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The Effects of Tranquillization:
Benzodiazepine Use in Canada
Health Canada Publication: 1982
2. OVERVIEW OF BENZODIAZEPINE USE
General Canadian Data
As of 1981 there were 10 different benzodiazepine drugs sold in Canada.[*1] This class of drug was first introduced as an anti-anxiety agent (chlordiazepoxide), then was recognized as also containing muscle relaxant properties (diazepam), then was marketed as an hypnotic (flurazepam), and most recently as an anticonvulsant (clonazepam). The benzodiazepines were introduced into Canada in 1960 with chlordiazepoxide (most popular trade name Librium), followed two years later by diazepam, most commonly prescribed as Valium. This latter drug quickly became the most popularly prescribed drug in the Western world.
Of some difficulty for both prescriber and consumer is the fact that some benzodiazepines are sold under a variety of trade and generic names. Diazepam, for example, is sold as 15 trade name products, including Valium, and four generics. Similarly, chlordiazepoxide can be purchased under 13 separate trade names and is also supplied by six companies under its generic name. Finally, oxazepam, most popularly sold as Serax, is distributed under three competing trade names and one generic.
Although the benzodiazepines are marketed as having a variety of functions, including anti-anxiety, hypnotic, and anticonvulsant, they "are all similar structurally and in their pharmacological actions. Few have specific advantages over others."[1] One factor which does differentiate these substances is the half-life of each drug. Half-life refers to the time required for the drug concentration in the plasma to decrease by one-half. The most popular benzodiazepine, diazepam, used as both a sedative and hypnotic, has a particularly long half-life. That is, it can be found in the plasma for a mean period of 30 hours, ranging from 20 to 170 hours. Flurazepam, the most commonly used hypnotic, has an active metabolite whose half-life has a range from 47 to 100 hours. In contrast, oxazepam has a short half-life, approximately four to seven hours, and has no active metabolite.[2] These variations in the half-life and in the pharmacological action of the metabolites of the drugs appear to be of significance for prescribing, especially for those who metabolize drugs slowly, such as the elderly or individuals with liver disease.
Another group of benzodiazepine drugs are 'mixed' or combination drugs which contain a benzodiazepine in addition to one or more other active ingredients. The most popular of these in Canada is Librax, a combination of chlordiazepoxide and an anticholinergic which is used in treating gastrointestinal disorders and peptic ulcer. Mixed drugs are more frequently identified by their more specific action rather than as anti-anxiety agents, with the consequence that many individuals are unaware they are consuming a benzodiazepine. From an epidemiological viewpoint, combinations are not generally identified as such in surveys or prescription studies.
Two methods are commonly used to assess prescribed drug use. The first utilizes sales data or prescriptions dispensed through pharmacies or other outlets. This method focuses on drug distribution in contrast to the survey method, which measures consumption. Major methodological problems exist with both methods. Studies of prescriptions generally collect data from retail pharmacies, thus omitting other institutions, such as hospitals, nursing homes, prisons. (Hospitals alone account for approximately eight per cent of all drugs dispensed). By counting prescriptions for a product one can only know that the prescription was filled, but can never identify whether the substance was consumed at all, by whom, and in what quantity.
In contrast to sales data, surveys ask directly about consumption. Typically, they are conducted using a random or other type of community sample and thus also omit the hospitalized or institutionalized. Surveys are, of course, limited by the questions they ask. Benzodiazepine use may go unrecorded unless specific drug names are requested under the broader headings such as 'tranquillizers' and 'sleeping pills'. Underreporting of consumption by high users, by those using a number of different drugs, and by those who feel some stigma attached to use, is common. Memory loss also accounts for underreporting if questions ask about consumption for more than a short time period.[3]
Neither of these methods is able to collect valid information on illicit use of benzodiazepines. Police records of pharmacy thefts would be necessary and assessment of street drug use requires other research methods. In summary, no one method of estimating consumption gives completely accurate data; combining data collected through both prescription studies and surveys provides the closest estimates of real use.
Cross-Canada data on benzodiazepine consumption is at best somewhat sketchy but is nonetheless reasonably consistent. Using surveys as a base, 13 per cent of Metro Toronto residents claimed to have used tranquillizers during 1971,[4] I4 per cent of Ontario residents claimed the same during 1976[5], and in a national survey conducted in 1977, almost six per cent of respondents said they had taken a tranquillizer during the previous 14 days.[*2][6]
While evidence exists that U.S. consumption is somewhat higher than Canadian for these drugs, it is of interest that 15 per cent of the American population said they had used diazepam during l979 and four per cent had used flurazepam during the same period.[7]
The Saskatchewan Prescription Drug Plan is the most comprehensive in Canada, covering virtually all residents and charging a set fee of $2.60 per prescription. All prescriptions are computerized, thus data on prescribed drug use are available for a total population. While it cannot be expected that prescribing will be identical across the country, these data are perhaps closest to generalizable of any collected in Canada. For the last year reported (1977), it was found that 20 per cent of the provincial population received a prescription for a mood-altering drug; about half, or almost 10 per cent of the population, were prescribed minor tranquillizers.[8a] In a preliminary analysis of prescription data from 1977 through 1979 in Saskatchewan, a slight decline was found in the prescribing of minor tranquillizers. Simultaneously, however, other benzodiazepine sedative-hypnotics increased in use, suggesting little change in total benzodiazepine distribution over the three-year period.[8b]
The Ontario Ministry of Health conducts a yearly sampling of prescriptions dispensed throughout the province. These figures are comparable to those from Saskatchewan, showing that close to half of all psychotropic drugs are accounted for by minor tranquillizers and that there has been a steady increase in the use of non-barbiturate hypnotics such as flurazepam.[9] This can be partially accounted for by the decline in the prescribing of the barbiturates as hypnotics.
Consistent throughout all of the above studies, whether Canadian, American or British, is variation among subgroups of the populations studied. That is, women almost invariably receive twice as many prescriptions for benzodiazepines as men and the elderly receive significantly more than younger populations. These variations will be demonstrated and discussed in the following section.
While the total number of prescriptions is valuable baseline information, of considerably greater importance is the identification of those segments of the population who use these drugs over extended periods. In a summary of a number of U.S. studies, it was found (depending on the method used) that anywhere from 33 to 85 per cent had used their drug for longer than two consecutive months.[10] A national survey of prescribed drug use in Britain conducted in 1977 reports that more than half of all psychotropic drugs had first been prescribed more than one year previously and almost half at least two years before.[11]
Repeat prescribing of these drugs appears to be common in Canada, as elsewhere. Bearing in mind that a prescription is typically written to last one month, the Saskatchewan study found that of those receiving prescriptions for mood-modifying drugs, 20 per cent received more than five prescriptions of the same drug type during one year.[12]
High Risk Groups[*3]
Given the proportion of the population who have used or are currently using benzodiazepines, it is almost inevitable that some segment of that population will have problems as a consequence of use. Those segments of the population who use the highest proportion of these drugs, i.e. those at highest risk, require particular study, both to document the extent of their use and to assess the effects of the drugs in these populations.
The major high risk populations in Canada, as elsewhere, are women, the elderly and the chronically ill. In view of the longer life expectancy of women, and the fact that chronic illness is more common among the elderly, it is hardly surprising that elderly women as a group are the highest consumers of minor tranquillizers.
1. Women
It has been consistently demonstrated that adult females at each age level receive more prescriptions for psychotropic drugs than males.[13-16] The studies show between 67 and 72 per cent of these drugs are prescribed to females.
Other studies demonstrate that not only are women in receipt of the most prescriptions for minor tranquillizers at any one point in time, they are also at highest risk for receiving more prescriptions per year than men, and for continuing on these drugs over more years. [17-19] For example, an analysis of data from an Ontario prescription insurance agency for a three-year period 1970 to 1973, both confirmed the existence of the typical two to one ratio of female to male prescriptions for each of the time periods, and found that women who received a psychotropic prescription in 1970 had an almost 50 per cent chance of receiving a similar prescription three years later. This was less true for the males. The same study found twice the number of females as males receiving 10 or more prescriptions in a year, indicating steady use.[20]
The excess prescribing to women over men might appear to be solely a function of the higher number of physician visits by women. However, in an examination of physician visits in Ontario it was shown that the difference between the sexes in number of visits does not account for all of the excess prescribing to women.[21]
One variable, that of work status, remains consistent in its relationship with psychotropic drug use among both sexes.[22] Those who are retired, unemployed, or not in the labour force, are the highest consumers of psychotropic drugs.[23,24]
These findings need careful examination since they could be due largely to age. One study, however, found that at each age level, women who worked outside their homes reported lower psychotropic drug use than those who did not.[25] A significant correlation existed in this study between the amount of time spent working outside the home and drug use:11 per cent of those in full-timejobs,19 per cent of those with part-time jobs, and 25 per cent of those at home fulltime, reported use in the previous two weeks. The same study asked about social activities outside the home such as club participation, sports and visits to friends. Relating this 'activity level' to psychotropic drug use, it was found that as activity decreases psychotropic drug use increases.
A possible explanation for the relationship between work status, activity level and drug use is general health. Holding age constant, it was found that use of psychotropics increased as the women's subjective health rating became more negative.[26] Another study also found higher use among those reporting a poorer health rating.[27]
The question remains then whether poor health or sex should be considered the critical causal factor in psychotropic prescribing. Three studies suggest that sex may well be the overriding variable. The first examined male-female differences in drug use among those admitted to medical and surgical wards in a large U.S. medical centre, and found 25 per cent of the women and 15 per cent of the men entering the hospital with prescriptions for psychotropics.[28] The second study found that prior to hospital admission to a Canadian psychiatric ward females had received more prescriptions than males for minor tranquillizers.[29]
An Ontario study also found that men and women with identical symptoms attending a family practice clinic received different numbers of minor tranquillizer prescriptions. The women received significantly more prescriptions than the men although there were few differences between them in the rate at which they received other therapies.[30]
Two hypotheses were tested in a study of a community mental health facility: 1) that women would be more likely than men to recognize the existence of their problems, and 2) that before seeking psychiatric help, women would be more likely to look to members of their intimate networks. This study concluded that women accept the self-label of psychiatric illness more willingly than men, and that having spoken to more intimates about their problem they enter treatment and accept the role of patient more readily than men, who are more typically pressured into treatment.[31]
Numerous studies have demonstrated a difference in men's and women's reporting of both physical and psychological symptoms. It has been shown that men have less awareness of both emotional disorders,[32] and physical symptoms.[33] These variations in levels of awareness may well be related to differences in roles filled by men and women.
For example, women are expected to be nurturing, which involves responsibility for the health care of family members.[*4] It also requires more contact with professionals through attendance at health care facilities with children and elderly parents, thus establishing comfortable and familiar relationships with health care staff.
Over 90 per cent of Canadian family practitioners are males, most of whom can be expected to hold traditional views of appropriate male and female behaviour. This would include greater expectation of and ease with expressive behaviour from females than from males. Having seen women patients frequently in a family context, doctors are again more likely to elicit information about family problems, emotional and social concerns. These may well be factors in the higher prescribing of benzodiazepines to women.
2. The Elderly
Widespread use of psychotropic drugs by the elderly poses a number of potential health hazards as the elderly have a diminished capacity to metabolize and eliminate drugs. Although the benzodiazepines are considered preferable to the barbiturates or other sedative-hypnotics, they are nonetheless problematic for the elderly. Since this population is most at risk for chronic illness and consequently for using a number of drugs concurrently, the risk of adverse drug reactions is higher among them. It has been shown that in a hospitalized population, adverse drug reactions occurred in three per cent of patients aged 20 to 29 but in 21 per cent of patients between 70 and 79.[34]
The elderly receive more than twice the number of prescriptions for psychotropic drugs as do younger people.[35] the ratio of the elderly in the population increases so can we expect increases in prescription and use of psychotropic drugs. All Canadian provinces now provide low cost or free prepayment prescription drug plans to those 65 and over. The Ontario Drug Benefit Plan covers approximately 1.2 million residents of the province, 800 000 of whom are age 65 and over. The average number of prescriptions for all drugs per eligible beneficiary has increased steadily since the introduction of the plan to the point where those 65 and over received 16 prescriptions per person by 1978-1979. The number of minor tranquillizing drugs dispensed under this plan continues to increase on a yearly basis, although at a slower rate than other drugs such as analgesics (pain killers). In Saskatchewan, the Joint Committee on Drug Utilization reported peak use of minor tranquillizers at age 75 for females and 65 for males.[36]
In Manitoba, 500 individuals over age 65 were studied who claimed their drugs under the province's Pharmacare program.[37] The benzodiazepines were the single most widely prescribed drugs with a high rate of steady use, 34 per cent in women and 22 per cent in men over 65 years of age. Converting to the whole population, not just those claiming under Pharmacare, the author concluded that over 20 per cent of Manitoba's females over age 65 were chronic users of benzodiazepines at the time of the study, 1975. Continuous use of two or more psychotropic drugs was found in 25 per cent of the women and 12 per cent of the men. In 1978 the author replicated his earlier study and found that the prescribing of psychotropic drugs had increased, especially for women.[38]
Concern regarding the potential health hazards of psychotropic drugs for the elderly is particularly relevant considering the findings of a recent English study.[39] Over 1000 repeat prescriptions of psychotropic drugs (given without the doctor seeing the patient) were examined from a population of over 100 000 patients. It was found that the longer repeat prescribing had taken place, the older the patients were likely to be, and the less closely were they to be monitored by their general practitioners. Sixty-six per cent of the drugs monitored were benzodiazepines.
Since telephone prescribing is permitted in Canada and not in the United Kingdom, one might expect an equal or greater amount of repeat prescribing in Canada.
3. The Chronically Ill
A comprehensive review of the efficacy of benzodiazepines in somatic disorders, largely of a chronic nature, states that, generally, evidence of improved outcome due to anxiolytic effects is lacking.[40] The authors conclude that the role of these drugs is primarily adjunctive, i.e. facilitating patient management and improving the feeling of well-being without 'curing'. The conditions in which these drugs appear to have value adjunctively are acute myocardial infarction, migraine and gastrointestinal disorders. They appear to be contraindicated in respiratory conditions. The authors recommend careful assessment as to their value in adjunctive therapy as well as recommending only short-term benzodiazepine treatment.
A large study of elderly chronically ill patients in Ontario found that psychotropic drugs had been prescribed to about one-fourth of the patients, with benzodiazepines the most frequently prescribed class. Of those patients receiving at least one psychotropic drug prescription, 27 per cent had been prescribed two or three psychotropic drugs simultaneously.[41]
Other studies, largely outside of Canada, have examined the range of indications given for the use of these drugs in medical practice. A sample of such findings follows. As shown, most of the conditions listed are of a chronic nature. or potentially so.
In an American study, market research data was used for an analysis of indications for diazepam prescribing by a random sample of physicians.[42] Non-psychiatric conditions accounted for 70 per cent of the diazepam users. Those included, in order of frequency, were musculoskeletal, circulatory, geriatric, medical-surgical aftercare, gastrointestinal, central nervous system disease, and genito-urinary problems. Diazepam had been prescribed in combination with other drugs in 64 per cent of the cases.
In a retrospective study of the indications for psychotropic drug treatment in general practice in Britain, it was found, the 13 per cent of the patients had been prescribed psychotropic drugs during the year.[43] Both barbiturate hypno-sedatives and the minor tranquillizers Librium and Valium were commonly prescribed for disorders of menstruation and menopausal symptoms and for digestive system disorders such as duodenal ulcer, gastric ulcer, and colitis. Poorly defined symptoms which may have anxiety components, such as insomnia, headache, nervousness, dizziness, debility, backache, vague chest pains, precordial pains, palpitations, and tachycardia accounted for almost one-third of all patients prescribed psychotropics.
In contrast to the above results, a Finnish study of general practitioners found that 21 per cent of the diagnoses resulted in psychotropic drug treatment.[44] Thirty-nine per cent of the psychotropics were prescribed for somatic diseases while this was true for 85 per cent of the hidden psychotropics (combined drugs containing a benzodiazepine).
It would appear from the data cited that minor tranquillizers have been prescribed for a broader range of chronic conditions than have been identified as appropriate.[45a] Hemminki, in Finland, concluded that broadening the indications for use to many somatic diseases was an effective mechanism in increasing the use of psychotropic drugs.[45b] It should be noted that advertisements in medical journals frequently advise physicians to prescribe benzodiazepines to patients with a wide variety of chronic illnesses.
4. The Institutionalized
Far fewer studies have been reported of the institutionalized than of other high risk populations. Yet, recently published data indicate that this population, residing in nursing homes, retardation centres and prisons, may be prescribed the largest quantity of psychotropics.
The most comprehensive study of the institutionalized was conducted in American long-term care facilities (largely consisting of nursing homes). This study examined diagnostic and prescribing information for almost 300 000 patients with chronic diseases and disabling conditions. Tranquillizers (both major and minor) were prescribed to all those institutionalized patients with a diagnosis of alcoholism, to 52 per cent with a diagnosis of angina or myocardial infarct and to 50 per cent with a diagnosis of neurological disorder. Among those with other chronic conditions, 42 to 48 per cent were prescribed tranquillizers, suggesting that prescription of these drugs may frequently be unrelated to specific diagnosis but, as concluded by the authors, may be used for the purpose of institutional control.[46]
Two Canadian studies on this topic have been reported in the medical literature. The first examined drug use among residents in five retardation centres in Eastern Ontario.[47] It was found that 42 per cent of the residents were given psychotropic prescriptions. The majority of these were major tranquillizers while 21 per cent had used a variety of sedatives and hypnotics (largely benzodiazepines). In these institutions, epileptics and non-epileptics received the same proportion of psychotropic drugs. While the author does not distinguish major from minor tranquillizers in his discussion, he nonetheless concludes that "it is quite clear that at least half of the subjects on psychotropics were given those agents unnecessarily." A study of prisoners at Millhaven Penitentiary with a history of aggressive behaviour was carried out specifically to assess the effect of benzodiazepines on aggression in this type of setting.[48] Using prisoners as their own controls, it was found that violent or aggressive incidents were most frequent when the men were using benzodiazepines.
Unfortunately, however, there is still a paucity of information on the use of benzodiazepines in Canadian institutional settings.
*1 Appendix A of this report gives the generic names of all 10 benzodiazepine drugs, their dates of introduction to Canada, the names of the manufacturers distributing in Canada, and the trade names under which the drugs are sold.
*2 Not all studies of consumption distinguish clearly between major and minor tranquilliser use. Many unfortunately inquire only of tranquillisers, thus limiting accurate estimation of minor tranquilliser use. When citing research, the terminology used will of necessity be that of the research reports.
*3 "High risk" is used here and throughout the paper to refer to those with the greatest statistical probability of being prescribed benzodiazepines.
*4 This requires women to be considerably more sensitive than men to the physical and emotional health status of others.
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