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Benzodiazepines and their effects
Professor Ian Hindmarch,
Head of Human Psychopharmacology Research Unit,
University of Surrey,
[Note: Although specific reference is made to flurazepam (Dalmane)
all comments apply equally to benzodiazepines in general]
The first benzodiazepine, chlordiazepoxide (Librium), was developed in the late 1950s and launched for the management of patients with anxiety early in the 1960s. Some three years later, diazepam (Valium) was launched, again primarily for use with anxious patients. In 1965, nitrazepam (Mogadon) was introduced for the management of patients with insomnia and other sleep related problems and, in 1973 flurazepam (Dalmane) was added to the growing number of benzodiazepines for use as an aid for sleep disturbed patients.
The benzodiazepines were well received by doctors and patients on an international basis due principally to their low toxicity in overdose, especially when compared to the barbiturates which were the drugs previously prescribed for anxiety and sleep problems.
All benzodiazepines possess, to a greater or lesser extent, a five-fold action which gives rise not only to their principal clinical uses, but also to their characteristic profile of benzodiazepine "side effects". The five pharmacological actions intrinsic to the benzodiazepine molecule are:
amnestic (producing forgetfulness and disturbing memory).
Those benzodiazepines with pronounced anticonvulsant action are marketed as antiepileptic agents (e.g. clonazepam, diazepam, clobazam), while the muscle relaxant effects of (e.g. diazepam) make it useful in sports medicine and for strain injuries. The tranquillising activity present in most derivatives led to benzodiazepines being used as anti-anxiety agents (e.g. lorazepam, chlordiazepoxide, medazepam, diazepam, clobazam); and some benzodiazepines with high amnesia producing properties (e.g. temazepam, lorazepam) were used as pre-medications before unpleasant surgical procedures. Flurazepam, along with nitrazepam and drugs like temazepam, lormetazepam and triazolam was specifically indicated, because of its sleep promoting and sedative properties as an hypnotic (sleeping pill) and was marketed as such by its manufacturers from 1973 onwards.
It has to be emphasised that there are no clear demarcation lines between the action profile of one benzodiazepine and another and to a great extent the side effects of the individual drugs are broadly similar to such an extent that it is possible to talk of effects due to benzodiazepines as a class. This is important as by far the greatest amount of research data has been generated from studies of diazepam, chlordiazepoxide, lorazepam and triazolam, whereas midazolam, medazepam, ketazolam, oxazepam are much less studied. Flurazepam, nitrazepam and temazepam probably form the middle ground as regards research effort. However, there is nothing clinically, or from the results of experimental investigations to suggest that flurazepam (Dalmane) is in any way idiosyncratic. Flurazepam has specific activity in the hypno/sedative (putting and keeping patients asleep) area.
Benzodiazepines do differ from each other in two important ways, although the manifestation of these differences in chronic clinical use is more difficult to determine. These two differences are to be found in pharmacokinetic (pK) and pharmacodynamic (pD) variables. The pK profile of a drug informs us of the fate of the drug in the body once the substance has been ingested. pK variables describe the rate at which the drug enters the blood and is distributed around the body, as well as showing how long is necessary for the drug to be metabolised and excreted. pK variables provide a profile of how the drug behaves in the patient. On the other hand, pD variables tell us how the patient behaves in response to the administration of the drug. There is no clear or causal relationship between pK and pD. For example, a particular drug may be eliminated from the body (pK measure) in a few hours, but the duration of a drug's effects (pD) in the patient, may last for more than a day. However, in discussing the duration of side effects of a drug, it is more than likely that those drugs taking a long time to be eliminated from the body (pK) will have a greater potential to alter a patient's behaviour (pD) simply because the drug is present in the body. In order to provide a simple classification to help prescribing doctors use benzodiazepines appropriately, the various compounds have been categorised into "short" or "long" acting. Short acting drugs are those whose principal effects occur within the first six to eight hours after taking them. Long acting drugs are those with a duration of action in excess of 24 hours. There are, of course, intermediary classifications. Flurazepam is classified as "long" acting since it takes more than a day to be metabolised and eliminated from the body (pK) and also some of the adverse side effects of its administration can be detected during the daytime following the previous night time ingestion of the drug (pD).
The extent, type and duration of side effects are, naturally, linked with the dose of benzodiazepine administered, with higher doses being associated with a greater number of side effects of a more severe nature and duration. Adjusting the dose can also change the pD profile and a drug which is effectively "short" acting can have its duration of clinically relevant action extended by increasing the dose.
The recommended dose of flurazepam to promote and maintain sleep is 15mg, although the possibility exists, (within the licence of the product) to use a more powerful dose (30mg) for patients with more severe or persistent problems and doses in excess of 30mg would not normally be found outside psychiatric practice. Benzodiazepines exert their characteristic effects by acting on specialised receptors in the brain. These receptors are also used by other drugs which have a similar action on the brain and if a benzodiazepine is taken together with another drug with an action on the brain (particularly if it acts on similar receptors), then the combined effects will be in excess of the effects of the individual drugs added together. This excess of effects is due to an interaction or "synergism" between the two drugs producing a total effect which is greater than the sum of the component parts.
Alcohol is one substance that uses part of the receptor which the benzodiazepines use and if alcohol is taken in conjunction with the benzodiazepines then a heightening of the effects of the benzodiazepines is made in a synergistic way. Although overdoses of benzodiazepines alone are rarely fatal, combinations of benzodiazepines with alcohol are dangerous and toxic. Physicians have been warned in the standard prescribers guides (British National Formulary; MIMS) issued to all doctors and required to take special precautions when prescribing benzodiazepines to patients who use alcohol.
As alcohol and benzodiazepines share similar receptors, they do have some effects in common and it is a useful comparison for appreciating the overall effects of benzodiazepines to refer to the action of alcohol. Both benzodiazepines and alcohol produce 'intoxication', forgetfulness, difficulty coordinating movements, confusion, tiredness, and also cause users to lose their inhibitions, become emotionally labile and sometimes angry or aggressive. This comparison is purely to indicate the sort of effects that are to be discussed and the sort of impact benzodiazepines might have on patients using them.
There are three sources of information regarding the effects of benzodiazepines which can be used to augment my own 25 year research experience of the drugs. They are: results from controlled clinical/scientific laboratory studies in both volunteers and patients; lists of effects provided by the manufacturers of the drugs for inclusion in their datasheet (package insert) and issued in accordance with the requirements of the medicine regulatory bodies; and findings from studies of patients under treatment with clinical dose regimens of benzodiazepines.
Controlled studies: These studies, usually carried out in non-patients, are aimed at measuring, in an accurate and scientific manner, the effects of benzodiazepines on human behaviour, mental abilities and state of mind. They reveal the intrinsic potential of the benzodiazepines and, of course, of individual drugs, to alter or impair aspects of human behaviour, essential for the performance of the intellectual, skilled and emotional demands of everyday living, particularly as regards thinking, decision making, judgement, memory, alertness, basic skills (car driving etc.) eye/hand coordination, problem solving, reasoning, mental arithmetic, speed of reaction, capacity for processing information and vigilance. It is essential for the integrity of an individual's intellectual and psychological well-being that these basic behaviours and skills remain unaffected and unimpaired by the administration of benzodiazepines. If for example, intellectual processes, memory and the ability to reason are directly changed by a benzodiazepine, then the patient will be confused, make mistakes and errors in judgement, forget to do things and in general be unable to function appropriately or correctly in his habitual daily environment. There would also be an increased risk of accident, should basic coordination and judgemental skills be impaired.
The results of these numerous basic laboratory studies from my own and other internationally renowned institutions, performed over the past 25-30 years are remarkably consistent with different centres of excellence replicating the results of others and concurring with the general findings that most benzodiazepines at clinical, and even sub-clinical, doses impair and compromise a wide range of basic skills which are absolutely necessary for coping with the intellectual and psychological demands of everyday living. There are some exceptions to this general rule, but flurazepam is not one of them.
Studies with benzodiazepines have shown that most compounds impair memory, as measured on a wide range of tests of verbal, visual and number recall, produce forgetfulness and impaired recognition of pictures and events and characteristically disrupt the process by which subjects intentionally try to retrieve information from their memories. A review (Wittenbom, 1988) of 12 different benzodiazepines assessed in 109 controlled instances showed statistically significant drug related impairment, on average, 82% of the times tested. Flurazepam produced a significant impairment 83% of the time.
The results from these controlled experiments demonstrate the profound intrinsic potential for benzodiazepines in general, and flurazepam in particular, to disrupt many aspects of memory. Since these studies are performed in non-patients, the impairment must be due directly to the drug administered. Although these studies tend to be of shorter duration than most clinical treatment regimens, it is evident that the disruption of memory and the amnestic effects persist in regular benzodiazepine users for as long as the drug is taken (e.g. 2 months, Curran et al., 1994) or more (Gorenstein et al., 1994; 1995).
Flurazepam at doses of 15mg and upwards has been shown to possess the general sedative, amnestic and skilled performance impairment of the benzodiazepines in general. Furthermore, flurazepam has been shown to impair mental arithmetic (reasoning) ability, tests of flexibility of thought and motor movement, motor control, eye/hand coordination, speed of mental reaction, information processing, (understanding, comprehension), vigilance, sustained attention (concentration) and divided attention (the ability for doing two or more things at once), (Saunders & Wauschkuhn, 1988).
Flurazepam is usually taken at night 20-30 minutes prior to going to bed, but its deleterious effects on behaviour and memory are experienced and measurable (Hindmarch, 1986; Ponciano et al., 1990) throughout the next day due, in great part, to the pK and pD characteristics of the drug and its long duration of both side effects and clinical activity (sleepiness).
Data sheets: Manufacturers are required by drug regulatory authorities to provide a product data sheet giving physicians details of the indication for which the drug has received the approval of the regulatory bodies and presenting appropriate guides as to dosing regimens. The side effects following use of the specific drug are also listed together with any special precautions that might be needed on behalf of the prescribing physician when using the product in a clinical context. Listing an effect or side effect on a product data sheet is an indication that the manufacturer has accepted evidence of the existence of the listed effects as a consequence of its product's administration.
In long term clinical use benzodiazepines have commonly been associated with numerous side effects (taken from manufactures data sheets late 1970s) including daytime drowsiness, sedation (a sort of sleepiness and detachment from the real world), unsteadiness, ataxia (loss of muscular coordination), lightheadedness, irritability, increased emotionality, visual disturbances, sleep disturbance, nervousness, dizziness, reduced alertness, headache and abnormal or uncharacteristic psychological reactions. More rarely, benzodiazepines have been associated with aggressive outbursts, confusion, excitement, psychotic manifestations, depression and suicidal tendencies.
The likelihood and the frequency and severity of these side effects will increase as the dose of the benzodiazepine and the duration of its use are increased. Flurazepam is no different from the class of benzodiazepines in its ability to produce side effects of the sort detailed above. In prolonged and regular daily use the drug will accumulate in the patient as there is not sufficient time for the body to metabolise and excrete the first dose before the next one is taken. With flurazepam this effectively means that the patient has an active drug in their body, capable of affecting behaviour and producing untoward side effects, continuously both night and day. It is most probably because of this that the drug's manufacturers recommend flurazepam for "short term treatment of insomnia where daytime sedation is acceptable". It can be seen that much of what is recorded in manufacturers' lists of side effects is totally in accordance with the results of controlled experiments. For example; "drowsiness" is reflected in longer reaction speeds, "unsteadiness, ataxia" in impaired performance of motor balance tests, "reduced alertness" in impaired mental abilities and "sedation" as poor information processing and decision making. It is also interesting to note (Currie et al., 1995) that patients who had taken benzodiazepines were 6.5 times more likely to be responsible for and the cause of the accident that placed them in accident and emergency care than those patients who were unwitting victims of accident and simply in the wrong place at the wrong time. To put this increased risk of accident into context, it should be remembered that 80mg% blood alcohol concentration (the legal limit in the UK) increases the risk of road traffic accident four-fold. Although accident causation is a complex issue, it is certain that defective judgement and/or forgetting, loss of coordination or balance, confusion, poor comprehension and decision making will feature as causal agents. Since these psychological behaviours are all impaired by the benzodiazepines it is not surprising that benzodiazepines are over-represented as causal agents in accidents at home, on the road or at work. While many people using benzodiazepines might not have an accident, the side effects of using the drug will still be there to compromise their daily cognitive and psychological abilities. This accident data is used here to indicate the serious nature of the action of benzodiazepines on psychological skills and is further evidence that patients using benzodiazepines have their daily behaviour compromised.
Clinical Trials: Drug regulatory agencies demand of manufacturers that they record the effects of benzodiazepines in a clinical context. This is often done using unstructured questionnaires and subjective impressions. They are, however, important sources of information as records of what happens in the real world when typical patients take typical dose regimens for typical lengths of time. Some of the earliest studies in the 1960s (Essig, 1966) reported various behavioural toxicities including disorientation, confusion, memory impairment, trance-like episodes, double-vision, impaired arithmetic abilities and rage reaction following benzodiazepines.
These effects were similar to those produced by other tranquillisers and occurred without any other drug or alcohol being present. In the early 80s a commentary on the side effects of benzodiazepines (Hallström, 1982) found in clinical studies, found drowsiness to be "common" and memory impairment and depression to be "important" side effects. The author also warned of the potentiation of the effects of alcohol and that the benzodiazepines can, both with and without alcohol, exacerbate violence and aggression.
The long term use of benzodiazepines has been associated with mental deterioration but even if such a consequence was not proven, the fact remains that flurazepam and the other benzodiazepines have the intrinsic potential to impair aspects of human decision making and other mental processes. The impairment shown to be produced with flurazepam will be potentiated by doses in excess of 15mg nightly, by prolonged treatment in excess of 2/3 weeks, and by the co-administration of alcohol. Patients treated with flurazepam could therefore be expected to experience, with a high degree of probability, disturbances of memory, (including forgetfulness, confusion and an inability to recognise or recall important information), disturbances of awareness (feeling "not part of the real world", detached and not able to handle environmental signals and process information), disturbances of alertness (feeling tired during the day, poor concentration and attention skills) and disturbance of balance/motor systems (dizziness, clumsiness and "intoxication").
There are legion other effects which could occur with a lower probability and these include emotional lability, light headedness, uncharacteristic behaviour, e.g. aggression, bad temper and anxiety or depression of mood.
The benzodiazepines are arguably, the most researched psychoactive drugs in the history of medicine. There is a most substantial body of research that confirms the effects of these drugs as broadly deleterious to lucid thought, comprehension, understanding, decision making and judgemental abilities. These effects will be compounded by using alcohol and by the use of high doses of the drug (in excess of 15mg flurazepam, for example) for long periods of time (in excess of 2/3 weeks flurazepam).
This is not to say that all patients will necessarily experience all possible effects of benzodiazepine administration, but with flurazepam (especially at high doses administered over a long time) there is more than sufficient evidence for concern that the majority of patients using this compound will be compromised in their abilities to make reasoned argument and decisions in their domestic, social and business dealings.
Professor Ian Hindmarch
30th January, 1997
Professor Ian Hindmarch, BSc, PhD, CPsychol, FBPsS, FRSA - Head of HPRU
Professor Ian Hindmarch is Professor of Human Psychopharmacology and Head of HPRU Medical Research Centre at the University of Surrey, Guildford, England. His research, over the past 30 years, has concentrated on the clinical activity, behavioural toxicity and side effects of psychoactive drugs in clinical use. Professor Hindmarch is a founding editor of Human Psychopharmacology: Clinical and Experimental and currently the Editor-in-Chief. He has edited 20 books and the results of his research have appeared in over 470 medical and scientific papers (including over 120 on the psychopharmacology of anxiety and depression). His current research interests focus on the development of new medicines for depression, anxiety, dementia and sleep disturbance, particularly as regards the possible side effects of drug treatment on the activities of patients performing the cognitive and psychomotor tasks for everyday living.
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