The Level of Benzodiazepine Dependence Risk in Humans


It is clear from the human experiments conducted by Hollister and others that if benzodiazepines (like most if not all psychotropic drugs) are given in large enough doses for a long enough period, physical dependence can result. It is equally clear from the observations reported on pp. 23 to 40 that dependence can also occur occasionally under conditions of abuse and when benzodiazepines are used medically. It is important to try to assess the level of risk and particularly the level relative to other central nervous system active drugs.

The concept of a dependence-producing ‘capacity’ or ‘potential’ which resides in a drug itself has been questioned by some authorities in respect of drugs other than narcotics. These authorities suggest that it is more relevant to speak of ‘dependence-prone individuals’ who abuse a variety of substances and can develop dependence upon any or all of them (see, for example, Edwards). Keilholz writes of a multiple determination in which the drug is only one of the elements, the others being the individual himself and the setting.

If the contributory role of the pharmacological action of drugs is accepted, it is now widely agreed that compared to the amphetamines and the barbiturates, the benzodiazepines have a very low potential for producing dependence (see, for example, among recent comments from world experts, Hollister, Ayd, Glatt, Wells, Kryspin-Exner).

Smith and Wesson have attempted to define what they call the addicting liability (doses to produce major withdrawal) of the common sedative hypnotics. Examination of their data for the benzodiazepines shows that it is entirely derived from the Hollister studies, the significance of which Hollister subsequently doubted ().

Later experience has shown the great variability in the susceptibility of individuals and the Smith and Wesson figures though often quoted and revised by others (e.g.) should be regarded with suspicion.

In their key monograph in 1970 Isbell and Chrusciel give an ‘abuse potential rating’ for the drugs that they consider. More recent experience suggests that some of their conclusions should be modified (e.g. methaqualone).

There is further evidence related to the dependence risk of the benzodiazepines in therapeutic use. Thus in Switzerland, Kielholz studied the extent of drug abuse in psychiatric clinics, policlinics and among a selected group of practising physicians. He found isolated instances of dependence on tranquillizers, but in view of their widespread use the small number of these cases showed that the risk of dependence on these drugs was slight. Kielholz established a ‘risk factor’ for the dependence on psychotropic drugs by correlating the sales figures, supplied by the industry, with the number of known cases of abuse. The rate of dependence on analgesics was arbitrarily given the value 1, that of other psychotropic drugs being calculated proportionately as hypnotics 2.7; central stimulants 3.8 and tranquillizers 0.2, i.e. a low dependence risk exists for tranquillizers.

One of the fallacies of reputed determination of dependence risk is exemplified in one of the recent studies. Clift attempted to compare the extent of development of dependence under general practice therapeutic use of amylobarbitone and nitrazepam. He concluded that the rate of psychological dependence at doses of amylobarbitone 100 mg and nitrazepam 5 mg were equal but unfortunately the study must be regarded as invalid as there is no clear evidence presented of dependence. The only measure of assessment adopted was the patients’ request for a prescription renewal one year after the original prescription was given. This was found in 8 per cent of the group studied, but no attempt was made at that stage to determine whether the patient could be persuaded to give up taking the tablets without difficulty as a result of a positive move by the physician.

In Sweden the health authority conducted two enquiries- separated by 5 years, in the same population to determine the extent of tranquillizer prescription. Of the 3000 individuals sampled in the initial 16-month period, 417 had obtained a single prescription for a hypnotic, a sedative or a minor tranquillizer and of these 76 had repeat prescriptions, at least once every 2 months. The total number of prescriptions had reduced over the 5 years for both the single prescription and the multiple prescription group. One individual had markedly increased the prescriptions on the second survey but five who it was thought might be abusing the drugs earlier had all reduced their consumption by up to 50 per cent in the second period. At the 6-year follow-up a similar general pattern emerged but signs of overuse or abuse to psychotropics were present in four patients, one a previously known addict. It is not clear which drugs were involved.

This decrease in tranquillizer use in the Swedish study has also been reported for other West European countries over the past few years.