Medical Aspects of Benzodiazepines: Intrinsic Safety


From the medical viewpoint, the availability of any drug must be based on a judgement of its therapeutic value compared with its safety. Therapeutic benefit exists when the level of improvement achieved exceeds the danger; this ratio must be related to the disease being treated. When the drugs with potential dependence liability are considered () it will be seen that the range of diseases for which they are used is wide. Thus, for example, the narcotic analgesics are the only effective drugs for the relief of the pain experienced in some terminal diseases and the availability of at least some powerful analgesics is important for this use. This, however, does not imply that they should be used medically for the relief of minor pain for here the dependence risk exceeds the benefit.

The hallucinogens cannabis and cocaine on the other hand have considerable dependence liability, sometimes coupled with other medical risks but no therapeutic merit and their availability cannot be justified medically. A similar situation exists for the amphetamines in terms of dependence liability and if the rare cases of hyper-kinetic syndrome are excluded, the amphetamines have no therapeutic merit and should therefore not be used.

The most difficult group for medical appraisal are the sedatives. The general picture for the whole group has been presented in a masterly monograph by Isbell and Chrusciel. This monograph gives the key references to papers on reputed dependence in the whole field of non-narcotic drugs and attempts to assess an abuse potential rating. With the exception of the phenothiazines and the butyrophenones they consider that all the sedative/tranquillizer group have some dependence liability, a conclusion which is consistent with the evidence they produce. The dependence is of ‘barbiturate type with psychological dependence, tolerance to a greater or lesser degree and physical dependence in those patients who increase their dosage above the therapeutic level. They divided the abuse potential rating into the categories high, moderate and low. For most ot the drugs quoted there can be little dispute about the rating, except as the authors point out, drugs that have only recently been introduced are favoured since there has been inadequate opportunity for dependence to be developed and assessed. This is perhaps best illustrated by methaqualone rated by Isbell and Chrusciel as ‘low to moderate’. They quote the British experience of higher abuse levels but obviously rely more heavily on American experience for the assessment. British and European and Japanese observers would now rate the abuse potential of methaqualone as high.

A second possible objection to the rating as given in this monograph is that it takes account not only of the risk that exists by virtue of the pharmacological efects of the drug but also the extent of availability for abuse as measured by the extent of licit usage. Thus some individual drugs are given a low rating not only because their low or recent availability has reduced the chance of dependence having developed, but because it also reduces the possibility of access for abuse.

This monograph rates the most widely available benzodiazepine as ‘moderate’ and the others as ‘low’, a probably artificial split based upon the availability. On the basis of the evidence discussed elsewhere () it is suggested that the Isbell monograph overstates the benzodiazepine abuse rating which should be regarded as ‘low’, a view which is in accord with that of many experts in the field.

But any assessment of the merits and demerits of the benzodiazepines must also take into account their toxicity and morbidity relative to other sedatives (e.g. the barbiturates) as well as the social psychotropics, alcohol and nicotine.

Psychotropics have a low mortality rate, indeed there is no clear evidence of any deaths from benzodiazepines used alone.

So far as morbidity is concerned, the following facts should be taken into account:

For alcohol: the commonest acute complications are acute alcoholic liver disease (25.1 %), peripheral neuropathy (19%), hypertension (16.9%), gastritis (13.5%) I the commonest chronic complications are chronic bronchitis (17.3%), cirrhosis (9.8%), brain syndrome (8.5%), epilepsy (7.5%), peptic ulcer (7.2%), while 11.2% of the patients had major traumatic injuries mainly resulting from road traffic accidents. These are apart from the general impairment of mental ability and related manifestations of the intoxication.

For tobacco: apart from carcinoma of the bronchus, smoking produces extensive morbidity (and mortality) by its role in the development of bronchitis, emphysema, coronary disease, peripheral arterial disease, abortion, stillbirths and small babies, carcinomas of the mouth, larynx, bladder, inter alia.

For barbiturates: there is impairment of mental ability, confusion, regression, emotional instability, dysarthria and ataxia.

While the waste of human life and happiness through dependence on alcoholism, tobacco and barbiturates is enormous, there is an additional economic loss to the community.

With alcohol, for example, this includes the support which has to be given to patient and family during unemployment and sickness, the maintenance of hospital beds and prison cells, the cost of accidents and above all the lowering of industrial efficiency. Thus, for example, the cost of alcoholism to Scotland’s industry alone is estimated to be £35 million per year while the estimate for excessive drinking costs in the States is well over $1000 million per year. For tobacco it has been estimated that 20 times the number of days lost per year from industrial disputes result from smoking and that between 5000 and 8000 hospital beds are occupied each day in the United Kingdom as a result of smoking. The estimate of the annual cost to the community in the United Kingdom resulting from smoking is £280 million.

For barbiturates the United Kingdom total number of annual hospital admissions for poisoning is estimated at about 14 000. If the cost of this care is added to the loss of industrial efficiency, then the cost to the community is well in excess of £2 million per year.