Benzodiazepine_withdrawal_syndrome

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Benzodiazepine withdrawal syndrome

Benzodiazepine withdrawal syndrome
Benzodiazepines Benzodiazepine List of benzodiazepines Benzodiazepine overdose Benzodiazepine dependence Benzodiazepine withdrawal syndrome Long term effects of benzodiazepines
Benzodiazepine withdrawal syndrome Classification and external resources ICD-10 F13..3

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 reduces the dosage too rapidly. Benzodiazepine withdrawal is similar to the alcohol withdrawal syndrome and barbiturate withdrawal syndrome.[1] 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.[2] Generally the higher the dose and the longer a benzodiazepine is used and the more rapidly a benzodiazepine is discontinued then the more likely severe withdrawal symptoms will occur. However, severe withdrawal symptoms can still occur during gradual dose reduction or from relatively low doses.[3] 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.[4][5]

Background
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 wellknown 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.[6]

Physiology of withdrawal
See also: Benzodiazepine dependence Withdrawal symptoms are a normal response in individuals who have chronically used benzodiazepines, and an adverse effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced.

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GABA is the second most common neurotransmitter in the central nervous system (after glutamate[7][8][9]) and by far the most abundant inhibitory neurotransmitter; roughly one-quarter to one-third of synapses use GABA.[10] The 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.[6] Benzodiazepine withdrawal represents in part excitotoxicity to brain neurons.[11] Rebound activity of the hypothalamic-pituitaryadrenocortical axis also plays an important role in the severity of benzodiazepine withdrawal.[12] Tolerance and the resultant withdrawal syndrome may be due to alterations in gene expression which results in long term changes in the function of the GABAergic neuronal system.[13][14] Studies in mice have found that discontinuation of benzodiazepines leads to decreased agonist affinity and increased inverse agonist affinity of the benzodiazepine receptors, essentially causing the receptors to reverse their natural function. This may explain at least in part the cause of the benzodiazepine withdrawal effects. This change in receptor sensitivity may be due to receptor uncoupling.[15] During withdrawal from full or partial agonists changes occur in benzodiazepine receptor with upregulation of some receptor subtypes

Benzodiazepine withdrawal syndrome
and down regulation of other sub receptor types.[16] Symptoms such as rebound insomnia and rebound anxiety may occur after only 7 days administration of benzodiazepines.[17] Another trial demonstrated rebound withdrawal effects after only 18 nights use of lorazepam as a benzodiazepine hypnotic.[18] 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.[19][20] Intermittent use of benzodiazepines even over a short period of time can cause rebound insomnia.[21] 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.[22] Day time withdrawal related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone.[23] 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.[24] 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.[25][26] Repeated benzodiazepines withdrawals, like with alcohol withdrawal, may lead to sensitisation or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse.[27][28][29] (See also alcohol withdrawal syndrome#Kindling)

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Benzodiazepine withdrawal syndrome
Photophobia[38] Paranoia[38] Hypnagogia-hallucinations[39] Nausea and vomiting[34] Elevation in blood pressure[40] Tachycardia[41] Hypertension[42] Postural hypotension[34] Depression (can be severe),[43][44] possible suicidal ideation • Tremor[45][46] • Perspiration[33] • Loss of appetite and weight loss[47] • Dysphoria[48][49] • Depersonalization[50][51] • Derealisation (Feelings of unreality)[52] • Obsessive compulsive disorder[53][54] • Tinnitus[55] • Paraesthesia[38][51] • Visual disturbances[51] • Mood swings[30] • Indecision[30] • Gastrointestinal problems (Irritable bowel syndrome)[56][57][58] 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[59][60] • Catatonia, which may result in death[61][62][63] • Coma[64] (rare) • Suicide[65][66] • Attempted suicide[51] • Suicidal ideation[67] • Self harm[51] • Hyperthermia[34] • Delusions[68] • Homicidal ideation[69] • Urges to shout, throw, break things or to harm someone[30] • Violence[70] • Post Traumatic Stress Disorder[5] • Organic brain syndrome[71] • Psychosis[72][73] • Confusion[74] • Mania[75][76] • Neuroleptic malignant syndrome like event[77] (rare) • delirium tremens[78][79][80] 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 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 improving over that time period. Without any psychological reason, symptoms can fluctuate in intensity with periods of good days and periods of bad days until recovering in time.[30][31][32] For this reason, many experts agree that after withdrawal from long term or even fairly short term use of benzodiazepine drugs, at least six months should have elapsed prior to re-evaluating the symptoms and updating a diagnosis. The 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[30][33] • Agitation and restlessness[30] • Hypochondriasis[30] • Impaired concentration[33] • Nightmares[34] • Insomnia[34] • Muscular spasms, cramps or fasciculations[35] • Electric shock sensations[6][36] • Blurred vision[30] • Dizziness[30] • Dry mouth[30] • Aches and pains[30] • Hearing disturbances[30] • Taste and smell disturbances[30] • Chest pain[30] • Flu like symptoms[30] • Impaired memory and concentration[30] • Increased sensitivity to sound[30] • Increased urinary frequency[30] • Numbness and tingling[30] • Hot and cold flushes[30] • Headache[33] • Rebound REM sleep[37] • Stiffness[30] • Fatigue and weakness[30] • Hyperosmia[38] • Restless legs syndrome[5] • Metallic taste[38]

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withdrawal from sedative hypnotic drugs may be influenced by a genetic component.[1] As withdrawal progresses patients often find that their physical and mental health improves with improved mood and improved cognition.

Benzodiazepine withdrawal syndrome

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.[81] 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.[6][82] 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.[83]

Diazepam 2 mg and 5 mg diazepam tablets, which are commonly used in the treatment of benzodiazepine withdrawal.

Chlordiazepoxide 5 mg capsules, which are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam it has a long elimination half life and long acting active metabolites. 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.[85] Fluoroquinolone antibiotics have been noted by Professor Heather Ashton and confirmed in a study as often causing serious complications in patients chronically taking

Benzodiazepine withdrawal management
See also Benzodiazepine half life and equivalency table

Management
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.[84] The slower the withdrawal rate the less intense the

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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.[6][86][87][88][89] NSAIDs have some mild GABA antagonistic properties and some may even displace benzodiazepines from their binding site according to animal research. Non steroidal antinflamatory drugs 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 and GABA toxicity which may result in seizures and other severe adverse effects (See Fluoroquinolone toxicity).[90][91][92] Benzodiazepine withdrawal related psychosis is generally unresponsive to antipsychotic agents.[36][93] Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including

Benzodiazepine withdrawal syndrome
convulsions.[94][95][96] The addition of an SSRI antidepressant has been found to have little value in the treatment of benzodiazepine withdrawal.[97] Avoidance of or reduction in caffeine intake is sometimes recommended due to reports of it worsening withdrawal symptoms and its stimulatory properties.[6] Interestingly at least one animal study has shown some modulation of the benzodiazepine site by caffeine which produces a lowering of seizure threshold.[98] 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 reexposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome.[99][100] 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.[6][101][102] 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.[6] It is strongly recommended that during benzodiazepine withdrawal that the drug

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used is diazepam (Valium) or chlordiazepoxide (Librium) as they have a longer half-life than most other benzodiazepines such as lorazepam (Ativan) or alprazolam (Xanax)and hence a smoother withdrawal.[103][104] 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.[105][106] 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 0.5 mg (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 wellbeing can be felt after 2–3 months of total abstinence. 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.[51]

Benzodiazepine withdrawal syndrome

Letter to patients
Sending a letter to patients warning of the adverse effects of long term use of benzodiazepines and recommending dosage reduction has been found to be successful and a cost effective strategy in reducing benzodiazepine consumption in general practice. Within a year of the letter going out there was found to be a 17% fall in the number of benzodiazepines being prescribed, with 5% of patients having totally discontinued benzodiazepines.[107][108] A study in Holland reported a higher success rate by sending a letter to patients who are benzodiazepine dependent. The results of the Dutch study reported 11.3% of patients discontinuing benzodiazepines completely within a year.[109]

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 behavioral 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 behavioral 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

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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.[110] Chronic use of hypnotic medications is not recommended due to their adverse effects on health and the risk of dependence. A gradual taper is usual clinical course in getting people off of benzodiazepines but even with gradual reduction a large proportion of people fail to stop taking benzodiazepines. The elderly are particularly sensitive to the adverse effects of hypnotic medications. A clinical trial in elderly people dependent on benzodiazepine hypnotics showed that the addition of CBT to a gradual benzodiazepine reduction program increased the success rate of discontinuing benzodiazepine hypnotic drugs from 38% to 77% and at 12 month follow-up from from 24% to 70%. The paper concluded that CBT is an effective tool for reducing hypnotic use in the elderly and reducing the adverse health effects that are associated with hypnotics such as drug dependence, cognitive impairments and increased road traffic accidents.[111] A study of patients undergoing benzodiazepine withdrawal who had a diagnosis of generalized anxiety disorder showed that those who received CBT had a very high success rate of discontinuing benzodiazepines compared to those who did not receive CBT. This success rate was maintained at 12 month follow up. Furthermore in patients who had discontinued benzodiazepines it was found that they no longer met the diagnosis of general anxiety disorder and that patients no longer meeting the diagnosis of general anxiety disorder was higher in the group who received CBT. Thus CBT can be an effective tool to add to a gradual benzodiazepine dosage reduction program leading to improved and sustained mental health benefits.[112]

Benzodiazepine withdrawal syndrome

Protracted withdrawal
Benzodiazepine dependence is a potentially clinically serious condition and its withdrawal syndrome is complex and often protracted in time course.[113] 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.[39] 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.[39] 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.[39][114] 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,

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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.[115] Another case report, reported similar phenomenomin a female patient who abruptly reduced her diazepam dosage from 30 mg to 5 mg per day. She developed electric shock sensations, depersonalisation, anxiety, dizziness, left temporal lobe EEG spiking activity, hallucinations, visual perceptual and sensorary distortions which persisted for one year.[36] 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.[55][116] 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.[117] 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.[118] 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.[119] Hoffmann–La Roche pharmaceutical company, the inventor of both the first few, as

Benzodiazepine withdrawal syndrome
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.[120]

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.[39]

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.[121] A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal.[30]

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Benzodiazepine withdrawal syndrome
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 epsiodic 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 followup 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.[122]

Elderly
Tobacco and alcohol are the most common substance that elderly people get a dependence on or misuse. The next most common substance that elderly people develop a drug dependence to and/or misuse is benzodiazepines. 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. Drug induced cognitive problems can have serious consequences for elderly people and can lead to confusional states and "pseudo-dementia". About 10% of elderly patients referred to memory clinics actually have a drug induced cause which most often is benzodiazepines. Benzodiazepines have also been linked to an increased risk of road traffic accidents and falls in the elderly. The long term effects of benzodiazepines are still not fully understood in the elderly or any age group. Long term benzodiazepine use is associated with attentional and visuospatial functional impairments. Withdrawal from benzodiazepines can lead to improved alertness and decreased forgetfulness in the elderly. Withdrawal led to statistical significant improvements in memory function and performance related skills in those who withdrew successfully from benzodiazepines whereas those who remained on benzodiazepines experienced worsening symptoms. 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. People who had withdrawn from benzodiazepines also felt their sleep was more refreshing making statements such as "I feel sharper when I wake up" or "I feel better, more awake", or "It used to take me an hour to fully wake up." This suggests that benzodiazepines may actually make insomnia worse in the elderly. The

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Benzodiazepine withdrawal syndrome
the reversal of tolerance and the normalization of receptor function. Flumazenil stimulates the up regulation and reverses the uncoupling of benzodiazepine receptors to the GABA receptor thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.[127][128] 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.[129]

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. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.[123]

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 1 - 2 taper of phenobarbital (a barbiturate) to prevent seizures. This method of coming off a benzodiazepine is highly controversial and often called "barbaric." It is no longer used in the UK but remains a fairly used option in the United States. 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, a less brutal method is replacement with phenobarbital followed by a slow gradual reduction of the phenobarbital. In a comparison study a rapid detoxification using benzodiazepines was found to be superior to a phenobarbital rapid detoxification.[124][125] 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.[39][6] Carbamazepine, an anticonvulsant was found to be ineffective in preventing status epilepticus from occuring during clonazepam withdrawal in two patients who were taking clonazepam as an anti epileptic agent for preexisting seizure disorder.[126] However, more recent research is showing promise with the use of flumazenil in the management of benzodiazepine detoxification. Flumazenil has been found to stimulate

See also
• • • • • • • • • Alcohol withdrawal syndrome Benzodiazepine dependence Benzodiazepine equivalence Benzodiazepine Fluoroquinolone toxicity Physical dependence Post Acute Withdrawal Syndrome Rebound effect SSRI discontinuation syndrome

References
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Health Research) 8 (8): 1–68. PMID 14960254. http://www.hta.ac.uk/ fullmono/mon808.pdf. [111] aillargeon L, Landreville P, Verreault R, B Beauchemin JP, Grégoire JP, Morin CM (November 2003). "Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial". CMAJ 169 (10): 1015–20. PMID 14609970. PMC: 236226. http://www.cmaj.ca/cgi/content/full/169/ 10/1015. [112] osselin P, Ladouceur R, Morin CM, G Dugas MJ, Baillargeon L (October 2006). "Benzodiazepine discontinuation among adults with GAD: A randomized trial of cognitive-behavioral therapy". J Consult Clin Psychol 74 (5): 908–19. doi:10.1037/ 0022-006X.74.5.908. PMID 17032095. [113] ’Connor RD (1993). "Benzodiazepine O dependence--a treatment perspective and an advocacy for control". NIDA Res Monogr 131: 266–9. PMID 8105385. [114] shton CH (March 1995). "Protracted A Withdrawal From Benzodiazepines: The Post-Withdrawal Syndrome". Psychiatric Annals (benzo.org.uk) 25 (3): 174–179. http://www.benzo.org.uk/pha-1.htm. [115] odell JG (Mar-Apr 1997). "Protracted M benzodiazepine withdrawal syndrome mimicking psychotic depression" (PDF). Psychosomatics (Psychiatry Online) 38 (2): 160–1. PMID 9063050. http://psy.psychiatryonline.org/cgi/ reprint/38/2/160.pdf. [116] usto U; Fornazzari L, Naranjo CA B (October 1988). "Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use of Benzodiazepines". J Clin Psychopharmacol 8 (5): 359–62. doi:10.1097/ 00004714-198810000-00010. PMID 2903182. http://www.benzo.org.uk/ busto.htm. [117] urran, Hv; Bond, A; O’Sullivan, G; C Bruce, M; Marks, I; Lelliot, P; Shine, P; Lader, M (Nov 1994). "Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder.". Psychological medicine 24 (4): 969–76. ISSN 0033-2917. PMID 7892364. [118] arker MJ; Greenwood KM, Jackson M, B Crowe SF (April 2004). "Persistence of cognitive effects after withdrawal from

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[127] erra G; Zaimovic A, Giusti F, Moi G, G Brewer C (October 2002). "Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebocontrolled study". Addict Biol 7 (4): 385–95. doi:10.1080/ 1355621021000005973. PMID 14578014. [128] ittle HJ (July 1991). "The L benzodiazepines: anxiolytic and withdrawal effects". Neuropeptides 19 Suppl: 11–4. doi:10.1016/ 0143-4179(91)90077-V. PMID 1679209.

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[129] uta J, Costa E, Davis JM, Guidotti A A (September 2005). "Imidazenil: an antagonist of the sedative but not the anticonvulsant action of diazepam". Neuropharmacology 49 (3): 425–9. doi:10.1016/j.neuropharm.2005.04.005. PMID 15964602.

External links
• Benzodiazepines: How they work and how to withdraw by Professor Heather Ashton • Benzodiazepine withdrawal syndrome at the Open Directory Project

Retrieved from "http://en.wikipedia.org/wiki/Benzodiazepine_withdrawal_syndrome" Categories: Pharmacology, Drug addiction, Drug rehabilitation, Neurology, Psychiatry, Substance-related disorders, Syndromes This page was last modified on 20 May 2009, at 15:01 (UTC). All text is available under the terms of the GNU Free Documentation License. (See Copyrights for details.) Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a U.S. registered 501(c)(3) taxdeductible nonprofit charity. Privacy policy About Wikipedia Disclaimers

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