Prescription of benzodiazepines for adults and older adults from a mental health clinic

Abstract

The aim of this study was to compare benzodiazepine (bzd) prescriptions for adults and older adults regarding appropriate use indicator. It is a cross-sectional study for collecting data on patients treated at the City’s Mental Health Clinic in Sorocaba/SP, between March and December 2013. Appropriate use indicators were used: appropriate drug, with adequate posology and period of use; as well as the use of a single bzd, as anxiolytic for less than 3 months in depression treatment with antidepressants, use for less than 2 months if associated to an antidepressant and no use of long-acting bzd in older adults. From the 330 participants, most were women, with a family history of mental disorders and bzd use, without monitoring of a psychologist and using other psychotropic and polypharmacy (p>0.05).The minority of prescriptions had indication for the use of bzd (37.5% for older adults and 32.4% for adults) (p>0.05). Only 5.8% of the prescriptions for older adults and 1.9 for adults were rational (p>0.05). The chronic use was observed in all adults and older adults with depressive and anxiety disorders (p>0.05). A minority of prescriptions for adults and older adults was appropriate.

Benzodiazepine; Unified Health System; Drug prescription; Rational use of drugs

Resumo

Foi objetivo deste estudo comparar as prescrições de benzodiazepínicos (bzd) em adultos e idosos quanto aos indicadores do uso apropriado. Estudo transversal de coleta de dados de pacientes atendidos no Ambulatório Municipal de Saúde Mental de Sorocaba/SP, entre março e novembro de 2013. Foram utilizados indicadores de uso apropriado: medicamento apropriado, com adequada posologia e duração de uso; como também, o uso de apenas um bzd, como ansiolítico por menos de 3 meses, no tratamento da depressão com antidepressivo, uso por menos de 2 meses se associado ao antidepressivo e o não uso de bzd de longa ação em idoso. Dos 330 participantes, a maioria era mulheres, com histórico familiar de transtorno mental e uso de bzd, não realizava acompanhamento com psicólogo e fazia uso de outros psicotrópicos e de polifarmácia (p > 0,05). A minoria das prescrições tinha indicação de uso do bzd (37,5% para idosos e 32,4% para adultos) (p > 0,05). Apenas 5,8% das prescrições para idosos e 1,9% para adultos eram racionais (p > 0,05). O uso crônico foi observado em todos os adultos e idosos com transtornos depressivos e ansiosos (p > 0,05). Uma minoria das prescrições de bzd para adultos e idosos era apropriada.

Benzodiazepínicos; Sistema Único de Saúde; Prescrição de medicamentos; Uso racional de medicamentos

Introduction

Benzodiazepines constitute a group of psychotropic more commonly used in the clinical practice due to their four main actions: anxiolytic, hypnotic, anticonvulsive and muscle relaxant^1-3. Generally, they are indicated to anxiety disorders, insomnia and epilepsy². The use of anxiolytics and hypnotics has considerably increased in the last decade⁴. In developed countries, such as Australia, France and Spain, these drugs are the most prescribed ones, and among them, benzodiazepines are the most common^4,5. Around 20 million prescriptions are written every year in the United States and approximately 10% of the population report having used benzodiazepine as a hypnotic⁶.

In Brazil, a research made in 2001 in 107 cities, with population over 200 thousand inhabitants showed that benzodiazepines were the third most used substance by the 8,589 individual interviwed⁷. A population study with 1,606 participants in the town of Bambuí (Minas Gerais, Brazil) observed the frequency of the use of these drugs in approximately 22% of the individuals with average age of 69, with prevalence in the use of long-acting benzodiazepines and for longer than 12 months⁸.

The effectiveness of these drugs for treating insomnia and anxiety disorders for a short period of time is described in literature. However, its use for long periods is not recommended, especially for older adults, due to the risk of developing addiction and other adverse effects^9,11.

The prolonged use of benzodiazepines, even in low dosages, is a risk factor for the development of adverse effects^12,13 which can be described as somnolence, vertigo, tiredness, mental confusion, headache, anxiety, lethargy, ataxia, postural hypotension, retrograde amnesia, accidents, tolerance, addiction^10,11 and increase in the frequency of falls^14,15.

Besides the period of use, there is some concern about the type of benzodiazepine prescribed, the long-acting ones are not recommended for older adults^10,16 because they take longer for the body to eliminate them and for being associated to alterations arising from the ageing process, they may become risk factors for adverse effects^2,15. Beers criteria, developed to help selecting potentially inappropriate drugs for older adults follows the same recommendation¹⁷.

Is spite of evidence in literature, benzodiazepines are largely used and commonly used inappropriately^9,11,13. The abuse, insufficiency or inadequacy in drug use harms the users and contributes to increasing expenses of public resources as well as to irrationality in its use¹⁸.

Thus, knowing the pattern of use of these psychotropic drugs at the Mental Health Clinic in the city of Sorocaba (São Paulo, Brazil) may contribute to decision making process of prescribers and health professionals when choosing those drugs. The benzodiazepines prescribed during the period of study were alprazolam, bromazepam, clonazepam, diazepam, estazolam, lorazepam, midazolam and nitrazepam. The present study aims to compare the benzodiazepines’ appropriate use indicators among adults and older adults.

Methods

Context outline

It is a cross-sectional study, conducted at the Mental Health Clinic in the city of Sorocaba, São Paulo state, Brazil. The clinic treats the average of 4,600 patients/month distributed in medical, psychiatric and psychological treatment, occupational therapy, nursing care and drug supply. Around 1,200 medical appointments are conducted monthly.

Study population

Patients using benzodiazepines who had a single doctor’s appointment at the clinic.

Eligibility criteria

Patients (18 years old or older) using benzodiazepines. Patients excluded were the ones that refused to participate in the study, which did not know the data asked during the interview and the ones whose medical charts were incomplete.

Data collection

All patients scheduled for a doctor’s appointment and using benzodiazepines were invited to participate in the study, each patient was interviewed only once during the period of the study. The interviews were conducted between Monday and Thursday (the days of the doctor’s appointment) in five periods of the week, between March and November, 2013.

The sample was calculated considering the frequency of 50% of inappropriate prescriptions (this figure enables a greater variance degree corresponding to the minimum size accepted for the sample to be representative of a base population), confidence interval of 95% and margin of error of 10%. For sample size adjustments, a finite population of 1,200 treatments/month and 10% rate of no answers were considered, thus the sample size of 320 individuals was obtained.

The use of benzodiazepines was previously verified in patients’ medical charts for the patients that would have a doctor’s appointment. In order to avoid a new interview with the patient, the number of the medical charts was previously checked.

Information about the diagnosis(es) of mental disorder(s); benzodiazepine(s) used; as well as dosage, frequency and routes of administration; and use of other psychotropic were collected in the medical charts. Other variables were collected during the interview.

Data analysis

For the description of adults’ and older adults’ profiles, information on social demographic variables were collected, such as gender, age, marital status, occupation, schooling, family history for mental disorders and use of benzodiazepines; and for the clinic, data on the number of benzodiazepines in use, individual or group follow-up with psychologist, use of other psychotropic and antidepressants, presence of comorbidities and chronic diseases, and number of drugs in use. Polypharmacy was considered as the use of three or more drugs by the patient¹¹. Chronic disease was defined as in need of continuous management and were divided into three categories: non-transmissible (cardiovascular diseases, cancer and diabetes), transmissible (HIV/AIDS) and incapacitating (amputations, blindness and articular problems)¹⁹.

In the comparison of older adults and adults regarding the appropriate use, benzodiazepine rational use indicators were used (appropriate drug: with indication for use, lack of contraindication and contraindicated or severe drug interactions; adequate posology: dose and frequency recommended according to age group; and adequate period of use: identified according to patient’s clinical diagnosis²⁰ and also other indicators (use of a single benzodiazepine for a period shorter that three months as hypnotic, anxiolytic, no use of alcohol, no neurodegenerative disturbances, except in the treatment for epilepsy, when chronic use is recommended; use for treating depression with antidepressants; use for a period shorter than two months when associated to antidepressants⁹; and no long-acting benzodiazepine in older adults¹⁰).

Indication, posology, period of treatment and lack of contraindication and contraindicated or severe drug interactions were verified according to the data contained in the drug information system for Anvisa (Brazilian Sanitary Surveillance Agency) and Drugdex System²¹. Mantley et al.⁹ recommendations were used when there was no information about the period of treatment. The interactions were characterized as severe (life-threatening, may or may not need medical intervention to prevent or minimize adverse effects) or contraindicated (which absolutely impede the continuation of the concomitant use of the drugs)²². The clinical diagnoses were classified according to the 10^th Edition of the International Classification of Disease (ICD 10).

Statistical Analysis

Categorical variables were presented through absolute and relative frequency while the quantitative ones with normal distribution through average and standard deviation. All variables were stratified into two populations: older adults and adults. Proportions were compare by chi-squared or Fisher exact tests and averages by student’s t-test. The level of significance was 5%. Excel (2010 version) and Bioestat (version 5.3, Mamirauá Institute) were used.

Ethical aspects

The study was approved by the Ethic and Research Committee from the University of Sorocaba (207,662). Patients received the necessary information regarding the study from the researchers and signed the Free and Clarified Consent Term.

Results

From the 369 eligible patients, 330 were included, 210 adults (63.8%) and 120 older adults (36.2%) (chi-squared, p ≤ 0.001). All patients who were invited to participate in the research accepted the invitation, but the exclusion criteria were lack of information during the interview (n = 30) or incomplete medical chart (n = 9) (Figure 1).

Figure 1
Flowchart of the selection of patients in the study.

Table 1 describes the variables that characterize adults and older adults. Most of them were women, married individuals, with a family history of mental disorders and using benzodiazepines, without monitoring of a psychologist, using other associated psychotropic (antidepressants were the highlights) and using polypharmacy (p > 0.05). Most older adults were retired or on sick leave from work and had up to three years of school (p ≤ 0.05). Chronic disease was the most frequent one in this group (p ≤ 0.05).

Table 1
Sociodemographic and clinical characteristics of patients using benzodiazepines.

^***

No statistical difference was observed between the adults and the older adults regarding the frequency of the prescribed benzodiazepines (p > 0.05), clonazepam and diazepam were the most prescribed drugs (Table 2). The average period of time that adults and older adults used benzodiazepines was 7.6 ± 6.9 years and 7.9 ± 7.3 years, respectively, p > 0.05.

Table 2
Frequency of prescribed benzodiazepines.

^*31**

From the 120 prescriptions for older adults, 45 (37.5%) had indication for use. In adults, this result was observed in 67 (32.4%) of the 210 prescriptions. A higher percentage of diagnoses with indication for use was observed for clonazepam in older adults (p > 0.05). No prescription of estazolam, midazolam and nitrazepam presents indication for use (Table 3).

Table 3
Frequency of the number of patients with indication for use (n) regarding the number of patients who used benzodiazepines (N).

^*

Severe drug interactions were observed in 21 adults and seven older adults, mainly due to the association of clonazepam to phenobarbital in adults (p ≤ 0.05) and diazepam to phenobarbital in both groups (p > 0.05), with consequent risk of respiratory failure (Table 4).

Table 4
Characterization of severe drug interactions and precaution in the use of benzodiazepines.

^*

Most of the use with precaution occurred with clonazepam (p > 0.05), and its use for a time period longer than one year requires monitoring of the liver function and blood cell count. Individuals suffering from depressive disorders should use alprazolam or diazepam with precautions due to the increased risk of mania and suicide, situations observed in both groups (p > 0.05) (Table 4).

No difference was found between adults and older adults regarding rational use of benzodiazepines indicators (p > 0.05). From the 120 prescriptions for older adults, in only 5.8% benzodiazepines were used for the correct period of time. In adults, only four prescriptions (1.9%) were rational. No prescriptions of alprazolam, diazepam and lorazepam were rational (Table 5).

Table 5
Frequency in appropriate use of benzodiazepines regarding rational drug use indicator and other appropriate use indicators.

^*

No differences were found between the groups regarding the other criteria of appropriate use of benzodiazepines (p > 0.05). However, the period of time for the use of benzodiazepines in the treatment of depressive and anxiety disorders was superior to the one preconized for all individuals (Table 5).

Discussion

The present study verified a predominance of benzodiazepine prescription for the adults treated at the mental health clinic. The inappropriate use of these psychotropic was observed in adults as well as in older adults, and a minority of the prescriptions was rational and had the recommended period of time for the use of benzodiazepines

The profile of the population studied was mainly women, married individuals, with a family history of mental disorders and using benzodiazepines, using other psychotropic and polypharmacy, and without the monitoring of a psychologist. The prevalence of the use of psychotropic in women, benzodiazepine among them, was observed in several studies^3,8,11,23-25, insomnia and anxiety were the main reasons women use these drugs³.

Antidepressants were the most prescribed psychotropic associated to benzodiazepine. This trend was also observed by Souza et al.³, who found that around 90% of the individuals interviewed used other psychotropic associated to benzodiazepine, mainly antidepressants; and by Netto et al.²³, who identified over 40 distinct therapeutic schemes involving benzodiazepines and antidepressants.

The association of benzodiazepines and antidepressants was referred to as the most common one in the beginning of the treatment of depression, due to the presence of symptoms such as anxiety and insomnia²⁶. However, scientific evidence recommend the use of benzodiazepine as an adjuvant in treating depression only during the first four weeks of the treatment, its prolonged use is not recommended due to adverse effects¹².

Anxiety Disorders Drug Treatment Guidelines²⁷ reports behavioral therapy as an effective measure in patients suffering from anxiety disorders and recommends it as first line of treatment. However, it was observed that less than 10% of patients had behavioral therapy with a psychologist.

Chronic diseases were more frequent in older adults, a fact that may be justified by physiological changes related to the aging process¹⁵. It was observed in adults a more frequent presence of four or more comorbidities, indicating a higher number of psychiatric diseases per individuals in this group. Polypharmacy was frequent in adults and older adults, which corroborates with the results from the older adults studied by Noia et al. ¹¹.

Clonazepam and diazepam were the most prescribed benzodiazepines in this study. This result differed from the ones found in the studies by Noia et al.¹¹, Netto et al.²³ and Firmino et al.²⁴, which reported diazepam as the most prescribed benzodiazepine in health system for basic care from the Brazilian cities studied. Vicente Sanchez et al.⁵ found lorazepam; and Alvarenga et al.⁸ observed bromazepam and diazepam as the most used ones. It is important to note that these divergences may occur due to the different groups studied and/or the several drugs that are part of the list from these cities.

A minority of prescriptions had indication for benzodiazepine use in adults and older adults; bromazepam and clonazepam were the drugs more adequately prescribed for adults and, mainly clonazepam for older adults. Estazolam, midazolam and nitrazepam were less prescribed and had no indication for use.

This could be justified by the fact that estazolam and nitrazepam are indicated for insomnia treatment²¹, and this diagnosis was not observed in the present study.

Alprazolam was prescribed for approximately 16% of the older adults of the study and only one prescription was appropriate. This dug should be used with precaution in this age group due to the risk of ataxia and oversedation, and the recommendation for dose adjustment was observed in only this prescription. Woelfel et al.²⁸ found that 20% used at least one potentially inappropriate drug, alprazolam the most common one. Similarly to alprazolam, three lorazepam prescriptions for older adults were inappropriate due to the risk of potentiating sedation²⁹.

Midazolam is preferably used as anxiolytic and sedative preoperatively due to its fast absorption, rapid onset and short elimination half-life². Therefore, its use is not recommended for clinical practices. In the present study, only one prescription for this drug was found.

It was observed that adults and older adults only used one benzodiazepine, which is adequate according to WHO recommendation³⁰. It was also observed that the majority of the depressed individuals used benzodiazepine associated to antidepressant, which is correct according to Mantley et al.⁹. However, the period of time using benzodiazepine for the treatment of depressive disorders (up to two months when associated to antidepressants) and anxiety (for a time period no longer than three months)⁹ was superior to the one preconized for all the individuals in the study, indicating a chronic use.

According to the Brazilian Psychiatric Guideline³¹, 50% of the individuals using benzodiazepine for over one year has an increased risk of abstinence syndrome, accidents, overdose (especially when associated to psychotropic), suicide attempt (especially in depressed individuals), reduction of the work capability and increase in the costs of hospitalization, exams and doctor’s appointments.

Beers criteria¹⁷ suggest that benzodiazepines should be avoided by older adults and particularly the prolonged half-life ones, because they take longer to be eliminated from the body and are more susceptible to adverse effects³². Nevertheless, they are still commonly used in this population which can be justified according to Paquin et al.³³ due to the concern of the prescribers regarding a relapse of the older adults in the occasion of the drug discontinuation

In spite of that, the authors did not find any report of severe adverse effects in reducing the use of these drugs in older adults, thus this procedure is encouraged.

A study conducted in Quebec evaluated, similarly to the present study, some adequacy criteria in the use of benzodiazepines in older adults. The authors observed that approximately 50% of the patients received an inappropriate prescription, and that in around 20% of the older adults the prescription resulted in severe drug interactions³⁴.

According to Smith and Tett³⁵, clinical guidelines and restriction campaigns contribute to raise awareness of inappropriate use of benzodiazepines. However, in most countries, especially the developing countries, patients are not treated in the private sector as well as in the public sector according to clinical guidelines based on scientific evidence¹⁸, which would benefit the prescriber in the decision-making process.

The way data were collected, through interviews conducted in some periods of the week and according to the availability of the researchers or access to the clinic, may be considered as limitations in the present study. However, the number of participants in the study allowed data statistical analysis. It is important to mention that the loss in patients’ number was small (around 10%) and the reason for it was either the lack of information given during the interviews or incomplete medical charts.

The study gathered some indicators described in scientific literature regarding the use of benzodiazepine aiming to delineate the use of this psychotropic in the City’s Mental Health Clinic. Hopefully, the results observed may be useful for the improvement of the service provided by the professional involved in the care of patients using those drugs in the public health system.

Final Considerations

Comparing benzodiazepine appropriate use indicator between adults and older adults treated at the mental health clinic, their inappropriate use was observed in both groups and for the majority of the criteria assessed. A minority of prescriptions was rational or adequate regarding period of use, and the chronic use of benzodiazepine in patients with depressive and anxiety disorders was also observed.

The fact that the prescriptions were adequate for only 1.9% for adults and 5.8% of older adults draws the attention to error related to the indication for use, non-recommended procedures for the age group and/or patient; risk of severe drug interactions; and problems related to dose, frequency, and, mainly period of treatment.

Observing the findings in literature, it is possible to verify that part of the results found are similar to other Brazilian cities and even countries, demonstrating the need for initiatives for planning interventions that aim the appropriate use of these drugs and that, consequently, benefit the patient. Incentives towards the improvement of professionals involved in the care of these patients and accuracy in the prescription of benzodiazepines could be some measures adopted aiming to provide the appropriate use of these psychotropic in this health service.

Referências

• ¹
  Correia JMS, Alves TCA. Hipnóticos. In: Silva P, organizador. Farmacologia 6ª ed. Rio de Janeiro: Guanabara Koogan; 2002. p. 358-366.
• ²
  Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine Pharmacology and Central Nervous System – Mediated Effects. Ochsner J 2013; 13(2):214-223.
• ³
  Souza ARL, Opaleye ES, Noto AR. Contextos e padrões de uso indevido de benzodiazepínicos entre mulheres. Cien Saude Colet 2012; 18(4):1131-1140.
• ⁴
  Hollingworth SA, Siskin DJ. Anxiolytic, hypnotic and sedative medication use in Australia. Pharmacoepidemiol Drug Saf 2010; 19(3):8-280.
• ⁵
  Vicente Sánchez MP, Macías Saint-Gerons D, de la Fuente Honrubia C, González Bermejo D, Montero Corominas D, Catalá-López F. Evolución del uso de medicamentos ansiolíticos e hipnóticos em España durante el período 2000-2011. Rev Esp Salud Pública 2013; 87(3):247-255.
• ⁶
  Buysse DJ. Insomnia. JAMA 2013; 309(7):706-716.
• ⁷
  Galfuróz JCF, Noto AR, Nappo SA, Carlini EA. Uso de drogas psicotrópicas no Brasil: pesquisa domiciliar envolvendo as 107 maiores cidades do Brasil – 2001. Rev Latino-am de Enfermagem 2005; 13(n. esp.):888-895.
• ⁸
  Alvarenga JM, Loyola Filho AI, Araújo JO, Firmo MFLM, Uchoa E. Prevalência e características sócio-demográficas associadas ao uso de benzodiazepínicos por idosos residentes na comunidade: projeto de Bambuí. Rev Bras de Psiquiatr 2007; 30(1):7-11.
• ⁹
  Mantley L, van Veen T, Giltay EJ, Stoop JE, Neven AK, Penninx BW, Zitman FG. Correlates of (inappropriate) benzodiazepine use: the Netherlandes Study of Despression and Anxiety (NESDA). Br J Clin Pharmacol 2010; 71(2):263-272.
• ¹⁰
  Mcintosch B, Clark M, Spry C. Benzodiazepines in older adults: a review of clinical effectiveness, cost-effectiveness, and guidelines. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2011.
• ¹¹
  Noia AS, Secoli SR, Duarte YAO, Lebrão ML, Lieber NSR. Fatores associados ao uso de psicotrópicos em idosos no município de São Paulo. Rev Esc Enferm USP 2012; 46(n. esp.):38-43.
• ¹²
  Furukawa TA, Streiner DL, Young LT. Antidepressants plus benzodiazepines for major depression. Cochrane Database Syst Rev 2001; (2):CD001026.
• ¹³
  Hirst A, Sloan R. Benzodiazepinas y fármacos relacionados para el insomnio en cuidados paliativos Cochrane Database Syst Rev 2013; 22(11):CD003346
• ¹⁴
  Softic A, Beganlic A, Pranjic N, Sulejmanovic S. The influence of the use of benzodiazepines in the frequency falls in the elderly. Med Arh 2013; 67(4):256-259.
• ¹⁵
  Ballokova A, Peel NM, Fialova D, Scott IA, Gray LC, Hubbard RE. Use of Benzodiazepines and Association with fall in Older People Admitted to Hospital: A Prospective Cohort Study. Drugs Aging 2014; 31(4):299-310.
• ¹⁶
  Canadian Psychiatric Association. Clinical practice guidelines management of anxiety disorders. Can J Psychiatry 2006; 51(8 Suppl 2):9S-91S.
• ¹⁷
  American Geriatrics Society. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults - The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. J Am Geriatr Soc 2012; 60(4):616-631.
• ¹⁸
  Brasil. Ministério da Saúde (MS). Secretária de Ciência, Tecnologia e Insumos Estratégicos. Uso Racional de Medicamentos – Temas selecionados Brasília: MS; 2012.
• ¹⁹
  Organização Mundial da Saúde (OMS). Cuidados inovadores para condições crônicas: componentes estruturais de ação: relatório mundial Brasília: OMS; 2003.
• ²⁰
  Ferreira TR. Barberato-Filho S, Borgatto AF, Lopes LC. Analgésicos, antipiréticos e anti-inflamatórios não esteroides em prescrições pediátricas. Cien Saude Colet 2013; 18(12):3695-3704.
• ²¹
  Klasco RK, editor. DRUGDEX System [Database on the Internet] Greenwood Village: Thomson Micromedex; 2013 [1974-2010].
• ²²
  Mazzola PG. Perfil e manejo de interações medicamentosas potenciais teóricas em prescrições de UTI. Rev Bras Farm Hosp Serv Saúde 2011; 2(2):15-19.
• ²³
  Netto MUQ, Freitas O, Pereira LRL. Antidepressivos e benzodiazepínicos: estudo sobre o uso racional entre usuários do SUS em Ribeirão Preto. Rev de Ciênc Farm Básica e Aplic 2012; 33(1):77-81.
• ²⁴
  Firmino KF, de Abreu MHNG, Perini E, Magalhães SMS. Fatores associados ao uso de benzodiazepínicos no serviço municipal de saúde da cidade de Coronel Fabriciano, Minas Gerais, Brasil. Cad Saude Publica 2011; 26(6):1223-1232.
• ²⁵
  Lima MC, Menezes PR, Carandina L, Cesar CL, Barros MB, Goldbaum M. Transtornos mentais comuns e uso de psicofármacos: impacto das condições socioeconômicas. Rev Saude Publica 2008; 42(4):717-723.
• ²⁶
  Fleck MP, Berlim MT, Lafer B, Sougey EB, Del Porto JA, Brasil MA, Juruena MF, Hetem LA. Revisão das Diretrizes da Associação Médica Brasileira para Tratamento da Depressão. Rev Bras Psiquiatr 2009; 31(Supl. 1):7-17.
• ²⁷
  Western Australian Therapeutic Advisory Group (WATAG). Anxiety disorders drug treatment guidelines Western Australian: WATAG; 2008.
• ²⁸
  Woelfel JA, Patel RA, Walberg MP, Amaral MM. Use of potentially inappropriate medications in an ambulatory Medicare population. Consult Pharm 2011; 26(12):913-919.
• ²⁹
  Lorazepam. Resp. Téc. Farm. Miriam O. Fujisawa. Campinas: Medley Indústria Farmacêutica Ltda Bula de medicamento.
• ³⁰
  Organización Mundial de La Salud (OMS). Promoción del uso racional de medicamentos: componentes centrales Ginebra: OMS; 2002.
• ³¹
  Nastasy H, Ribeiro M, Marques ACPR. Abuso e dependência dos benzodiazepínicos Projeto diretrizes Rio de Janeiro: Associação Brasileira de Psiquiatria; 2008.
• ³²
  Griffin CE III, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system – mediated effects. Ochsner J 2013; 13(2):214-223.
• ³³
  Paquin AM, Zimmerman K, Rudolph J. Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf 2014; 13(7):919-934.
• ³⁴
  Préville M, Bossé C, Vasiliadis HM, Voyer P, Laurier C, Berbiche D, Pérodeau G, Grenier S, Béland SG, Dionne PA, Gentil L, Moride Y. Correlates of potentially inappropriate prescriptions of benzodiazepines among older adults: results from the ESA study. Can J Aging 2012; 31(3):313-322.
• ³⁵
  Smith AJ, Tett SE. Improving the use of benzodiazepines: is it possible? A non-systematic review of interventions tried in the last 20 years. BMC Health Serv Res 2010; 10:321.

Publication Dates

• Publication in this collection
  Apr 2016

History

• Received
  01 Dec 2014
• Accepted
  13 Aug 2015
• Reviewed
  15 Aug 2015