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CMAJ
See also practice article by Wolkove and Baltzan on page 1517 and at www.cmaj.ca/lookup/doi/10.1503/cmaj.130260
B
enzodiazepines and other sedative- declared.
hypnotic drugs are prescribed to many hypnotic drugs be prevented?
Disclaimer: Jayna
older adults despite the nearly 5-fold Holroyd-Leduc is an
increased risk of adverse cognitive events asso- Prescribing sedative-hypnotic drugs in hospital Associate Editor of CMAJ
ciated with their use (95% confidence interval has a substantial impact on long-term use. A and was not involved in the
[CI] 1.47 to 15.47),1,2 the 2.6-fold increased risk casecontrol study of new benzodiazepine pre- editorial decision-making
process for this article.
of adverse psychomotor events (95% CI 1.12 to scriptions found that cases were 3 times more
6.09), the association with falls and hip frac- likely than controls to have been admitted to hos- This article has been peer
reviewed.
tures3,4 and the 5-fold increased risk of hospital pital within 30 days after the index date.12 In
admission after a motor vehicle collision.5 The another study, at 1 month after discharge, patients Correspondence to:
Jacqueline M. McMillan,
number needed to treat with a sedative-hypnotic were more likely to stop previous benzodiazepine jacqueline.mcmillan
drug for improved quality of sleep is 13, use if they did not receive them during the hospi- @albertahealthservices.ca
whereas the number needed to harm is 6.1 Harm tal stay (OR 3.58, 95% CI 1.56 to 8.21) and were CMAJ 2013. DOI:10.1503
can include drowsiness, fatigue, headache, more likely to start taking benzodiazepines if /cmaj.130025
nightmares and gastrointestinal disturbances.1 they were prescribed them during the hospital
In the 2012 updated Beers criteria for poten- stay (OR 3.57, 95% CI 1.66 to 8.08).13 No litera-
tially inappropriate medication use in older ture was identified around the role of counselling
adults, a strong recommendation based on high- or other strategies to prevent long-term use.
quality evidence has been made to avoid all ben-
zodiazepines in older adults.6 Yet, 16%33% of
older people living in the community use benzo-
Are non-benzodiazepine sedative-
diazepines,7,8 and 54% use them daily.9 The most hypnotic drugs a safer alternative?
widely reported indication is insomnia (64%).7
People who take benzodiazepines tend to be Medications commonly used to treat insomnia
older women, to have lower education levels, to include the Z drugs (non-benzodiazepine seda-
consume less alcohol but more tobacco, to have tive-hypnotic drugs, of which zopiclone and
higher depression and anxiety scores and to use zolpidem have been approved for use in
other psychotropic drugs.2,7
The appropriate assessment and management
of chronic insomnia is crucial. Insomnia affects Key points
quality of life and has been shown to be an inde- Long-term benzodiazepine use in older patients is associated with
pendent risk factor for falls (adjusted odds ratio many adverse outcomes.
[OR] 1.52, 95% CI 1.38 to 1.66).10 A current evi- Hospital admission may play a pivotal role in both the initiation and
dence-based consensus guideline can assist clini- discontinuation of sedative-hypnotic drugs.
cians in managing chronic insomnia.11 There is a paucity of long-term safety and efficacy data for the use of
In this review, we address questions regarding non-benzodiazepine sedative-hypnotics.
sedative-hypnotic drugs, their discontinuation Cognitive behavioural therapy, brief behavioural interventions and
and effective alternative options among older benzodiazepine-tapering protocols have shown proven benefit in
benzodiazepine discontinuation.
adults. This review is based on a systematic liter-
Nonpharmacologic interventions, such as cognitive behavioural
ature search (Box 1). Most of the relevant evi- therapy and brief behavioural interventions, are of proven benefit in
dence identified consisted of small, short-term, improving sleep parameters.
randomized trials.
2013 Canadian Medical Association or its licensors CMAJ, November 19, 2013, 185(17) 1499
Review
Canada), melatonin, ramelteon, diphenhy- either safe or effective when used long-term in
dramine, antidepressants and atypical antipsy- older adults. Until their long-term use has been
chotics. A systematic analysis of the pharmaco- studied, these medications should be prescribed
logic treatment of insomnia in patients over 60 with caution to frail older adults.
years old found that, although sleep was better
with sedatives than with placebo, adverse cogni- Melatonin
tive events were more common (OR 4.78, 95% The data for the effectiveness of melatonin as a
CI 1.47 to 15.47),1 as were adverse psychomotor sleep aid are mixed. In a study of melatonin ver-
events (OR 2.25, 95% CI 0.93 to 5.41), although sus placebo, there was lack of significant effect
the latter did not reach significance.1 on sleep time, sleep latency, number of awaken-
ings and sleep efficiency.20 However, pooled data
Z drugs from randomized double-blind trials of pro-
We found 2 randomized trials that compared longed-release melatonin showed statistically
zopiclone with triazolam in older adults 14,15 significant improvement in quality of sleep
(Table 1). Overall, the studies were small (n = (9.2 mm v. 3.7 mm with placebo, as mea-
1041) and of short duration (1517 days). sured by the Leeds Sleep Evaluation Question-
Therefore, although the results showed improve- naire visual analog scale) and decrease in sub-
ment in some sleep-quality indices, there was jective sleep latency (26 min v. 8 min with
insufficient evidence to support the efficacy and placebo; p = 0.02).21
safety of long-term use. Ramelteon, a prescription melatonin agonist,
Two randomized trials were found that com- was recently approved in the United States and
pared zolpidem with triazolam in older adults Japan but is not currently available in Canada. A
(Table 1).16,17 Although the number of participants systematic review of ramelteon found improve-
was greater than in the studies of zopiclone (n = ments in total sleep time (9 min, 95% CI 4.94 to
205335), the duration was short (2128 days). 12.49) and in latency to persistent sleep (4 min,
As a result, the efficacy and safety of zolpidem 95% CI 5.66 to 2.77).22 However, in subgroup
for long-term use remains unclear. In a case analysis, there were no significant improvements
control study of Medicare and Medicaid data among those over 65 years.22
from one US state, the risk of hip fracture was
increased with zolpidem use compared with no Diphenhydramine
use (adjusted OR 1.95, 95% CI 1.09 to 3.51) and In a 14-day crossover trial of diphenhydramine
similar compared with benzodiazepines 50 mg versus temazepam 15 mg versus placebo,
(adjusted OR 1.47; 95% CI 0.74 to 2.93).18 Fur- total sleep time, sleep quality and sleep latency
thermore, Health Canada has issued an advisory were not significantly improved in the diphenhy-
for zolpidem following reports of complex sleep- dramine arm.23 In a trial involving 14 healthy older
related behaviours.19 volunteers (mean age 71.6 yr), psychomotor
Overall, trials of the Z drugs have shown impairment was present after 75 mg of diphenhy-
improvement in some sleep domains. However, dramine versus placebo; however, no psychomo-
it is premature to presume that these drugs are tor impairment was detected with 50-mg dose.24
The updated Beers criteria strongly advise against
the use of diphenhydramine in older adults
Box 1: Methods because of its anticholinergic effects.6
We searched MEDLINE (1946September 2012), Embase (1980September
2012) and the Cochrane Database of Systematic Reviews (2005September Doxepin
2012) using the following key search terms: MeSH and Embase terms for
benzodiazepines, sleep initiation and maintenance disorders, and drug
Doxepin, a histamine H1-receptor antagonist,
withdrawal and abuse, as well as key words for sleep, addiction, was shown to significantly increase subjective
dependence, insomnia, specific drug names, and terms for taper, withdrawal total sleep time by 18 minutes, from 317 to 335
and alternative therapies. Further details about the literature search are minutes (p < 0.01) after 1 week of treatment in
available from the authors upon request. We retrieved 284 unique citations older adults.25 In this trial, there were no reports
and reviewed 190 full articles. Each citation and full article was
independently reviewed for inclusion by 2 of us, so that each of us reviewed of anticholinergic effects or memory impairment
two-thirds of all citations. in the doxepin group.25
We included articles if the majority of patients studied were over the age of
65 years; the study was a systematic review, randomized controlled trial, cohort Other agents
study or casecontrol study; and the focus of the study was use of We found no data on the use of atypical antipsy-
benzodiazepines or comparative interventions as a sleep aid, or about their chotics, trazodone or other antidepressants for
discontinuation. We excluded articles if they were not written in English;
benzodiazepine use was primarily for a reason other than sleep aid; the article sleep in older adults, despite the use of these
was a case report, case series or editorial; or only the abstract was available. medications for their sedating properties. In the
general population, data supporting the use of
trazodone for sleep in the absence of a coexisting As part of the work-up for insomnia, it is nec-
mood disorder are lacking.26 essary to investigate the reason for long-term
sedative-hypnotic use and to rule out other axis I
When should problematic use of disorders such as mood and anxiety disorders.
Other sleep-related disorders should also be
sedative-hypnotics be suspected? considered, such as obstructive sleep apnea, rest-
less leg syndrome, sleep walking and narcolepsy.
In a randomized controlled discontinuation trial,
patients who used more than 10 mg of diazepam
equivalent, who had high scores on a noncompli-
What strategies are effective
ance measure or who drank more than 2 units of for stopping sedative-hypnotic
alcohol per day failed to achieve long-term absti- drug use?
nence (defined as receiving no benzodiazepine
prescriptions during 15 months of follow-up).27
In a longitudinal study involving older people, Effective strategies, used alone or in combina-
long-term benzodiazepine use was associated tion, include simple recommendations to stop,
with treatment for nervous conditions, restless tapering protocols, cognitive behavioural therapy
sleep, being female, being divorced and having and melatonin. In particular, there is evidence for
increased contact with medical services.7 Simi- combining tapering protocols with cognitive
larly, associations between benzodiazepine use behavioural therapy.
and depressive or anxious symptoms, increased Cognitive behavioural therapy is administered
use of nonpsychotropic drugs and female sex by registered psychologists and psychiatrists who
were found in a study involving older benzodi- have received special training. Sessions are usually
azepine users in France.8 90 minutes long and often occur weekly over a
Table 1: Randomized controlled trials of non-benzodiazepine sedative-hypnotic drugs versus benzodiazepines for the treatment of
insomnia
Drug, dose
Venter Zopiclone Triazolam 17 41 76.8 The zopiclone group woke up once on average and
et al.14 7.515 mg 0.250.5 mg the triazolam group woke up nearly twice on
average (mean 1.7; p = 0.06)
Adverse events reported in 35% of zopiclone and
38% of triazolam patients; difference not significant
Mouret Zopiclone Triazolam 15 10 65 Subjective aspects of sleep did not differ between
et al.15 7.5 mg 0.25 mg groups
Sleep recordings did not differ between groups
Leppik Zolpidem Triazolam 28 335 69 Subjective sleep latency with zolpidem decreased
et al.16 5 mg 0.125 mg, or significantly from baseline by 32.7 to 39.7 min per
temazepam night for weeks 1 through 4; difference was
15 mg, or significant compared with placebo for a given week
placebo (p < 0.05)
Subjective sleep latency with temazepam decreased
significantly from baseline by 3039.4 min per night
for weeks 1 through 4; difference was not significant
compared with placebo at any time
Subjective sleep latency did not differ significantly
between zolpidem and temazepam groups
Duration of subjective sleep did not change in any
of the treatment groups compared with placebo
Roger Zolpidem Triazolam 21 205 81 Questionnaire results, subjective sleep quality, and
et al.17 5 or 10 mg 0.25 mg number of awakenings at night and in early
morning improved in both groups (p < 0.01)
Proportion of patients who fell asleep in less than
30 min increased from 20% to 65% in both groups
based on questionnaire responses (p < 0.001)
The increase in mean total sleep time was 1.5 h in
the 5-mg zolpidem group v. about 2 h in the 10-mg
zolpidem group and the triazolam group (p < 0.001)
defined period. Treatments consist of behavioural, benzodiazepines decreased by 35% in the interven-
cognitive and educational interventions that target tion group and increased by 4% in the controls.30
different aspects of insomnia.28 Interventions Among patients with insomnia who had been
include sleep restriction (limiting time in bed to using hypnotic-sedative drugs for at least 1 month,
actual sleep time), stimulus control (re-associating cognitive behavioural therapy resulted in signifi-
the bedroom with sleep) and cognitive therapy cant reductions in Pittsburgh Sleep Quality Index
designed to change faulty beliefs about sleep.28 scores from 13 at baseline to 3 at 3-month follow-
In a cohort study involving 31 patients taking up to 2 at 6-month follow-up (lower scores indi-
benzodiazepines or a Z drug who received a recom- cate reduced severity of sleep disturbance); reduc-
mendation to alter their sedative drug use, 68% tions in sleep latency from 60 minutes at baseline
were adherent at follow-up.29 In a trial involving to 28 minutes at 3-month follow-up to 30 minutes
591 patients, those in the intervention group were at 6-month follow-up; and improvement in sleep
given instructions to withdraw, reduce or change efficiency score (representing the percentage of
psychotropic medications, in addition to a 1-hour time in bed spent asleep) improved from 2.2 at
lecture about the drugs and their adverse effects. baseline to 0.7 at both the 3- and 6-month follow-
The number of patients who were regular users of up assessments (Table 2).31 Patients who received
Table 2: Results of randomized controlled trials of the effect of cognitive behavioural therapy on sleep quality
Study group
Duration of Mean
Study treatment Participants age, yr Intervention Comparator Outcomes
Morgan 6 wk of 209 people using 68 Six 50-min Usual care At 3 mo, intervention group had significant
et al.31 active benzodiazepines sessions of with crossover improvement in Pittsburgh scores (mean
treatment; for > 1 mo; mean cognitive to cognitive difference 3.8, 95% CI 4.8 to 2.8), decrease
follow-up duration of use behavioural behavioural in sleep latency (mean difference 24.1, 95% CI
at 3 and 13.4 yr therapy therapy 37.2 to 11.1), improvement in sleep efficiency
6 mo (mean difference 0.9, 95% CI 1.2 to 0.6) and
increase in total sleep time (mean difference
0.5 min, 95% CI 0.1 to 0.8); 47.4% v. 17.3%
reported low-frequency use (p < 0.001); 30% v.
11% reported zero hypnotic drug use over 7-d
follow-up assessment period (p = 0.005)
At 6 mo, intervention group had significant
decrease in sleep latency (mean difference
27.9 min (95% CI 43.4 to 12.6) and
improvement in sleep efficiency score (mean
difference 1 (95% CI 1.3 to 0.6); 54% v. 18%
reported low-frequency use (p < 0.001); 33% v.
8% reported zero hypnotic drug use (p < 0.001)
Morin 10 wk 76 chronic 62.5 Combined Benzodiazepine Overall, 90% reduction in quantity of
et al.32 benzodiazepine benzodiazepine tapering alone benzodiazepine consumption and 80%
users (> 50% of tapering and or cognitive reduction in frequency of medicated nights
nights for > 3 mo); cognitive behavioural across the 3 groups; 63% of patients were
mean 6.7 nights behavioural therapy alone benzodiazepine free within 7 wk on average;
per wk; mean therapy 85% in combined treatment arm were
duration of use benzodiazepine free after initial intervention
19.3 yr v. 48% in tapering arm and 54% in cognitive
behavioural therapy arm
Baillargeon 8 wk 65 daily 67.4 Combined Benzodiazepine 77% in combined treatment arm v. 38% in
et al.33 benzodiazepine benzodiazepine tapering alone tapering arm were benzodiazepine free
users for > 3 mo; tapering and immediately after treatment (OR 5.3, 95% CI
mean duration cognitive 1.8 to 16.2); this outcome persisted at 12 mo,
of use 152 mo behavioural with 70% benzodiazepine free in combined
(12.7 yr) therapy (90-min treatment arm v. 24% in tapering only arm
group session (OR 7.2, 95% CI 2.4 to 23.7)
weekly for 8 wk)
Voshaar 3 mo 180 regular 63.4 Benzodiazepine Usual care 62% in tapering arm and 58% in combined
et al.34 benzodiazepine tapering alone or treatment arm were successful with
users for > 3 mo; combined with discontinuation v. 21% in usual care arm
mean duration cognitive
of use 165 mo behavioural
(13.8 yr) therapy (2-h session
weekly for 5 wk)