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

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Antidepressants are the most important adjuvant drugs to consider in withdrawal. As mentioned before, depression can be a real problem in withdrawal and can sometimes be severe enough to pose a risk of suicide, though this is unusual with slow tapering. Like any other depression, the depression in withdrawal responds to antidepressant drugs and is probably caused by the same chemical changes in the brain. Both the “old fashioned” tricyclic antidepressants (doxepin [Sinequan], amitriptyline [Elavil]) and the selective serotonin reuptake inhibitors (SSRIs; fluoxetine [Prozac], paroxetine [Paxil]) can be effective and an antidepressant drug may be indicated if depression is severe. There is a school of thought, mainly amongst ex-tranquilliser users, that is opposed to the taking of any other drugs during withdrawal. But suicides have occurred in several reported clinical trials of benzodiazepine withdrawal. If depression is severe during benzodiazepine withdrawal as in any other situation, it seems foolhardy to leave it untreated.

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 If they have already withdrawn, should they reinstate benzodiazepines and start the withdrawal process again?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. These sensations return towards normal as withdrawal progresses, and some people are pleased with the new, seemingly extraordinary, clarity of their perceptions. Only in withdrawal do they realise how much their senses have been obscured by benzodiazepines. One lady described how thrilled she was when she could suddenly see individual blades of grass in her newly bright green lawn; it was like the lifting of a veil. Thus, these sensations need not give rise to fear; they can be viewed as signs of recovery. Depersonalisation, derealisation In my clinic, nerve conduction studies in patients with such symptoms revealed nothing abnormal – for example, there was no evidence of peripheral neuritis. However, the symptoms were sometimes enough to puzzle neurologists. Three patients with a combination of numbness, muscle spasms and double vision were diagnosed as having multiple sclerosis. This diagnosis, and all the symptoms, disappeared soon after the patients stopped their benzodiazepines. 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 cognitionDo 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.”

Tolerance to the anticonvulsant effects of benzodiazepines makes them generally unsuitable for long-term control of epilepsy. Tolerance to the motor effects of benzodiazepines can develop to a remarkable degree so that people on very large doses may be able to ride a bicycle and play ball games. However, complete tolerance to the effects on memory and cognition does not seem to occur. Many studies show that these functions remain impaired in chronic users, recovering slowly, though sometimes incompletely, after withdrawal. 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. Benzodiazepines are potent anticonvulsants. They can be life-saving in status epilepticus (repeated fits, one after another) and in fits caused by overdose of certain drugs (for example, tricyclic antidepressants). However, rapid withdrawal, especially from high potency benzodiazepines, can precipitate epileptic fits as a rebound reaction. Such an occurrence is extremely rare with slowly eliminated benzodiazepines (e.g. diazepam) or with slow dosage tapering. If a fit does occur in these circumstances, it is usually only a single fit and causes no lasting damage. Other phenomena seen in rapid withdrawal are psychotic symptoms, severe confusion and delirium, but again these hardly ever occur with slow dosage tapering. By following the withdrawal schedules outlined in Chapter II, you can be confident of avoiding these complications. EXTRA MEDICATION DURING BENZODIAZEPINE WITHDRAWAL 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.

Discontinuing after short-term use

Table 3 shows the symptoms most likely to be long-lasting. These include anxiety, insomnia, depression, various sensory and motor symptoms, gastrointestinal disturbances, and poor memory and cognition. The reasons why these symptoms persist in some people are not clear. Probably many factors are involved, some directly due to the drug and some to indirect or secondary effects (See Table 4). TABLE 3. SOME PROTRACTED BENZODIAZEPINE WITHDRAWAL SYMPTOMS Symptoms 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. These equivalents do not agree with those used by some authors. They are firmly based on clinical experience but may vary between individuals. 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.

There is still much to discover about endozepines. Some inhibit diazepam binding and may therefore be anxiogenic while others appear to act like diazepam and enhance GABA activity (as explained in the Manual, Chapter 1). It seems likely that the balance between different endozepines acting at the GABA-A receptor may determine an individual's susceptibility to anxiety and response to benzodiazepine drugs by acting as 'fine-tuners' of GABA-A function.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.

Fig. 1. Diagram of mechanism of action of the natural neurotransmitter GABA (gamma-aminobutyric acid) and benzodiazepines on nerve cells (neurons) in the brain They have taken benzodiazepines in prescribed "therapeutic" (usually low) doses for months or years. 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. 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. Depression may be caused or aggravated by chronic benzodiazepine use, but is also a feature of the withdrawal syndrome. Depressive symptoms may appear for the first time after withdrawal, sometimes after a delay of a few weeks, and it can be severe and protracted for some months. It is not clear whether people who have had depression before, or have a family history of depression, are more prone to this complication, and its causes are not understood. As discussed in Chapters I and II, benzodiazepines disrupt the function of many neurotransmitters and hormones and depression could be the result, for example, of low serotonin activity combined with the stress of withdrawal. If severe enough to require definitive treatment, the depression in withdrawal responds to antidepressant drugs and/or cognitive therapy and usually diminishes gradually over 6-12 months. InsomniaTeaches patients to understand their thinking patterns so that they can react differently to anxiety-provoking situations