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The Effects of Tranquillization:
Benzodiazepine Use in Canada
Health Canada Publication: 1982
4. UNDESIRABLE PHYSIOLOGICAL AND PSYCHOSOCIAL
CONSEQUENCES OF BENZODIAZEPINE USE
Any pharmacologically active substance which has positive effects is, unfortunately, likely to have negative effects on some individuals and under some conditions. Additionally, drugs which affect the central nervous system and alter mood are also likely to be used recreationally and inappropriately, regardless of their legal status. This section, then, will deal with some of the undesirable pharmacological and psychological consequences of use as well as problems associated with polydrug use, cross-addiction, overdose and self-poisoning.
Tests to determine the safety and efficacy of prescription drugs are generally carried out on populations who are not typical of users of the substances. Clinical trials and laboratory studies are most commonly conducted on young, healthy, frequently male subjects under carefully controlled conditions. As shown earlier, the majority of benzodiazepine users are older, largely female and often using other medications for a variety of chronic conditions. Thus the applicability of the clinical test findings is seldom clear. However, combining clinical test results with actual cases reported in medical journals and data from benzodiazepine users permits a multifaceted view of the consequences of use of these drugs.
Most of the following discussion relates to continuous and long-term use of more than four months duration among people taking benzodiazepines at normal or above normal dose levels. Those problems which can arise after shorter use, such as motor impairment, will be identified as such.
1. Dependence and Withdrawal
Divisions of opinion exist regarding the dose and time necessary to produce dependence on benzodiazepines, although there is no longer any disagreement that dependence of a physical and/or psychological nature can occur. The major indication of dependence is the development of withdrawal symptoms, which have now been clearly established at therapeutic dose levels.[71-73]
There have been few systematic studies of problems associated with withdrawal following normal use, and it is extremely difficult to establish any figures for the numbers of individuals currently dependent on these drugs. One such carefully controlled study of withdrawal symptoms in patients who had been on low doses of benzodiazepines for a mean of 3.6 years, found between 27 and 45 per cent evidencing clear withdrawal symptoms, varying by the measure of withdrawal used. Significantly, follow-up after three months found those who either refused to participate in the study or had dropped out during it had largely returned to benzodiazepine use while those who had successfully completed the withdrawal remained drug free. The authors concluded that, "The high incidence of withdrawal symptoms suggests that a substantial minority of patients taking benzodiazepines chronically are pharmacologically dependent."
Many individuals will attempt withdrawal and quickly resume drug use because of symptoms such as lack of energy, sleeplessness, headache, trembling and nausea. These symptoms appear from 24 hours to 10 days following cessation of use, depending on the half-life of the benzodiazepine taken. In severe cases, where high doses are ingested, withdrawal can take forms similar to that found with alcohol or barbiturates, such as muscle twitches, seizures, weakness and tremors, confusion and psychosis.
Many of the minor symptoms described above are common to drug effects as well as to the anxiety that may have precipitated the drug use initially. Consequently, it has been frequently thought that all such reactions were the result of the predisposing condition. This cannot be so in all cases for a number of reasons: 1) neonates born to drug-dependent women have shown withdrawal symptoms; 2) acute anxiety is only one of many indications for use of these drugs and even that is generally episodic in nature; 3) in some patients withdrawal symptoms do not resemble those of anxiety, such as abrupt weight loss.
Short-term therapy lasting less than four weeks with these drugs is not thought to produce dependence and withdrawal problems.
2. Motor and Cognitive Impairment
A number of clinical and experimental studies have demonstrated psychomotor, learning and memory impairment following use of benzodiazepines.[79-81] Performance on a variety of commonly used tests, such as vigilance, memory, digit symbol substitution, and flicker fusion have all shown deficits in normal young adults using low doses of drugs. In a review of the literature which covered only controlled studies, it was found that learning and immediate memory are impaired by these drugs, that is, the deficit is particularly evident regarding the learning of new material. Memory for material learned prior to drug ingestion is not impaired. The implications of this for continuous users of benzodiazepines may be considerable in terms of daily performance.
Numerous laboratory studies have demonstrated motor impairment following use of low doses of benzodiazepines.[83,84] Studies under naturalistic conditions are few in number, since they are costly and difficult to administer. The first such large-scale study of driving impairment under 'natural' conditions, conducted in Britain, compared the prescribed medicines used by people in the three months prior to their injury or death driving a car, motorcycle or bicycle to those medicines used by a large number of matched controls.
There was a highly significant association between use of minor tranquillizers and the risk of a serious road accident. The risk was also increased for antihistamines but not for a wide variety of noncentral nervous system drugs.[*1]
Benzodiazepines as Hypnotics
A major American study has pointed out the lack of any standardized criteria for defining insomnia and unclear evidence of efficacy of any drugs for patients' complaints of insomnia. Hypnotic drugs apparently reduce the time needed to fall asleep by only 10 to 20 minutes and lengthen total sleep time by 20 to 40 minutes thus raising a number of questions about the importance of hypnotics. Some researchers, however, suggest that the use of hypnotics provides other benefits when used for short periods.
While initially focussing on the barbiturates, the report also examined the benzodiazepine hypnotics and found some potentially hazardous attributes of the longer acting benzodiazepines such as flurazepam (Dalmane) and diazepam which are not found with barbiturate hypnotics. These include: 1) an increased likelihood of adverse drug reactions with advancing age of the patient, and 2) a greater likelihood of adverse drug reactions in patients with diminished kidney function. The following hazards are common with both benzodiazepines and barbiturates: 1) there is a potential danger for overdose when combined with other depressant drugs; 2) following nighttime drug use, there are deficits demonstrated the following day on tests of visual-motor coordination; and 3) benzodiazepines and barbiturates are equally likely to lead to nightly reliance on drugs for sleep. (After a week of such use the impairment caused by long-acting benzodiazepines is greater than that resulting from nightly use of a barbiturate.)
Polydrug Use and Cross-Addiction
Polydrug use, or the concurrent use of more than one psychotropic substance, is a common pattern among benzodiazepine users. This multiple drug use reflects the widespread acceptance and easy availability of these drugs. Among the most commonly used drugs taken in combination are benzodiazepines with alcohol, other sedative-hypnotics, and narcotics. Studies of the extent and implications of polydrug use are relatively recent and not as comprehensive as is desirable. Concern with this phenomenon is with both deliberate and accidental overdose, the increased possibility of adverse drug interactions, and motor impairment resulting in traffic and other accidents.
It would appear that youthful experimenters and steady users tend to combine a variety of psychotropic drugs. A survey conducted for The National Commission on Marijuana and Drug Abuse in the United States found that young people who had consumed alcohol within the previous seven days were almost twice as likely to report ever using tranquillizers.
Studies of adult drug users also report a high proportion of multiple users. A survey of Toronto adults reported that users of tranquillizers were over four times as likely to also be users of stimulants or barbiturates as were non-tranquillizer users.
A Canada-wide survey of drug consumption found 27 per cent of those using tranquillizers simultaneously using sedative drugs, 10 per cent using antidepressants, five per cent using antispasmodics, five per cent antihistamines, and 15 per cent using analgesics. Conversely, half of the respondents who reported using a sedative in the previous three days also reported use of a tranquillizer during that period.
The three studies described above do not indicate the source of the drugs consumed. However, a range of psychotropic drugs and other prescription drugs are often prescribed concurrently by one or more treating physicians. It is not uncommon for an individual to be sent to a specialist and be given a prescription for a psychotropic drug while simultaneously using psychotropic medications prescribed by his general practitioner.
While surveys of large populations report considerable use of tranquillizers in combination with other licit drugs, studies of illicit drug users or abusers have shown an increased use of benzodiazepines among these populations. For example, CODAP, the Client Oriented Data Acquisition Process, presents data on clients admitted to treatment centres across the United States. Of those reporting tranquillizers as the primary drug of abuse in 1978, 73 per cent also reported abusing a second drug, usually alcohol. Those abusing alcohol and tranquillizers in combination tended to be older than those abusing other combinations of drugs.
Benzodiazepines have rarely been systematically studied as an illicit drug. However, in a study of clients of the Philadelphia Veterans Administration Drug Dependence Centre, it was found that 29 per cent of the drug abuse patients had used street purchased diazepam in the month preceding the survey. In 1975, patients on the methadone maintenance program at both the Narcotic Addiction Foundation of British Columbia and the Addiction Research Foundation of Ontario were assessed for benzodiazepine content in their urines. The study found 47 per cent and 65 per cent positives, respectively, in Vancouver and Toronto. Because of the high incidence of use the Toronto investigators conducted 15 consecutive weekly screenings for benzodiazepines. They concluded that approximately 44 per cent of the methadone patients use benzodiazepines regularly or most of the time, receiving the drugs from physicians and other sources outside the Foundation.[*2]
It is clear from these Canadian and American reports that benzodiazepines have become major street drugs. This should be expected of any popular and readily available mood-altering substance. As street drugs they are not likely to be used alone but rather in combination with either alcohol or hard drugs.
A hazard of polydrug use which has received relatively little study to date is the potential for increased motor impairment leading to traffic fatalities and industrial accidents. Major reasons for this are the high cost and methodological difficulties entailed in such research. The Traffic Injury Research Foundation of Canada analysed the presence of at least 90 psychotropic and other substances from drivers and pedestrians fatally injured in Ontario between 1978 and I979. Of those found with diazepam in their bodies (three per cent of the victims), 44 per cent were also positive for alcohol; 38 per cent of the diazepam cases involved drugs other than alcohol. However, there was no mention in the report of other benzodiazepines studied. This one Canadian study unfortunately analysed only traffic fatalities rather than including traffic injuries. One could hypothesize that heavy consumers of benzodiazepines, such as women and the elderly, are less likely 1) to be driving cars, and 2) to be driving at speeds likely to result in fatalities. In addition, it would have been desirable to obtain data on the presence of benzodiazepines in a matched control group of non-accident drivers.
In a study reviewing the data on drugs, alcohol and driving, its authors state that the high consumption of antianxiety drugs make them the most important group of prescription drugs in terms of traffic safety. They conclude that anti-anxiety drugs per se can increase traffic accident risk and the risk will be further increased when those drugs are combined with alcohol.
Overdose and Poisoning
From Canadian and other sources it is clear that the drugs used in overdose reflect their availability.[96-98] Many overdoses are impulsive acts and therefore the individual tends to consume those substances readily at hand in the liquor or medicine cabinet. As sales of barbiturates have declined in recent years, overdose with these drugs has similarly declined and, conversely, benzodiazepine overdoses have risen with increased sales.
Because of the greater safety of benzodiazepines compared to the barbiturates, there are virtually no lethal overdoses reported for these drugs taken alone. However, in combination with alcohol or other drugs benzodiazepines can be lethal.
The Drug Abuse Warning Network (DAWN) in the United States, covering emergency room overdose data between 1973 and 1976, found tranquillizer-involved cases accounted for the largest subgroup (43 per cent) of the emergency room suicide attempt cases. Valium was the second most frequently mentioned drug of abuse while alcohol in combination with other drugs was the most frequent.
Studies conducted in emergency rooms of Canadian hospitals found from one-third to one-half of patients having used benzodiazepines.[101-103] Many of them had used these drugs in combination with alcohol.
The only national data source in Canada collecting overdose information is the Poison Control Program. Statistics are compiled annually from reports originating from hospitals designated as Poison Control Centres. Excluded are reports from the majority of hospitals in Canada, data from industry, physicians and paramedical personnel and from persons who attempt to handle this situation themselves. One group of researchers studying the data concluded that this federal system was probably aware of only 20 to 25 per cent of the total poisonings. Bearing in mind these limitations, this data is useful in demonstrating trends over time. For example, there was a 46 per cent increase in the reporting of Valium poisonings over the years 1970 to 1976. Over 13 per cent of all poisoning cases were accounted for by four benzodiazepines. Unlike ASA, iron preparations, Ex-Lax and acetaminophen, which were ingested primarily by children under four, the benzodiazepines studied were consumed largely by adults, suggesting fewer accidental occurrences and more deliberate overdoses.
An overdose study conducted in 21 Toronto hospitals found that patients using benzodiazepines with a long half-life, such as flurazepam, arrived at hospital drowsier and required inpatient care, in contrast to those who had ingested drugs with a shorter half-life. In view of the increased sales of benzodiazepines with a shorter half-life (oxazepam, lorazepam), we may find equal numbers coming to emergency departments of hospitals but fewer admissions resulting from overdose with these drugs.
*1 Unfortunately, alcohol consumption and its possible role in these accidents could not be determined because of the design of this study.
*2 The use of benzodiazepines as street drugs is frequently documented in newspaper accounts. For example, a recent seizure by Montréal police yielded 544 kilograms of diazepam powder illegally imported for purposes of trafficking. (The Globe and Mail, Toronto. May 22, 1981).
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