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The Still Unfinished Story
Professor C Heather Ashton DM, FRCP,
to the Beat The Benzos Campaign
Croydon, London, England
Wednesday, November 1, 2000
See also Professor Ashton's:
Benzodiazepine withdrawal: An Unfinished Story,
British Medical Journal · Vol 288 · April 14, 1984
The Ashton Manual · Professor Ashton's Main Page
Title Slide [Slide 1]
(note: the slides referred to are not yet available)
Benzodiazepines (the tranquillisers and sleeping pills) made a large impact on public consciousness in the 1980s. There was an outcry from many long-term prescribed benzodiazepine users who discovered that the drugs were far from the panacea for all ills they were reported to be. There was widespread media coverage in the press and on television, a large though unsuccessful litigation case, new medical evidence that long-term prescribed benzodiazepine use could cause drug dependence and a burgeoning of self-help groups and withdrawal clinics. As a result there was a reduction in prescribing levels of benzodiazepines from its height of 32 million to the present nearly 18 million prescriptions per year in the UK.
So, in 2000 the problem is generally perceived to have gone away. NHS withdrawal clinics have shut down; the media no longer find benzodiazepines newsworthy; very few doctors have training in benzodiazepine withdrawal methods and self help groups receive almost no public financial support.
But the problem has not gone away; in fact it has insidiously got worse.
Skeleton surveying skull [Slide 2]
The skeletons were merely shut in the closet and now some worms have been crawling out of the woodwork.
For example, there are still around one million long-term benzodiazepine users in this country, an average of over 150 in every GP practice. These people get very little help if they try to withdraw.
There is an enormous and growing problem of illegal benzodiazepine abuse: benzodiazepines have entered the drug scene and are used by over 90% of alcohol and illicit drug abusers. Benzodiazepines are affecting people at all stages of life - from the elderly who take them chronically as sleeping pills or are given them in old people's homes; to psychiatric patients discharged into the community still taking benzodiazepines prescribed in hospital; to young adult drug abusers; to women still being prescribed them in pregnancy and to their developing foetuses and newborn infants.
It is time for the skeletons to come out of the closet. We need to expose the bones and make decisions about the steps needed to achieve a more rational use of benzodiazepines.
That is the main purpose of this conference.
To make a reasoned decision; we need to be clear about what benzodiazepines are and what they do. As to what they are their names are already well known: Librium, Valium, Mogadon, Ativan, Xanax, Halcion and others have become household words that hardly need reporting. What they do is affect the brain.
GABA/BZ receptor distribution in the brain [Slide 3]
A dose of Valium or any other BZ rapidly enters the brain. Here the drugs react chemically with specific molecular sites (receptors) which are widely distributed. They permeate every brain area form the cerebral cortex (necessary for rational thought, the limbic system (responsible for emotions), the hippocampus (an important centre for memory) and the brainstem (which controls vital bodily functions such as breathing). This chemical reaction enhances all the effects of a natural neurotransmitter, GABA (gamma-amino-butyric acid) which acts as the brain's own endogenous tranquilliser.
GABA action on neurons [Slide 4]
This slide shows what GABA does to a brain cell: it stops it firing. Secondarily it reduces the brain's output of excitatory neurotransmitters such as noradrenaline and serotonin. Benzodiazepines exaggerate this natural action, causing a profound biochemical disturbance of brain function. Activity throughout the brain is depressed, with the effects on almost every body system. This generalised action is responsible for both the therapeutic and adverse effects of benzodiazepines.
Therapeutic effects of benzodiazepines [Slide 5]
When used short-term, benzodiazepines are rapidly effective, relatively safe and efficient and have a number of valuable therapeutic effects:
Because they quieten the brain, they make good hypnotics and sedatives.
Because they damp down emotions they are good anxiolytics (tranquillisers).
Because they decrease excitatory activity they are good anticonvulsants.
Because they impair memory for unpleasant events they are good to take as premedication before surgery and for minor surgical procedures.
Because they relax muscles they are helpful for spastic conditions.
Because of these valuable and sometimes life saving actions there is no question of banning benzodiazepines altogether, but we do need to be very careful in prescribing them. Adverse effects of benzodiazepines usually result from excessive dosage, interactions with other drugs and particularly long term use. I will mention some of these, though most of them will be familiar to the audience.
Acute toxicity of benzodiazepines [Slide 6]
Benzodiazepines have always been regarded as remarkably non-toxic drugs. However, they are not completely safe. They are involved in up to 40% of all self poisoning incidents. Between 1980 and 1989 there were 1512 suicides attributed to benzodiazepine overdose. In 2/3 of these cases the drug was taken alone, in 1/3 with alcohol.
Temazepam, the commonest hypnotic used today, turned out to be the most toxic. The risk of a fatal outcome form benzodiazepine overdosage is greatly increased in the elderly and in people with lung disease, and benzodiazepines increase the risks of fatality if taken with many other drugs not included in this analysis. The combination of benzodiazepines with opiates causes almost 100 deaths each year among drug abusers in Glasgow alone. The cause of benzodiazepine fatalities is depression of respiration: They impair function in brain centres vital for breathing.
Oversedation [Slide 7]
Oversedation is a dose-related extension of the sedative/ hypnotic effects of benzodiazepines. Symptoms include drowsiness, poor concentration, mental confusion, muscle weakness and impaired balance and coordination. These symptoms may persist as "hangover" effects from hypnotics taken at night and long-acting benzodiazepines taken regularly tend to accumulate in the body. For example, active metabolites of diazepam (Valium) are present in the body 200 hrs (over a week) after a single dose.
Elderly patients are most vulnerable to oversedation, but it can also occur in young people and the effects are additive with other depressant drugs including alcohol, cannabis, and some prescribed drugs.
These effects have been shown to contribute to falls and fractures in the elderly, to traffic accidents and other accidents at home and at work. A recent study published in the Lancet estimated that benzodiazepines cause 1600 traffic accidents and 110 driving-related deaths each year in the UK.
Impairment of memory [Slide 8]
Benzodiazepines specifically impair memory functions. They make it difficult to learn and retain new information and in particular cause amnesia for recent events. These effects are again most marked in elderly patients and may falsely lead to a diagnosis of dementia or Alzheimer's disease. Professor Lader remarked in 1995 that forgetfulness, amnesic episodes or confusion should not be ascribed facilely to "old age" or "dementia" in older patients taking benzodiazepines. Yet many occupants of homes for the elderly are prescribed benzodiazepine hypnotics. Case studies show that memory improves when these are stopped and sleep is also better.
In younger people benzodiazepines can also cause memory lapses or blackouts and have led to patients being charged with shoplifting. Benzodiazepines are often prescribed for acute stress-related anxieties and may indeed provide initial relief from distress in catastrophic accidents and bereavement. However, continued use can impair psychological adjustment to such trauma, leaving the situation unresolved and the symptoms perpetuated. In anxiety states, including panic disorders and agoraphobia, benzodiazepines inhibit the alternative stress-coping strategies including cognitive behavioural treatment.
Emotional effects: aggression, depression, emotional blunting [Slide 9]
Like alcohol, benzodiazepines can occasionally cause apparently paradoxical stimulation with increased aggression, anger, violence and antisocial behaviour. Benzodiazepines have been linked with baby-battering, "wife beating" and "grandma bashing". Less dramatically, increases in irritability and argumentativeness are often remarked on by patients on long-term benzodiazepines and by their families. These effects are thought to result from disinhibition of usually controlled behaviour.
On the other side of the coin, benzodiazepines can actually cause depression: most long-term benzodiazepine users, like alcoholics, are depressed. Benzodiazepines can also aggravate depression if already present and can precipitate suicidal tendencies in such patients. For this reason the Committee on Safety of Medicines recommended in 1988 that benzodiazepines should not be used to treat depression or anxiety associated with depression though they are still prescribed for depressed and anxious patients.
Another long-term use of theses drugs is to "emotional anaesthesia", a blunting of the ability to feel pleasure or pain or to empathise with others. Former long-term benzodiazepine users often bitterly regret their lack of emotional response family events while they were taking these drugs. Children brought up in such households often say things like "it was no use telling mother anything; she couldn't understand what we were feeling and wouldn't remember it anyway" - a mixture of emotional blunting and impairment of memory caused by the benzodiazepines.
Effects in pregnancy [Slide 10]
Benzodiazepines cross the placenta and if taken regularly by the mother, even in therapeutic doses, have adverse effects on the foetus and neonate. The developing and newborn baby metabolise benzodiazepines very slowly so that appreciable concentrations may persist for two or more weeks after birth, resulting in the "floppy infant syndrome" with poor muscle tone and difficulties in breathing and suckling. Infants regularly exposed to benzodiazepines in utero may also develop delayed withdrawal symptoms with irritability, crying and feeding difficulties.
There is some evidence that benzodiazepines taken maternally during pregnancy may impair intrauterine growth and may possibly contribute to cot deaths and later neurological abnormalities.
Weight, height and head circumference in infants exposed to benzodiazepines in utero [Slide 11]
This slide shows the findings of a Swedish study (Laegried et al. 1992) of 17 children whose mothers had taken prescribed doses of benzodiazepines during pregnancy. The exposed infants had lower birth weight, length and head circumference than the babies of control groups. By 19 months the exposed infants had nearly caught up with the others in height and weight, But not in head circumference. Five of the children had abnormalities similar to those of alcoholic mothers. We are still waiting for a follow up, but there is a suggestion from user groups in this country that such children may be at risk in later life of attention deficit disorder and possibly a spectrum of autistic disorders. This would be consistent with animal work which shows that intrauterine exposure to drugs which affect the brain can impair its normal development with lasting cognitive and behavioural impairments.
Benzodiazepine dependence [Slide 12]
Then we come to benzodiazepine dependence, a subject no doubt close to the hearts of many people here. There is no doubt that benzodiazepines are potentially addictive drugs. With regular use for only a few months or even weeks the body comes to depend on them both psychologically and physically for normal function. A degree of tolerance develops so that larger doses are needed to produce the initial effects. If dosage is insufficient, because of tolerance, if the dosage is reduced, or if the drug is stopped withdrawal symptoms develop. Long-term users, even while continuing drug use, suffer from both the adverse effects I have already mentioned and also from withdrawal psychological and physical effects. In fact long-term use is commonly accompanied by increasing illness.
Morbidity in 50 patients [Slide 13]
This slide shows some of the symptoms in 50 consecutive patients attending my benzodiazepine withdrawal clinic in the 1980s. They had been on so called "therapeutic doses" of benzodiazepines for 5 - 20 years and wished to withdraw because they did not feel well.
While taking the drugs:
20% had taken drug overdoses requiring hospital admission.
20% had developed incapacitating agoraphobia (in addition to the vast majority who had panic attacks).
18% had undergone GI investigations (irritable bowel).
10% had undergone neurological investigations (3 wrongly diagnosed with ME).
In addition, 62% had received other psychotropic drugs (mainly antidepressants) since starting benzodiazepines and 28% were taking a combination of two benzodiazepines.
These symptoms were not the original cause for starting benzodiazepines, but developed during the course of prolonged use. It seems clear that long-term use of benzodiazepines actually aggravates or causes further anxiety or depression. In this series over 90% of the patients withdrew successfully and after withdrawal, there were no more overdoses, agoraphobia, panic attacks and neurological symptoms disappeared. The fact that patients improve after withdrawal is a strong argument that these symptoms were related to the benzodiazepines and were not due to some underlying psychiatric disorder as many psychiatrists have claimed. There are no doubt people in the audience who can attest to this experience.
Acute withdrawal syndrome [Slide 14]
I will not say much about withdrawal symptoms or the management of benzodiazepine withdrawal since these topics will be dealt with by other speakers. Acute withdrawal symptoms are largely the opposite of the initial therapeutic actions so that hypnotic effects are replaced by insomnia, tranquillity by increased anxiety, muscle relaxation by increased muscle tension and spasms. There are also many physical symptoms such as pain, numbness, muscle tension and twitches.
Protracted withdrawal symptoms [Slide 15]
In some subjects the withdrawal syndrome can be protracted, lasting months or even years. Protracted symptoms include insomnia, depression and a variety of neurological and gastrointestinal symptoms which can be very distressing and may sometimes be permanent. There is no time to go into the symptoms in detail, but they have raised the question of whether long-term benzodiazepine use can cause permanent cognitive or neurological damage.
So far there is no clear evidence of structural damage to the brain, though it has been suggested in some studies. Other studies have clearly shown long-lasting, cognitive deficits in long-term benzodiazepine users who have withdrawn.
Memory tests in ex-benzodiazepine users [Slide 16]
(Gorenstein et al. 1995)
A recent study looked at cognitive performance in 28 patients who had taken prescribed low dose benzodiazepines for a mean of 10 years compared with a matched group of anxious patients not on benzodiazepines, and healthy volunteers.
The benzodiazepine patients were tested before withdrawal and 3 weeks and 10 months after withdrawal. This slide shows the results on simple memory tests (digit span forwards and backwards, immediate and delayed story recall). As you can see, the benzodiazepine patients were impaired before and still 10 months after withdrawal compared to the control groups. Many ex-benzodiazepine users complain that it is years before their mental capacity returns.
Illicit benzodiazepine abuse [Side 17]
The most recent and possibly the most menacing worm crawling out of the woodwork is that of so-called recreational benzodiazepine abuse. There are probably over 100,000 illicit benzodiazepine abusers in the UK and the number is still rising. Up to 90% of opiate, cocaine and amphetamine users report that benzodiazepines increase the "high" obtained from opiates and alleviate the withdrawal effects when supplies are limited. Users of stimulants such as cocaine, amphetamines and even ecstasy use benzodiazepines as "downers" to overcome the effects of their "uppers". Benzodiazepines have already crept into the "rave" scene. Benzodiazepines are already used by alcoholics attending for detoxification and are often obtained illegally. They are taken partly to alleviate the anxiety associated with alcohol use, but also because the mixture of alcohol and benzodiazepines produces a desirable effect. Temazepam and lager is a popular combination.
There are also some who use benzodiazepines alone or as their main drug because they have discovered that high doses can give them a kick. Just about all the benzodiazepines can be used and delivered orally, by injection or snorted as snuff. Temazepam is the most popular benzodiazepine in the UK and intravenous users in Liverpool reported injecting over 3000 mgs in one go. They said that such injections not only provide a "buzz" and relaxation, but also give confidence to engage in criminal activities.
Some street users have moved on to taking large amounts of oral benzodiazepines in combination with injected opiates such as buprenorphine. This combination, temazepam and Temgesic (Tem-Tem) causes about 100 deaths in Glasgow alone. A popular youth craze is to ride on the buses all day in gangs "wobbling" on oral temazepam fortified by high strength lager and cannabis. Needless to say these practices are not without adverse effects. Complications of IV injection included abscesses and venous and arterial thrombosis. When their arms are affected, users may progress to injecting in the groin and this has resulted in gangrene.
Eye complications [Slide 18]
This subject who had a leg amputation because of gangrene, injected temazepam into his eye and became blind in both eyes as a result. Injecting users are also at risk of hepatitis and HIV infection.
Both oral and IV users suffer blackouts and cognitive impairments. Benzodiazepines users appear to be particularly prone to needle-sharing and risk-taking sexual behaviour, increasing the risk of HIV infection. In any resulting pregnancies the foetus is at extra risk because of the high doses used. Thus the effects are passed to the next generation.
And like therapeutic dose users, benzodiazepine abusers become dependent and can suffer severe withdrawal effects including withdrawal fits. The health and social hazards of benzodiazepine abuse are summarized in the next slide.
Health and social hazards of benzodiazepine abuse [Slide19]
The tragedy about benzodiazepine abuse is that it is our own fault. It could have been foreseen and could have been prevented. The history of benzodiazepine abuse is the same as that of the amphetamines. Mandrax, glutethamide and many others originated as prescribed drugs and later entered the drug scene. In the case of benzodiazepines a couple of decades of widespread prescribing elapsed before the abuse potential was discovered at a time when benzodiazepines were lying around in nearly every household. Within a few years they became the most widespread of IV drugs of abuse in the UK.
The source is almost entirely from pharmaceutical supplies and from prescriptions. Some users attend several GPs for the drugs; some GP patients (often elderly) sell their supplies; some children obtain them from their parents' prescriptions; and large amounts are stolen from chemists and warehouses. Benzodiazepines are still cheap and easy to obtain on the street. Now diazepam, temazepam and other benzodiazepines are coming in from Europe, a signal that it may already be too late to prevent illegal benzodiazepine abuse.
A temazepam abuser [Slide 20]
At present benzodiazepine abusers, like this one, are small in numbers compared to the number of prescribed long-term users and also ex-users whose lives are also affected, sometimes permanently, but they add urgency to the need to rationalise benzodiazepine prescribing.
Steps needed to reduce benzodiazepine prescribing [Slide 21]
We need urgently to:
Impress upon doctors the need to adhere to short-term prescriptions if benzodiazepine are indicated in new patients (2 weeks only in minimal dosage).
Educate Doctors, pharmacists and other health care workers in the management of benzodiazepine withdrawal in long-term users.
Provide financial aid for benzodiazepine support groups and withdrawal clinics. Also residential accommodation.
Seriously consider rescheduling benzodiazepines.
Educate doctors and the public about prescribing new drugs with abuse potential (eg. Zopiclone and Zolpidem, non-benzodiazepines which have already caused addiction problems and perhaps also need to be rescheduled).
These and related questions will be addressed by other speakers.
Socioeconomic costs of inappropriate benzodiazepine use [Slide 22]
Finally this slide summarises some of the socioeconomic costs of inappropriate benzodiazepine prescribing. (unnumbered slide)
Curbing benzodiazepine prescriptions would not only save the NHS millions of pounds, but would also help to allay and prevent the suffering of current and potential prescribed and illicit benzodiazepine users. Public pressure, such as we have here in this campaign, combined with reasonable suggestions about the actions required may be the best way to influence current practices.
The Ashton Manual · Professor Ashton's Main Page
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