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withdraw from benzodiazepines owing to concerns of adverse effects from prolonged use and many people have successfully withdrawn from the drugs world-wide.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.
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.
There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates, and the nonbenzodiazepine drugs, corticosteroids which all act by enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor.
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.
Common symptoms include:
An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:
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.
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".
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.
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.
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.