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If sleep is really a problem, a small dose of a tricyclic antidepressant with sedative effects (see antidepressants, above) is a possible option. Alternatively, an antihistamine with sedative effects (e.g. diphenylhydramine [Benadryl], promethazine [Phenergan]) may be used temporarily. Neither antidepressants nor antihistamines act by the same mechanisms as benzodiazepines. 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. Drug withdrawal reactions in general tend to consist of a mirror image of the drugs’ initial effects. In the case of benzodiazepines, sudden cessation after chronic use may result in dreamless sleep being replaced by insomnia and nightmares; muscle relaxation by increased tension and muscle spasms; tranquillity by anxiety and panic; anticonvulsant effects by epileptic seizures. These reactions are caused by the abrupt exposure of adaptations that have occurred in the nervous system in response to the chronic presence of the drug. Rapid removal of the drug opens the floodgates, resulting in rebound overactivity of all the systems which have been damped down by the benzodiazepine and are now no longer opposed. Nearly all the excitatory mechanisms in the nervous system go into overdrive and, until new adaptations to the drug-free state develop, the brain and peripheral nervous system are in a hyperexcitable state, and extremely vulnerable to stress. Acute withdrawal symptoms
Such experiences probably represent a normal defensive reaction evolved as a protection against intolerable suffering. They may involve a primitive brain mechanism similar to the “freezing” of some animals when presented with an inescapable danger. Like other benzodiazepine withdrawal symptoms, these feelings resolve in time and should not be interpreted as abnormal or crazy. Hallucinations, illusions, perceptual distortions Some people have no problems at all with their digestive systems during or after withdrawal, and may even notice that they are enjoying their food more. Others, perhaps more prone constitutionally, may complain of a range of symptoms associated with “irritable bowel syndrome” (IBS). These can include nausea, vomiting, diarrhoea, constipation, abdominal pain, flatulence, gaseous distension and heartburn. Quite a few have found these symptoms so uncomfortable that they have undergone hospital gastrointestinal investigations, but usually no abnormality is found. The symptoms may be partly due to overactivity in the autonomic nervous system, which controls the motility and secretions of the gut and is very reactive to stress, including the stress of benzodiazepine withdrawal. In addition, there are benzodiazepine receptors in the gut. It is not clear what the functions of these receptors are or how they are affected by benzodiazepines or benzodiazepine withdrawal, but alterations in these receptors may play some part in increasing gut irritability. Coping skills therapy/anxiety management (learning techniques) to avoid anxiety-provoking situations and to deal with anxiety (if it occurs) Socioeconomic costs of long-term benzodiazepine use. The socio-economic costs of the present high level of long-term benzodiazepine use are considerable, although difficult to quantify. Most of these have been mentioned above and are summarised in Table 3. These consequences could be minimised if prescriptions for long-term benzodiazepines were decreased. Yet many doctors continue to prescribe benzodiazepines and patients wishing to withdraw receive little advice or support on how to go about it. The following chapter gives practical information on withdrawal which, it is hoped, will be of use both to long-term benzodiazepine users and to their physicians. Regular moderate exercise is recommended during withdrawal as it maintains general fitness, builds up stamina, increases the circulation to brain, muscle and skin and improves mood, but there is no point in slavishly doing exercises that you hate. The aim is to lead a healthy lifestyle which by definition includes some exercise in a form that is enjoyable for you. Smoking
Discontinuing after short-term use
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. Thus these sensory symptoms, though disconcerting, are usually nothing to worry about. Very occasionally, they may persist (see section on protracted symptoms). Meanwhile, the same measures suggested under muscle symptoms ( above) can do much to alleviate them, and they usually disappear after withdrawal. Heart and lungs On the whole, different approaches suit different individuals and need to be personalised. If you believe in a certain approach, it will probably do you good. Sensory hypersensitivity Dependence. Benzodiazepines are potentially addictive drugs: psychological and physical dependence can develop within a few weeks or months of regular or repeated use. There are several overlapping types of benzodiazepine dependence.
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. 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 days when multi-ethnic populations, including many people of Asian extraction, exist world-wide, doctors and psychiatrists may need to be reminded that in Asian patients, benzodiazepine (and antidepressant or antipsychotic) prescriptions, if considered necessary, should be started at half the standard dose in case they are poor or slow metabolisers. Sensory symptoms: tinnitus, tingling, numbness, deep or burning pain in limbs, feeling of inner trembling or vibration, strange skin sensationsApart from their therapeutic effects in depression and anxiety, some antidepressants have a sedative effect which patients who are particularly plagued with insomnia have found helpful. Low doses (10-50mg) of amitriptyline (Elavil) or doxepin (Sinequan) are remarkably effective in promoting sleep if taken at bed-time. These can be taken for short periods of a few weeks and stopped by reducing the dosage stepwise or taking the drug every other night. Withdrawal is not a problem when small doses are taken for short periods or intermittently. TABLE 2. ANTIDEPRESSANT WITHDRAWAL SYMPTOMS 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).
Ashton, H. Toxicity and adverse consequences of benzodiazepine use. Psychiatric Annals (1995) 25,158-165.
Tolerance. Tolerance to many of the effects of benzodiazepines develops with regular use: the original dose of the drug has progressively less effect and a higher dose is required to obtain the original effect. This has often led doctors to increase the dosage in their prescriptions or to add another benzodiazepine so that some patients have ended up taking two benzodiazepines at once. Take 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.” A dilemma faced by some people in the process of benzodiazepine withdrawal, or after withdrawal, is what to do if they have intolerable symptoms which do not lessen after many weeks. If they are still taking benzodiazepines, should they increase the dose? If they have already withdrawn, should they reinstate benzodiazepines and start the withdrawal process again? This is a difficult situation which, like all benzodiazepine problems, depends to some degree on the circumstances and the individual, and there are no hard and fast rules. 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.
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. 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 Table 1 gives a list of symptoms which were spontaneously described by patients in my withdrawal clinic. It is clearly a long list and is probably not inclusive. Of course, not all patients get all the symptoms, and none of the symptoms are inevitable. Withdrawal often seems to seek out the individual’s most vulnerable points: if he is prone to headaches, worse headaches may feature in withdrawal; if he is prone to “irritable bowel”, digestive symptoms may be aggravated. Such symptoms are nearly always temporary and can be minimised. They are less frightening and seem less important or bizarre if their cause is understood. Furthermore, patients can learn techniques to alleviate or control many of the symptoms: there is a lot they can do to help the TABLE 1. BENZODIAZEPINE WITHDRAWAL SYMPTOMS Sports – aerobics, jogging, swimming, “pilates”, walking and anything active that you find enjoyable 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 sensationsOnce started on an antidepressant for depression, the treatment should be continued for some months (usually about 6 months) to avoid recurrence of the depression. Benzodiazepine tapering can continue during this time, and the antidepressant will sometimes act as a welcome umbrella during the last stages of withdrawal. It is important to finish the benzodiazepine withdrawal before starting to withdraw the antidepressant. Quite often, people taking long-term benzodiazepines are already taking an antidepressant as well. In this case they should stay on the antidepressant until the benzodiazepine withdrawal is complete. 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. 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 system Duration of effects. The speed of elimination of a benzodiazepine is obviously important in determining the duration of its effects. However, the duration of apparent action is usually considerably less than the half-life. With most benzodiazepines, noticeable effects usually wear off within a few hours. Nevertheless the drugs, as long as they are present, continue to exert subtle effects within the body. These effects may become apparent during continued use or may appear as withdrawal symptoms when dosage is reduced or the drug is stopped. A controlled study of long-term benzodiazepine users using brain function techniques would have to be carefully designed and would involve a large number of age and sex matched subjects, probably over 100 in both control and user groups. In the benzodiazepine group it would have to take into account dose, type of benzodiazepine, duration of use, psychiatric history, symptoms, use of alcohol and other drugs, and a number of other factors. Such a study would be expensive and funding would be difficult to obtain. Drug companies would be unlikely to offer support, and to date 'independent' bodies such as the Medical Research Council, the Wellcome Foundation and the Department of Health have shown little interest. Thus the question of whether benzodiazepines cause brain or other organ damage remains unanswered.
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