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

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For a discussion of half-lives and equivalencies see also the Benzo FAQ document. Benzodiazepines 1 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. 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.

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 It is not unusual to experience recurrence of apparent benzodiazepine withdrawal symptoms years after a successful withdrawal and a return to normal health. The particular pattern of symptoms is unique to the individual, depending on his physical and psychological makeup, and no doubt on the innate density of his/her benzodiazepine receptors and the balance of his endozepines (see above). The experience of benzodiazepine withdrawal is deeply etched into the mind and memory of those who have been through it, and is actually physically present in the strength and connections of their neural synapses, as all memories are. These recurrent symptoms are all signs of GABA underactivity with its accompanying increased output of excitatory neurotransmitters, resulting in a hyperactive, hypersensitive central nervous system. The mechanism is exactly the same as that of benzodiazepine withdrawal, which is why the symptoms are the same. A normal diet includes a normal amount of fluid consumption. Requirements for water and salt vary with body size, environmental temperature, amount of exercise, etc. so cannot be stated categorically. However, there is no need to drink extra amounts of fluid during withdrawal with the idea of “flushing out impurities/toxins”. The body is very good at doing this, even at minimal fluid consumption, and surplus water is simply excreted. Ashton, H. Benzodiazepine Abuse, Drugs and Dependence, Harwood Academic Publishers (2002), 197-212, Routledge,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. Contributions to marital/domestic disharmony and breakdown due to emotional and cognitive impairment.

Therapeutic actions of benzodiazepines. Regardless of their potency, speed of elimination or duration of effects, the actions in the body are virtually the same for all benzodiazepines. This is true whether they are marketed as anxiolytics, hypnotics or anti-convulsants ( Table 1). All benzodiazepines exert five major effects which are used therapeutically: anxiolytic, hypnotic, muscle relaxant, anticonvulsant and amnesic (impairment of memory) ( Table 2). The advice and explanations given in the Supplement may seem inadequate. They no doubt illustrate how much more we still need to know about benzodiazepines. However, it is important to remember that by far the greatest majority of long-term benzodiazepine users do recover from withdrawal - given time. Even protracted symptoms tend to decrease gradually, sometimes over years. The individual needs to know that the actual drug withdrawal is only the first step towards recovery. It may be followed by a prolonged period of convalescence during which the damage caused to the person's body - and often to his whole life - needs to be repaired as far as possible. But the brain, like the rest of the body, has an enormous capacity for adapting and self-healing. That is how life survives and how ex-benzodiazepine 'addicts' can be optimistic about their future.Ashton, H. Toxicity and adverse consequences of benzodiazepine use. Psychiatric Annals (1995) 25,158-165. The advice given to prescribed benzodiazepine users (and their doctors) in the 'Ashton Manual' remains relevant today and requires little updating. This supplement adds further information in response to questions that have frequently been asked by benzodiazepine users during and after withdrawal. Such questions are difficult to answer because, like most benzodiazepine problems, they depend on many individual factors. Such factors include personality and genetic make-up, reasons for benzodiazepine prescription, dose, duration and type of benzodiazepine use, present symptoms, environmental stresses and others. Individuals seeking answers from the general information provided in this supplement need to work out which factors apply to them personally. 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). At the same time, the nerves to the muscles are hyperexcitable, leading to tremor, tics, jerks, spasm and twitching, and jumping at the smallest stimulus. All this constant activity contributes to a feeling of fatigue and weakness (“jelly-legs”). In addition, the muscles, especially the small muscles of the eye, are not well co-ordinated, which may lead to blurred or double vision or even eyelid spasms (blepharospasm). T he benzodiazepine withdrawal symptom that raises most fear of going mad is hallucination. Terrifying hallucinations have occurred in people undergoing rapid or abrupt withdrawal from high doses, but the reader can be reassured that they are exceedingly rare with slow dosage tapering as outlined in Chapter II. If hallucinations occur, they are usually visual – patients have described hallucinations of a large bat sitting on the shoulder, or the appearance of horns sprouting from a human head – but auditory, olfactory and tactile hallucinations can also occur. Somewhat less frightening are hallucinations of small creatures, usually insects, which may be associated with the sensations of insects crawling on the skin (similar hallucinations occur in cocaine and amphetamine withdrawal). Sometimes hallucinations merge with illusions and misperceptions. For example, a coat hanging on the door may give the illusion of being a person. Floors apparently tilting and walls that seem to slope inwards are perceptual distortions.

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 WITHDRAWALPoor sleep is a common accompaniment of both anxiety and depression. In anxiety there is typically a difficulty in falling asleep, while depression is associated with early morning waking as well as frequent wakings during the night. Insomnia is also common as an acute withdrawal symptom along with nightmares and other sleep disturbances. Occasionally, however, insomnia (sometimes with “restless legs” and muscle jerks) persists as an isolated symptom after other symptoms have disappeared, and may last for many months. However, poor sleepers can be reassured that an adequate sleep pattern does return at last. There are powerful natural mechanisms in the body which ensure that the brain does not become severely sleep-deprived. Sensory and motor disturbances 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. Once 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. Fig. 1. Diagram of mechanism of action of the natural neurotransmitter GABA (gamma aminobutyric acid) and benzodiazepine on nerve cells (neurons) in the brain During benzodiazepine withdrawal, symptoms characteristically wax and wane, varying in severity and type from day to day, week to week, and even during the course of a day. Some symptoms come and go; others may take their place. There is no need to be discouraged by these wave-like recurrences; the waves become less severe and less frequent as time passes. Typically “Windows” of normality, when you feel positively well for a few hours or days, appear after some weeks; gradually the “Windows” become more frequent and last longer, while any intervening discomfort ebbs away.