To attempt to write an impartial account of the benzodiazepines (Table 10.1) is all but impossible. 14 A number of excellent histories of these drugs have come out in recent years. 15 and 16 When they were first introduced, these drugs were seen as being of major benefit. They were widely regarded as extremely safe and obviously effective. They were popular with physicians, consumers and the pharmaceutical industry. However, during the 1980s the benzodiazepines came to be described as one of the greatest menaces to society in peacetime. They were then seen as the epitome of the psychotropic drug juggernaut–a group of drugs that were more difficult to stop than heroin.
Generic drug name
UK trade names
US trade names
Diazepam
Formerly Valium
Formerly Valium
Chlordiazepoxide
Librium
Librium
Lorazepam
Ativan
Ativan
Bromazepam
Lexotan
Lexotan
Oxazepam
Serenid
Serax
Alprazolam
Xanax
Xanax
Clobazam
Frisium
Frisium
Medazepam
Nobrium
Nobrium
Clorazepate
Tranxene
Tranxene
Clonazepam
Rivotril
Klonopin
Long
Intermediate
Short
Ultra-short
Chlordiazepoxide
Flunitrazepam
Alprazolam
Midazolam
Clorazepate
Nitrazepam
Lorazepam
Triazolam
Diazepam
Lormetazepam
Oxazepam
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Benzodiazepine anxiolytics
As these things played out in the media in the late 1980s and early 1990s, benzodiazepine dependence was portrayed as the only case of drug dependence in which the dependent person was viewed with sympathy. He or she was portrayed as a victim of forces beyond their control rather than as the author of their own destiny. 17 The benzodiazepine crisis marked a point where consumers took up arms against the medicopharmaceutical complex rather than simply against the dangers of a particular group of drugs.
The other half of the argument put forward by medical practitioners and the pharmaceutical industry was that these drugs remained remarkably safe, that reports of dependence and withdrawal reactions were exaggerated, and that withdrawal phenomena were probably more linked to the personality of the sufferer than to the pharmacology of the drugs.
These opposing views became so polarised that it is difficult to write an account of the benzodiazepines that will not alienate someone. The position taken here will be that the benzodiazepines are far safer for most people than they were perceived to be some years ago, but that there is a large group of individuals who, through no fault of their own, will encounter serious difficulties with them. Or, put somewhat differently, the hazards of the benzodiazepines are no greater than those posed by the selective serotonin-reuptake inhibitors (SSRIs). The benzodiazepines provided something of a stick with which to beat the pharmaceutical industry, perhaps the wrong stick but the choosing of these things is rarely a calculated matter: it is much more likely to result from a combination of accidental factors interacting with the spirit of the times. Another way to frame this issue is that Valium, for most, seems like a darker drug than Prozac, so much so that the brand name Valium has been withdrawn and diazepam is all that is available, but in fact Prozac and the SSRI group of drugs almost certainly pose far greater hazards to takers than Valium ever did. The behaviour of the respective pharmaceutical companies has probably always had the same motivation but the capacity of a company to do damage today is greater than it was during the 1960s and 1970s.
When the benzodiazepines came on the market in 1960, the available alternatives were the barbiturates or the first antipsychotics. There were serious drawbacks to the barbiturates: excessive sedation, a high risk of dependence and substantial fatalities in overdose. The antipsychotics, while not afflicted with these problems, had their own drawbacks, as outlined in Section 1, and their prescription was seen by many as inappropriate for milder or neurotic disorders. The irony now is these same drugs are being blithely prescribed to children from infancy onwards.
The benzodiazepines, in contrast, had none of the side effects of the antipsychotics. Compared with the barbiturates, they appeared to produce a relatively mild sedation, to be free of the risk of physical dependence and, most of all, to be very safe in overdose. They became increasingly popular and widely prescribed. A wide-scale chemical tranquillisation of anxiety ensued.
We now recoil from what happened during the 1960s and 1970s. There is evidence that many patients do as well with brief counselling from general practitioners as they do on benzodiazepines, and that they are as happy with such counselling. General practitioners today often squirm in the face of such findings, but before the large-scale prescription of benzodiazepines there was a great deal of chemical management of neurotic and anxiety disorders with barbiturates and painkillers, and there is now a wholly comparable use of SSRIs for just the same problems. The question of finding a balance in this area seems to be an issue that is with us always. Hence it may be somewhat naive to ascribe the dark side of the benzodiazepine story solely to the pharmaceutical industry following the siren call of the profit motive.
MECHANISM OF ACTION OF THE BENZODIAZEPINES
We know more about how benzodiazepines work than we do about almost any other psychotropic drug. The first development in our understanding of the benzodiazepines came with the discovery that a compound called gamma-aminobutyric acid (GABA) is one of the most plentiful neurotransmitters – much more common than serotonin or noradrenaline (norepinephrine). It is the brain’s principal inhibitory neurotransmitter. Benzodiazepines neither block messages through the GABA system nor create artificial messages but rather modulate normal functioning of the GABA system by binding to one of three types of BZ receptor, BZ1, BZ2 and BZ3, which mediate sedative, myorelaxant and anxiolytic effects, respectively.
It has emerged that there are a number of natural compounds within the brain that bind to the same sites on the GABA receptor as the benzodiazepines. The implication of this is that there are a set of natural compounds in the brain performing much the same function that benzodiazepines perform. The best candidates for these natural compounds seem to be a group of compounds called the beta-carbolines.
One surprising finding has been that beta-carbolines may both alleviate anxiety and produce relaxation just as benzodiazepines do, but also that other beta-carbolines may cause anxiety, tension and convulsions. This finding has led to significant changes in our understanding of how neurotransmitters and receptors work naturally. It had previously been thought that neurotransmitters acted on receptors and that drugs might either mimic this action or antagonise it. It now seems clear that some compounds may produce opposite actions at the same receptor site. Where actions on benzodiazepine receptors are concerned, we can now produce compounds that relieve anxiety, compounds that increase anxiety and compounds that block both of these effects. These three types of compound differ, but all act at the same receptor site.
Another interesting feature of the benzodiazepines is that, in contrast to other neurotransmitters such as noradrenaline (norepinephrine), dopamine and serotonin, which are found in single-celled or quite simple organisms, benzodiazepine receptors are confined mostly to cortical areas of the brain and have emerged only in, relatively speaking, higher animals.
CLASSES OF BENZODIAZEPINES
By convention the benzodiazepines are divided up according to their half-life – the length of time it takes for the amount of the drug in the blood to decrease to half its initial level after a standard dose. There was a great deal of interest in this concept during the 1970s, as it was thought that producing a benzodiazepine with a short half-life might overcome problems such as the hangover sedation apparent with some of the earlier compounds, such as diazepam. The half-life of some of the earlier compounds was so long that taking the pills regularly meant that a first pill had not washed out of the system by the time a second was taken, and so on. This led to a steady accumulation of the drug, which in the elderly was a particular problem. However, even in the case of the supposedly shorter-acting compounds, it should be kept in mind that, while the duration of action depends on the chemical make-up of the compound, it also depends on how much of the drug is given: a large amount of a short-acting compound will act for a long time (Box 10.1)
Box 10.1
enzodiazepines classified by duration of action
Benzodiazepines give a relaxing warm glow, like alcohol. There is a sense of muscular release and a soothing feeling that most people describe as pleasant. In one sense they are one of the 20th century’s greatest inventions. After 2000 years of trying to improve on alcohol, they represent success in some respects. They can be used for the same purposes as alcohol: for general relaxation purposes, as anti-anxiety agents for acute crises such as interviews or whatever, and they are just generally pleasant in the way alcohol is. Furthermore they do not cause liver, heart, joint or gut problems, or the generalised brain cell loss that alcohol causes.
Anxiolysis
To say that benzodiazepines are anxiolytic seems rather superfluous. They are, but they are by no means universally anxiolytic. They are of benefit in anxiety states that have a significant muscular tension or dissociative component to them. The anxiolytic effect of benzodiazepines appears to resemble most the effects of alcohol. This effect differs from the ‘anxiolytic’ effect of the antipsychotics, which work best in distraught and agitated rather than in anxious states. Benzodiazepine anxiolysis also differs from the anxiolysis brought about by beta-blockers, which work best in states characterised by increased heart rate, palpitations, butterflies in the stomach and other shakes of the hand. It also differs from the serenic effect produced by SSRIs and other compounds acting on the serotonin system.
The above description of the anxiolytic effects of benzodiazepines is only approximate. Greater precision is not possible at present, which seems remarkable given that so many benzodiazepines have been prescribed and taken in the past 30 years. One might expect that there would be a better appreciation of just what kind of anxiolysis they bring about. This is a major indictment of the way we develop drugs at present.
Anticonvulsant
