Regular Prescriptions for Benzodiazepines: a Cross- Sectional Study of Outpatients at a University Hospital

□ ORIGINAL ARTICLE □

Regular Prescriptions for Benzodiazepines: A Cross- Sectional Study of Outpatients at a University Hospital

Kyoko Nomura, Mutsuhiro Nakao, Mikiya Sato and Eiji Yano

Abstract

Objective To investigate 1) the patterns of regular prescriptions for benzodiazepines among department clinics in a university teaching hospital, 2) the effects of patient’s characteristics on regular benzodiazepine prescriptions, and 3) the patterns of benzodiazepine prescriptions among department clinics from the perspective of pharmacological half-life. Patients Patients were 22,099 outpatients (51% female; mean age: 56 years) who were prescribed any drug three or more times. Methods Cross-sectional study of patient-based data (July 2002 to August 2003) from the database of a computer ordering system at a university hospital. The patterns of regular prescriptions for benzodiazepines were compared among the clinical departments (i.e., ‘Internal Medicine’, ‘Psychiatry’, and ‘Others’). A logistic regression model was used to assess the effects of patient gender and age, and the clinic visited on the is- suing of regular prescriptions for benzodiazepines. Results Regular benzodiazepine users were 3,204 (14.5%). Benzodiazepines were more likely to be prescribed for women (61.3%) than for men and were prescribed most often by psychiatrists (31.7%), followed by internists (20.1%). Multivairate logistic regression model showed that being female and elderly, and being prescribed by a psychiatrist were significantly associated with regular benzodiazepine prescriptions. With regard to the pharmacological half-life, internists were more likely to prescribe short half-life benzodiazepines than were psychiatrists (p < 0.001). Conclusion A large number of outpatients at a Japanese university hospital appeared to be maintained on a regular supply of benzodiazepine drugs. Educational programs are needed to promote the rational prescribing of benzodiazepines.

Key words: age, benzodiazepines, female, pharmacological half-life, regular prescription, university hospital

(DOI: 10.2169/internalmedicine.45.1758)

50% of these subjects having used the drugs for five or Introduction more years (5). Benzodiazepines are remarkably useful drugs for psycho- Benzodiazepines are known worldwide to be very useful logical illnesses. However, with regular use, their benefits psychotropic agents (1-4). Their therapeutic actions as anx- are outweighed by their adverse effects, which include the iolytics, sedative hypnotics, anticonvulsants, and muscle re- development of tolerance, psychomotor impairment, cogni- laxants have led to their use as first-line treatments, and they tive and memory changes, physical and pharmacological de- have become one of the most prescribed classes of drugs. pendence, and withdrawal reactions upon discontinuation. About 2% of the adult populations of the USA (i.e., four Dependence usually develops within a few weeks or months million people) and UK (i.e., one million people) have been of regular use, and withdrawal reactions, such as anxiety or reported to use prescription benzodiazepine hypnotics or sleep disturbance, occur when patients discontinue the tranquilizers regularly for 12 or more months, with almost drugs, making it very difficult for the majority of regular

Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo Received for publication February 7, 2006; Accepted for publication August 3, 2006 Correspondence to Dr. Kyoko Nomura, Department of Hygiene and Public Health, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605

1279 DOI: 10.2169/internalmedicine.45.1758 benzodiazepine users to stop taking the medication (6-8). The department clinics were categorized into three Those reports suggest that the patient characteristics of fe- groups: ‘internal medicine’, ‘psychiatry’, and ‘others’. The male gender and elderly affect the regular use of benzodi- psychiatry group included prescriptions by physicians at azepines (6-8). psychosomatic medicine clinic. During the study period, In 1999, the Teikyo University School of Medicine in- there were 190 prescribing physicians in the ‘internal medi- stalled a computer ordering system (COS), which has been cine’ group, 60 in ‘psychiatry,’ and 441 in ‘others’. The used to monitor drug prescriptions among various depart- number of prescriptions from the psychosomatic medicine ment clinics at the hospital. An analysis of the patterns of clinic represented only 5.1% of the total number of prescrip- regular benzodiazepine prescriptions with respect to patient tions from the psychiatry clinic. gender and age would enable us to compare the results with Benzodiazepines previous findings in Western countries (5-8) and to develop more rational schemes for prescribing benzodiazepines. Fur- The benzodiazepines studied included alprazolam, bro- thermore, given that dependency and withdrawal reactions mazepam, brotizolam, chlordiazepoxide, clotiazepam, cloxa- are enhanced by the regular use of short half-life benzodi- zolam, diazepam, estazolam, ethyl loflazepate, etizolam, azepines (9), it is important to assess the regular prescription fludiazepam, flunitrazepam, flutoprazepam, lorazepam, lor- of benzodiazepines from the perspective of pharmacological metazepam, medazepam, nitrazepam, oxazolam, quazepam, half-life. rilmazafone, and triazolam. The cases were defined as pa- Hence, the purpose of the present study was three-fold: (i) tients who received benzodiazepine drugs, and patients with- to compare the patterns of regular prescriptions for benzodi- out benzodiazepine prescriptions were regarded as controls. azepines among department clinics at a university teaching The mean (± SD) period of a benzodiazepine prescription hospital in Japan; (ii) to determine the effects of patient gen- was 12 (± 1.9) months. Precise information on the half-life der and age, and department clinic visited on regular pre- of pharmacological action was integrated into the dataset. scriptions for benzodiazepines; and (iii) to compare the pat- According to the literature (6), the following benzodi- terns of prescriptions for benzodiazepines among the differ- azepines were categorized by half-life (range of average ent department clinics from the perspective of pharmacologi- half-life of metabolites), i.e. short half-life (shorter than 10 cal half-life. hours): brotiazepam, clothiazepam, etizolam, lormetazepam, tofisopam, and triazolam; intermediate half-life (10―35 Subjects and Methods hours): alprazolam, bromazepam, estazolam, flunitrazepam, lorazepam, nitrazepam, oxazolam, and rilmazafone hydro- Dataset and patients chloride; and long half-life (longer than 35 hours): cloxazo- lam, diazepam, ethyl loflazepate, flurazepam, medazepam, A dataset (patient-based data) was developed from a COS and quazepam. database (prescription-based data) at Teikyo University Ita- Statistical analysis bashi Hospital, Tokyo, Japan (1,154 hospitalized beds). This university teaching hospital has 21 department clinics, of The patterns of benzodiazepine prescriptions classified by which approximately 60,000 outpatients visit every year. pharmacological half-life (i.e., short, intermediate, and long) Data syntheses were conducted using Access 2000 and SQL were compared between the internal medicine and psychia- server 2000 (Microsoft, Inc., Japan). The prescriptions for try groups, between the psychiatry and other groups, and be- benzodiazepines written for individual patients were identi- tween the internal medicine and other groups, using chi- fied according to the department clinics visited by the pa- squared tests. tients. A logistic regression model was used to assess the effects The subjects included in the dataset were outpatients who of patient gender and age, and department group visited on visited our hospital and were prescribed medicine by physi- regular benzodiazepine prescriptions. Univariate and ad- cians between July 2002 and August 2003. Patients were ex- justed odds ratios (OR) of regular prescriptions for benzodi- cluded if they were younger than 15 years of age, were pre- azepines were computed along with the 95% confidence in- scribed any drugs fewer than three times during one study tervals (CI). With regard to p values in the multivariate year, or were prescribed benzodiazepines at two or more dif- models, the Cochrane-Amitage trend test was used for age, ferent clinics. Thus, the analysis included 22,099 patients and the Wald-chi-squared test was used for department (51% female) with a mean age of 56 ± 18 years (mean ± groups. The analyses were conducted with a significance SD). For the purpose of the analyses, age was categorized level at 5% and using the SAS ver. 8.12 for Windows soft- into seven groups with 10-year intervals. However, because ware. of the small sizes of their groups, the 15- to 19-year-old (y/o) subjects were combined with the 20―29 y/o subjects, Results and subjects >90 y/o were combined with the 80―89 y/o group. Of the 22,099 patients analyzed in the present study, 15%

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Table 1. Clinical Characteristics of Regular Users of Benzodiazepines and Control Population and the Risk of Regular Use of Benzodiazepines (n=22099)

gender was a significant predictor of regular benzodiazepine prescriptions in both the univariate and multivariate models. Compared with patients aged 15 to 29 years, patients in the older age groups were more likely to be prescribed benzodiazepines when adjusting for patient gender and department group visited; the percentage of prescriptions for these drugs increased as age increased (p < 0.0001 in trend tests). Com- Figure 1. The patterns of benzodiazepine prescription by pared to psychiatrists, internists and other physicians were department clinics from the perspective of pharmacological less likely to prescribe benzodiazepines. half-life. Compared with the psychiatry group, physicians in Fig. 1 shows the patterns of benzodiazepines prescription internal medicine and other groups were more likely to pre- by department clinics from the perspective of pharmacologi- scribe short half-life benzodiazepines, followed by intermedi- cal half-life (i.e., internal medicine, psychiatry, and others). ate half-life agents (p<0.0001), and internists prescribed these Compared with the psychiatry group, the physicians in the drugs more often than physicians in the other departments internal medicine and other groups were more likely to pre- (p<0.0001). scribe short half-life benzodiazepines, followed by intermediate half-life benzodiazepines (p < 0.0001), and internists received benzodiazepines. The patterns of regular benzodi- prescribed these drugs more often than physicians in the azepine prescriptions tabulated by patient gender and age, other departments (p < 0.0001). and department group are shown in Table 1. Regular benzodiazepine use was higher in women than in men. Patient age Discussion distribution did not differ between benzodiazepine users and the control subjects. One-third of the control subjects re- The present study determined the patterns of regular ben- ceived prescriptions from internists, whereas the majority of zodiazepine prescriptions in a university hospital setting in regular users of benzodiazepines received prescriptions from Japan using the database from a computer ordering system. psychiatrists, followed by internists. When the gender differ- The results of our study clearly demonstrate the following ence was investigated from the perspective of age and de- three points: (i) 15% of the outpatients who received pre- partment group, it was not obvious in patients aged 40―70 scriptions were regular users of benzodiazepines; (ii) regular y/o, while female gender was dominant in patients aged 39 benzodiazepine prescriptions were prescribed more fre- and younger (52―57%) and 70 and older (50―56%). More quently for women and elderly subjects, and were predomi- than half of the patients (60%) in the psychiatry department nantly issued by psychiatrists; and (iii) compared with psy- group were female, while 47―50% of the patients were fe- chiatrists, internists were more likely to prescribe short half- male in the department groups “internal medicine” and “oth- life benzodiazepines. The interpretation of the results is dis- ers”. cussed below in light of the limitations and strengths of the Table 1 also shows the unadjusted and adjusted odds ra- study. tios of regular prescriptions for benzodiazepines. Female In the present study, female gender was a significant and

1281 DOI: 10.2169/internalmedicine.45.1758 independent risk factor for regular benzodiazepine prescription of benzodiazepines should be interpreted with caution. tions. Various studies suggest that the female predominance Since several physicians at each department clinic prescribed in the use of benzodiazepines refers to the fact that psycho- benzodiazepines during the study period, the effect of de- logical ill health and anxiety are significantly more common partment clinics might reflect the educational influence in in women than in men (10-12). Consequently, it is possible each department clinic regarding the prescribing of benzodi- that women are more likely to develop psychological and azepines. Alternatively, psychiatrists see patients who need physiological dependency than men, and the clinical impli- to be treated with benzodiazepines more often than physi- cation is that women are the subjects in whom physicians cians at other department clinics, and therefore the effect of actively intervene to provide rational prescribing for benzo- department clinics observed in our study might represent the diazepines. According to several reports (13, 14), an alterna- characteristics of the diseases treated by the various depart- tive explanation is that women are more likely than men to ment clinics. complain of psychological symptoms. Hence, being female Our result of pharmacological half-life among department is the cause or the result of the higher prevalence of mental clinics shows that internists were more likely to prescribe ill health in women is debatable. Unfortunately, our study short half-life benzodiazepines while psychiatrists were more did not adjust for health status information, and accordingly, likely to prescribe intermediate agents. According to the lit- the interpretation of the effect of female gender on the use erature (8, 19), short half-life compounds increase the risk of benzodiazepine requires further exploration in future of dependency, which results in the long-term use of benzo- studies. diazepines, although these compounds might decrease the Although warnings have been repeatedly issued regarding frequency of falls and cognitive impairment. Therefore, we the long-term use of benzodiazepines (5-9), in the present recommend that internists consider the pharmacological ac- study, regular prescriptions of benzodiazepines were found tions of benzodiazepines before prescribing them. to increase with age. The earlier finding showed that psy- In conclusion, our results indicate that a large number of chological illnesses, such as generalized anxiety disorders, outpatients are maintained on a regular supply of benzodi- are less prevalent in older adults than in younger adults azepines. For rational prescribing, primarily based on lim- (15). The discrepancy raises important questions about the ited use (i.e., short-term or intermittent use at minimal effec- evaluation of these elderly patients regarding “whether their tive doses), appropriate mental assessment is essential. In mental statuses need to be treated with benzodiazepines”. addition, the influence of patients’ characteristics (i.e., sex Benzodiazepine drug use among seniors leads to serious and age) and adverse effects related to pharmacological half- health problems such as falls and hip fracture (16-18). One life need to be included in educational programs for rational clinical implication of the results of the present study is that benzodiazepine prescription. physicians should carefully assess the mental health status of each elderly patient, to determine the requirement for benzo- We thank Mr. Hidefumi Tomisawa, Teikyo University Hospital, diazepine medication. for his assistance with the data collection. The effect of department clinics on the regular prescrip-

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