Benzodiazepine withdrawal syndrome is caused by stopping benzodiazepines or during dosage reduction of benzodiazepines. Benzodiazepine withdrawal syndrome is the cluster of symptoms which appear when a patient who has taken the drug for a period of time stops taking the drug. Benzodiazepine withdrawal is similar to the alcohol withdrawal syndrome and barbiturate withdrawal syndrome. Chronic exposure to benzodiazepines causes physical adaptations in the brain to 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.

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withdraw from benzodiazepines owing to concerns of adverse effects from prolonged use and many people have successfully withdrawn from the drugs world-wide. 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.

Physical dependence and addiction

Regular use of benzodiazepines at prescribed levels for six weeks was found to produce a significant risk of dependence, with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone. However, with abrupt withdrawal after six weeks of treatment with buspirone, no withdrawal symptoms developed. Various studies have shown between 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.

Benzodiazepine dependence is a frequent complication when they are prescribed for or taken for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis, and epileptic seizures. The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, and use of potent short-acting benzodiazepines among those with certain pre-existing personality characteristics such as dependent personalities, and those prone to drug abuse.

Previously, physical dependence on benzodiazepines was largely thought to occur only in people on high-therapeutic-dose ranges, and low- or normal-dose dependence was not suspected until the 1970s; and it wasn't until the early 1980s that it was confirmed. However, low-dose dependence is now a recognized clinical disadvantage of benzodiazepines, and severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction. Low dose dependence has now been clearly demonstrated in both animal studies and human studies.

In an animal study of four baboons on low-dose benzodiazepine treatment, three out of the four baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment. Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms because low-dose benzodiazepine therapy was continued over a period of 6–10 months, suggesting rapid onset of dependence with benzodiazepines and suggesting that physical dependence was complete after two weeks of chronic, low-dose benzodiazepine treatment. In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment, and withdrawal signs appeared after only three days after high-dose treatment, which demonstrated the extremely rapid development of tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines sensitized baboons to the development of physical dependence.

In humans, chronic, low-therapeutic-dose dependence was demonstrated in experimentally precipitated withdrawal using flumazenil to show physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic therapeutic low-dose subjects included increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch. Healthy control subjects who were not dependent on benzodiazepines exhibited no benzodiazepine withdrawal like effects or notable side effects. In another study of 34 low-dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who received flumazenil whereas those receiving placebo experienced no withdrawal signs. It was also found that those dependent on low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to flumazenil precipitated benzodiazepine withdrawal. It has been estimated that 30–45% of chronic low dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days to avoid dependence.

Some controversy remains, however, in the medical literature as to the exact nature of low-dose dependence and the difficulty in getting patients to discontinue their benzodiazepines, with some papers attributing the problem to predominantly drug-seeking behavior and drug craving, whereas other papers have found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users.

Cross tolerance

Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABA_A receptor. Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. Benzodiazepines are often used for this reason to detoxify alcohol-dependent patients, and can have life-saving properties in preventing and/or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremens. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics. However, alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in alcoholics.

There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates, and the nonbenzodiazepine drugs, corticosteroids which all act by enhancing the GABA_A receptor's function via modulating the chloride ion channel function of the GABA_A receptor.

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3–14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours upon cessation of short acting; and 3–10 days after cessation of longer acting benzodiazepines. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhea.

Physiology of withdrawal

Withdrawal symptoms are a normal response in individuals who have chronically used benzodiazepines, and a side effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABA receptors are the most common receptor system in the central nervous system and use of benzodiazepines has a profound effect on almost every aspect of brain and body function, either directly or indirectly. Benzodiazepines cause a decrease in norepinephrine (noradrenaline), serotonin, acetylcholine and dopamine. These neurotransmitters are needed for normal memory, mood, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control. With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that when benzodiazepines are withdrawn, various neurotransmitter systems go into overdrive due to the lack of inhibitory GABA-ergic activity. Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the adaptions (physical dependence) which have occurred in the CNS.

Withdrawal symptoms typically consist of a mirror image of the drug's effects: sedative effects and suppression of REM and SWS stages of sleep can be replaced by insomnia, nightmares, and hypnogogic hallucinations; its antianxiety effects are replaced with anxiety and panic; muscle relaxant effects are replaced with muscular spasms or cramps; and anticonvulsant effects with seizures, especially in cold turkey or overly-rapid withdrawal.

Clinical trials have shown that benzodiazepines cause an extremely rapid development of tolerance and dependence. Withdrawal symptoms including rebound insomnia and rebound anxiety occurs 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, 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. 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, become distressed, weight loss, panics and depression, felt unreal, 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.

Patients consuming 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 withdrawal symptoms such as rebound anxiety between doses and craving for the next dose of short acting benzodiazepine.

Withdrawal 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. 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.

Common symptoms include:

• Electric shock sensations
• Muscular spasms, cramps or fasciculations
• Insomnia
• Headache
• Rebound REM sleep
• Hyperosmia
• Metallic taste
• Photophobia
• Paranoia
• Hypnagogia-hallucinations
• Nausea and vomiting
• Nightmares
• Anxiety, possible panic attacks
• Impaired concentration
• 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)
• Tinnitus
• Paraesthesia
• Visual disturbances
• Gastrointestinal problems (Stomach and abdomen)

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)
• Temporal lobe epilepsy
• Suicide
• Attempted suicide
• Suicidal ideation
• Self harm
• Hyperthermia
• Delusions
• Homicidal ideation
• Violence
• Post Traumatic Stress Disorder
• Psychosis
• Confusion
• Mania
• Effects similar to delirium tremens

Time of appearance and duration

Withdrawal symptoms can occur whilst 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.

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.

As withdrawal progresses after some weeks or months many individuals begin to experience "windows of normality", where they experience little or no symptoms. These windows can last for hours or days. Over time these windows increase in frequency until withdrawal symptoms completely abate. A theory for this phenomenon is the affinity for GABA of the benzodiazepine receptor is switching from one state to the other as tolerance to the drug is beginning to reverse.

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.

Reasons for withdrawing

Chronic benzodiazepine users decide to withdraw from benzodiazepines for a variety of reasons including worsening mental and physical health caused by benzodiazepines or increasing cognitive side effects caused by chronic benzodiazepine use. Long term users of benzodiazepines show impairments in visual-spatial ability and sustained attention and posterior cortical cognitive function. Cognitive impairments including verbal learning and verbal memory, psychomotor, visuo-motor and visuo-conceptual abilities showed some improvements after 6 months post withdrawal from therapeutic doses of benzodiazepines.

Chronic long term use of benzodiazepines is associated with an increased risk of impulsive, aggressive and violent behaviour. A study showed that 53% of long term benzodiazepine users showed violent characteristics where as only 5.3% of patients receiving psychotherapy developed violent or aggressive behavioural patterns. Studies have shown that long term use of benzodiazepines is associated with causing depression as well as a markedly raised suicide risk as well as an overall increased mortality risk. Daily users of benzodiazepines are also at a higher risk of experiencing psychotic symptomatology such as delusions and hallucinations.

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that long term use of benzodiazepines causes a wide range of psychological and physiological disorders. It was found that after several years of chronic benzodiazepine use that a large portion of patients developed various mental and physical health problems including agoraphobia, irritable bowel syndrome, paraesthesiae, increasing anxiety and panic attacks which were not preexisting. The mental health and physical health symptoms induced by long term benzodiazepine use gradually improved significantly over a period of a year following a slow withdrawal. Three of the 50 patients had wrongly been told at one time that they had multiple sclerosis when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken drug overdoses whilst on benzodiazepines despite only two of the patients having had any prior history of depressive symptomatology. After withdrawal no patients took any further overdoses and after 1 year post withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal type symptoms emerged despite a stable prescribed doses being taken. Another theory is that chronic benzodiazepine use causes subtle increasing toxicity which in turn leads to increasing psychopathology in long term users of benzodiazepines.

The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry sponsored trials on their own results showing that use of hypnotics is correlated with depression. The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that "major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia. Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. There have been 15 epidemiologic studies which have shown that hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. Not only are benzodiazepines associated with an increased risk of cancer, the benzodiazepine receptor agonist Z-drugs also are associated with cancer in humans in these studies. Initially FDA reviewers did not want to approve the Z drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer. The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer".

Benzodiazepine withdrawal management

See also Benzodiazepine half life and equivalency table

The success rate of a slow withdrawal schedule is approximately 65%. 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. 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 or 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.

People withdrawing from benzodiazepines should be careful that they do not supplement their benzodiazepines for drugs which work through the same or similar GABA mechanism including alcohol, barbiturates and the nonbenzodiazepine Z drugs otherwise they may keep the dependency going.

Fluoroquinolone antibiotics have been noted by Professor Heather Ashton and confirmed in a study as often causing serious complications in patients taking 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.

Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions. The addition of an SSRI antidepressant has been found to have little value in the treatment of benzodiazepine withdrawal.

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 for between four months and two years, depending on personal biochemisty. 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.

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 strongly recommended that during benzodiazepine withdrawal that the drug used is diazepam (Valium) or chlordiazepoxide (Librium) as they has a longer half-life than most other benzodiazepines such as Lorazepam (Ativan) and hence a smoother withdrawal. It is virtually impossible to withdraw successfully if the addiction is to a short to intermediate half-life hypnotic benzodiazepine such as Temazepam (Normison), the toll on the body is too high and debilitating. It is also critical that whilst the early and mid part of withdrawal should be managed with a 1 mg (for diazepam) or 5 mg (for chlordiazepoxide) reduction every 2 weeks, the reduction down to 5 mg (for diazepam) or 12.5 mg (for chlordiazepoxide) daily is a key milestone. From 5 mg down to 0 mg (for diazepam) or 12.5 mg to 0 mg (for chlordiazepoxide) a taper of 0.5mg (for diazepam) or 1.25 mg (for chlordiazepoxide) reduction every three weeks makes this much more tolerable on the mind and body. Usually, for most people, once off the drug, a sense of relief and well-being can be felt after 2–3 months of total abstinence.

It is very important to use the correct benzodiazepine equivalencies when switching benzodiazepines either therapeutically or in the management of withdrawal. This importance 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 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.

High dose withdrawal

Abrupt withdrawal from very high doses can cause severe withdrawal effects. Withdrawal from high dose abuse of nitrazepam have caused severe hypoperfusion of the whole brain with diffuse slow activity on EEG. After withdrawal, abnormalities in hypofrontal brain wave patterns persist beyond the withdrawal syndrome which suggested organic brain damage occurs from chronic high dose abuse of benzodiazepines. High dose abusers of benzodiazepines have enlarged cerebrospinal fluid spaces with associated brain shrinkage. Neuropsychological function can be permanently affected by abuse of benzodiazepines with brain damage similar to alcoholic brain damage, as was shown in a 4– to 6-year follow-up study of benzodiazepine abusers by Borg and others of the Karolinska Institute. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in hypnotic benzodiazepine abusers, it is often permanent. An earlier study by Borg et al. found evidence of cerebral disorder in those that exclusively abused benzodiazepines, suggesting that cerebral disorder was not the result of other substances of abuse.

Variations

Some people experience little or no withdrawal when stopping long term benzodiazepine usage. It is not known for sure why there is such a variation between patients but recent research in animals suggests that withdrawal from sedative hypnotic drugs may be influenced by a genetic component. As withdrawal progresses patients often find that their physical and mental health improves with improved mood and improved cognition.

Complications

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 Post Traumatic Stress Disorder as a result. A slow withdrawal regime coupled with reassurance seems to improve the outcome for individuals undergoing benzodiazepine withdrawal.

Protracted withdrawal

Benzodiazepine dependence is a potentially clinically serious condition and its withdrawal syndrome is complex and often protracted in time course.

Protracted withdrawal symptoms refers to symptoms persisting for a protracted time, perhaps 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 strong anecdotal evidence that a slow-withdrawal rate significantly reduces the risk of a protracted and/or severe withdrawal state. About 10–15% of people who discontinue benzodiazepines develop protracted withdrawal syndrome. 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.

Disturbances in mental function can persist for several months or sometimes longer. Psychotic depression persisting for more than a year following benzodiazepine withdrawal has been documented in the medical literature. The patient had no prior psychiatric history. The symptoms reported in the patient included, major depressive disorder with psychotic features, including persistent depressed mood, poor concentration, decreased appetite, insomnia, anhedonia, anergia and psychomotor retardation. The patient also had paranoid ideation believing she was being poisoned and persecuted by co-employees, and sensorary hallucinations. Symptoms developed after abrupt withdrawal of chlordiazepoxide and persisted for 14 months. Various psychiatric medications were trialed which were unsuccessful in alleviating the symptomatology. Symptoms were completely relieved by recommencing chlordiazepoxide for irritable bowel syndrome 14 months later. Sensorary 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 meta-analysis found that the literature shows that cognitive impairments due to benzodiazepines use shows improvements after 6 months after withdrawal but the remaining cognitive impairments may be permanent or may require more than 6 months to return to normal.

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 manufacturer of Klonopin (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, 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.

Cognitive behavioral therapy

Nitrazepam, temazepam and zopiclone are the most frequently prescribed hypnotics in the United Kingdom. Hypnotic drugs are of poor value for the management of chronic insomnia. Hypnotic drug consumption has been shown to reduce work performance, increase absenteeism, increase road traffic accidents, increased morbidity, increase mortality and is associated with an increased incidence of deliberate self harm. In the elderly, increases in falls and fractures associated with sedative hypnotic drug use has been found. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly which compounds the problem of chronic hypnotic drug use. Cognitive behavioural therapy has been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers in the UK. Meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large scale trial utilising cognitive behavioural therapy in chronic users of sedative hypnotics including nitrazepam, temazepam and zopiclone found CBT to be a significantly more effective long term treatment for chronic insomnia than sedative hypnotic drugs. Persisting improvements in sleep quality, sleep onset latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3, 6 and 12 month follow up was found in those receiving cognitive behavioural therapy. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia was flexible, practical and a cost effective treatment and it was also concluded that CBT leads to a reduction of benzodiazepine drug intake in a significant number of patients.

Detox Controversy

In some instances, a "Detox" or other inpatient facility will take a patient off a benzodiazepine "cold turkey" — replacing it with a short taper of Phenobarbital (a barbiturate) to prevent seizures. This method of coming off a benzodiazepine is highly controversial and often called "barbaric." 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.

However, 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 normalisation of receptor function. Flumazenil stimulates the upregulation and reverses the uncoupling of benzodiazepine receptors to the GABA receptor thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.

See also

• Alcohol withdrawal syndrome
• Benzodiazepine equivalence
• Benzodiazepine
• Post Acute Withdrawal Syndrome
• SSRI discontinuation syndrome

References

External links

• Benzodiazepines: How they work and how to withdraw by Professor Heather Ashton