Benzodiazepines: Uses and Abuses SUMMARY SOMMAIRE Anxiety Is Ubiquitous in Our Society
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-m iiiiiiiiiiiiiii m Brian F. Hoffman Gerald Shugar Benzodiazepines: Uses and Abuses SUMMARY SOMMAIRE Anxiety is ubiquitous in our society. L'anxiete est omnipresente dans notre societe. Bien Although non-drug treatments should qu'on devrait toujours faire usage de therapies non-m6dicamenteuses, les benzodiazepines sont des always be used, benzodiazepines are the medicaments de choix lorsqu'une medication est drugs of choice when drugs are indicated. indiquee. Dans des etudes a double insu, les In double blind studies the benzodiazepines benzodiazepines sont superieures aux placebo pour are superior to placebo in controlling acute controler l'anxiete aigue et la suractivite dans les anxiety and autonomic over-activity in desordres psychosomatiques. Elles sont aussi utiles pour une variete d'autres etats tels que le traitement psychosomatic disorders. They are also ou la prevention des spasmes et douleurs useful in a variety of other conditions such musculaires, le status epilepticus, le syndrome de as the treatment or prevention of muscle sevrage medicamenteux, les desordres du sommeil spasms and pain, status epilepticus, drug de stade 4 et l'akathisie. Toutefois, les withdrawal, stage 4 sleep disorders and benzodiazepines comportent de nombreux effets akathisia. secondaires, occasionnent les syndromes de However, benzodiazepines have tolerance, de dependance et de retrait et on devrait many side effects, produce tolerance, en faire un usage prudent. I1 n'y a pas d'evidence dependence and withdrawal syndromes que les benzodiazepines soient utiles dans le and should be used cautiously. There is no traitement de l'anxiet6 chronique. Les medicaments evidence that benzodiazepines are useful in a courte dur6e d'action sont plus su'rs pour les chronic The are personnes agees et celles souffrant de maladie anxiety. short-acting drugs hepatique ou d'hypoalbuminemie. Des prescriptions safer with elderly patients and those with de petites quantites de benzodiazepines devraient hepatic disease or hypoalbuminemia. Small etre faites pour une peiode la plus courte possible. amounts of prescription benzodiazepines On devrait augmenter le nombre de programmes should be used for the shortest possible educationnels concernant l'usage approprie des period. Educational programs concerning benzodiazepines. the proper use of benzodiazepines should be increased. (Can Fam Physician 1982; 28:1630-1639). Dr. Hoffman is a staff THE EFFICACY and ethics of patient for being too demanding and psychiatrist at the Clarke Institute using minor tranquilizers are fre- the pharmaceutical industry for exces- of Psychiatry and an assistant quently debated in our society. Two sive advertising. 3 4 professor of medicine at the opposite points of view emerge. The In the 'liberal' view, a person in this University of Toronto. Dr. Shugar 'conservative-stoic' view is that anxi- highly complex, technological, anxi- is chief of in-patient services at the ety is normal and must be coped with; ety-provoking society has the right to Clarke Institute of Psychiatry and the person who resorts to using benzo- use any available methods to cope with an associate professor of medicine diazepines is weak in character and the his individual stresses.: The benzodia- at the University of Toronto. use of such pills will decrease his will- zepines are the least of several evils- Reprint requests to: Dr. B. F. power, motivation and problem- they are less dangerous than incapaci- Hoffman, Cla,rke Institute of solving abilities. 1 2 This viewpoint tating anxiety, alcoholism or other Psychiatry, 250 College Street, blames the overuse of these drugs on addictions. Toronto, ON. M5T 1R8. the physician for over-prescribing, the These two extreme views ignore a 1630 CAN. FAM. PHYSICIAN Vol. 28: SEPTEMBER 1982 rational approach based on knowing respiratory, digestive, skin, etc.) chlordiazepoxide or diazepam pro- who takes benzodiazepines and why, (46%) duces more rapid and reliable clinical for what conditions, with what effi- Patients with physical disorders are effects than IM injections of the same cacy and with what dangers. It is im- given benzodiazepines as frequently, dose. IM administration results in de- portant to know how these drugs work, even though the basic indications for layed and incomplete absorption of what alternative coping mechanisms prescribing these drugs are the preven- chlordiazepoxide and diazepam, as and treatments are available and how tion or alleviation of psychic and emo- well as delayed appearance of their ac- the decision to use medication is tional distress. 6' 10 tive desmethyl metabolites, because reached. The stereotyped image of the benzo- the drug crystallizes in muscles. El- diazepine abuser is a pill-popping, derly patients and those with hepatic bored, middle-class, self-indulgent, disease metabolize these drugs more Extent of Use young suburban housewife. In fact, slowly and are more likely to have side benzodiazepine abusers are most effects or toxicity. They should there- Over 10% of adult Canadians and frequently middle-aged housewives fore receive only half of the usual Americans take benzodiazepines by (working outside the home or not) dose. Some of the long-acting benzo- prescription in any one year.5 This is from the lowest socioeconomic stra- diazepines (e.g., diazepam) are similar to rates in Europe, although tum with less than grade school educa- quickly absorbed and highly lipid solu- France and Belgium have even higher tion, trying to cope with many real bi- ble so that they have a rapid onset of rates.3 The use of minor tranquilizers ological, psychological and socio- action. They may be useful hypnotics is more common than the total use of cultural problems.3 in the short term. all other psychotropic medications, in- Conversion of the short-acting drugs cluding antidepressants and antipsy- Pharmacological Action by conjugation to an inactive glu- chotics. Diazepam is probably the curonide is extrahepatic and is not most commonly used drug in the west- All the benzodiazepines are similar decreased by age or liver dis- ern world. in structure and pharmacological ac- ease. 2 8, 12, 13 Therefore, cumulative Females take these drugs twice as tion. Although differences in their me- effects during prolonged therapy are frequently as males (20% versus tabolism include absorption, distribu- much less significant than with the 8%). 3, 6 We do not know whether this tion, degradation and excretion, these long-acting drugs. If the short-acting is due to role stereotyping, the nature must be interpreted cautiously because drugs are used as daytime anxiolytics, of the relationship between female pa- of high variation in individuals' me- divided doses (at least bid) are re- tients and male physicians, or the bio- tabolism and sensitivity to the clinical quired. Maximum effects are reached logical concomitants of being female effects of benzodiazepines. For in- within a few days and residual effects (menstrual cycle, pregnancy, child- stance, the dose of diazepam required terminate quickly. birth, and menopause). Probably for relaxation for gastroscopy may males more frequently employ other vary 22-fold.2 Nevertheless, rational Neurotransmitters remedies for anxiety, including the use use of the benzodiazepines does re- of alcohol and marijuana. quire some knowledge of the various The effects of the benzodiazepines Similarly, the elderly receive a dis- compounds' pharmacokinetics. are mediated by several distinct mech- proportionate number of prescriptions The benzodiazepines can be divided anisms. 1416 The neurotransmitters that for benzodiazepines.5 7 They are more into two groups based on the half-lives have been implicated include norepin- likely to have difficulty metabolizing of parent compounds and their active ephrine, serotonin, GABA and gly- the long-acting benzodiazepines and metabolites: the long-acting and the cine. Specific benzodiazepine recep- are therefore more likely to have un- short-acting groups.2' 5, 8, 11-13 (See tors have been identified in human wanted side effects and toxicity.2' 8, 9 Table 1.) brain tissue, 17 suggesting that there They are also more likely to be taking may be specific benzodiazepine-like TABLE 1 molecules in the brain whose activity other drugs and to suffer from complex Half Lives (Hours) of drug regimens and interactions. Al- Benzodiazepines Marketed in Canada produces an endogenous anxiolytic ef- though the depressive syndromes are fect. more prevalent in this age group, anti- Long-Acting Drugs Short-Acting Drugs Stimulation of the benzodiazepine' receptors enhances the effects of depressants are as underused as tran- Clorazepate 50-100 Oxazepam 5-20 quilizers are overused.4 Flurazepam 40-100 Lorazepam 10-15 GABA, the principal inhibiting neuro- Most prescriptions for benzodiaze- Diazepam 20-50 Triazolam 2- 5 transmitter. 8 14 The resulting depolari- pines are written by family physicians Chlordiazepoxide zation and decreased production of 5-30 Temazepam 8-10 norepinephrine and serotonin cause se- and internists.3' 6 Ofpatients who have Nitrazolam 18-28 Bromazepam 10-15 used a psychotherapeutic drug, 85% Ketazolam 30-50 Alprazolam 6-20 dation and anti-anxiety effects by de- have never seen a psychiatrist. A na- Clonazepam 18-50 creasing electrical activity in'the pun- tional survey3 showed that benzodia- ishment and inhibitory areas of the zepines were prescribed for the follow- The long-acting drugs accumulate brain. Diazepam is also a glycine re- ing diagnoses: when taken daily. They are converted