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Medication as a Risk Factor for Falls: Critical Systematic Review

Authors:
  • University of Eastern Finland, Institute of Public Health and Clinical Nutrition

Abstract and Figures

Falls in older people are associated with poor prognosis. Medication use is a potential cause of falls. Our aim was to systemically review all original articles examining medication use as a risk factor for falls or fall-related fractures in people aged >/=60 years. We searched English articles in Medline (1996-2004) indexed under "falls" or "accidental falls" and "pharmaceutical preparations" or specific groups of drugs. We excluded studies not meeting the age criterion, not controlled with nonusers of target medicines or nonfallers, or with no clear definition of target medication. Twenty-eight observational studies and one randomized controlled trial met the inclusion criteria. The number of participants ranged from 70 to 132,873. The outcome measure was a fall in 22 studies and a fracture in 7 studies. The main group of drugs associated with an increased risk of falling was psychotropics: benzodiazepines, antidepressants, and antipsychotics. Antiepileptics and drugs that lower blood pressure were weakly associated with falls. Central nervous system drugs, especially psychotropics, seem to be associated with an increased risk of falls. The quality of observational studies needs to be improved, for many appear to lack even a clear definition of a fall, target medicines, or prospective follow-up. Many drugs commonly used by older persons are not systematically studied as risk factors for falls.
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Review Article
Medication as a Risk Factor for Falls: Critical
Systematic Review
Sirpa Hartikainen,
1,2
Eija Lo¨nnroos,
1,3
and Kirsti Louhivuori
4
1
School of Public Health and Clinical Nutrition, Department of Geriatrics, University of Kuopio, Finland.
2
Social and Health Centre of Kuopio, Finland.
3
Central Finland Hospital, Jyva¨skyla¨, Finland.
4
School of Public Health and Clinical Nutrition, Department of Public Health, University of Kuopio, Finland.
Background. Falls in older people are associated with poor prognosis. Medication use is a potential cause of falls. Our
aim was to systemically review all original articles examining medication use as a risk factor for falls or fall-related
fractures in people aged 60 years.
Methods. We searched English articles in Medline (1996–2004) indexed under ‘‘falls’ or ‘accidental falls’ and
‘pharmaceutical preparations’ or specific groups of drugs. We excluded studies not meeting the age criterion, not
controlled with nonusers of target medicines or nonfallers, or with no clear definition of target medication.
Results. Twenty-eight observational studies and one randomized controlled trial met the inclusion criteria. The number
of participants ranged from 70 to 132,873. The outcome measure was a fall in 22 studies and a fracture in 7 studies. The
main group of drugs associated with an increased risk of falling was psychotropics: benzodiazepines, antidepressants, and
antipsychotics. Antiepileptics and drugs that lower blood pressure were weakly associated with falls.
Conclusions. Central nervous system drugs, especially psychotropics, seem to be associated with an increased risk of
falls. The quality of observational studies needs to be improved, for many appear to lack even a clear definition of a fall,
target medicines, or prospective follow-up. Many drugs commonly used by older persons are not systematically studied as
risk factors for falls.
T
HE incidence of falls and the severity of fall-related
complications increase with age (1,2). Each year, 8% of
people 70 years old or older seek care for fall-related
injuries in accident and emergency departments (3). Falls
are associated with a poor prognosis, including excess mor-
tality and premature institutionalization (4). The majority of
falls have a multifactorial etiology. Risk factors for falling
can be categorized as environmental (e.g., poor lighting,
loose carpets, slippery flooring, lack of handrails), intrinsic
(e.g., weak muscle strength or impairment in balance, gait,
vision, or cognition), and extrinsic such as use of certain
medicines or polypharmacy (5,6).
Leipzig and colleagues (7,8) conducted two meta-analyses
that evaluated an association between medication use and
falls in older people. None of the studies were randomized
controlled trials (RCT), so the evidence between medication
use and falls was based on observational data from 69 English
articles published from 1966 through March 1996. The use
of psychotropic drugs (antidepressants, mainly tricyclic,
antipsychotics, long- and short-acting benzodiazepines) was
associated with an increase in the risk of falls (7). With respect
to cardiovascular drugs, a weak association was reported
between falls and use of any diuretic, digoxin, or type IA
antiarrythmic medicine (8). However, no statistically signifi-
cant associations were found between falls and use of thiazides,
loop diuretics, angiotensin-converting enzyme (ACE) inhib-
itors, or calcium channel blockers. Analgesics were not signif-
icantly associated with falls. Older adults taking more than
three or four medicines were at increased risk of recurrent falls.
The studies included in the meta-analyses had minimal adjust-
ment for confounding factors such as an underlying indication
for drug use, dosage, or duration of pharmacotherapy.
New pharmaceutical preparations, such as selective sero-
tonin reuptake inhibitors (SSRIs), new atypical antipsy-
chotics, benzodiazepine-like sleeping pills, and angiotensin
II antagonists, have come on the market since the mid-
1990s, and the use of medications as well as polypharmacy
have increased among elderly persons (9,10). Our focus was
to detect medicines that could potentially increase the risk of
falling. Thus, we excluded those articles concerning the
withdrawal of drugs or the protective effects of drugs on
falling or fractures. The purpose of this article is to system-
atically review studies that were published in 1996–2004
and reported an association between the use of medicines
and a risk of falls or fall-related fractures in people 60 years
old or older.
M
ETHODS
Literature Search
We searched Medline for original English articles pub-
lished from January 1996 through December 2004 using the
1172
Journal of Gerontology: MEDICAL SCIENCES Copyright 2007 by The Gerontological Society of America
2007, Vol. 62A, No. 10, 1172–1181
Medical Subject Headings (MeSH) terms ‘‘accidental falls’
and ‘‘pharmaceutical preparations.’ This search yielded only
20 hits. Combinations of the terms ‘falls’’ and ‘medication’’
or ‘medicines’ or specific groups of medications (benzo-
diazepines, antidepressants, antiepileptics, analgesics, anti-
hypertensive agents, statins, cholinesterase inhibitors) gave
altogether 673 hits. We also searched the Cochrane library
and examined the reference lists of the retrieved articles.
Study Selection
The abstracts of the articles found in the literature search
were read. Full-text copies of potentially includable articles
were retrieved, and 48 original articles (11–58) that reported
on an association between medication use and falls or fall-
related fractures in older people were found. Of the 48
studies, 19 (11–29) were excluded for the following reasons:
1. Not controlled with nonfallers or nonusers of the target
medications (11–14);
2. Persons younger than 60 years were included, and results
for older persons were not reported separately (15–18);
3. Definition of target medications was missing (19–22);
4. The time between medication ascertainment and out-
come of falls or fall-related fractures was . 1 year
(23–28); and
5. The participation rate was , 70% (29).
The remaining 29 studies (30–58) were included in this
review.
Definition and Classification of Medicines
In this review, we classify medicines according to the
Anatomical Therapeutic Chemical (ATC) classification sys-
tem recommended by the World Health Organization (WHO)
(59). The classification divides medicines into 14 main
groups according to the organ or system on which they act and
into five different levels on the basis of their chemical,
therapeutic, and pharmacological properties. For example,
citalopram is coded N06AB04 (N ¼ nervous system, N0 ¼
antidepressants and psychostimulants, N06A ¼ antidepres-
sants, N06AB ¼ SSRIs, N06AB04 ¼ citalopram). Based on
the ATC, central nervous system (CNS) medicines are de-
fined as including psychotropics (hypnotics, sedatives, anxi-
olytics, antipsychotics, and antidepressants), antiepileptics,
drugs for Parkinson’s disease and Alzheimer’s disease, and
opioids.
Statistical Methods
The strength of the association between medication use
and falls was evaluated using odds ratios (OR) and 95%
confidence intervals (CI) if they were reported in the
original articles. The results were categorized by medication
groups or by specific medicines reflecting the level at which
they were reported in the original articles.
R
ESULTS
Description of Included Studies
Table 1 presents a summary of the 29 studies (30–58)
included in this systematic review. Only one study was an
RCT (31), whereas the others were based on observations of
prospective cohorts (30,32,35,38–40,44,52,53,56–58), ret-
rospective cohorts (33,36,45,46,49,50,55), or cases and
controls (34,37,41–43,47,48,51,54).
Of the 29 studies, 8 were population-based (33,37,41–
43,51,55,57), 7 concerned community-dwellers (30,34–
36,38,44,50), 12 were performed in residential care settings
(31,39,40,45–47,49,52–54,56,58), 1 consisted of community-
dwellers and nursing home residents (48), and 1 was per-
formed in four different types of geriatric care settings (32).
The number of participants ranged from 70 persons in resi-
dential care to 132,873 persons in a register database study.
Medication use as a risk factor for falls or fall-related
fractures was the main objective in 20 studies (31,32,34–
37,39,41–43,45–51,54,55,57), whereas the others focused
on multiple risk factors for falls (30,33,38,40,44,52,53,56,58).
The outcome measure was a fall (single or recurrent) (31–
33,35,36,38–40,44–46,49,50,52,53,55,56), an injurious fall
(30,34,54,57,58), a hip fracture (37,41–43,48,51), or a femur
fracture (47). The term ‘‘fall’ was not defined in eight
studies (31,33,45,48–50,52,55).
The data on falls were based on recall (33,36,50,55),
or the participants filled in fall calendars and/or were
contacted by phone or by postcard (30,35,38,44,56). Falls
were recorded by staff in 10 institutional care studies
(31,32,39,40,45,46,49,52,53,58), whereas hospital registers
were the principal sources of information in 10 surveys
concerning injurious falls or fall-related fractures (34,37,41–
43,47,48,51,54,57).
The data on medication use in the 28 observational stud-
ies were obtained by interviewing the participants (30,33,35,
36,38,44,50,55,56), from prescription databases (34,37,41,
42,51,57), from nursing home records (32,39,40,45–47,49,52–
54,58), or through blood tests (43,48). Six studies classified
medicines according to the ATC system (30,36,39,44,53,56),
five used other classifications (33–35,54,55), and 18 studies
did not report the use of any classification (31,33,37,38,40–
43,45–52,57,58).
The effects of duration of drug use were evaluated in
eight studies (37,39,41,46,49,51,54,57). The effects of dos-
ing were assessed in six studies by the following methods:
Patients were randomized on fixed doses (31), the doses of
different benzodiazepines were converted to diazepam
equivalents (41,46), and the doses used were compared
with the defined daily doses (DDD) (47,49,51).
In the RCT, the baseline characteristics of the groups
randomized for different treatment were homogenous, and
the indication for pharmacotherapy was defined. The trial
was also controlled for the degree of wandering behavior
and use of other psychotropic drugs.
All nine case–control studies were controlled for age and
sex (34,37,41–43,47,48,51,54). Of the 19 observational stud-
ies without a case–control framework, 14 were controlled
for age (30,32,33,35,39,40,45,46,49,50,53,56–58), 10 for
sex (32,39,45,46,49,50,53,56–58), and four included only
women (30,33,35,36). At least one chronic condition was
considered as a potential confounder in relation to the
reported association between medication use and falls in all
the case–control studies (34,37,41–43,47,48,51,54), and in
12 of 19 other observational studies (32,33,35,36,39,40,46,
49,50,53,55,58). Cognitive status was the most often
1173MEDICATION AS A RISK FACTOR FOR FALLS
Table 1. Summary of the 29 Studies Included in the Systematic Review
Reference
Study Type
Setting/Study Population
Number and Age
of Participants
Target
Medication
Outcome Measure Association
Between Medication Use and Falls
Bergland and Wyller,
2004 (30)
P
CD
N ¼ 307 women
Age 75
All Injurious falls:
" antihypertensives
No association: other medication groups
Katz et al., 2004 (31) RCT
RC
N ¼ 537 persons
Mean age ¼ 83
Risperidone Falls among residents with dementia:
# risperidone 1 mg/d
" risperidone 2 mg/d
Kallin et al., 2004 (32) P, CS
RC, NH
Re, H
N ¼ 3669 persons
Age 65
All Falls:
" antidepressants, antipsychotics
Lawlor et al., 2003 (33) R, CS
PB
N ¼ 4050 women
Age 60
All Any falls:
" hypnotics/anxiolytics, antidepressants
No association: analgesics,
cardiovascular/endocrine/respiratory system drugs
Kelly et al., 2003 (34) CC
CD
N ¼ 11,390 persons
Age 66
All Injurious falls:
" opioids, anticonvulsants, antidepressants
No association: other medication groups
Ensrud et al., 2002 (35) P
CD
N ¼ 8127 women
Age 65
CNS drugs Falls/recurrent falls:
" BZDs, antidepressants, anticonvulsants
No association: opioids
Rozenfeld et al., 2003 (36) R, CS
CD
N ¼ 634 women
Age 60
All Falls/recurrent falls:
" Diuretics, beta-blockers, anxiolytics/sedatives
Hubbard et al., 2003 (37) CC, R
PB
N ¼ 46,230 persons
Mean age
¼ 79
SSRIs TCAs Hip fracture:
" TCAs, SSRIs
Heitterachi et al.,
2002 (38)
P
CD
N ¼ 70 persons
Age 62
All Falls:
No association: antihypertensives, antidepressants
Neutel et al., 2002 (39) P
NH
N ¼ 227 persons
Age 65
All Falls:
" five or more medicines
" a new prescription of BZDs or antipsychotics
No association: other medication groups
Kallin et al., 2002 (40) P
RC
N ¼ 83 persons
Mean age ¼ 80
All Falls:
" antidepressants (SSRIs)
Wang et al., 2001 (41) CC, R
PB
N ¼ 6110 persons
Age 65
BZDs Hip fracture:
No association: BZD , 3 mg/d in diazepam
equivalents
" BZD 3 mg/d in long- and short-term use
Wang et al., 2001 (42) CC, R
PB
N ¼ 6110 persons
Age 65
Psychotropics Hip fracture:
" zolpidem, BZDs, antipsychotics, antidepressants
Pierfitte et al., 2001 (43) CC
PB
N ¼ 1062 persons
Age 65
BZDs Hip fracture:
No association: exposure to BZD
" lorazepam in plasma, reported use of 2 BZDs
Tromp et al., 2001 (44) P
CD
N ¼ 1285 persons
Mean age ¼ 75
All Falls:
" use of 4 drugs, BZDs, antiepileptics
Arfken et al., 2001 (45) R
NH
N ¼ 368 persons
Age 60
Antidepressants Falls:
" SSRIs
Ray et al., 2000 (46) R
NH
N ¼ 2510 persons
Age 65
BZDs Falls:
" BZDs 2 mg/d in diazepam equivalents
" BZDs . 8 mg/d in diazepam equivalents
" BZD, BZD started within 1 wk, BZD use . 30 d
No association: elimination half-life , 12 h
" nightly falls when half-life , 12 h
" elimination half-life 12 h
Sgadari et al., 2000 (47) CC
NH
N ¼ 46,803 persons
Age 65
BZDs Hip fracture:
" nonoxidative BZDs
No association: BZDs as a group, oxidative BZDs
Schwab et al., 2000 (48) CC
CD
NH
N ¼ 187 persons
Mean age ¼ 80.0
TCA Barbiturates
BZD
Hip fracture:
No association: BZD use based on history/prescription
data
" BZD use based on serum analysis
Thapa et al., 1998 (49) R
NH
N ¼ 2428 persons
Age 65
Antidepressants Falls:
" TCAs, SSRIs, trazodone
Chaimowicz et al.,
2000 (50)
R
CD
N ¼ 161 persons
Age 65
Psychoactive drugs Falls:
" BZDs, BZDs, and/or antidepressants
Liu et al., 1998 (51) CC, R
PB
N ¼ 49,648 persons
Age 66
Antidepressants Hip fracture:
" SSRIs, TCAs
1174 HARTIKAINEN ET AL.
addressed confounder (32,34,35,39,40,46–49,51,53–55,58).
Physical performance (activities of daily living, ambulatory
status) was considered as a confounder in 10 studies
(32,35,43,46,47,49,53,54,56,58), and the use of other med-
icines was considered as a confounder in 14 studies (34,37,
39,40–43,46,47,49–51,57,58).
Psychotropic and Other CNS Drugs
Twenty-seven studies reported results from CNS drugs,
and all of them included at least one psychotropic drug
or drug group. Benzodiazepines as a group or by certain
preparations were associated with falls or fall-related frac-
tures in 17 studies (33,35,36,39,41–44,46–48,50,52–55,57)
(Figure 1). The risk of falling increased after a new pre-
scription (39,41,46,54,57), in long-term use (41,46), and
regardless of the preparation’s half-life (35,41,46,57). Only
one benzodiazepine-like sleeping pill (zolpidem) was studied,
and it proved to be as risky as traditional benzodiazepines
(42). Concomitant use of two or more benzodiazepines in-
creased the risk of hip fracture 2-fold (43). In contrast, three
studies found no association between the use of benzodia-
zepines and falls (30,40,56).
Antidepressants, including tricyclic antidepressant (TCA)
preparations and SSRIs, were associated with falls or frac-
tures in 12 studies (32–35,37,40,42,45,49–51,55) (Figure 2).
The risks varied from 1.20- to 6-fold. Within 2 weeks after
a new prescription for SSRIs (fluoxetine or paroxetine),
the OR for hip fracture was 6.30 (95% CI, 2.65–14.97),
and for TCAs it was 4.76 (95% CI, 3.06–7.41) (35). The risk
of falls remained elevated in long-term use of antidepres-
sants, and it was dose-dependent (49). An increased risk
of falls or injurious falls was not found in five studies
(30,39,44,54,56).
Antipsychotic drugs were associated with increased risk
of falls or fractures (31,32,39,42,52,54) (Figure 3). Only
two studies gave results for new atypical antipsychotics
(31,32). Risperidone (OR 1.26; 95% CI, 0.81–1.95) and
olanzapine (OR 1.89; 95% CI, 0.99–3.62) were not
significantly associated with falls in the Swedish study,
though antipsychotics as a group were found to increase the
risk of falls (32). The risk was dose dependent in the RCT,
with risperidone 2 mg/d increasing the risk of falls in
demented persons with low levels of wandering, although
1 mg/d did not (31). No association between antipsychotics
and falls was found in three studies (30,40,55).
Use of antiepileptics was related to an increased risk of
falls in three studies (34,35,44), the OR values ranged from
1.5 to 3.5 (34,35,44), whereas one study showed no elevated
risk (OR 1.07; 95% CI, 0.65–1.76) (32). Cholinesterase
inhibitors for Alzheimer’s disease were included in only one
study (32), which found no association between this group
of drugs and falls. Opioids were associated with falls in one
study (OR 1.68; 95% CI, 1.39–2.03) (34), but not in another
(OR 1.02; 95% CI, 0.79–1.31) (35).
Other Medications and Polypharmacy
Data on the use of medicines other than CNS drugs were
collected in 12 surveys (30,32–34,36,38–40,44,53,54,56).
Three of these studies (30,36,56) reported an association
between cardiovascular drug use and an increased risk of
falling. Use of antihypertensives increased risk for injurious
falls (OR 2.4; 95% CI, 1.1–6.5) (30), use of beta-blockers
(OR 2.2; 95% CI, 1.2–4.0) (36) and peripheral vaso-
dilatators (OR 3.8; 95% CI, 1.4–10.2) (56) for recurrent
falls, and nitrates (OR 2.2; 95% CI, 1.3–3.9) for any falls.
Cardiovascular drugs, as a whole or by examined group,
were not associated with falls in nine studies (32–34,38–
40,44,53,54). The definitions and groupings of these drugs
varied considerably, and the results of risk calculations were
not reported in three of these studies (40,44,53).
Three studies (33,39,44) reported that the risk of falling
increased with the number of drugs taken. In a nursing home
population, use of 5–9 drugs increased the risk 4-fold (OR
4.0; 95% CI, 1.6–9.9), and use of 10 drugs carried an even
Table 1. Summary of the 29 Studies Included in the Systematic Review (Continued)
Reference
Study Type
Setting/Study Population
Number and Age
of Participants
Target
Medication
Outcome Measure Association
Between Medication Use and Falls
Kiely et al., 1998 (52) P
NH
N ¼ 18,855 persons
Age 65
Psychotropics Falls:
" antipsychotics, anxiolytics
Nygaard, 1998 (53) P
LTC
N ¼ 118 persons
Median age ¼ 85
All Falls:
No association with any group of drugs
" psychotropics in mentally impaired patients
Mustard and Mayer,
1997 (54)
CC, R
NH
N ¼ 2972 persons
Age ¼ 83
12 categories of
medications
Injurious falls:
" antipsychotics, anxiolytics/sedatives/hypnotics
# inotropic agents
Ebly et al., 1997 (55) R
PB
N ¼ 2034 persons
Age 65
CNS drugs Falls in cognitively normal persons:
" BDZs, antidepressants
Graafmans et al.,
1996 (56)
P
RC
N ¼ 354 persons
Age 70
A few classes
of medication
Falls:
" nitrates, peripheral vasodilators
Neutel et al., 1996 (57) P
PB
N ¼132,873 persons
Age 60
BZDs Injurious falls:
" within 4 weeks after a new prescription: triazolam,
flurazepam, diazepam, lorazepam, oxazepam
Thapa et al., 1996 (58) P
NH
N ¼ 1228 persons
Age 65
Psychotropics Injurious falls:
" psychotropics among ambulatory users
Note:CC¼ case control; CS
¼ cross-sectional; P ¼ prospective; R ¼ retrospective; RCT ¼ randomized controlled trial; PB ¼ population-based; CD ¼ community-
dwelling; H ¼ hospital; LTC ¼ long-term care; NH ¼ nursing home; Re ¼ rehabilitation; RC ¼ residential care; BZD ¼ benzodiazepine; CNS ¼ central nervous system;
TCA ¼ tricyclic antidepressants; SSRI ¼ serotonin reuptake inhibitor. increase; decrease.
1175MEDICATION AS A RISK FACTOR FOR FALLS
higher risk (OR 5.5; 95% CI, 1.9–15.9) than that associated
with the use of 4 drugs (39). Among community-dwellers,
use of 4 drugs increased the risk of falling by 30% (OR
1.3; 95% CI, 1.0–1.7) (44). However, among older women,
the association with falls was stronger for multiple pathol-
ogies than for polypharmacy (33).
D
ISCUSSION
Benzodiazepines are one of the main risk factors for falls
and fractures in older people. They seem to be associated
with an increased risk of falls, not only in long-term use but
also after a new prescription. Similar findings were reported
in a recent meta-analysis of 24 studies (60). Benzodiaze-
pines have negative effects on cognition, gait, and balance,
and the pharmacodynamic responses of benzodiazepines
tend to change with advancing age; the concentration that
produces half of a full response (EC
50
) for sedation is
reduced by 50% in elderly persons (61–63). Most studies
included in this review and in the previous meta-analysis (7)
overlooked the active metabolites of benzodiazepines or the
effect of age on half-life.
Antidepressants, particularly TCAs and SSRIs, seem to
be associated with a high risk for falling. The previous meta-
analysis (7) included only one study of SSRIs, and it was
hoped that they would be safer (in terms of falling) than
TCAs. However, as shown by the studies in this review,
SSRIs might carry even higher risks for falling than do
traditional antidepressants. Whether antidepressants that
inhibit both serotonin and noradrenalin reuptake (SNRI)
are safer than TCAs or SSRIs has yet to be studied.
Differences between the risk profiles of TCAs and SSRIs
are not as marked as we clinicians hoped. Both affect the
serotonergic system and can cause serotonin syndrome
when used in higher doses or concomitantly with other
Figure 1. Benzodiazepines and risk of falls. Medication classes or medicines and reference numbers of studies are on vertical axis. a, in persons with postural
hypotension; b, use of 2 benzodiazepines; c, dose 2 mg/d in diazepam equivalents; d, dose . 8 mg/d in diazepam equivalents; e, in plasma sample; f, in mentally
impaired persons. *Upper bound ¼ 15.28. OR ¼ odds ratio; CI ¼ confidence interval.
1176 HARTIKAINEN ET AL.
serotonergic drugs. Both TCAs and SSRIs can promote in-
appropriate antidiuretic hormone secretion (SIADH) and
hyponatremia (64,65) and can cause cardiovascular depres-
sant effects by inhibiting cardiac Na
þ
and Ca
2þ
channels (66).
Antipsychotic drugs as a group seem to be associated with
an increased risk of falling. This association was stronger than
that found in the meta-analysis of Leipzig and colleagues (7).
In this review, the relative risk of falls ranged between 1.21
and 11.4, whereas in the meta-analysis, the pooled OR was
0.41 for psychiatric inpatients and 1.66 for other participants.
More evidence is needed to show whether the new atypical
antipsychotic drugs are safer than the traditional ones in terms
of the risk of falling. Only two studies reported on them; one
study found no significant association, whereas the other
showed that the risk was dose-dependent (31,32). The
extrapyramidal adverse effects of antipsychotic drugs are
one explanation for the increased risk of falls, but also the
anticholinergic properties and effects on alpha-adrenergic
receptors may contribute to the risk of falling (67,68).
In addition, other CNS drugs, like antiepileptics, may also
increase risk for falls. As clinicians, we need to adhere to
well-grounded indications and carefully weigh risks and
benefits of treatment. Polypharmacy (the use of five or more
drugs) multiplies the risk for falling. The reason for this
might not be just the number but also the type of prep-
arations included in the medication. After adjustment for
comorbid conditions, polypharmacy remained a risk factor
for falls only when the medication included at least one drug
known to pose a risk for falling (69). Especially concomitant
use of several CNS drugs should be avoided.
Although cardiovascular drugs are the most commonly
used drugs among elderly persons (10,70), few studies
reported results on the use of them. Preparations that lower
blood pressure were associated with an increased risk of
Figure 2. Antidepressants and risk of falls. Medication classes or medicines and reference numbers of studies are on vertical axis. a, in mentally impaired persons; b,
exposed for 14 days; c, exposed for 15–42 days; d, secondary amine tricyclic antidepressant (TCA); e, tertiary amine TCA; *Upper bound ¼ 14.97; **upper bound ¼
24.93. SSRIs ¼ selective serotonin reuptake inhibitors; OR ¼ odds ratio; CI ¼ confidence interval.
1177MEDICATION AS A RISK FACTOR FOR FALLS
falling (30,36,56). Different groups of cardiovascular medi-
cations act differently and on different receptors, thus
necessitating their study by medication group and by spe-
cific preparation. We need to know which preparations and
doses are the safest for patients who often have other
significant risk factors for falls, like weak muscular strength.
Drugs may get new indications as well. For example, alpha-
blockers used for hypertension are now indicated for pros-
tatic hyperplasia, and orthostatic hypotension related to this
group of drugs may increase the risk of falling (71,72).
Design and Methodology of Studies
An important issue in any epidemiological study is to
define outcome measures. In this review, one in every four
of the studies failed to define the term ‘fall.’ This failure
seems to be common even in RCTs (31,73). Moreover, the
target medication was often inadequately defined, with more
than half of the studies not using any systematic classi-
fication of medicines. These omissions significantly de-
crease the quality, consistency, and comparability of these
studies, not to mention their clinical implementation.
Recruiting appropriate controls is critical for case–control
studies. In hospital-based case–control studies, controls
often consist of hospitalized patients. It is appropriate to get
hip-fracture patients from hospitals, but how can we ensure
that drug use in controls represents the average drug use
among older persons in the general population (74)?
Only one study was an RCT (31), thus indicating that
they are still as absent today as they were in the mid-1990s.
An indication for drug use is defined in an RCT, whereas
indications are not accurately known in observational
studies, especially in retrospective or register database
studies. Nor is it known whether the indications are current
anymore. Observational studies are also confounded by
different doses and durations of drug use. Dosage was only
taken into account in every fifth study, and the duration of
pharmacotherapy in every fourth study. Anyhow, this is an
improvement compared with the previous meta-analyses
(7,8). The incidence of falls and fall-related fractures is
known to increase with age and to some extent with female
gender; therefore, age and gender need to be considered as
potential confounders in the studies examining the associ-
ation between medication use and falls.
Many studies included in this review were controlled for
at least some chronic condition. However, when adjusting
the final models for diseases like hypertension or coronary
heart disease, essential findings can be easily overlooked. A
drug can increase the risk of falling regardless of the ap-
propriateness of the indication. In observational studies, it is
not known what aspects were considered when a certain
preparation was prescribed. Thus, there is a possibility of
selection bias regarding the use of target medication; there-
fore, observational studies might either underestimate or
overestimate the harmful effects of drugs in terms of falling.
Exposure to a medicine is often difficult to determine, and
the source of information used has an effect on the results.
In most studies, the information on medicine use was based
on self-reports or medical records. When data obtained from
medical records or self-reports were supplemented with
plasma concentrations, more users of target medicines were
found (48,74). This finding may indicate that studies tend to
underestimate the strength of the association between use of
benzodiazepines and falls or fractures. Such underreporting
may also be common with other CNS drugs. In contrast, the
drug can still be active in tissues and on receptors, even
though it remains undetectable in the plasma. This is
Figure 3. Antipsychotic drugs and risk of falls. Reference numbers of studies are on vertical axis. a, in mentally impaired persons. OR ¼ odds ratio; CI ¼ confidence
interval.
1178 HARTIKAINEN ET AL.
especially true with liposoluble drugs like benzodiazepines
with active metabolites.
A problem in observational studies is that medication is
supposed to remain unchanged throughout the follow-up
period, and conclusions are made on that basis. Another
suggestion is that participants use only one potentially risky
medicine. The medicines in use can be changed many times
a year, and the same person may concomitantly use several
drugs that can potentially increase the risk of falls.
Excessive polypharmacy and the use of psychotropics in-
crease with advancing age (9,10,70). Even concomitant use
of several psychotropic drugs is not rare (10). Thus, the
current temporal relationship between drug use and falls,
the effect of risky drug combinations, as well as the con-
founding effects of other drugs should be assessed in these
studies.
Suggestions for Forthcoming Trials
The drugs on the market and those used by elderly
persons are not systematically studied as potential risk
factors for falls. Studies with a large number of participants
are needed to determine whether new drugs are associated
with an increased risk of falls. Falls as harmful side effects
should also be included in the protocols of clinical trials of
pharmaceutical preparations applying for a license for the
market. We are awaiting studies regarding new CNS drugs,
like new antiepileptics, new medicines for Parkinson’s
disease, cholinesterase inhibitors and memantine for
Alzheimer’s disease, SNRI antidepressants, and new atyp-
ical antipsychotics. Moreover, other medicines commonly
used by elderly persons need to be studied as risk factors
for falls, including serum lipid-modifying agents, dipyrida-
mole, nonsteroidal analgesics, coxibs, alpha-receptor inhib-
itors for prostatic hyperplasia, and cardiovascular medicines
like ACE inhibitors and angiotensin II antagonists. Sugges-
tions for improving the quality of observational studies are
listed in Table 2.
Conclusion
CNS medicines, especially psychotropic drugs, seem to
be associated with an increased risk of falling. Yet, many
observational studies still fail to provide proper definitions
of falls and target medications as well as prospective follow-
up of falls and drug use. These problems significantly
decrease the quality, consistency, and comparability of
studies, not to mention clinical implementation. More RCTs
are needed, and falls as an adverse effect should be included
in the protocols of the clinical trials of medicines intended
for elderly persons.
ACKNOWLEDGMENTS
We thank the Prevention of Falls Network Europe (ProFaNE) Workshop
2 attendees for their valuable comments regarding this manuscript. Contact
http://www.profane.eu.org. Drs. Hartikainen and Lo¨nnroos are participants
of ProFaNE, which is funded by the European Commission (QLRT-2001-
02705).
We thank statistician Piia Lavikainen for her help in drawing the figures.
Sirpa Hartikainen and Eija Lo¨nnroos designed this review, searched the
literature, and wrote the manuscript. Their contributions to this review
article were equal. Kirsti Louhivuori contributed to the interpretation of the
statistical methods of the original articles and prepared the figures.
C
ORRESPONDENCE
Sirpa Hartikainen, MD, PhD, School of Public Health and Clinical
Nutrition, Department of Geriatrics, University of Kuopio, P.O. Box 1627,
FI-70211 Kuopio, Finland. E-mail: sirpa.hartikainen@uku.fi
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Received June 19, 2006
Accepted January 9, 2007
Decision Editor: Darryl Wieland, PhD, MPH
1181MEDICATION AS A RISK FACTOR FOR FALLS
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... Except opioids, as only a few patients receive these medications, there might be limitations in analysing the relationship between medications and patient fall in this study. In addition, some studies did not show clear a correlation between treatment with these medications and falls (Hartikainen et al., 2007;Lawlor et al., 2003;Sterke et al., 2008). It is known that anticoagulant is associated with fall-related injuries rather than falls (Hartikainen et al., 2007). ...
... In addition, some studies did not show clear a correlation between treatment with these medications and falls (Hartikainen et al., 2007;Lawlor et al., 2003;Sterke et al., 2008). It is known that anticoagulant is associated with fall-related injuries rather than falls (Hartikainen et al., 2007). ...
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... Some studies show that antipsychotics are used between 21% and 46% of cases to manage agitation and aggression (18)(19)(20). Atypical antipsychotics are the most commonly used to reduce the frequency and severity of episodes of agitation and aggression (21,22) which, however, in most patients, are poorly controlled by the drug (23), thus leading to consequences (24,25) increased risk of falls and fractures (26), development of cerebrovascular accidents, reduced quality of life and increased mortality (27)(28)(29)(30). For these reasons, the guidelines of the American Psychiatric Association from 2007 onwards have been recommending (31) non-pharmacological interventions as the first choice (32)(33)(34). ...
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Objectives: To investigate the effect of the number of cohabitating household members on falls among an disabled aging Korean population. Methods: We used data from the first to the fourth waves of the Korea Longitudinal Study of Aging. Using the first wave at baseline, data included 1414 individuals aged 45 years and older who needed assistance for performance of activities of daily living (ADL) or instrumental activities of daily living (IADL). We classified falls as overall falls, falls requiring medical treatment, and hip fractures caused by falls. The number of cohabitating family members was classified as none (living alone), one, two, or more. A generalized estimating equation with logit link was used to examine the association between the number of cohabitating household members with overall falls and injuries caused by falls. Results: Compared to living with two or more household members, living alone was associated with higher odds of overall falls, falls needing medical treatment, and hip fractures caused by falls (odds ratio (OR) 2.13, 95% confidence interval [CI] 1.36-3.34; OR 2.13, 95% CI 1.28-3.53; OR 1.93, 95% CI 1.01-3.69, respectively). These associations were particularly strong in individuals with cognitive decline. Conclusions Living alone is associated with higher odds of overall falls, falls needing medical treatment, and hip fractures caused by falls, particularly for those with cognitive decline. Conclusions: Intervention programs to prevent falls in disabled, aging adults, especially those living alone and those with declined cognitive function, need to provide home care services and promote the use of safety equipment.
... medication) factors are now collected as part of routine care in RACFsproviding unique opportunities to develop and test dynamic falls risk prediction tools [36,37]. Several studies have identified that certain medications that are used for the treatment of conditions affecting cardiovascular (e.g., beta-blockers, diuretics) or central nervous systems (e.g., antipsychotics, sedatives) are known to increase the risk of falling [38][39][40][41][42][43][44][45]. As older people in RACFs are the primary users of these medications, it is important to utilise medication data as one of the main time-varying factors to obtain a robust and accurate dynamic prediction and monitoring of falls risk over time. ...
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Background The Peninsula Health Falls Risk Assessment Tool (PH-FRAT) is a validated and widely applied tool in residential aged care facilities (RACFs) in Australia. However, research regarding its use and predictive performance is limited. This study aimed to determine the use and performance of PH-FRAT in predicting falls in RACF residents. Methods A retrospective cohort study using routinely-collected data from 25 RACFs in metropolitan Sydney, Australia from Jul 2014-Dec 2019. A total of 5888 residents aged ≥65 years who were assessed at least once using the PH-FRAT were included in the study. The PH-FRAT risk score ranges from 5 to 20 with a score > 14 indicating fallers and ≤ 14 non-fallers. The predictive performance of PH-FRAT was determined using metrics including area under receiver operating characteristics curve (AUROC), sensitivity, specificity, sensitivity Event Rate(ER) and specificity ER . Results A total of 27,696 falls were reported over 3,689,561 resident days (a crude incident rate of 7.5 falls /1000 resident days). A total of 38,931 PH-FRAT assessments were conducted with a median of 4 assessments per resident, a median of 43.8 days between assessments, and an overall median fall risk score of 14. Residents with multiple assessments had increased risk scores over time. The baseline PH-FRAT demonstrated a low AUROC of 0.57, sensitivity of 26.0% (sensitivity ER 33.6%) and specificity of 88.8% (specificity ER 82.0%). The follow-up PH-FRAT assessments increased sensitivity ER values although the specificity ER decreased. The performance of PH-FRAT improved using a lower risk score cut-off of 10 with AUROC of 0.61, sensitivity of 67.5% (sensitivity ER 74.4%) and specificity of 55.2% (specificity ER 45.6%). Conclusions Although PH-FRAT is frequently used in RACFs, it demonstrated poor predictive performance raising concerns about its value. Introducing a lower PH-FRAT cut-off score of 10 marginally enhanced its predictive performance. Future research should focus on understanding the feasibility and accuracy of dynamic fall risk predictive tools, which may serve to better identify residents at risk of falls.
... A meta-analysis of 10 studies by Sithamparanathan et al. [33] suggested that risk of adverse effects due to benzodiazepines use among elderly people found to be 2.45 times than in general population. Hartikainen et al. [42] found that the benzodiazepines were a prominent risk factor for falls among the elderly. Barker et al. [43] analyzed 13 studies assessing the neuropsychological effects of benzodiazepine use and found that long-term use of benzodiazepines was associated with neuropsychological deficits. ...
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Substance use disorders in the elderly population can be assessed through scales and questionnaires. These scales are used for not only screening for substance use disorders but also for assessment for improvement with time and/or intervention. Validity parameters of these scales help us know how do they perform during application in the clinical or community setting. The objective of the review was to (1) review available validated screening tools for substance use disorders, (2) summarize elderly-focused studies, and (3) provide recommendations for use in clinical care. We aimed to review the validated scales of substance use disorders in the geriatric population. We looked at PubMed and Web of Science databases for identifying English language peer-reviewed publications that reported at least one validity parameter for scale in geriatric patients with substance use disorders. We identified 22 studies, with majority of them focusing on alcohol use disorder. Alcohol Use Disorder Identification Test and Cut Down, Annoyed, Guilty, and Eye-Opener Questionnaire (CAGE) were the most common scales used in the population. While most of the studies reported acceptable area under receiver operator curve, sensitivity, and specificity, some of the studies reported lower sensitivity/specificity at optimal cutoff. Validity parameters of various scales have been assessed in the geriatric population. Using suitable cutoffs, they can be useful in the screening of elderly individuals with substance-related problems, so that due evaluation and care can be provided. More instruments need to be assessed for validity to diagnose tobacco use disorders, benzodiazepine use disorders, and other substance use disorders.
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Objective The purpose of the study was to develop and validate a model to predict the risk of experiencing a fall for nursing home residents utilizing data that are electronically available at the more than 15 000 facilities in the United States. Materials and Methods The fall prediction model was built and tested using 2 extracts of data (2011 through 2013 and 2016 through 2018) from the Long-term Care Minimum Dataset (MDS) combined with drug data from 5 skilled nursing facilities. The model was created using a hybrid Classification and Regression Tree (CART)-logistic approach. Results The combined dataset consisted of 3985 residents with mean age of 77 years and 64% female. The model’s area under the ROC curve was 0.668 (95% confidence interval: 0.643–0.693) on the validation subsample of the merged data. Discussion Inspection of the model showed that antidepressant medications have a significant protective association where the resident has a fall history prior to admission, requires assistance to balance while walking, and some functional range of motion impairment in the lower body; even if the patient exhibits behavioral issues, unstable behaviors, and/or are exposed to multiple psychotropic drugs. Conclusion The novel hybrid CART-logit algorithm is an advance over the 22 fall risk assessment tools previously evaluated in the nursing home setting because it has a better performance characteristic for the fall prediction window of ≤90 days and it is the only model designed to use features that are easily obtainable at nearly every facility in the United States.
Article
What is known and objective: The use of hypnotics, especially benzodiazepines (BZs), increases the risk of falls. Regarding the association of orexin receptor antagonists with fall risk, consistent results have not been obtained for suvorexant, and studies of lemborexant have not been reported. Therefore, this study investigated whether orexin receptor antagonists, including lemborexant, increase the risk of falls. Methods: Data were obtained from the medical records of patients hospitalized at Saga University Hospital in Japan between July 2020 and April 2021. Patients were retrospectively divided into the fall and non-fall groups, and the groups were compared for medication usage. Results and discussion: The fall and non-fall groups included 132 and 6857 patients respectively. A significantly higher proportion of patients in the fall group used hypnotics (40.2% vs. 21.7%; p < 0.0001). Hypnotics remained significantly associated with a higher risk of falls after adjusting for confounders (adjusted odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.13-2.48, p = 0.01). In particular, the use of benzodiazepines was associated with a significantly higher risk of falls (adjusted OR = 2.08, 95% CI = 1.38-3.15, p = 0.0005). Meanwhile, suvorexant use was not linked to the risk of falls, and lemborexant use was associated with a significantly lower risk of falls (adjusted OR = 0.27, 95% CI = 0.09-0.84, p = 0.02). What is new and conclusion: The use of hypnotics is a risk factor for falls, but orexin receptor antagonists may represent a safe option for patients requiring hypnotics. Our results provide evidence supporting the safety of these drugs.
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Introduction Hypnotherapy is increasingly used in general medicine in France to manage health problems such as insomnia. There is some evidence to support the efficacy of hypnosis in treating insomnia but this evidence is based on methodologies of various strengths. This review aims to explore the methodological elements employed in hypnotherapy research to manage insomnia. Method We performed a narrative review of the literature using systematic review methods focusing on treating insomnia with hypnosis. PubMed, Psycinfo, BASE and Cochrane databases and Google scholar were searched. Results Overall, 25 studies were included consisting of 10 case studies, 11 randomised, controlled trials and 4 pre and post intervention studies. The study designs, intervention, control and comparators were heterogeneous, as were the hypnosis definitions and techniques. Also, detailed descriptions of the hypnosis techniques were lacking. Most studies used non-quantifiable measurement criteria and sample numbers were too small to show significance or be representative. No double-blind study was found. Conclusion Our results indicate that the current research concerning the efficacy of hypnosis to relieve insomnia is lacking in key methodological elements. The evaluation research process requires robust methodology. We propose applying the IDEAL framework, which recommends research steps to evaluate non-pharmacological and other complex therapies to evaluate the efficacy of hypnosis to manage insomnia.
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Objective: To determine whether benzodiazepines are associated with an increased risk of hip fracture. Design: Case-control study. Participants: All incident cases of hip fracture not related to traffic accidents or cancer in patients over 65 years of age. 245 cases were matched to 817 controls. Setting: Emergency department of a university hospital. Main outcome measures: Exposure to benzodiazepines and other potential risk or protective factors or lifestyle items. Results: The use of benzodiazepines as determined from questionnaires, medical records, or plasma samples at admission to hospital was not associated with an increased risk of hip fracture (odds ratio 0.9, 95% confidence interval 0.5 to 1.5). Hip fracture was, however, associated with the use of two or more benzodiazepines, as determined from questionnaires or medical records but not from plasma samples. Of the individual drugs, only lorazepam was significantly associated with an increased risk of hip fracture (1.8, 1.1 to 3.1). Conclusion: Except for lorazepam, the presence of benzodiazepines in plasma was not associated with an increased risk of hip fracture. The method used to ascertain exposure could influence the results of case-control studies.
Article
OBJECTIVE: To determine the frequency of falls and identify risk factors for falls among older Mexican-American women.DESIGN: A prospective cohort study with an average follow-up of 2.7 years.SETTING: A clinical center at the Palo Alto Veterans Affairs Medical Center, California.PARTICIPANTS: 152 community-dwelling Mexican-American Caucasian women aged 59 years or older.OUTCOME MEASURES: Falls and injurious falls, as determined by monthly telephone interviews.RESULTS: The rate of falls was 508 per 1000 person-years (95% confidence interval (CI), 440-577). Injurious falls requiring medical attention occurred at a rate of 79 per 1000 person-years (95% CI, 52-107). Factors that were associated independently with an increased risk of falling were older age, a history of arthritis or rheumatism, a history of high thyroid, having fainted at least once in the year before baseline, current use of psychotropic medications, and walking fewer than 5 blocks a day. Those persons with an average time for the chair stand test had a lower risk of falling than those with the slowest times or the fastest times.CONCLUSIONS: The frequency of falls and injurious falls in this cohort of 152 relatively acculturated, healthy, older Mexican-American women was similar or slightly higher than previously reported rates for non-Hispanic Caucasian). Many of the factors associated with falls in this study were similar to those reported for non-Hispanic Caucasian women, suggesting that fall prevention measures tested mainly among non-Hispanic Caucasian women would also be appropriate for Mexican-American women. J Am Geriatr Soc 47:1371-1378,1999.
Article
Objective Exposure in pharmacoepidemiologic studies can rely on various sources such as medical records, patient questionnaires, or plasma samples, which do not always concur. This study endeavored to compare sources of information on current exposure to benzodiazepines in elderly subjects.Methods In a study in a hospital admissions department, 1136 elderly subjects included in a case-control study each completed a structured questionnaire. In addition, an inspection of the medical records of each subject was performed, as well as screening of a plasma sample (high-pressure liquid chromatography-diode array detector) for current exposure to benzodiazepines.ResultsBenzodiazepines were found in the plasma of 33% of 1013 patients, in the records of 31% of patients, and in the questionnaires of 36% of 797 respondents. With use of the plasma results as a standard, questionnaires had 11% false positives and 28% false negatives; medical records had 14% false positives and 23% false negatives. The κ for concordance between questionnaires and records was 0.63. Most of the errors were related to the unexpected presence in plasma of clorazepate, commonly used as a hypnotic agent.Conclusions Patient recall and medical records are not reliable measures of current exposure to benzodiazepines in elderly persons, although this unreliability may be more marked with certain drugs used as hypnotic agents.Clinical Pharmacology & Therapeutics (2001) 69, 445-450; doi: 10.1067/mcp.2001.116147
Article
This large prospective cohort study was undertaken to construct a fall-risk model for elderly. The emphasis of the study rests on easily measurable predictors for any falls and recurrent falls. The occurrence of falls among 1285 community-dwelling elderly aged 65 years and over was followed during 1 year by means of a “fall calendar.” Physical, cognitive, emotional and social functioning preceding the registration of falls were studied as potential predictors of fall-risk. Previous falls, visual impairment, urinary incontinence and use of benzodiazepines were the strongest predictors identified in the risk profile model for any falls (area under the curve [AUC] = 0.65), whereas previous falls, visual impairment, urinary incontinence and functional limitations proved to be the strongest predictors in the model for recurrent falls (AUC = 0.71). The probability of recurrent falls for subsequent scores of the screening test ranged from 4.7% (95% Confidence Interval [CI]: 4.0–5.4%) to 46.8% (95% CI: 43.0–50.6%). Our study provides a fall-risk screening test based on four easily measurable predictors that can be used for fall-risk stratification in community-dwelling elderly.
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Background: Treatment of benign prostatic hyperplasia (BPH) with nonselective alpha1 antagonists such as terazosin, doxazosin, and prazosin results in blood pressure reduction due to vasodilation. Objective: Using claims data from a large Medigap plan, we examined the effect of initiating nonselective alpha1-antagonist therapy on the incidence of hypotension-related adverse events likely to be associated with vascular alpha-adrenoreceptor antagonism in patients with BPH. Methods: Medical and prescription claims data were obtained from the MEDSTAT Group for 53,824 men with a diagnosis code for BPH during the study period (January 1995-December 1997). We examined the rate of possible hypotension-related adverse events (diagnosis codes for hypotension, syncope, dizziness, fractures, and other injuries) per 10,000 person-days for men who began therapy with alpha1 antagonists and for a random sample of nonusers, stratified by prior use of other antihypertensive agents. Results: After adjusting for baseline differences in event rates, those who initiated alpha1-antagonist therapy (n = 1564) had a significantly greater increase in hypotension-related adverse-event rates in the 4 months after initiation (vs the 4 months before initiation) than randomly selected nonusers (n = 8641) (increase of 1.82 vs decrease of 0.02 events per 10,000 person-days among those not taking antihypertensive agents; increase of 0.94 vs 0.69 events per 10,000 person-days among those taking other antihypertensive agents; P < 0.01). This increase began earlier and lasted longer among patients taking other antihypertensive agents. Those who discontinued their alpha1 antagonist had a higher rate of hypotensive events at baseline than those who did not (5.09 vs 3.19 events per 10,000 person-days among those using other antihypertensive agents; 3.62 vs 2.27 events per 10,000 person-days among those not using other antihypertensive agents; P < 0.05). Conclusions: Initiation of nonselective alpha1-antagonist therapy for the treatment of BPH increases the risk of a cluster of clinical events consistent with vascular alpha-adrenoreceptor antagonism. This effect is seen during a 4-month period around the initiation date. Prior initiation of other antihypertensive medication increases this effect. Urologists should consult with a patient's primary care physician about use of other antihypertensive agents before initiating nonselective alpha1-antagonist therapy for BPH.
Article
Objective We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect.Methods Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model.ResultsThe total doses needed to reach the defined end points were 71 ± 9 mg and 35 ± 6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399 ± 91 and 388 ± 97 mL/min; steady-state volume of distribution, 85 ± 22 and 104 ± 11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522 ± 236 ng/mL; elderly subjects, 223 ± 56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age.Conclusions These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.Clinical Pharmacology & Therapeutics (1999) 65, 630-639; doi: 10.1016/S0009-9236(99)90084-X