Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome, caused by withdrawal or dosage reduction of benzodiazepines, is the symptoms which appear when a patient who has taken the drug for a period of time stops taking the drug. Chronic exposure to benzodiazepines causes physical adaptions in the brain to counteract the drug's effects. This is known as a physical dependence. When the drug is removed or dosage reduced in an individual physically dependent on benzodiazepines, numerous withdrawal symptoms both physical and psychological may appear and will remain present until the body reverses the physical dependence by making adaptions to the drug free environment and thus returning the brain to normal function.
Many patients wish to withdraw from benzodiazepines due to concerns of adverse effects from prolonged use and many people have successfully withdrawn from benzodiazepines world wide. As a result benzodiazepine dependency and withdrawal has been extensively researched in the medical literature. A summary of the medical literature regarding, how benzodiazepines work and how to withdraw, combined with the clinical expertise of Professor Heather Ashton in psychopharmacology, psychiatry and from running a benzodiazepine withdrawal clinic for 12 years has led to the most well known withdrawal guide, known as The Ashton Manual.
Almost anyone can withdraw successfully if sufficiently motivated and knowledgable in how to withdraw from benzodiazepines. However the important thing is that individuals shouldn't be forced, against their wishes, by prescribers to withdraw if they are long term users and dependent on benzodiazepines.
A slower withdrawal rate mitigates the symptoms.
Some of the withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed. The ability to determine the difference between relapse and rebound is very important during the withdrawal phase and can often lead to a misdiagnosis. For this reason, many experts agree that after withdrawal from long term or even fairly short term use of benzodiazepine drugs, at least six months should have elapsed prior to re-evaluating the symptoms and updating a diagnosis.
Commons symptoms include:
- elevation in pulse and blood pressure
- weight loss
- muscular spasms or cramps, fasciculations
Withdrawal symptoms are a normal response in individuals who have chronically used benzodiazepines, and a side effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABA receptors are the most common receptor system in the central nervous system and use of benzodiazepines has a profound effect on almost every aspect of brain and body function, either directly or indirectly. Benzodiazepines cause a decrease in norepinephrine (noradrenaline), serotonin, acetylcholine and dopamine. These neurotransmitters are needed for normal memory, mood, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control. With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that when benzodiazepines are withdrawn, various neurotransmitter systems go into overdrive due to the lack of inhibitory GABA-ergic activity. Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the adaptions (physical dependence) which have occurred in the CNS.
Withdrawal symptoms typically consist of a mirror image of the drug's effects: sedative effects and suppression of REM and SWS stages of sleep can be replaced by insomnia, nightmares, and hypnogogic hallucinations; its antianxiety effects are replaced with anxiety and panic; muscle relaxant effects are replaced with muscular spasms or cramps; and anticonvulsant effects with seizures, especially in cold turkey or overly-rapid withdrawal.
Time of appearance and duration
Withdrawal symptoms can occur whilst on a stable dose of benzodiazepines due to the "tolerance withdrawal" phenomenon, where the body experiences "withdrawal effects" and craves increasing doses to feel normal which can lead to dosage escalation, but most often withdrawal symptoms occur during dosage reduction. Onset of the withdrawal syndrome from long half-life benzodiazepines might be delayed for up to 3 weeks, although withdrawal symptoms from short-acting benzodiazepines often presents early usually within 24-48 hours. 
The acute benzodiazepine withdrawal syndrome generally lasts for about 2 months but clinically significant withdrawal symptoms may persist, although gradually declining, for many months or even several years. The severity and length of the withdrawal syndrome is likely determined by various factors including rate of tapering, length of use of benzodiazepines and dosage size and possibly genetic factors.
As withdrawal progresses after some weeks or months many individuals begin to experience "windows of normality", where they experience little or no symptoms. These windows can last for hours or days. Over time these windows increase in frequency until withdrawal symptoms completely abate. A theory for this phenomenon is the affinity for GABA of the benzodiazepine receptor is switching from one state to the other as tolerance to the drug is beginning to reverse.
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 diazepam for its long half life 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. Fluoroquinolone antibiotics have been noted by Professor Heather Ashton as often causing complications in patients taking or undergoing withdrawal from benzodiazepines. This is probably the result of fluoroquinolones GABA antagonistic effect at the GABAa-BZD receptor complex.
However, if withdrawal is carried out slow enough and preferably using an equivalent dose of diazepam 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. Those who have withdrawn slow enough but still experience withdrawal effects typically find that their withdrawal symptoms have largely disappeared after a few months.
Detoxification of a benzodiazepine dependent individual is often carried out using an equivalent dose of diazepam 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.
Some people experience little or no withdrawal when stopping long term benzodiazepine usage. It is not known for sure why there is such a variation between patients but recent research in animals suggests that withdrawal from sedative hypnotic drugs may be influenced by a genetic component. As withdrawal progresses patients often find that their physical and mental health improves with improved mood and improved cognition.
Over-rapid withdrawal and lack of explanation and failure to reassure individuals that what they are experiencing is withdrawal symptoms and is temporary have led some people to experience increased panic and fears that they are going mad, with some people developing Post Traumatic Stress Disorder as a result. A slow withdrawal regime coupled with reassurance seems to improve the outcome for individuals undergoing benzodiazepine withdrawal.
Protracted withdrawal symptoms
Protracted withdrawal symptoms refers to symptoms persisting for a protracted time, perhaps year or more (and not to the mitigated symptoms achieved by a protracted withdrawal rate). 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.
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.
Mitigation with flumazenil
A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2-2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested that the most likely explanation is that past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and that the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but it was noted that further research is required.
In some instances, a "Detox" or other inpatient facility will take a patient off a benzodiazepine "cold turkey" - replacing it with a short taper of Phenobarbital (a barbiturate) to prevent seizures. This method of coming off a benzodiazepine is highly controversial and often called "barbaric." Most Physicians and medical authorities agree that in the majority of cases a slow taper is preferred to a rapid taper or "cold turkey" withdrawal from a benzodiazepine.
- Professor Heather Ashton (2002). "Benzodiazepines: How They Work and How to Withdraw".
- Kliniska Färdigheter: Informationsutbytet Mellan Patient Och Läkare, LINDGREN, STEFAN, ISBN 91-44-37271-X (Swedish)
- [] (2007). "Hypnotics and anxiolytics". British National Formulary. Unknown parameter
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- Hood, HM (2006). "Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11". Genes, brain, and behavior. 5(1): 1–10. PMID 16436183. Unknown parameter
- Committee on Safety of Medicines (2007). "Hypnotics and anxiolytics". British National Formulary. Unknown parameter
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- Tagashira E (1981). "Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents". Jpn J Pharmacol. 31 (5): 689–99. PMID 6118452. Unknown parameter
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- Professor Heather Ashton (2004). "Protracted Withdrawal Symptoms From Benzodiazepines". Comprehensive Handbook of Drug & Alcohol Addiction.
- Professor Malcolm Lader (1992). "A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal". Journal of Psychopharmacology.