in addition to having a longer half-life than most other benzodiazepines such as lorazepam (Ativan) which is more preferable in partient

with liver diseas.

In some instances, a "detox" or other inpatient facility will take a person off a benzodiazepine "cold turkey" — replacing it with a short 1 – 2 week taper of phenobarbital (a barbiturate) to prevent seizures. Most physicians and medical authorities agree that in the majority of cases a slow taper is preferred to a rapid taper or "cold turkey" withdrawal from a benzodiazepine. A less harsh method is replacement with phenobarbital followed by a slow reduction of the phenobarbital. In a comparison study a rapid detoxification using benzodiazepines was found to be superior to a phenobarbital rapid detoxification.[1is a potentially clinically serious condition and its withdrawal syndrome is complex and often protracted in time course.[121] Patients often have persisting withdrawal symptoms for 6 months to a year or more.[23] Symptoms can include anxiety, irritability, insomnia and an increased sensitivity to light and sound. A small number of people withdrawing from benzodiazepines experience a severe protracted withdrawal syndrome which can include symptoms such as paresthesias, psychosis. These symptoms occur despite no pre-existing history of these symptoms. It is important to distinguish between a return of any pre-existing disorder, a worsening of the pre-existing disorder due to protracted withdrawal and pure protracted withdrawal. Symptoms of protracted withdrawal over time gradually improves whereas symptoms due to other causes typically doesn't improve. Protracted withdrawal syndrome can mimic a range of medical and psychiatric disorders including schizophrenia, agitated depression, generalised anxiety disorder, panic disorder and complex partial seizures. Protracted withdrawal symptoms can be punctuated by periods of good days and bad days. When symptoms increase periodically during protracted withdrawal physiological changes may be present including dilated pupils as well as an increase in blood pressure and heart rate.[4]

The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.[3]

Protracted withdrawal symptoms refers to symptoms persisting for a protracted time, perhaps a year or more. Patients who experience protracted withdrawal from benzodiazepines, which more commonly occurs from over-rapid withdrawal, can be reassured that the evidence shows that symptoms do continue to fade and return to normal over a

period of many months or several years. A figure of 10–15% of patients withdrawing from benzodiazepines may experience a protracted withdrawal syndrome. There is evidence that a slow-withdrawal rate significantly reduces the risk of a protracted and/or severe withdrawal state. There is no known cure for protracted benzodiazepine withdrawal syndrome except time.[6] The post withdrawal syndrome may linger for many months in 10–15% of people and for a smaller number of unfortunate patients for several years. Studies following people up beyond the initial acute withdrawal stage have shown that for many patients symptoms continue to improve the longer they stay off the drug, often to the point where they can eventually resume their normal lives even after years of incapacity imposed by chronic benzodiazepines.[3]

The causes of persisting benzodiazepine withdrawal symptoms are a combination of pharmacological factors such as persisting drug induced receptor changes, psychological factors both caused by the drug and separate from the drug and possibly in some cases, particularly high dose users structural brain damage or structural neuronal damage.[6][122]

Sensory withdrawal related disturbances which can be acute or protracted in duration and are among the clinical features of the benzodiazepine withdrawal syndrome. Protracted tinnitus has been found to be a complication of discontinuation of benzodiazepines with tinnitus persisting for many months or up to a year or more after discontinuation of therapeutic doses of benzodiazepines. Appearance of the tinnitus occurs during dose reduction or discontinuation of benzodiazepines and is alleviated by recommencement of benzodiazepines.[56][123]

A clinical trial of patients taking the benzodiazepine alprazolam (Xanax) for as little as 8 weeks triggered protracted symptoms of memory deficits which were still present after up to 8 weeks post cessation of alprazolam.[124]

A meta-analysis found that the literature shows that cognitive impairments due to benzodiazepine use shows improvements after 6 months after withdrawal but the remaining cognitive impairments may be permanent or may require more than 6 months to reverse.[125]