Benzodiazepines: How They Work and How to Withdraw (aka The Ashton Manual)

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Most of the people attending the clinic had been taking benzodiazepines prescribed by their doctors for many years, sometimes over 20 years. They wished to stop because they did not feel well. They realised that the drugs, though effective when first prescribed, might now be actually making them feel ill. They had many symptoms, both physical and mental. Some were depressed and/or anxious; some had "irritable bowel", cardiac or neurological complaints. Many had undergone hospital investigations with full gastrointestinal, cardiological and neurological screens (nearly always with negative results). A number had been told (wrongly) that they had multiple sclerosis. Several had lost their jobs through recurrent illnesses. Speed of elimination. Benzodiazepines also differ markedly in the speed at which they are metabolised (in the liver) and eliminated from the body (in the urine) ( Table 1). For example, the "half-life" (time taken for the blood concentration to fall to half its initial value after a single dose) for triazolam (Halcion) is only 2-5 hours, while the half-life of diazepam is 20-100 hours, and that of an active metabolite of diazepam (desmethyldiazepam) is 36-200 hours. This means that half the active products of diazepam are still in the bloodstream up to 200 hours after a single dose. Clearly, with repeated daily dosing accumulation occurs and high concentrations can build up in the body (mainly in fatty tissues). As Table 1 shows, there is a considerable variation between individuals in the rate at which they metabolise benzodiazepines. Flumazenil is thought to act by “resetting” GABA/benzodiazepine receptors (See Chapter I) so that they are more receptive to the inhibitory actions of GABA. The results suggest that some protracted symptoms are due to the failure of the receptors to revert to their normal state after they have become unresponsive to GABA, due to the development of tolerance (See Chapter I). The response to flumazenil also shows that benzodiazepines can cause longer-lasting pharmacological effects than previously believed. The same principles apply to food. Humans are singularly well adapted through evolution to obtain the nutrients they need from a wide variety of diets and to eliminate unwanted products. A normal healthy diet which includes generous amounts of fruit and vegetables and a source of protein and fats (from meat or vegetables), and not too much pure sugar or “junk foods”, provides all the nutrients a person needs. There is no general need for dietary supplements or extra vitamins or minerals or for “detoxifying” measures. All these can be harmful in excess. Advice to cut out white flour, white sugar etc. may help certain individuals but I have also observed that overly restrictive diets can have adverse effects. Some people say they have felt much better after going on a particular diet – this makes one wonder what sort of diet they were eating before! Some products which people have tried and found to be at best useless, at worst harmful include: mineral and vitamin supplements, valerian, St. John's Wort, kava-kava, melatonin, Rescue Remedy, BeCalm'd, choline, Noni juice, 5htp, SAMe and GABA. Most recently someone reported adverse effects from a product called Exhilarin (see Terri's Story).

A fascinating symptom in patients undergoing benzodiazepine withdrawal is that they often mention the occurrence of what seem to be intrusive memories. Their minds will suddenly conjure up a vivid memory of someone they have not thought about or seen for years. Sometimes the other person’s face will appear when looking in the mirror. The memory seems uncalled for and may recur, intruding on other thoughts. The interesting thing about these memories is that they often start to occur at the same time that vivid dreams appear; these may be delayed until one or more weeks after the dosage tapering has started. Since recent sleep research indicates that certain stages of sleep (REMS and SWS) are important for memory functions, it is likely that the dreams and the memories are connected. In both cases the phenomena may herald the beginning of a return in normal memory functions and, although sometimes disturbing, can be welcomed as a sign of a step towards recovery. Symptoms of a chronic hyperactive nervous system persisting after withdrawal are listed in the Manual Chapter 3, Table 3.

Discontinuing after short-term use

It has long been known that there is a wide variation between individuals in the rate at which they metabolise psychotropic drugs, including benzodiazepines, antidepressants and antipsychotics. People can be poor or slow metabolisers, normal metabolisers, or extensive metabolisers for these drugs, depending on the genetically determined activity of certain drug metabolising enzymes (CYP450 2D6 enzymes). In particular, there appear to be more poor and slow metabolisers among Asian patients than in European populations, according to an important US study. This means that Asian patients respond to lower doses and experience There has been little clinical progress in the benzodiazepine world since 2002 when the last edition of "Benzodiazepines: How they work and how to withdraw" appeared on www.benzo.org.uk. Benzodiazepines are still over-prescribed globally, often in excessive doses and frequently for too long. Prescriptions for benzodiazepines and the similar 'Z-drugs' are actually increasing in many countries. There is a tendency to prescribe the more potent agents such as clonazepam (Klonopin) and, in the U.S. particularly, alprazolam (Xanax) and zolpidem (Ambien), while lorazepam (Ativan) is still the most commonly prescribed drug for anxiety. The availability of benzodiazepines on the internet has increased their use as 'self-medication' in the general public who are often unaware of their adverse effects and dependence potential. This availability has also added to benzodiazepine use in multidrug abusers. Sensory symptoms: tinnitus, tingling, numbness, deep or burning pain in limbs, feeling of inner trembling or vibration, strange skin sensations Depression, emotional blunting. Long-term benzodiazepine users, like alcoholics and barbiturate-dependent patients, are often depressed, and the depression may first appear during prolonged benzodiazepine use. Benzodiazepines may both cause and aggravate depression, possibly by reducing the brain's output of neurotransmitters such as serotonin and norepinephrine (noradrenaline). However, anxiety and depression often co-exist and benzodiazepines are frequently prescribed for mixed anxiety and depression. Sometimes the drugs seem to precipitate suicidal tendencies in such patients. Of the first 50 of the patients attending my withdrawal clinic ( reported in 1987), ten had taken drug overdoses requiring hospital admission while on chronic benzodiazepine medication; only two of these had a history of depressive illness before they were prescribed benzodiazepines. The depression lifted in these patients after benzodiazepine withdrawal and none took further overdoses during the 10 months to 3.5 years follow-up period after withdrawal. In 1988 the Committee on Safety of Medicines in the UK recommended that "benzodiazepines should not be used alone to treat depression or anxiety associated with depression. Suicide may be precipitated in such patients".

I hardly dare to mention smoking in view of present day attitudes to this unfortunate addiction, but for those who are smokers it is probably asking too much to attempt to stop smoking and withdraw benzodiazepines at the same time. Many people have found that giving up smoking is easier when they are off benzodiazepines, when the desire for nicotine may even wane somewhat. In general, excessive worrying over your undesirable habits (or your diet) can add to the stress of withdrawal. It is better to relax a bit and be gentle with yourself. COURSE OF WITHDRAWAL Ashton, H. Benzodiazepine withdrawal: outcome in 50 patients. British Journal of Addiction (1987) 82,665-671. One mechanism which might be involved in long-term (and possibly permanent) effects of benzodiazepines is an alteration in the activity of benzodiazepine receptors in brain GABA neurones. These receptors down-regulate (become fewer) as tolerance to benzodiazepines develop with chronic use. Such down-regulation is a homeostatic response of the body to the constant presence of the drugs. Since benzodiazepines themselves enhance the actions of GABA, extra benzodiazepine receptors are no longer needed, so many are, in effect, discarded. These down-regulated receptors are absorbed into neurones where, over time, they undergo various changes including alterations in gene expression. When these receptors are slowly reinstated after drug withdrawal, they may return in a slightly altered form. They may not be quite so efficient as before in increasing the actions of GABA, the natural 'calming' neurotransmitter. As a result, the brain may be generally less sensitive to GABA and the individual is left with heightened central nervous system excitability and increased sensitivity to stress. Molecular biologists point out that changes in gene expression can be very slow, or even unable, to reverse. (The action of benzodiazepines at GABA receptors is explained more fully in the Manual).For twelve years (1982-1994) I ran a Benzodiazepine Withdrawal Clinic for people wanting to come off their tranquillisers and sleeping pills. Much of what I know about this subject was taught to me by those brave and long-suffering men and women. By listening to the histories of over 300 "patients" and by closely following their progress (week-by-week and sometimes day-by-day), I gradually learned what long-term benzodiazepine use and subsequent withdrawal entails. Adverse effects in the elderly. Older people are more sensitive than younger people to the central nervous system depressant effects of benzodiazepines. Benzodiazepines can cause confusion, night wandering, amnesia, ataxia (loss of balance), hangover effects and "pseudodementia" (sometimes wrongly attributed to Alzheimer’s disease) in the elderly and should be avoided wherever possible. Increased sensitivity to benzodiazepines in older people is partly because they metabolise drugs less efficiently than younger people, so that drug effects last longer and drug accumulation readily occurs with regular use. However, even at the same blood concentration, the depressant effects of benzodiazepines are greater in the elderly, possibly because they have fewer brain cells and less reserve brain capacity than younger people. There are many measures that will alleviate these symptoms, such as muscle stretching exercises as taught in most gyms, moderate exercise, hot baths, massage and general relaxation exercises. Such measures may give only temporary relief at first, but if practised regularly can speed the recovery of normal muscle tone – which will eventually occur spontaneously. Bodily sensations

Readers may well ask: Why do we have specific benzodiazepine receptors in our brain? They have clearly not evolved over thousands and millions of years just to sit there and wait until Valium arrived! Most drugs that affect the brain act on receptors that are already there, and all of these drugs have subsequently been found to take the place of natural substances synthesised within the body. For example, the receptors for morphine react with natural endogenous endorphins and enkephalins, the physiological pain-killers; the receptors for cannabis are normally stimulated by natural substances called anandamides (named after the Sanskrit word ananda, which means "bliss"); nicotine in tobacco reacts with nicotine receptors for the natural neurotransmitter acetylcholine; all the psychotropic drugs like antidepressants and antipsychotics affect the receptor for natural neurotransmitters such as serotonin, noradrenaline and dopamine. The conclusion from such discoveries is that there must exist a natural benzodiazepine which normally modulates the activity of GABA at GABA/benzodiazepine receptors, like diazepam, and acts as an inborn, calming, sleep-inducing and anticonvulsant agent. Feelings of depersonalisation and of unreality are associated with benzodiazepine withdrawal, although they also occur in anxiety states. They occur most often during over-rapid withdrawal from potent benzodiazepines and are, anecdotally, particularly marked on withdrawal from clonazepam (Klonopin). In these states, the person seems detached from his body and seems almost to be observing it from the outside. Similar experiences are described in near-death states when the individual feels that he is hovering above his body, detached from the events occurring below. They are also described by people involved in extreme emergencies and in individuals subjected to torture. They are clearly not specific to benzodiazepines. Benzodiazepines undoubtedly have effects on the endocrine system, but these have not been closely studied in humans, either during long-term benzodiazepine use or in withdrawal. Many women complain of menstrual problems but these are common in the general population and there is no clear evidence that they are directly attributable to benzodiazepines. A proportion of female long-term benzodiazepine users have had hysterectomies, but again there is no evidence of a direct link with benzodiazepine use. Occasionally both men and women on benzodiazepines complain of breast swelling or engorgement and it is possible that benzodiazepines affect secretion of the hormone prolactin. Endocrine symptoms that are due to benzodiazepines improve after withdrawal. Fits, convulsions Considerable loss of weight (8-10lb or more) sometimes occurs in withdrawal. This may be due to a rebound effect on appetite, since benzodiazepines have been shown to increase appetite in animals. On the other hand, some people gain weight in withdrawal. In any case, weight changes are not severe enough to worry about and normal weight is soon regained after withdrawal. A few people have difficulty in swallowing food – the throat seems to tighten up especially if eating in company. This is usually a sign of anxiety and is well-known in anxiety states. Practising relaxation, eating alone, taking small well chewed mouthfuls with sips of liquid and not hurrying make things easier and the symptom settles as anxiety levels decline. It cannot be too strongly stressed that withdrawal symptoms can be minimised and largely avoided by slow tapering, tailored to the individual’s needs as outlined in Chapter II. However, some long-term benzodiazepine users begin to experience “withdrawal” symptoms even though they continue taking the drug. This is due to the development of drug tolerance ( Chapter I) which sometimes leads doctors to increase the dosage or add another benzodiazepine. Analysis of the first 50 patients who attended my benzodiazepine withdrawal clinic showed that all of them had symptoms on first presentation while still on benzodiazepines (12 of them were taking two prescribed benzodiazepines at once). Their symptoms included the full range of psychological and physical symptoms usually described as benzodiazepine withdrawal symptoms. The process of slow benzodiazepine tapering in these patients caused only slight exacerbation of these symptoms, which then declined after withdrawal.Unfortunately, flumazenil does not at present offer a practical cure for protracted symptoms. The drug has to be infused intravenously and is very short acting so that symptom relief is only temporary. The drug cannot be given to a person who is still taking benzodiazepines as it precipitates an acute withdrawal reaction. However, although protracted sensory and motor symptoms may sometimes seem to be almost permanent, they do in fact decline in severity over the years, even without flumazenil, and they do not signify a major neurological illness. Such symptoms may be partially alleviated by relaxation techniques; some motor and sensory systems may respond to carbamazepine (Tegretol) and motor symptoms may respond to propranolol (Inderal). Poor memory and cognition Potency. A large number of benzodiazepines are available ( Table 1). There are major differences in potency between different benzodiazepines, so that equivalent doses vary as much as 20-fold. For example, 0.5 milligrams (mg) of alprazolam (Xanax) is approximately equivalent to 10mg of diazepam (Valium). Thus a person on 6mg of alprazolam daily, a dose not uncommonly prescribed in the US, is taking the equivalent of about 120mg of diazepam, a very high dose. These differences in strength have not always been fully appreciated by doctors, and some would not agree with the equivalents given here. Nevertheless, people on potent benzodiazepines such as alprazolam, lorazepam (Ativan) or clonazepam (Klonopin) tend to be using relatively large doses. This difference in potency is important when switching from one benzodiazepine to another, for example changing to diazepam during the withdrawal, as described in the next chapter. Do not move on until you feel the tension flowing out of your hands. With each deep breath you should feel your tension flowing away and, as it does, your symptoms will lessen or disappear.” The most prominent effect of benzodiazepines is an anti-anxiety effect – that is why they were developed as tranquillisers. As a consequence, nearly all the acute symptoms of withdrawal are those of anxiety. They have been described in anxiety states in people who have never touched a benzodiazepine and were recognised as psychological and physical symptoms of anxiety long before benzodiazepines were discovered. However, certain symptom clusters are particularly characteristic of benzodiazepine withdrawal. These include hypersensitivity to sensory stimuli (sound, light, touch, taste and smell) and perceptual distortions (for example sensation of the floor undulating, feeling of motion, impressions of walls or floors tilting, sensation of walking on cotton wool). There also appears to be a higher incidence than usually seen in anxiety states of depersonalisation, feelings of unreality, and tingling and numbness. Visual hallucinations, distortion of the body image (“my head feels like a football/balloon”), feelings of insects crawling on the skin, muscle twitching and weight loss are not uncommon in benzodiazepine withdrawal but unusual in anxiety states.

People with such worries can be reassured. All the evidence shows that a steady decline in symptoms almost invariably continues after withdrawal, though it can take a long time – even several years in some cases. Most people experience a definite improvement over time so that symptoms gradually decrease to levels nowhere near as intense as in the early days of withdrawal, and eventually almost entirely disappear. All the studies show steady, if slow, improvement in cognitive ability and physical symptoms. Although most studies have not extended beyond a year after withdrawal, the results suggest that improvement continues beyond this time. There is absolutely no evidence that benzodiaze If on short-acting benzodiazepines ( Table 1) they develop anxiety symptoms between doses, or get craving for the next dose. Most digestive symptoms get better after withdrawal but in a few people they persist and become a protracted symptom, raising fears of food allergy or candida infection. These questions are discussed further in the section on protracted symptoms. Immune systemTake much slower and deeper breaths, making sure that you get air deep down into the lungs instead of just at the top of the chest.” One reassuring finding from many clinical studies is that eventual success in withdrawal is not affected by duration of use, dosage or type of benzodiazepine, rate of withdrawal, severity of symptoms, psychiatric diagnosis, or previous attempts at withdrawal. Thus from almost any starting point, the motivated long-term user can proceed in good heart. PROTRACTED WITHDRAWAL SYMPTOMS These equivalents do not agree with those used by some authors. They are firmly based on clinical experience but may vary between individuals. Oversedation persists longer and is more marked in the elderly and may contribute to falls and fractures. Acute confusional states have occurred in the elderly even after small doses of benzodiazepines. Oversedation from benzodiazepines contributes to accidents at home and at work and studies from many countries have shown a significant association between the use of benzodiazepines and the risk of serious traffic accidents. People taking benzodiazepines should be warned of the risks of driving and of operating machinery.