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Benzodiazepines
Chemical structure diagram of a benzene ring fused to a diazepine ring. Another benzene ring is attached to the bottom of the diazepine ring via a single line. Attached to the first benzene ring is a side chain labeled R7; to the second, a side chain labeled R2'; and attached to the diazepine ring, two side chains labeled R1 and R2.
The core structure of benzodiazepines.
"R" labels denote common locations of
side chains, which give different
benzodiazepines their unique properties.
Benzodiazepine
List of benzodiazepines
Benzodiazepine overdose
Benzodiazepine dependence
Benzodiazepine drug misuse
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] and can in severe cases provoke life threatening withdrawal symptoms such as seizures.[2]

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.[3] 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.[4]

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.[5][6]

Contents

[edit] Background

Sedative hypnotics, such as benzodiazepines, barbiturates and alcohol cause the most serious medical complications during withdrawal. They are considered more clinically hazardous to withdraw from than opiates.[7] Inappropriate long-term use of benzodiazepines by patients is common. Due to tolerance and physical and psychological dependence, benzodiazepines are generally recommended only for short-term use, several weeks, followed by a dose titration off of the medication.[8] The over-prescribing of benzodiazepines on a long-term basis can cause dependence and have many adverse effects on health.[9] Patients typically receive little advice and support from their doctors.[10] As long-term treatment even using low doses of benzodiazepines is associated with adverse effects such as cognitive impairments withdrawal from benzodiazepines is advised.[11]

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withdraw from benzodiazepines owing to concerns of adverse effects from prolonged use and many people have successfully withdrawn from the drugs worldwide.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

[edit] Time of appearance and duration

Withdrawal symptoms can occur while on a stable dose of benzodiazepines due to the "tolerance withdrawal" phenomenon, where the body experiences "withdrawal effects" and craves increasing doses to feel normal which can lead to dosage escalation, but most often withdrawal symptoms occur during dosage reduction. Onset of the withdrawal syndrome from long half-life benzodiazepines might be delayed for up to 3 weeks, although withdrawal symptoms from short-acting benzodiazepines often presents early usually within 24–48 hours.[13]

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.[12][14]

Titrating reduction speed against withdrawal symptoms with a flexibility during the withdrawal phase is the most effective way of reducing the intensity and duration of withdrawal symptoms. Some people may not fully stabalize between dose reductions even when the rate of reduction is slowed down. Such people sometimes simply need to persist with coming off of benzodiazepines as they may not feel better until they have been fully withdrawn from benzodiazepines for a period of time.[15]

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.[16]

It has been found that those who have a prior history of withdrawing from benzodiazepines are less likely to succeed the next time around.[17] 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.[18][19][20] (See also alcohol withdrawal syndrome#Kindling)

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.[21][22]

Symptoms such as rebound insomnia and rebound anxiety may occur after only 7 days administration of benzodiazepines.[23] Another trial demonstrated rebound withdrawal effects after only 18 nights use of lorazepam as a benzodiazepine hypnotic.[24] Rebound day time anxiety and tension develops after only 7 days use of short acting benzodiazepine hypnotics. On withdrawal of benzodiazepines after 7 nights use, withdrawal related insomnia rebounds worse than baseline.[25][26] Intermittent use of benzodiazepines even over a short period of time can cause rebound insomnia.[27] 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.[28] Day time withdrawal related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone.[29] 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.[30]

[edit] 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.[31][32][33] 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:

An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:

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

[edit] Benzodiazepine withdrawal management

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.

See also Benzodiazepine half life and equivalency table

[edit] Management and outcome

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.[81] Withdrawal from benzodiazepines does not lead to an increased switching over to antidepressants.[82] 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.[83]

[edit] Medications and interactions

Fluoroquinolone antibiotics have been noted by Professor Heather Ashton and confirmed in a study as often causing serious complications in patients chronically taking benzodiazepines or undergoing withdrawal from benzodiazepines. This is probably the result of the GABA antagonistic effect of fluoroquinolones. Fluoroquinolones have also been found to competitively displace benzodiazepines from benzodiazepine receptors which can precipitate acute withdrawal symptoms in benzodiazepine dependent subjects. A study reported higher than usual CNS toxicity from fluoroquinolones in subjects who were dependent on or in withdrawal from benzodiazepines. Of the general public 1 - 4% of the public will experience CNS toxicity from fluoroquinolones which may be severe. The incidence of severe CNS toxicity occurs significantly more frequently in the benzodiazepine dependent population. The CNS adverse reactions from fluoroquinolones were similar to those seen in benzodiazepine withdrawal and persisted for weeks or months before subsiding. The symptoms included depression, anxiety, psychosis, paranoia, severe insomnia, parathesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. The study confirmed that fluoroquinolone CNS toxicity can be serious, occurs more frequently in benzodiazepine dependent subjects and concluded that fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. A person with an already compromised GABA system for example one going through benzodiazepine withdrawal is likely to be at an even greater risk of severe adverse reactions.[12][84][85][86][87] 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).[88][89][90]

Benzodiazepine withdrawal related psychosis is generally unresponsive to antipsychotic agents.[37][91] Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions.[92][93][94][95] Some antipsychotic agents may be more risky during withdrawal than others especially clozapine, olanzapine or low potency phenothiazines eg chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.[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.[12] 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 re-exposures 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.[12][100][101]

[edit] Withdrawal process

Detoxification of a benzodiazepine dependent individual is often carried out using an equivalent dose of either diazepam or chlordiazepoxide to the benzodiazepine the individual is dependent on and by reducing in steps of 10% every 2–4 weeks depending on the severity of the dependency and the patient's response to reductions. However, if withdrawal is carried out slow enough and preferably using an equivalent dose of diazepam or chlordiazepoxide to withdraw, many benzodiazepine dependent patients find that they experience little or sometimes no withdrawal when it comes time to come off the last 0.5 mg dose of diazepam or 5 mg dose of chlordiazepoxide. Those who have withdrawn slow enough but still experience withdrawal effects typically find that their withdrawal symptoms have largely disappeared after a few months.[12] It is important to note that the elimination half life of diazepam and chlordiazepoxide as well as other long half-life benzodiazepines is twice as long in the elderly compared to younger individuals. Many doctors do not adjust benzodiazepine dosage according to age in elderly patients.[102]

It is strongly recommended that during benzodiazepine withdrawal that the drug used is diazepam (Valium) or chlordiazepoxide (Librium) as they are available in low potency doses in addition to having a longer half-life than most other benzodiazepines such as lorazepam (Ativan) or alprazolam (Xanax)and hence a smoother withdrawal.[12][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 important that while 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 well-being 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.[52]

[edit] Protracted withdrawal

Benzodiazepine dependence is a potentially clinically serious condition and its withdrawal syndrome is complex and often protracted in time course.[107] Patients often have persisting withdrawal symptoms for 6 months to a year or more.[15]

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.[40]

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.[40] 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.[40][108]

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.[109]

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.[37]

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.[56][110]

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.[111]

A meta-analysis found that the literature shows that cognitive impairments due to benzodiazepine use shows improvements after 6 months after withdrawal but the remaining cognitive impairments may be permanent or may require more than 6 months to reverse.[112]

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.[113]

Hoffmann–La Roche pharmaceutical company, the inventor of both the first few, as well as most Benzodiazepines, such as Librium (chlordiazepoxide), Valium (diazepam), Rohypnol (flunitrazepam), Dormicum (midazolam) and Klonopin/Rivotril (clonazepam), in a 2007 product information publication, acknowledges the existence of protracted benzodiazepine withdrawal syndromes and recommends that its product flumazenil is not used to treat protracted benzodiazepine withdrawal syndromes.[114]

[edit] 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.[40]

[edit] 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.[115] A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal.[31]

[edit] Elderly

A study of the elderly who were benzodiazepine dependent found that withdrawal could be carried out with few complications and could lead to improvements in sleep and cognitive abilities. At 52 weeks after successful withdrawal a 22% improvement in cognitive status was found as well as improved social functioning. Those that remained on benzodiazepines experienced a 5% decline in cognitive abilities which seemed to be faster than that seen in normal aging suggesting that the longer the intake of benzodiazepines the worse the cognitive effects become. Some worsening of symptoms were seen in the first few months of benzodiazepine abstinence but at 24 week follow up elderly subjects were clearly improved compared to those who remained on benzodiazepines. Improvements in sleep were seen at 24 and 52 week follow up. The authors concluded that benzodiazepines were not effective in the long term for sleep problems except in suppressing withdrawal related rebound insomnia. Improvements were seen between 24 and 52 weeks post withdrawal in many factors including improved sleep and improvements in several cognitive and performance abilities. There were some cognitive abilities which did not improve which are sensitive to benzodiazepines as well as age such as 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 follow-up indicating ongoing improvements with benzodiazepine abstinence. Younger people on benzodiazepines also experience cognitive deterioration in visual spacial memory but are not as vulnerable as the elderly to the cognitive effects of benzodiazepines. Improved reactions time were noted at 52 weeks in elderly patients free from benzodiazepines. This is an important function in the elderly especially if they drive a car due to the increased risk of road traffic accidents in benzodiazepine users. At 24 week follow up it was found that 80% of people had successfully withdrawn from benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence on benzodiazepines when the elderly patients realised that they had completed their gradual reduction several weeks previously and had only been taking placebo tablets. This helped reassure them that they could sleep without their pills. The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs.[116]

[edit] Neonatal withdrawal syndrome

Benzodiazepines, especially when taken during the third trimester can cause a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.[117]

[edit] 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 week 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.[118][119]

The success rate of abrupt or over-rapid withdrawal is quite low with high numbers of drop outs and failures. With a slow gradual withdrawal program the success rate is between 88 - 100 percent.[15]

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.[12][40]

Carbamazepine, an anticonvulsant was found to be ineffective in preventing status epilepticus from occurring during clonazepam withdrawal in two patients who were taking clonazepam as an anti epileptic agent for pre-existing seizure disorder.[120]

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 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.[121][122] 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.[123]

[edit] See also

[edit] References

  1. ^ MacKinnon GL, Parker WA (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". Am J Drug Alcohol Abuse 9 (1): 19–33. doi:10.3109/00952998209002608. PMID 6133446. 
  2. ^ Evans, Katie; Sullivan, Michael J. (1 March 2001). Dual Diagnosis: Counseling the Mentally Ill Substance Abuser (2nd ed.). Guilford Press. pp. 52. ISBN 978-1572304468. http://books.google.co.uk/books?id=lvUzR0obihEC. 
  3. ^ Allgulander C, Bandelow B, Hollander E, et al (August 2003). "WCA recommendations for the long-term treatment of generalized anxiety disorder". CNS Spectr 8 (8 Suppl 1): 53–61. PMID 14767398. 
  4. ^ Lader M (December 1987). "Long-term anxiolytic therapy: the issue of drug withdrawal". J Clin Psychiatry 48 Suppl: 12–6. PMID 2891684. 
  5. ^ Onyett SR (April 1989). "The benzodiazepine withdrawal syndrome and its management" (PDF). J R Coll Gen Pract 39 (321): 160–3. PMID 2576073. PMC 1711840. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1711840&blobtype=pdf. 
  6. ^ a b c Ashton H (1991). "Protracted withdrawal syndromes from benzodiazepines". J Subst Abuse Treat (benzo.org.uk) 8 (1-2): 19–28. doi:10.1016/0740-5472(91)90023-4. PMID 1675688. http://www.benzo.org.uk/ashpws.htm. 
  7. ^ Lindsay, S.J.E.; Powell, Graham E., eds (28 July 1998). The Handbook of Clinical Adult Psychology (2nd ed.). Routledge. p. 363. ISBN 978-0415072151. http://books.google.co.uk/books?id=a6A9AAAAIAAJ&pg=PA363. 
  8. ^ Karch, Steven B. (20 December 2006). Drug Abuse Handbook (2nd ed.). United States of America: CRC Press. p. 617. ISBN 978-0849316906. http://books.google.co.uk/books?id=F0mUte90ATUC. 
  9. ^ Tyrer, Peter; Silk, Kenneth R., eds (24 January 2008). "Treatment of sedative-hypnotic dependence". Cambridge Textbook of Effective Treatments in Psychiatry (1st ed.). Cambridge University Press. pp. 402. ISBN 978-0521842280. http://books.google.co.uk/books?id=HLPXELjTgdEC&pg=PA402. 
  10. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM. et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome.". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  11. ^ Heberlein, A.; Bleich, S.; Kornhuber, J.; Hillemacher, T. (Jan 2009). "[Benzodiazepine dependence: causalities and treatment options]". Fortschr Neurol Psychiatr 77 (1): 7-15. doi:10.1055/s-0028-1100831. PMID 19101875. 
  12. ^ a b c d e f g h i Professor Heather Ashton (2002). "Benzodiazepines: How They Work and How to Withdraw". http://benzo.org.uk/manual/index.htm. 
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[edit] External links

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Benzodiazepines (N05BA, N05CD)
1,4-Benzodiazepines
1,5-Benzodiazepines
2,3-Benzodiazepines
Triazolobenzodiazepines
Imidazobenzodiazepines
Oxazolobenzodiazepines
Thienodiazepines
Pyridodiazepines
Pyrazolodiazepines
Pyrrolodiazepines
Benzodiazepine Prodrugs
Others
Retrieved from "http://en.wikipedia.org/wiki/Benzodiazepine_withdrawal_syndrome"



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