Benzodiazepine withdrawal syndrome

Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence, stops taking benzodiazepine drug(s) or during dosage reductions. Benzodiazepine withdrawal is similar to alcohol withdrawal syndrome and barbiturate withdrawal syndrome and can in severe cases provoke life threatening withdrawal symptoms such as seizures. Severe and life threatening symptoms are mostly limited to abrupt or over-rapid dosage reduction from high doses. A protracted withdrawal syndrome may develop in a proportion of individuals with symptoms such as anxiety, irritability, insomnia and sensory disturbances. In a small number of people it can be severe and resemble serious psychiatric and medical conditions such as schizophrenia and seizure disorders. A serious side effect of benzodiazepine withdrawal is suicide.

The protracted withdrawal can be minimised in intensity and severity by a slow gradual reduction in dosage. Withdrawal of benzodiazepines is usually beneficial due to the adverse effects associated with the long-term use of benzodiazepines. However, it has been recommended that long-term users of benzodiazepines not be forced to withdraw against their will.

Chronic exposure to benzodiazepines causes physical adaptations in the brain that counteract the drug's effects. This is known as a tolerance and physical dependence. When the drug is removed or dosage reduced in an individual physically dependent on benzodiazepines, numerous withdrawal symptoms both physical and psychological may appear and will remain present until the body reverses the physical dependence by making adaptions to the drug-free environment and thus returning the brain to normal function. Generally, the higher the dose and the longer a benzodiazepine is used and the more rapidly a benzodiazepine is discontinued, the more likely severe withdrawal symptoms will occur. However, severe withdrawal symptoms can still occur during gradual dose reduction or from relatively low doses.

In certain selected patient groups the occurrence of withdrawal symptoms is as high as 100%, whereas in unselected patient groups more than 50% of subjects are able to discontinue benzodiazepines with mild or even no withdrawal symptoms at all. Withdrawal symptoms may persist for weeks or months after cessation of benzodiazepines. In a smaller subset of patients withdrawal symptoms may continue at a sub acute level for many months or even a year or more. Long term use of benzodiazepines may lead to withdrawal like symptoms emerging despite a constant therapeutic dose. Correctly attributing previously misdiagnosed withdrawal symptoms such as anxiety to the withdrawal effects of benzodiazepines, individualised taper strategies according to withdrawal severity, the addition of alternative strategies such as reassurance and referral to benzodiazepine withdrawal support groups increase the success rate of withdrawal. Withdrawal symptoms can resemble psychiatric symptoms which doctors often interpret as evidence for the need of benzodiazepines which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often to higher doses.

Background
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. Inappropriate long-term use of benzodiazepines by patients is common. Due 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. The over-prescribing of benzodiazepines on a long-term basis can cause dependence and have many adverse effects on health. Patients typically receive little advice and support from their doctors. As long-term treatment even using low doses of benzodiazepines is associated with adverse effects such as cognitive impairments, withdrawal from benzodiazepines is advised.

Many patients wish to withdraw from benzodiazepines owing to concerns of adverse effects from prolonged use and many people have successfully withdrawn from the drugs worldwide. As a result benzodiazepine dependency and withdrawal have been extensively researched in the medical literature. A summary of the medical literature on benzodiazepines and techniques for withdrawal, combined with the clinical expertise of Professor Heather Ashton in psychopharmacology, psychiatry and the running of a withdrawal clinic for 12 years, has led to a well-known patient's guide:The Ashton Manual. With sufficient motivation and the proper approach, almost all patients can successfully withdraw from benzodiazepines. However, long term users who are dependent on benzodiazepines must not be made to stop abruptly, as they are at high risk of a severe and possibly life threatening withdrawal syndrome. A slower withdrawal rate with a gradually tapered dose typically mitigates this risk.

Signs and symptoms
Some of the withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed. The ability to determine the difference between relapse and rebound is very important during the withdrawal phase and can often lead to a misdiagnosis. 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. 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.

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. 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 benzodiazepines or opioids occur after infusions are withdrawn are common among pediatric intensive care patients. The risk of this syndrome developing is increased by total duration of infusion treatment and the total dose given.

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.

Altering reduction speed according to withdrawal symptom severity is the most effective way of reducing the intensity and duration of withdrawal symptoms. Some people may not fully stabilize between dose reductions even when the rate of reduction is slowed down. Such people sometimes simply need to persist with coming off of benzodiazepines as they may not feel better until they have been fully withdrawn from benzodiazepines for a period of time.

Long term use of benzodiazepines causes cognitive, neurological and intellectual impairments. After one year of abstinence from benzodiazepines cognitive, neurological and intellectual impairments had returned to normal.

Patients who are physically dependent on short-acting anxiolytic benzodiazepines may experience what is known as interdose withdrawal. Interdose withdrawal are withdrawal symptoms which occur between doses when the previous dose wears off. This can lead to symptoms such as rebound anxiety between doses and craving for the next dose of short-acting benzodiazepine.

Symptoms such as rebound insomnia and rebound anxiety may occur after only 7 days administration of benzodiazepines. Another trial demonstrated rebound withdrawal effects after only 18 nights use of lorazepam as a benzodiazepine hypnotic. Rebound day time anxiety and tension develops after only 7 days use of short-acting benzodiazepine hypnotics. On withdrawal of benzodiazepines after 7 nights use, withdrawal related insomnia rebounds worse than baseline. Intermittent use of benzodiazepines even over a short period of time can cause rebound insomnia. Use of short-acting hypnotics while being effective at initiating sleep worsen the second half of sleep due to withdrawal effects. Day time withdrawal symptoms are commonly associated with triazolam. This is due to its very short half life. After only 10 nights of triazolam use patients report anxiety, distress, weight loss, panics and depression, derealization, and develop paranoia. These reactions occurred more commonly with triazolam than lormetazepam which has an intermediate half life. Thus the more short acting a benzodiazepine hypnotic the more severe the day time withdrawal symptoms. Day time withdrawal related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone. 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.

The following symptoms may emerge during gradual dosage reduction but can usually be reduced in intensity or eliminated altogether by reducing the rate of reduction:
 * Anxiety, possible terror and panic attacks
 * Agitation and restlessness
 * Hypochondriasis
 * Dilated pupils
 * Impaired concentration
 * Nightmares
 * Insomnia
 * Muscular spasms, cramps or fasciculations
 * Electric shock sensations
 * Blurred vision
 * Dizziness
 * Dry mouth
 * Aches and pains
 * Hearing impairment
 * Taste and smell disturbances
 * Chest pain
 * Flu like symptoms
 * Impaired memory and concentration
 * Increased sensitivity to touch
 * Increased sensitivity to sound
 * Sounds louder than usual
 * Objects moving
 * Increased urinary frequency
 * Numbness and tingling
 * Hot and cold flushes
 * Headache
 * Rebound REM sleep
 * Stiffness
 * Fatigue and weakness
 * Hyperosmia
 * Restless legs syndrome
 * Metallic taste
 * Photophobia
 * Paranoia
 * Hypnagogia-hallucinations
 * Nausea and vomiting
 * Elevation in blood pressure
 * Tachycardia
 * Hypertension
 * Postural hypotension
 * Depression (can be severe), possible suicidal ideation
 * Tremor
 * Perspiration
 * Loss of appetite and weight loss
 * Dysphoria
 * Depersonalization
 * Derealisation (Feelings of unreality)
 * Obsessive compulsive disorder
 * Tinnitus
 * Paraesthesia
 * Visual disturbances
 * Mood swings
 * Indecision
 * Gastrointestinal problems (Irritable bowel syndrome)

An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:
 * Convulsions, which may result in death
 * Catatonia, which may result in death
 * Coma (rare)
 * Suicide
 * Attempted suicide
 * Suicidal ideation
 * Self harm
 * Hyperthermia
 * Delusions
 * Homicide ideations
 * Urges to shout, throw, break things or to harm someone
 * Violence
 * Post Traumatic Stress Disorder
 * Organic brain syndrome
 * Psychosis
 * Confusion
 * Mania
 * Neuroleptic malignant syndrome like event (rare)
 * Delirium tremens

As withdrawal progresses patients often find that their physical and mental health improves with improved mood and improved cognition.

Mechanism and pathophysiology
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. It has been found that those who have a prior history of withdrawing from benzodiazepines are less likely to succeed the next time around. 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.

Management
The success rate of a slow withdrawal schedule is approximately 65%, however, some studies have found higher success rates of between 88 – 100 percent. Studies have shown that psychiatric patients have a similar success rate of staying off benzodiazepines after a slow withdrawal schedule at 2 year followup post withdrawal. Withdrawal from benzodiazepines does not lead to an increased switching over to antidepressants. The slower the withdrawal rate the less intense the withdrawal symptoms and there is strong anecdotal evidence that slower withdrawal rates decrease the risk of developing a severe protracted benzodiazepine withdrawal syndrome. The rate of withdrawal preferably utilising either diazepam, chlordiazepoxide, for their long half lifes and low potency dose forms, is best carried out according to the withdrawing patient's body response to dose cuts. The British National Formulary, a medical guidance book which is issued to all British doctors, states that it is better to withdraw too slowly rather than too quickly from benzodiazepines.

Medications and interactions
Fluoroquinolone antibiotics have been noted by Professor Heather Ashton and confirmed in a study as often causing serious complications in patients chronically taking benzodiazepines or undergoing withdrawal from benzodiazepines. This is probably the result of the GABA antagonistic effect of fluoroquinolones. Fluoroquinolones have also been found to competitively displace benzodiazepines from benzodiazepine receptors which can precipitate acute withdrawal symptoms in benzodiazepine dependent subjects. A study reported higher than usual CNS toxicity from fluoroquinolones in subjects who were dependent on or in withdrawal from benzodiazepines. Of the general public 1 – 4% of the public will experience CNS toxicity from fluoroquinolones which may be severe. The incidence of severe CNS toxicity occurs significantly more frequently in the benzodiazepine dependent population. The CNS adverse reactions from fluoroquinolones were similar to those seen in benzodiazepine withdrawal and persisted for weeks or months before subsiding. The symptoms included depression, anxiety, psychosis, paranoia, severe insomnia, parathesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. The study confirmed that fluoroquinolone CNS toxicity can be serious, occurs more frequently in benzodiazepine dependent subjects and concluded that fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. A person with an already compromised GABA system for example one going through benzodiazepine withdrawal is likely to be at an even greater risk of severe adverse reactions. NSAIDs have some mild GABA antagonistic properties and some may even displace benzodiazepines from their binding site according to animal research. They do not cause as potent antagonism of GABA function as fluoroquinolones. However, NSAIDs taken in combination with fluoroquinolones causes a very significant increase in GABA antagonism which may result in very severe GABA antagonism, GABA toxicity, and seizures and other severe adverse effects (see fluoroquinolone toxicity).

Benzodiazepine withdrawal related psychosis is generally unresponsive to antipsychotic agents. Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions. Some antipsychotic agents may be more risky during withdrawal than others especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.

The addition of an SSRI antidepressant has been found to have little value in the treatment of benzodiazepine withdrawal. Similarly the addition of progesterone has been found to be ineffective for managing benzodiazepine withdrawal.

Avoidance of or reduction in caffeine intake is sometimes recommended due to reports of it worsening withdrawal symptoms and its stimulatory properties. Interestingly at least one animal study has shown some modulation of the benzodiazepine site by caffeine which produces a lowering of seizure threshold.

Once the benzodiazepine addicted or physically dependent individual has successfully withdrawn from benzodiazepines they should avoid taking even occasionally benzodiazepines or cross tolerant drugs such as alcohol, barbiturates or the nonbenzodiazepines Z drugs which all have a similar mechanism of action for between at least four months and two years, depending on personal biochemistry. This is because tolerance to benzodiazepines has been demonstrated to be still present in patients who have discontinued benzodiazepines between four months and two years post withdrawal. In these patients, even once off low dose, re-exposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome. Alcohol, even mild to moderate use, has been found to be a significant predictor of withdrawal failure probably because of its cross tolerance with benzodiazepines.

Withdrawal process
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. 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.

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) and hence a smoother withdrawal. It can be very difficult to withdraw successfully if the addiction is to a short to intermediate half-life hypnotic benzodiazepine such as temazepam (Normison), lorazepam (Ativan) or alprazolam (Xanax), as the intensity of the withdrawal syndrome can be too high and debilitating.

Failure to use the correct benzodiazepine equivalencies when switching benzodiazepines either therapeutically or in the management of withdrawal may produce severe withdrawal reactions. This was illustrated in a case reported in the medical literature of a man who had been taking doses of lorazepam and alprazolam equivalent of 60 mg of diazepam. He was then switched from the lorazepam and alprazolam to only 7 mg of diazepam per day. Within 36 hours the patient developed somatic symptoms and became convinced that he had an underlying pathology and impulsively attempted suicide by stabbing himself in the abdomen causing himself serious injury requiring emergency surgery. His symptoms and suicide attempt were diagnosed by his GP and psychiatrist as benzodiazepine withdrawal. The patient again tried to withdraw from benzodiazepines but did so too rapidly with erratic dosage reductions and again attempted suicide by inflicting serious stab wounds to his neck and chest which resulted in admittance to a psychiatric unit. The author warned that self harm can be a feature of benzodiazepine withdrawal.

Controversy
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. Often individuals dependent on benzodiazepines are judged to be "an addict" when presenting to their doctor with withdrawal symptoms and inappropriately referred to a substance abuse center. Such referrals are only appropriate for substance abusers and not for non-abusers who are physically dependent on benzodiazepines.

Detoxification from benzodiazepines can be very problematic due to the extremely prolonged and severe withdrawal symptoms that it can provoke. This can lead to collapse of marriages, business failures, bankruptcy, committal to hospital and the most serious adverse effect which is suicide. The success rate of abrupt or over-rapid withdrawal is quite low with high numbers of drop outs and failures. With a slow gradual withdrawal program the success rate is between 88 – 100 percent.

Over-rapid withdrawal and lack of explanation and failure to reassure individuals that what they are experiencing is withdrawal symptoms and is temporary have led some people to experience increased panic and fears that they are going mad, with some people developing a condition similar to Post Traumatic Stress Disorder as a result. A slow withdrawal regime coupled with reassurance seems to improve the outcome for individuals undergoing benzodiazepine withdrawal.

More recent research is showing promise with the use of flumazenil in the management of benzodiazepine detoxification. 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 benzdiazepine 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. Due to only limited research and experience and possible risks involved the flumazenil detoxification method is controversial and can only be done as an inpatient procedure under medical supervision.

A further drug called imidazenil has received some research for management of benzodiazepine withdrawal but is not currently used in the treatment of benzodiazepine withdrawal. Carbamazepine, an anticonvulsant was found to be ineffective in preventing status epilepticus from occurring during clonazepam withdrawal in two patients who were taking clonazepam as an anti epileptic agent for pre-existing seizure disorder.

Prognosis
Benzodiazepine dependence is a potentially clinically serious condition and its withdrawal syndrome is complex and often protracted in time course. Patients often have persisting withdrawal symptoms for 6 months to a year or more. 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. The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.

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. 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.

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.

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.

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.

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.

Neuropsychological testing of a group of patients with persistent benzodiazepine withdrawal symptoms found that psychophysiological markers differed from normal anxiety markers. The study of the group of patients concluded that protracted withdrawal symptoms were a genuine iatrogenic condition caused by the long term prescription of benzodiazepines.

Hoffmann–La Roche pharmaceutical company, the inventor of both the first few, as well as most benzodiazepines, such as Librium (chlordiazepoxide), Valium (diazepam), Rohypnol (flunitrazepam), Dormicum (midazolam) and Klonopin/Rivotril (clonazepam), in a 2007 product information publication, acknowledges the existence of protracted benzodiazepine withdrawal syndromes and recommends that its product flumazenil is not used to treat protracted benzodiazepine withdrawal syndromes.

Examples
Some common protracted withdrawal symptoms include: cognitive deficits, gastrointestinal complaints, insomnia, tinnitus, paraesthesiae (tingling and numbness), pain (usually in limbs and extremities), muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, and blepharospasm.

Effect of flumazenil
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, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested that the most likely explanation is that past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and that the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but it was noted that further research is required. A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal, due the dearth of studies on the subject.

In the elderly
A study of the elderly who were benzodiazepine dependent found that withdrawal could be carried out with few complications and could lead to improvements in sleep and cognitive abilities. At 52 weeks after successful withdrawal a 22% improvement in cognitive status was found as well as improved social functioning. Those that remained on benzodiazepines experienced a 5% decline in cognitive abilities which seemed to be faster than that seen in normal aging suggesting that the longer the intake of benzodiazepines the worse the cognitive effects become. Some worsening of symptoms were seen in the first few months of benzodiazepine abstinence but at 24 week follow up elderly subjects were clearly improved compared to those who remained on benzodiazepines. Improvements in sleep were seen at 24 and 52 week follow up. The authors concluded that benzodiazepines were not effective in the long term for sleep problems except in suppressing withdrawal related rebound insomnia. Improvements were seen between 24 and 52 weeks post withdrawal in many factors including improved sleep and improvements in several cognitive and performance abilities. There were some cognitive abilities which did not improve which are sensitive to benzodiazepines as well as age such as episodic memory. The authors however cited a study in younger patients who at 3.5 year follow-up showed no memory impairments and speculated that certain memory functions take longer to recover from chronic benzodiazepine use and that further improvements in elderly peoples cognitive function may occur beyond 52 weeks post withdrawal. The reason that it took 24 weeks for improvements to be seen after cessation of benzodiazepine use was due to the time it takes the brain to adapt to the benzodiazepine free environment. At 24 weeks significant improvements were found including accuracy of information processing improved but a decline was seen in those who remained on benzodiazepines. Further improvements were noted at 52 week follow-up indicating ongoing improvements with benzodiazepine abstinence. Younger people on benzodiazepines also experience cognitive deterioration in visual spacial memory but are not as vulnerable as the elderly to the cognitive effects of benzodiazepines. Improved reactions time were noted at 52 weeks in elderly patients free from benzodiazepines. This is an important function in the elderly especially if they drive a car due to the increased risk of road traffic accidents in benzodiazepine users. At 24 week follow up it was found that 80% of people had successfully withdrawn from benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence on benzodiazepines when the elderly patients realised that they had completed their gradual reduction several weeks previously and had only been taking placebo tablets. This helped reassure them that they could sleep without their pills. The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs.

Neonatal withdrawal syndrome
Benzodiazepines, especially when taken during the third trimester can cause a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.

Withdrawal during pregnancy
Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic effects of the medications has a high risk of causing serious complications and therefore is not recommended. For example abrupt withdrawal of benzodiazepines or antidepressants has a high risk of causing extreme withdrawal symptoms including suicidal ideation and a severe rebound effect of the underlying mental health disorder if present. This can lead to hospitalisation of the pregnant mother and may potentially lead to suicide attempts and thus potentially the death of the mother and fetus. One study reported that one third of mothers who suddenly discontinued or very rapidly tapered their medications became acutely suicidal due to 'unbearable symptoms'. One woman had a medical abortion as she felt that she could no longer cope and another woman used alcohol in a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines. The study reported that physicians in general are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.