CHAPTER THREE (PART 2) CONTENTS

Protracted withdrawal symptoms

• Anxiety
• Depression
• Insomnia
• Sensory and motor disturbances
• Possible mechanisms of persisting sensory and motor symptoms
• Poor memory and cognition
• Do benzodiazepines cause structural brain damage?
• Gastrointestinal symptoms
• Coping with protracted symptoms
• How long do benzodiazepines stay in the body after withdrawal?

Epilogue

• Education
• Research
• Treatment methods
• Provision of facilities

Further reading

Table 3. Some protracted benzodiazepine withdrawal symptoms
Table 4. Some possible causes of protracted benzodiazepine withdrawal symptoms

It has been brought to my attention that some doctors/people are interpreting the section on Protracted Withdrawal Symptoms as suggesting one would need to be on benzodiazepines for an extended period of about 20 years in order to experience protracted withdrawal symptoms.

The mention that many people had been taking benzodiazepines for 20 years or more was an example only and by no means suggests that one would need to be on benzodiazepines for this length of time to develop protracted withdrawal symptoms.

Indeed some people have developed problems with protracted withdrawal symptoms after being prescribed regular (therapeutic) doses of benzodiazepines for only less than a year. In addition, people who have a traumatic withdrawal, even after a few months of potent benzodiazepines, not infrequently have protracted symptoms and possibly post-traumatic stress disorder (PTSD) which can be very prolonged.

C. H. Ashton, June 2013

A minority of people who have withdrawn from benzodiazepines seem to suffer long-term effects - protracted symptoms that just don't go away after months or even years. It has been estimated that perhaps 10-15 per cent of long-term benzodiazepine users develop a "post-withdrawal syndrome". Many of these people have taken benzodiazepines for 20 years or more and/or have had bad experiences in withdrawal. The incidence of protracted symptoms in those who have undergone a slow taper under their own control is almost certainly very much lower.

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

Table 4. Some Possible Causes of Protracted Benzodiazepine Withdrawal Symptoms

(?) indicates possible mechanisms for which at present there is no scientific evidence

Anxiety

Anxiety persisting after the acute phase of withdrawal may be partly due to the uncovering of a learning defect caused by the benzodiazepines. These drugs specifically impair the learning of new skills, including stress-coping strategies. Such skills are normally acquired continuously from childhood to middle age or later as experience of life accumulates. Their development may be blocked for a period of years during which benzodiazepines are taken. After withdrawal the ex-user is left in a vulnerable state with a decreased ability to deal with stressful situations. Full recovery may require many months of learning new stress-coping strategies to replace the years when this facility was blanketed by pills.

Secondly, benzodiazepine withdrawal may uncover life problems that have never been fully addressed. For example, the impairment of memory caused by benzodiazepines may prevent the normal resolution of personal stresses such as bereavement or a car crash. Such buried or half-forgotten experiences may have to be faced after withdrawal and may prolong both anxiety and depression. It is not uncommon for a widow or widower, first prescribed benzodiazepines on the death of the spouse, to go through the grieving process for the first time after withdrawal, even though the bereavement had occurred many years previously.

A third factor may operate in people who have had frightening experiences during withdrawal. This is not uncommon in those who have undergone rapid withdrawal without adequate explanation, often in hospital or detoxification centres but sometimes at home when their doctor has withdrawn prescriptions. Such people may develop symptoms of post-traumatic stress disorder (PTSD) in which their experiences are constantly repeated as flashbacks or nightmares and so prolong the anxiety.

In addition, many (though by no means all) long-term benzodiazepine users are constitutionally highly strung, sensitive people with relatively low self-esteem, whose anxiety problems have led to the prescription of benzodiazepines in the first place and whose continuing anxiety (possibly heightened by the benzodiazepines) has prompted the doctor to go on prescribing the drugs. It may take a long time for these people to regain, or attain, full confidence in themselves.

Despite these factors, protracted anxiety symptoms, including agoraphobia and panics, do tend to subside gradually and rarely last more than a year. The process may be hastened by good psychological support and by the measures described under acute anxiety symptoms. Believe it or not, people often feel more self-confident after withdrawal than they did before starting to take benzodiazepines.

Depression

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.

Insomnia

Poor 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

There is no doubt that benzodiazepine withdrawal leaves in its wake a nervous system that is exquisitely sensitive to all sensory and motor stimuli. Usually this state settles in a few weeks but occasionally disturbing sensations persist.

One of the most distressing sensory symptoms is tinnitus, a constant ringing or hissing in the ears which has been noted in several studies of benzodiazepine withdrawal. One lady described her tinnitus as a "needle of sound" piercing deep inside her head. Tinnitus is often associated with a degree of hearing loss and is not uncommon in people with partial nerve deafness who have never taken benzodiazepines. Nevertheless, it often makes its first appearance during benzodiazepine withdrawal in people who have had hearing loss for years. Also, it may be unilateral or precisely localised, even in those with symmetrical bilateral hearing loss. Whether people who have taken long-term benzodiazepines are particularly prone to tinnitus and if so why, is not known. It can persist for years and does not always respond to the usual treatments for tinnitus (maskers, etc); nor is it always relieved by restarting benzodiazepines. However, people with persisting tinnitus after withdrawal should seek the advice of a hearing specialist and may be lucky enough to find a clinic which specialises in this symptom.

A number of unpleasant bodily sensations may persist after withdrawal including tingling, "pins and needles" or patches of numbness in the trunk, face, limbs and fingers. These may be accompanied by burning pain or aches that sometimes seem to originate deep in the muscles or bones. Some people complain of an "inner trembling" or a sense of vibration, and some have described bizarre sensations as of water or slime running over the body or a serpent-like writhing on the scalp. Motor symptoms that may persist include muscle tension, weakness, cramps, jerks, spasms and shaking attacks.

Possible mechanisms of persisting sensory and motor symptoms

Although the above symptoms are often made worse by stress, they are clearly not simply due to anxiety. They suggest a dysfunction in motor and sensory pathways in the spinal cord and/or brain. A possible clue to their mechanism is provided by a trial with flumazenil (Anexate, Romazicon) a benzodiazepine receptor antagonist, published by Lader and Morton (Journal of Psychopharmacology 1992, 6, 357-63). This drug, when infused intravenously brought rapid relief of protracted symptoms (muscle tension, "pins and needles", weakness, muscle cramps or jerks, burning, tremor or shaking) that had been present for 5-42 months post-withdrawal in 11 patients. The symptoms were improved by 27-82 percent and the greatest response occurred in patients with the lowest anxiety ratings. There was no response to infusions of saline solution.

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.

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

Although it is well known that benzodiazepines impair memory and some cognitive functions, particularly the ability to sustain attention, some long-term users complain of continued loss of intellectual abilities persisting after withdrawal. There have been several studies on this question which indicate that improvement may be very slow. The longest studies in therapeutic dose long-term users extend for only 10 months after withdrawal. Cognitive impairment, though slowly improving, persisted for at least this time and was not related to anxiety levels (Tata et al. Psychological Medicine 1994, 24, 203-213). Some Swedish studies have found that intellectual impairment, although improved, was still present 4-6 years after cessation of benzodiazepine use, but it was not clear whether high dosage and/or alcohol use were added factors.

Do benzodiazepines cause structural brain damage?

These results have raised the question of whether benzodiazepines can cause structural brain damage. Like alcohol, benzodiazepines are fat soluble and are taken up by the fat-containing (lipid) membranes of brain cells. It has been suggested that their use over many years could cause physical changes such as shrinkage of the cerebral cortex, as has been shown in chronic alcoholics, and that such changes may be only partially reversible after withdrawal. However, despite several computed tomography (CT) scan studies, no signs of brain atrophy have been conclusively demonstrated in therapeutic dose users, and even the results in high dose abusers are inconclusive. It is possible that benzodiazepines can cause subtle changes which are not detected by present methods, but on the available evidence there is no reason to think that any such changes would be permanent.

Gastrointestinal symptoms

Gastrointestinal symptoms may be prolonged after withdrawal, usually in people who have a previous history of digestive troubles. Such people may develop apparent intolerance to certain foods, although reliable tests for true food allergy (e.g. antibodies against specific food constituents) are nearly always negative. Nevertheless many sufferers feel that they have damage to the immune system or have developed intestinal candidiasis. There is at present no clear scientific evidence on these topics, though as mentioned before, benzodiazepine receptors are present in the gut and benzodiazepine use or withdrawal may affect immune responses. There is some evidence that chronic hyperventilation provokes the release of histamine (a substance released in allergic reactions) and that the incidence of food-intolerance and "pseudo-allergic" reactions is high in chronic hyperventilators. Advice on diet, breathing and candida infections is given in books by Shirley Trickett quoted at the end of this chapter. It is usually inadvisable to stick to a strict exclusion diet; with a normal balanced diet and sensible general health measures, including regular exercise, gastrointestinal symptoms due to withdrawal gradually abate.

Coping with protracted symptoms

A number of people are expressing fears that some benzodiazepine withdrawal symptoms last for ever, and that they can never completely recover. Particular concerns have been raised about impairment of cognitive functions (such as memory and reasoning) and other lingering problems such as muscle pains and gastrointestinal disturbances.

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 benzodiazepines cause permanent damage to the brain, nervous system or body.

People bothered by long-term symptoms can do a lot to help themselves. For example:

1. Exercise your body. Physical exercise improves the circulation and function of both brain and body. Find an exercise that you enjoy: start at low level, work up gradually and keep it up regularly. Exercise also helps depression, decreases fatigue and increases general fitness.

2. Exercise your brain. Use your brain to devise methods to improve its efficiency: make lists, do crossword puzzles, find out what bothers you most - there is always a way round it. Cognitive retraining helps people to find ways around their temporary impairment.

3. Increase your interests. Finding an outside interest which you have to work at employs the brain, increases motivation, diverts attention away from your own symptoms and may even help others.

4. Calm your emotions. Above all, stop worrying. Worry, fear and anxiety increase all withdrawal symptoms. Many of these symptoms are actually due to anxiety and not signs of brain or nervous system damage. People who fear withdrawal have more intense symptoms than those who just take it as it comes and think positively and confidently about recovery.

How long do benzodiazepines stay in the body after withdrawal?

This question is often asked by people with long-term symptoms. Is it possible that one cause of protracted symptoms is that benzodiazepines remain in the body even after months, lurking perhaps deep in such tissues as brain and bones? Could slow elimination from these sites keep the withdrawal symptoms going?

Like many other issues concerning benzodiazepines, the answers to these questions are still unclear. Benzodiazepine concentrations in the blood have been measured and shown to reach undetectable levels in 3-4 weeks after cessation of use in people withdrawn from clinical doses. Information on benzodiazepine concentrations in the brain and other tissues is difficult to obtain, especially in humans. Benzodiazepines certainly enter the brain and also dissolve in all fatty (lipid-containing) tissues including fat deposits all over the body. It is possible that they linger in such tissues for some time after blood levels have become undetectable. However, most body tissues are in equilibrium with the blood that constantly perfuses them, and there is no known mechanism whereby benzodiazepines could be "locked up" in tissues such as the brain. There is no data on how long benzodiazepines remain in bones, which have a lower fat content but also a slower rate of cell turnover.

Nevertheless, the concentration of benzodiazepines remaining in body tissues after withdrawal must be very low, otherwise the drugs would leak back into the blood in discernible amounts. It is difficult to imagine that such concentrations would be sufficient to produce clinical effects or that any direct effects could last for months or years. However, it is not inconceivable that even low concentrations might be enough to prevent the return of GABA/benzodiazepine receptors in the brain to their pre-benzodiazepine state. If so, the receptors would continue to be resistant to the natural calming actions of GABA (See Chapter I), and the effect could be to prolong the state of nervous system hyperexcitability. Possible factors contributing to protracted symptoms are outlined in Table 4.

(1) Education

All doctors and paramedicals need to acquire greater knowledge and to receive better training on the prescription of benzodiazepines (short-term only), their adverse effects (especially dependence), and methods of withdrawal (slow tapering of dosage combined with adequate support). Such education should include family physicians, psychiatrists, other specialists, staff in detoxification units, pharmacists, psychologists and other therapists and community nurses. Increased general awareness and pressure from the public could speed these measures.

(2) Research

More research is needed on the effects of long-term benzodiazepine use. Particular areas include effects on the brain structures, using modern techniques such as magnetic resonance imaging (MRI) and brain blood flow (fMRI), combined with neuropsychological testing. Further work is also needed in the little researched fields of benzodiazepine actions on endocrine, gastroenterological and immune systems.

(3) Treatment methods

Better methods for treatment of anxiety and insomnia need to be developed. It is doubtful if any drug will ever "cure" anxiety or insomnia but it may be possible to develop pharmacological agents with fewer side-effects. For example, rats treated with the benzodiazepine antagonist flumazenil along with a benzodiazepine do not develop tolerance but still apparently experience an anxiolytic effect. Such a combination might work in humans but long-acting benzodiazepine antagonists that can be taken by mouth have not been subjected to trials. Alternatively, mood-stabilising anticonvulsants such as gabapentin, tiagabine and pregabalin may hold promise since their mode of action is different from that of benzodiazepines. At the same time, psychological therapies for treating anxiety and insomnia could be improved and more widely taught. And it may well be possible to develop better methods than those described in this monograph for drug withdrawal in people who have become dependent on benzodiazepines.

(4) Provision of facilities

Facilities for benzodiazepine dependent people need to be developed. Detoxification units, dealing with dependence on alcohol and illicit drugs, are not appropriate for prescribed benzodiazepine users who have unwittingly become dependent through no fault of their own. Such places usually withdraw the drugs too rapidly and apply rigid "contract" rules which are quite unsuitable for benzodiazepine patients struggling with withdrawal symptoms. Much needed are clinics specialising in benzodiazepine withdrawal where clients can receive individualised, flexible, understanding and supportive counselling. At present only too few voluntary support groups valiantly strive to fill this gap with minimal finances. Proper financing would also allow provision of residential accommodation where clients in need could go for short breaks in a supportive, non-hospital, atmosphere at crucial times during their withdrawal process.

Finally, it is a tragedy that in the 21^st century millions of people worldwide are still suffering from the adverse effects of benzodiazepines. Nearly 50 years after benzodiazepines were introduced into medical practice in the 1950s there should be no need for a monograph such as this. However, I hope that the experience from many patients described in this book will help to raise awareness amongst the medical profession and the public of the problems associated with long-term benzodiazepine use and withdrawal.

FURTHER READING

• Ashton, H. (1994) Benzodiazepine withdrawal: unfinished story. British Medical Journal 288,135-40.

• Ashton, H. (1991) Protracted withdrawal syndromes from benzodiazepines. Journal of Substance Abuse Treatment 8,19-28.

• Ashton, H. (1995) Protracted withdrawal from benzodiazepines: The post-withdrawal syndrome. Psychiatric Annals 25,174-9.

• Ashton, H. (1994) The treatment of benzodiazepine dependence. Addiction 89,1535-41.

• Trickett, S. (1998) Coming Off Tranquillisers, Sleeping Pills and Antidepressants. Thorsons, London.

• Trickett, S. (1994) Coping with Candida. Sheldon Press, London 1994.

• Tyrer, P. (1986) How to Stop Taking Tranquillisers. Sheldon Press, London.