Rev Psiquiatr Salud Ment (Barc.).

2018;11(1):12---18

www.elsevier.es/saludmental

ORIGINAL ARTICLE

Benzodiazepine prescriptions and falls in older men

and women夽
Monica Martinez-Cengotitabengoa a,b,∗ , Maria Jose Diaz-Gutierrez c ,
Ariadna Besga a,d,e , Cristina Bermúdez-Ampudia a , Purificación López a ,
Marta B. Rondon f , Donna E. Stewart g , Patricia Perez a , Miguel Gutierrez a,e ,
Ana Gonzalez-Pinto a,e

a
CIBERSAM, Departamento de Psiquiatría, Hospital Universitario Araba, BioAraba Research Institute, Vitoria, Spain
b
Universidad Nacional de Educación a Distancia (UNED)-Centro Asociado en Vitoria, Vitoria, Spain
c
Farmacia Inés Barrenechea, Getxo, Spain
d
Servicio de Urgencias, Hospital Universitario Araba, Vitoria, Spain
e
Universidad del País Vasco, Vitoria, Spain
f
Unidad de Psiquiatría y Salud Mental, Departamento de Medicina, Universidad Cayetano Heredia, Lima, Peru
g
University Health Network, Centre for Mental Health, University of Toronto, Toronto, Canada

Received 21 June 2016; accepted 9 January 2017

Available online 25 May 2017

KEYWORDS Abstract
Benzodiazepines; Objective: Despite cautions by professional associations, benzodiazepines (BZD) and Z hyp-
Accidental falls; notics (BZD/Z) are widely prescribed to older adults who are particularly susceptible to insomnia
Aged; and anxiety, but who are also more sensitive to drugs adverse events. In this study, we assessed
Gender the prescription of BZD/Z drugs in a sample of older adults (≥65) who presented for emergency
care after a fall.
Methods: We collected the type, number and dose of BZD/Z drugs prescribed and explored
gender differences in the prescription.
Results: BZD/Z drugs were prescribed to 43.6% of the sample (n = 654) and more frequently
to women; 78.4% of prescriptions were for BZD/Z drugs with a short half-life. The majority
of patients (83.5%) were prescribed only one type of BZD/Z, but 16.5% had been prescribed
multiple BZD/Z drugs, with no gender difference. Doses higher than those recommended for
older adults were prescribed to 58% of patients, being the doses significantly higher for men
compared to women (70.0% vs 53.1%).

夽
Please cite this article as: Martinez-Cengotitabengoa M, Diaz-Gutierrez MJ, Besga A, Bermúdez-Ampudia C, López P, Rondon MB, et al.
Prescripción de benzodiacepinas y caídas en mujeres y hombres ancianos. Rev Psiquiatr Salud Ment (Barc). 2018;11:12---18.
∗ Corresponding author.

E-mail address: [email protected] (M. Martinez-Cengotitabengoa).

2173-5050/© 2017 SEP y SEPB. Published by Elsevier España, S.L.U. All rights reserved.
Benzodiazepine prescriptions and falls in older men and women 13

Conclusions: Over 40% of older adults presenting for emergency care after a fall had previously
been prescribed BZD/Z drugs. Some important gender differences in the prescription of BZD/Z
drugs were seen, especially prescription above the recommended dose and of drugs with a
long-half life.
© 2017 SEP y SEPB. Published by Elsevier España, S.L.U. All rights reserved.

PALABRAS CLAVE Prescripción de benzodiacepinas y caídas en mujeres y hombres ancianos

Benzodiacepinas;
Resumen
Caídas accidentales;
Objetivo: A pesar de las advertencias de numerosas asociaciones profesionales, las
Ancianos;
benzodiacepinas (BZD) y los hipnóticos Z (Z) son ampliamente prescritos a los ancianos ya
Género
que son especialmente susceptibles de padecer insomnio y ansiedad, pero a su vez resultan
especialmente sensibles a la aparición de efectos secundarios a dichos medicamentos. En este
estudio evaluamos la prescripción de BZD/Z en una muestra de ancianos (≥65) que se presentan
en el servicio de urgencias de un hospital por haber sufrido una caída.
Métodos: Recogimos información del tipo, número y dosis de los fármacos BZD/Z prescritos y
exploramos la presencia de diferencias de género en dicha prescripción.
Resultados: Las BZD/Z habían sido prescritas a un 43,6% de la muestra (n = 654), más fre-
cuentemente a las mujeres. El 78,4% de las prescripciones fueron de BZD/Z de vida media
corta. La mayoría de los pacientes (83,5%) tomaban solamente un fármaco BZD/Z, pero un
16,5% consumían más de una BZD/Z, sin diferencias de género. Un 58% de los pacientes con-
sumían dosis de BZD/Z más elevadas que las recomendadas para ancianos, siendo la proporción
significativamente más elevada para los hombres (70% vs. 53,1%).
Conclusiones: Alrededor de un 40% de los ancianos que acuden a un servicio de urgencias por
haber sufrido una caída se encontraban tomando BZD/Z. Hemos hallado algunas diferencias de
género en la prescripción de BZD/Z, especialmente en la prescripción por encima de la dosis
recomendada para ancianos y de fármacos de vida media larga.
© 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.

Introduction most commonly prescribed drugs in older adults because of

their proven efficacy, but care must be taken as their use
Despite cautions by many national regulatory agencies and and abuse may lead to unwanted effects, including cogni-
professional associations, a recent publication about benzo- tive deterioration,7 motor incoordination, ataxia, falls8---10
diazepine (BZD) use reinforced the efficacy of these drugs and respiratory failure.11---13
in the treatment of anxiety disorders and insomnia, and Clinical guidelines recommend that BZDs and the related
claimed that their use in older adults is generally accepted group of non-benzodiazepine Z-drugs (zolpidem, zaleplon,
by geriatricians when short half-life compounds and low zopiclone) should be used at the lowest possible dose, and
doses are prescribed.1 However, the beneficial effects of selecting those with the shortest half-lives.14,15 However,
BZDs are often disputed and concerns expressed about in the real world, there is evidence that various types and
their adverse events and high rates of prescription in older doses of these BZD/Z drugs are frequently prescribed in the
adults.2,3 Certainly, prescription decisions have to be made geriatric population,16 especially in women.3
on a case-by-case basis and patients should be informed of Falls, especially in older patients, are a serious adverse
both the risks and benefits of any prescribed medication.1 event of BZD/Z-drugs use, often causing hip fracture and
These decisions are not easy. Older adults are espe- can have a serious impact on mobility, morbidity and
cially difficult to treat because they often have multiple mortality.17,18 While the association between BZD/Z drugs
morbidities that require polypharmacy.4 Also, changes in and falls in older adults is well established, less is known
body composition and organ function during the ageing pro- about the characteristics of patients sustaining injuri-
cess can alter drug disposition and make older individuals ous falls and the prescription of BZD/Z drugs in such a
more vulnerable to medication-associated adverse events.5 population
In particular, there is an age-related increase in the rate The objectives of this study are to describe the previ-
and severity of adverse effects of drugs that act on the cen- ous prescription of BZD/Z drugs in a sample of older adults
tral nervous system, which often results from a decrease attending a general hospital emergency service after sus-
in the number of neurons and synapses and greater per- taining a fall and to explore potential gender differences in
meability of the blood-brain barrier.6 BZDs are one of the the type, number and dose of BZD/Z drugs prescribed.
14 M. Martinez-Cengotitabengoa et al.

Methods differences in the number of BZD/Z drugs prescribed con-

currently (X2 = 0.497, p = 0.92).
This is a record linkage study, of older patients aged at Women were prescribed BZD/Z drugs significantly more
least 65 years who consecutively attended the emergency often than men (47.6% prescribed women vs 36.1%
department of Araba University Hospital in Vitoria (Spain) prescribed men; X2 = 8.097, p = 0.004). Overall, 243 prescrip-
(between January and December 2010) due to a fall. The tions were to women and 100 to men. A logistic regression
study was approved by the hospital’s Ethics Committee. We model assessed whether the older age of women had an
collected data on patient sociodemographic characteristics influence on their greater prescription of BZD/Z drugs, using
and information about their previous prescription of BZD/Z BZD/Z drug prescription (yes/no)as the dependent variable
drugs (active ingredients and dosage). and gender as the independent variable, adjusting the model
To assess whether the study subjects were prescribed for patient age. We found that gender was still statistically
short- or long-acting BZD/Z drugs, we classified the pre- significant, despite adjusting for age in the model (OR = 1.53,
scriptions into two groups: (1) drugs with an ultra-short p = 0.013, CI: 1.094---2.137).
or short half-life (<20 h) (alprazolam, brotizolam, lopra- Table 1 shows the half-life category of BZD/Z drug taken
zolam, lorazepam, lormetazepam and zolpidem), and (ultra-short/short or medium/long) and whether the dose
(2) drugs with a medium or long half-life (>20 h) (bro- prescribed exceeded the recommended DDD. As seen in
mazepam, clonazepam, clorazepate, diazepam, ketazolam Table 1, 21.6% of prescriptions were for BZD/Z drugs with
and tetrazepam). a medium or long half-life, with a tendency for such drugs
To assess whether the prescribed dose of BZD/Z drug was to be prescribed more to women than to men (24.3% vs
similar to the recommended dose, we determined the rec- 15%; X2 = 3.606, p = 0.058). Moreover, 58.0% of prescriptions
ommended defined daily dose (DDD) in non-geriatric adults were for a dose above the recommended DDD in older
(DDDadults ) and in older adults(≥65 years old) (DDDolder adults ), adults (DDDolder adults ) in, with a significantly higher per-
based on the drug fact sheet produced by the Spanish Agency centage in men (70.0%) than women (53.1%) (X2 = 8.467,
of Medicines and Medical Devices19 and the recommenda- p = 0.014). We performed logistic regression analysis taking
tions of the World Health Organization.20 whether the dose was consistent with DDDolder adults as the
dependent variable, and patient gender as the independent
variable, controlling for age. We found that men had a sig-
Statistical analysis
nificantly greater chance of being prescribed BZD/Z drugs in
excess of the DDD for older adults (OR = 2.30, p = 0.008, CI:
Descriptive statistics were used to describe socio- 1.210---4.251). Furthermore, 54 prescriptions (15.8%) were
demographic and ‘‘dose of BZD’’ variables of the study for a dose that exceeded the DDD in non-geriatric adults
population: numbers and percentages (%) were shown for (DDDadults ), but there was no significant gender difference.
qualitative variables and means and standard deviations The BZD/Z drugs most frequently prescribed above
(SDs) for quantitative variables. Comparisons between men DDDolder adults were lormetazepam (91.1% of 112 prescrip-
and women were made using the chi-square (2 ) test for tions), zolpidem (73.1% of 26 prescriptions) and lorazepam
qualitative variables (dose of BZDs/Z drug prescribed) and (56.6% of 99 prescriptions), with no significant gender dif-
the Student’s t test for independent samples for qualitative ferences.
variables (DDDolder adults , DDDadults ). The influence of gender
on BZD/Z drug prescription or whether the prescribed dose
exceeded the DDD was examined using logistic regression Discussion
models with a dichotomous dependent variable (e.g.,
BZD/Z drug prescription yes vs no) and a dichotomous Our results show that almost half of all older adults who pre-
independent variable too (gender) adjusting the model sented for emergency care after a fall had been prescribed
by age. Results are reported as odds ratios (OR) and 95% BZD/Z drugs during the 2 weeks prior to the fall, mostly
confidence intervals with p values. for short-acting compounds in accordance with current clin-
ical guidelines.14,15 Psychiatry is tending towards precision
Results medicine,21 but until it achieves this, we base it on clinical
guidelines prepared by expert consensus. It still often pre-
We examined the records of 654 adults aged at least 65 scribed on a trial and error basis, but medications that are
years (230 men and 424 women), of whom 285 (43.6%) had good for some patients do always work for others, and there
been prescribed some type of BZD/Z drug up to 2 weeks is no way to predict this before trying it. However, a substan-
before they attended the hospital due to a fall (83 men and tial proportion (21.6%) of prescriptions was for medium or
202 women). The mean age of all recruited patients was long half-life BZD/Z drugs, particularly among women (24.3%
79.9 ± 8.5 years. Women were significantly older than men vs 15% in men). In addition, 16.5% of patients were pre-
(80.7 ± 8.4 years old vs 78.4 ± 8.4 years; t = 3302, p = 0.001). scribed multiple BZD/Z drugs and over the half of all BZD/D
Among the 285 people with a BZD/Z drug prescription drug prescriptions were for doses higher than those recom-
before their fall, there were 343 prescriptions of BZD/Z mended for older adults, with 70% of prescriptions in men
drugs, or 1.2 prescriptions per patient. Some patients being above the DDDolder adults .
were prescribed multiple BZD/Z drugs: 238 patients (83.5%) The reasons why almost one-quarter of BZD prescrip-
were prescribed one BZD/Z drug,13% (37 patients) two tions in women were for long-acting drugs are unknown. The
BZD/Z drugs, 3.2% (9 patients) three BZD/Z drugs and symptoms of anxiety and insomnia are sometimes difficult to
0.4% (1 patient) four BZD/Z drugs. There were no gender control in older people.22 It has been reported that BZDs with
Benzodiazepine prescriptions and falls in older men and women 15

Table 1 Type and dose of BZDs/Z drugs prescribed.

Total (Na = 343) Men (Na = 100) Women (Na = 243) Statistics p
Half-life of BZD/Z drug prescribed, n (%)
Ultrashort or short 269 (78.4) 85 (85.0) 184 (75.7) X2 = 3.61 0.058
Medium or long 74 (21.6) 15 (15.0) 59 (24.3)
Dose prescribed exceeded the recommended DDDb older adults , n (%)
No 119 (34.7) 24 (24.0) 95 (39.1) X2 = 8.47 0.014
Yes 199 (58.0) 70 (70.0) 129 (53.1)
Unknown dose 25 (7.3) 6 (6.0) 19 (7.8)
Dose prescribed exceeded the recommended DDDadults , n (%)
No 264 (77.4) 75 (75.0) 189 (78.4) X2 = 1.34 0.511
Yes 54 (15.8) 19 (19.0) 35 (14.5)
Unknown dose 25 (7.3) 6 (6.0) 19 (7.8)
a N value given is the number of prescriptions.
b DDD = defined daily dose.

ultra-short half-lives may cause rebound anxiety,23 espe- older patients, and suggests there may be underutilization
cially in the geriatric population. Hence, BZDs with a long of non-pharmacologicalinterventions,36 such as counselling
half-life may be used for short periods to provide better about sleep hygiene37 and the use of cognitive behavioural
symptom control after other non-pharmacological methods therapy38 or mindfulness-based meditation,39 that have
have failed. However, prolonged use of long-acting BZDs been shown to be effective in treating insomnia and anxiety,
should be avoided due to the risk of accumulation and asso- including in older people.
ciated adverse effects.24 Also, even when used for a short Our results show that BZD/Z drugs were often pre-
time, BZDs with long half-lives are more likely to have resid- scribed at significantly higher doses than the recommended
ual effects the next day, including sedation, which would DDDolder adults , especially in men (70%), but also in women
increase the risk of sustaining a fall. It is important to care- (58%). In some cases, the dose even exceeded the DDD in
fully follow-up older patients who have been prescribed long non-geriatric adults. This is in accordance with a previous
half-life BZDs, especially older women, who are more prone observational study of older patients (mean age of 75 years)
to falls than older men.25 There are many risk factors for falls hospitalized in an intensive care unit, which found that men
in older people, including decreased muscle mass/strength received higher doses of BZD (lorazepam) than women, after
and balance.26 BZD/Z drugs have also been reported to adjusting for variables such as age and severity of disease.40
decrease balance27 and physical strength,28 thereby further Further, a population-based study in Taiwan found that being
increasing the fall risk in older patients. There is evidence male and elderly were significantly associated with higher
that the use of BZD/Z drugs with long half-lives and the rates of continuation of BZDs once started.41 The reasons
prolonged use of any BZD/Z drug is associated with a signifi- why BZD/Z drugs are frequently used at higher than recom-
cant decrease in physical performance of older women29 and mended doses, especially in older men, are unclear. They
worse functional status.30 Thus, more care should be taken could be attributed to the perception that, in case of agita-
about the type, dose and duration of BZD/Z drugs prescribed tion, men’s behaviour could be aggressive, or due to men’s
to older women as they can impact on the risk of falls. higher body mass or metabolic differences between men and
Early studies of BZD use in older patients showed women.
that many (48%)were prescribed long-actingcompounds.31 The frequent use of BZDs above the recommended dose
Ourfinding that 21.6% of prescriptions for BZD/Z drugs were underlines the importance of implementing additional inter-
for compounds with a medium/long half-life are consis- ventions to decrease insomnia and anxiety in older people.
tent with a recent American study, which reported that 25% In Spain, an estimated 11.4% of the general population use
of adults receiving BZDs were using long half-life BZDs.32 benzodiazepines, with a higher likelihood of use in women,
In accordance with a French study of psychoactive drug older patients and people suffering from a mental disorder.42
prescription,33 we found that the prescription of BZD/Z According to the PROTECT-EU project, developed in 7 Euro-
drugs was higher in women than in men, independent of pean countries including Spain, BZD/Zs prescription rates
age. This finding may be attributable to the fact that (that is, number of prescriptions) varies from 5.7% to 16%
anxiety and insomnia are more common in women than and those rates were 1.5---2 times higher for women than
men.34 men, especially in older patients.43
Although the majority of patients were prescribed only A small, open-label, randomized study has shown that a
one type of BZD/Z drug, almost two out of every ten combination of BZD (lormetazepam 0.5 mg/day) with sleep
patients received inappropriate prescribing of multiple hygiene therapy is more effective at improving sleep archi-
BZD/Z drugs, despite evidence that such combinations have tecture in older adults with insomnia than sleep hygiene
no benefits over monotherapy,35 and that this practice is therapy alone.44 Aslormetazepam 1 mg can cause postural
contraindicated in older adults.23 This polypharmacy may instability lasting up to 8 h in older people,45 which is likely
reflect the difficulties in controlling insomnia and anxiety in related to an increased risk of falls, it is good practice to
16 M. Martinez-Cengotitabengoa et al.

use lower doses in older patients, if possible, to balance the Ethical responsibilities
benefits and risks of BZD treatment.
Chronic insomnia and anxiety are difficult to treat, Protection of human and animal subjects. The authors
especially in older adults. A recent study confirms that psy- declare that the procedures followed were in accordance
chotropic medication, especially BZD, is an independent risk with the regulations of the relevant clinical research ethics
factor for falls,46 and that this risk is generally associated committee and with those of the Code of Ethics of the World
with a cumulative effect of BZD doses used in the weeks Medical Association (Declaration of Helsinki).
prior to the fall.47 Nevertheless, using the lowest effective
doses of BZD/Z drugs and avoiding polypharmacy are tar- Confidentiality of data. The authors declare that they have
gets that can be reached and could be an easy and effective followed the protocols of their work centre on the publica-
way to decrease the fall risk in older adults. Our findings tion of patient data.
suggest that special care must be taken when prescribing
BZD/Z drugs to women. Right to privacy and informed consent. The authors
Given the high use of BZD/Z drugs in older people, var- declare that no patient data appear in this article.
ious interventions have been examined for reducing such
use. In some patients, it is possible to progressively and Conflicts of interest
slowly taper the dose of BZD/Z drug. One report suggests
that it may take more than one year to completely stop None.
the treatment without incurring symptoms.48 A recent meta-
analysis of randomized controlled trials concluded that BZD Acknowledgements
withdrawal tends to be more effective if combined with
psychological therapy,49 especially cognitive behavioural This work was supported by health research funds from the
therapy when cognition is not severely impaired. Clini- Spanish Government, cofinancing FEDER (PS09/02002, EC10-
cal guidelines should consider that there will always be 333, PI10/01430, PI10/01746, PI11/01977, PI11/02708,
a residual group of patients in whom it will not be pos- 2011/1064, 1677-DJ-030, EC10-220, PI12/02077,
sible to decrease the BZD doses, and these individuals PI13/02252, PI13/00451 and PI14/01900); European
will require special supervision.50 This may include the Regional Development Funds (Mastermind is partially
use of fall prevention strategies and mobility aids. Special funded under the ICT Policy Support Programme (ICT PSP)
care should be taken in patients with concurrent men- as part of the Competitiveness and Innovation Frame-
tal disorders who require careful evaluation and optimal work Programme by the European Community) (FI-STAR
psychopharmacology. project has received funding from the European Union’s
Our study has several limitations that must be taken Seventh Programme for research, technological devel-
into consideration. First, the cross-sectional design means opment and demonstration under grant agreement No.
we are unable to draw any conclusions about causal rela- 604691); local grants from the Department of Education,
tionships in the reported findings. Second, the patients Linguistic Policy and Culture of the Basque Country Govern-
were included in the study on arrival at the emergency ment (2008111010, 2009111047, 2010111170, 2010112009,
department and the reason for diagnosis underlying the 2011111110, 2011111113, 2013111162, and KRONIK 11/010);
prescription of BZD/Z drugs was not always clear. Third, the Basque Foundation for Health Innovation and Research
we could not confirm ingestion of these drugs (despite (BIOEF); Networking Center for Biomedical Research in
their prescription) within the 2 weeks before the fall. Mental Health (CIBERSAM); the Spanish Clinical Research
Fourth, there is no control group in this study. Finally, the Network (CAIBER; 1392-D-079) and the University of the
study was conducted in one Spanish hospital and may not Basque Country (GIC10/80, GIC12/84). The psychiatric
reflect practice elsewhere. Fourth, this is a single cen- research department in University Hospital Araba is sup-
tre study so external validity should be jeopardize, but ported by the Stanley Research Foundation (03-RC-003).The
the Emergency Department of the University Hospital of founding sources had no role in the study design, collection
Alava covers the entire population of the province (around and interpretation of data, writing the manuscript or in the
320 000 people). decision to submit the article for publication.
To conclude, we found that BZD/Z drugs were prescribed
to over 40% of older adults who sought emergency care in a
Spanish general hospital after a fall. We found certain gen- References
der differences in the prescribing of BZD/Z drugs to older
adults, specifically higher rates of prescription of BZD/Z 1. Balon R, Fava GA, Rickels K. Need for a realistic appraisal of
benzodiazepines. World Psychiatry. 2015;14:243---4.
drugs and of long half-life benzodiazepines to women. Also,
2. Touitou Y. Sleep disorders and hypnotic agents: medical, social
doses higher than recommended were prescribed to many
and economical impact. Ann Pharm Fr. 2007;65:230---8.
patients, especially in men. These inadequate practices may 3. Bourin M. The problems with the use of benzodiazepines in
be reduced by avoiding high doses and prolonged use of ben- elderly patients. Encéphale. 2010;36:340---7.
zodiazepines with long half-lives, especially considering the 4. Burrage DR, Lonsdale EV, Lonsdale DO, Baker E. Prescribing for
special characteristics of ageing and the high morbidity asso- elderly people. Br J Hosp Med Lond Engl. 2014;75:C119---21.
ciated with falls. It is important however, to bear in mind, 5. Reeve E, Wiese MD, Mangoni AA. Alterations in drug dis-
that it is best to entirely avoid, if possible, prescribing BZD/Z position in older adults. Expert Opin Drug Metab Toxicol.
drugs to the elderly. 2015;11:491---508.
Benzodiazepine prescriptions and falls in older men and women 17

6. Oakley R, Tharakan B. Vascular hyperpermeability and aging. 27. De Groot MH, van Campen JPCM, Moek MA, Tulner LR, Beijnen
Aging Dis. 2014;5:114---25. JH, Lamoth CJC. The effects of fall-risk-increasing drugs on pos-
7. Stewart SA. The effects of benzodiazepines on cognition. J Clin tural control: a literature review. Drugs Aging. 2013;30:901---20.
Psychiatry. 2005;66 Suppl. 2:9---13. 28. Corsonello A, Onder G, Maggio M, Corica F, Lattanzio F. Medi-
8. Woolcott JC, Richardson KJ, Wiens MO, Patel B, Marin J, cations affecting functional status in older persons. Curr Pharm
Khan KM, et al. Meta-analysis of the impact of 9 medication Des. 2014;20:3256---63.
classes on falls in elderly persons. Arch Intern Med. 2009;169: 29. Gray SL, Penninx BWJH, Blough DK, Artz MB, Guralnik JM,
1952---60. Wallace RB, et al. Benzodiazepine use and physical perfor-
9. Ungar A, Rafanelli M, Iacomelli I, Brunetti MA, Ceccofiglio A, mance in community-dwelling older women. J Am Geriatr Soc.
Tesi F, et al. Fall prevention in the elderly. Clin Cases Miner 2003;51:1563---70.
Bone Metab. 2013;10:91---5. 30. Peron EP, Gray SL, Hanlon JT. Medication use and functional
10. Huang AR, Mallet L, Rochefort CM, Eguale T, Buckeridge DL, status decline in older adults: a narrative review. Am J Geriatr
Tamblyn R. Medication-related falls in the elderly: causative Pharmacother. 2011;9:378---91.
factors and preventive strategies. Drugs Aging. 2012;29:359---76. 31. Lechevallier N, Fourrier A, Berr C. Benzodiazepine use in
11. Gueye PN, Lofaso F, Borron SW, Mellerio F, Vicaut E, Harf A, et al. the elderly: the EVA study. Rev Epidémiol Santé Publique.
Mechanism of respiratory insufficiency in pure or mixed drug- 2003;51:317---26.
induced coma involving benzodiazepines. J Toxicol Clin Toxicol. 32. Olfson M, King M, Schoenbaum M. Benzodiazepine use in the
2002;40:35---47. United States. JAMA Psychiatry. 2015;72:136---42.
12. Kamijo Y, Hayashi I, Nishikawa T, Yoshimura K, Soma K. Phar- 33. Plancke L, Benoît E, Chantelou M-L, Amariei A, Vaiva G.
macokinetics of the active metabolites of ethyl loflazepate Recourse to psychotropic medication in the Nord ---- Pas-de-
in elderly patients who died of asphyxia associated with Calais Region (France). Thérapie. 2009;64:279---87.
benzodiazepine-related toxicity. J Anal Toxicol. 2005;29: 34. Krystal AD. Depression and insomnia in women. Clin Corner-
140---4. stone. 2004;6 Suppl. 1B:S19---28.
13. Guilleminault C. Benzodiazepines, breathing, and sleep. Am J 35. San-José A, Agustí A, Vidal X, Formiga F, Gómez-Hernández
Med. 1990;88:25S---8S. M, García J, et al. Inappropriate prescribing to the oldest old
14. McIntosh B, Clark M, Spry C. Benzodiazepines in older adults: a patients admitted to hospital: Prevalence, most frequently used
review of clinical effectiveness, cost-effectiveness, and guide- medicines, and associated factors. BMC Geriatr. 2015;15:42.
lines [Internet]. Ottawa (ON): Canadian Agency for Drugs and 36. Molen YF, Carvalho LBC, do Prado LBF, do Prado GF.
Technologies in Health; 2011. Available from: http://www. Insomnia: psychological and neurobiological aspects and
ncbi.nlm.nih.gov/books/NBK174561/ [accessed 01.09.15]. non-pharmacological treatments. Arq Neuropsiquiatr.
15. Gobierno Vasco, Departamento de Sanidad y Consumo. 2014;72:63---71.
Guía Farmacoterapéutica para los pacientes geriátricos. 37. Godard M, Barrou Z, Verny M. Geriatric approach of
España; 2012. Available from: http://www.osakidetza.euskadi. sleep disorders in the elderly. Psychol Neuropsychiatr Vieil.
eus/contenidos/informacion/publicaciones informes estudio/ 2010;8:235---41.
es pub/adjuntos/guia pacientes geriatricos.pdf [accessed 38. Gooneratne NS, Vitiello MV. Sleep in older adults: normative
01.09.15]. changes, sleep disorders, and treatment options. Clin Geriatr
16. Neutel CI, Skurtveit S, Berg C. What is the point of guidelines? Med. 2014;30:591---627.
Benzodiazepine and z-hypnotic use by an elderly population. 39. Zhang J-X, Liu X-H, Xie X-H, Zhao D, Shan M-S, Zhang X-L,
Sleep Med. 2012;13:893---7. et al. Mindfulness-based stress reduction for chronic insom-
17. Van Strien AM, Koek HL, van Marum RJ, Emmelot-Vonk MH. Psy- nia in adults older than 75 years: a randomized, controlled,
chotropic medications, including short acting benzodiazepines, single-blind clinical trial. Explore N Y N. 2015;11:180---5.
strongly increase the frequency of falls in elderly. Maturitas. 40. Pisani MA, Bramley K, Vest MT, Akgün KM, Araujo KLB, Murphy
2013;74:357---62. TE. Patterns of opiate, benzodiazepine, and antipsychotic drug
18. Boyle N, Naganathan V, Cumming RG. Medication and falls: risk dosing in older patients in a medical intensive care unit. Am J
and optimization. Clin Geriatr Med. 2010;26:583---605. Crit Care. 2013;22:e62---9.
19. AEMPS. Centro de Información online de Medicamentos de 41. Fang S-Y, Chen C-Y, Chang I-S, Wu EC-H, Chang C-M, Lin K-M.
la AEMPS (CIMA). Available from: http://www.aemps.gob. Predictors of the incidence and discontinuation of long-term
es/cima/pestanias.do?metodo=accesoAplicacion [accessed use of benzodiazepines: a population-based study. Drug Alcohol
14.04.15]. Depend. 2009;104:140---6.
20. WHOCC. ATC/DDD index [Internet]. Available from: http:// 42. Codony M, Alonso J, Almansa J, Vilagut G, Domingo A, Pinto-
www.whocc.no/atc ddd index/ [accessed 14.04.15]. Meza A, et al. Psychotropic medications use in Spain. Results
21. Vieta E. Personalised medicine applied to mental health: pre- of the ESEMeD-Spain study. Actas Esp Psiquiatr. 2007;35 Suppl.
cision psychiatry. Rev Psiquiatr Salud Ment (Barc). 2015;8: 2:29---36.
117---8. 43. Huerta C, Abbing-Karahagopian V, Requena G, Oliva B, Alvarez
22. McMillan JM, Aitken E, Holroyd-Leduc JM. Management of Y, Gardarsdottir H, et al. Exposure to benzodiazepines (anxiolyt-
insomnia and long-term use of sedative-hypnotic drugs in older ics, hypnotics and related drugs) in seven European electronic
patients. Can Med Assoc J. 2013;185:1499---505. healthcare databases: a cross-national descriptive study from
23. Chouinard G. Issues in the clinical use of benzodiazepines: the PROTECT-EU Project. Pharmacoepidemiol Drug Saf. 2016;25
potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65 Suppl. 1:56---65.
Suppl. 5:7---12. 44. De Vanna M, Rubiera M, Onor ML, Aguglia E. Role of
24. Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacoki- lormetazepam in the treatment of insomnia in the elderly. Clin
netics of anxiolytics and hypnotics in the elderly. Therapeutic Drug Investig. 2007;27:325---32.
considerations (Part I). Clin Pharmacokinet. 1991;21:165---77. 45. Allain H, Bentué-Ferrer D, Tarral A, Gandon J-M. Effects on
25. Kannus P, Parkkari J, Koskinen S, Niemi S, Palvanen M, Järvinen postural oscillation and memory functions of a single dose
M, et al. Fall-induced injuries and deaths among older adults. of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1
JAMA. 1999;281:1895---9. mg in elderly healthy subjects. A randomized, cross-over,
26. Boelens C, Hekman EEG, Verkerke GJ. Risk factors for falls of double-blind study versus placebo. Eur J Clin Pharmacol.
older citizens. Technol Health Care. 2013;21:521---33. 2003;59:179---88.
18 M. Martinez-Cengotitabengoa et al.

46. Williams LJ, Pasco JA, Stuart AL, Jacka FN, Brennan SL, Dobbins from: http://benzo.org.uk/manual/bzsched.htm [accessed
AG, et al. Psychiatric disorders, psychotropic medication use 03.07.15].
and falls among women: an observational study. BMC Psychiatry. 49. Gould RL, Coulson MC, Patel N, Highton-Williamson E, Howard
2015;15:75. RJ. Interventions for reducing benzodiazepine use in older
47. Sylvestre M-P, Abrahamowicz M, Čapek R, Tamblyn R. Assessing people: meta-analysis of randomised controlled trials. Br J Psy-
the cumulative effects of exposure to selected benzodiazepines chiatry. 2014;204:98---107.
on the risk of fall-related injuries in the elderly. Int Psychogeri- 50. Paquin AM, Zimmerman K, Rudolph JL. Risk versus risk: a review
atr. 2012;24:577---86. of benzodiazepine reduction in older adults. Expert Opin Drug
48. Ashton C.H. Benzodiazepines: how they work & how to with- Saf. 2014;13:919---34.
draw, Prof C.H. Ashton, DM, FRCP; 2002 [Internet]. Available