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G3 Bain KT. Management of chronic insomnia in elderly persons. Am J Geriatr Pharmacother 2006;4(2):168-192.
Study
Bain 2006
USA
Systematic Review
Meta Analysis
Purpose
To review the literature on
the management of
chronic insomnia in
elderly persons.
Sources
Search methodology / Databases searched
MEDLINE (1/1966 to 3/2006)
Product information (pharmacokinetic and
pharmacodynamic) from manufacturers
Reference lists from retrieved articles
Inclusion criteria
Nonpharmacologic therapies
Pharmacologic therapies
Meta analyses
Evidence based reviews
Randomized controlled trials
Clinical trials (in the absence of above
categories)
Exclusion criteria
Not described
Definition of insomnia
DSM IV-R
ICSD
ICD-9-CM
Diagnostic/classification criteria for insomnia
differ in each system
Studies of insomnia develop their own
definitions
-Clinical research definitions typically include
(one or more):
-subjective/objective evidence of sleep
latency >30 min
-sleep duration <6 hours
->3 awakenings per night
Primary vs secondary
-If secondary, underlying condition is treated
first
Measures of Sleep
Polysomnography (PSG)
Subjective measures
Evaluation Methods for Included Studies
Not described
Summary
Nonpharmacologic interventions
Not summarized
Pharmacologic therapies
Characteristics of the ideal sedative hypnotic (no
currently available agent possesses all of these
properties)
-has rapid onset of action
-prevents nocturnal and early-morning awakenings
-maintains normal sleep architecture
-produces not daytime sedation or adverse effects
-lacks active metabolites of parent compound
-has defined duration of action
-has few residual effects
-has no drug-drug interactions
-is metabolized through a mechanism other than the
hepatic cytochrome P450 system
-has no potential for abuse, tolerance, or rebound
insomnia after discontinuation
-is safe in overdose
-has fixed dosing with no need to reduce the optimal
dose in elderly patients
-addresses the physiologic condition underlying
insomnia
General recommendations
-risk benefit analysis of potential agents should be
conducted
-pharmacologic therapy should be initiated only when
nonpharmacologic options are not feasible or have
been exhausted
-nightly sedative-hypnotic use = short term
-long term sedative-hypnotic use = intermittent
Selection of sedative hypnotic based on:
-type and duration of insomnia
-age
-concurrent medical conditions
-concomitant medications
-previous treatment response
-consideration of route of metabolism, drug half life
and adverse effect profile
Chloral hydrate and barbiturates
Chloral hydrate
-gastrointestinal irritation
-rapid development of tolerance
-multiple drug-drug interactions
-overdose potential (fatal)
Summary (continued)
Barbiturates
-secobarbital and pentobarbital
-high incidence of adverse effects
-rapid development of tolerance
-potential for chemical dependence
-potential for withdrawal syndromes
-high overdose potential
-significant potential for drug-drug interactions (induction
of hepatic cytochrome P450 enzyme system)
OTC and prescription antihistamines
-diphenhydramine or doxylamine
-anticholinergic potential to cause mental confusion,
urinary retention, constipation
-may cause impaired daytime functioning
-not effective when used chronically
-tolerance develops after 1-2 weeks of continuous use
Dietary supplements
Not summarized
Sedating antidepressants
Sedative hypnotic drugs should be used with caution in
patients exhibiting signs and symptoms of depression
-unintentional overdose
-suicidal tendencies
Tricyclic antidepressants
-unfavorable anticholinergic adverse effect profile
-amitriptyline and doxepin considered inappropriate
Tetracyclic antidepressants
-mirtazapine – use with caution
-not warranted for use in primary insomnia
-for insomnia associated with depression may improve
sleep architecture and sleep efficacy without affecting REM
sleep
Trazodone
Lack of RCT data on effects in primary insomnia
PSG studies
-associated with increase in slow wave sleep (SWS)
-REM latency appeared to be longer
-proportion of REM sleep did not appear to be affected
Small RCTs or case series
-trazodone 100 mg has been shown to be more effective
than 50 mg for sleep, but produced no difference in
depressive symptoms
-trazodone dose ranging from 100 to 400 mg given at
bedtime has shown efficacy for sleep
Risk of adverse effects
-significant cardiac AEs (induction or aggravation of atrial
and ventricular arrhythmias
-hypotension and blurred vision (increase risk of falls)
-priapism
-use with other antidepressants = risk of serotonin syndrome
Page 2 Bain 2006
Summary (continued)
Nefazodone
Similar structure to trazodone
-lacks risk for major cardiovascular toxicity
-black box warning for rare hepatic failure leading to
transplantation or death
-generic products available; brand name withdrawn from
manufacturing and marketing in US in 2004
(NOTE: studies re efficacy/safety not summarized due to
withdrawal from market)
Summary (continued)
Benzodiazepine (BZ) sedative-hypnotics
Potential for altered pharmacokinetics (except temazepam)
-age related changes in drug metabolism
-possible drug-drug interactions with competing CYP inducers,
inhibitors and substrates (especially triazolam)
-triazolam contraindicated for concomitant administration with
-itraconazole
-ketoconazole
-nefazodone
Benzodiazepine (BZ) sedative-hypnotics
Indicated for the treatment of insomnia in the US
-estazolam
-flurazepam
-quazepam
-temazepam
-triazolam
Similar effects on sleep architecture
-decrease sleep latency (SL)
-increase stage II sleep
-slight decrease in delta-wave and REM sleep
-usually increase total sleep time (TST)
Similar (class) adverse effects
-excessive sedation
-motor incoordination
-cognitive impairment (decreased concentration)
-anterograde amnesia
Differences in safety profiles and pharmacologic properties of
individual agents
-basis of drug selection
-dose important in frequency and severity of AEs
Role of BZ in management of chronic insomnia unclear
-lack of well controlled studies
-long term use not recommended
-elderly patients often at risk for high chronic dosing of BZ agents
Choice of benzodiazepine
-for sleep initiation (choose rapid onset of action: triazolam)
-for sleep maintenance (choose duration of action:
Intermediate = temazepam or estazolam)
-choosing BZ for elderly patients
-rapid onset (usually best)
-no active metabolites
-relatively short elimination half-life
-minimal drug-drug interaction
Elimination half life
-with the exception of temazepam, BZ sedative hypnotics
may have a prolonged elimination half lives
-shorter acting BZ are more likely to cause rebound insomnia,
psychological dependence and anxiety
-long elimination half life associated with less rebound
insomnia, less daytime anxiety, fewer early morning
awakenings
-benefits offset by next day residual sedation and potential
impairment of cognitive and/or motor function
Nonbenzodiazepine sedative-hypnotics
Differ in pharmacokinetic profiles
Zolpidem
-rapid onset of effect
-relatively short but variable duration of action
-approved for short term treatment for insomnia (not >7 to 10 d)
-trials of use >4 weeks (some including elderly subjects)
-effective for primary, secondary and chronic insomnia
-little evidence of tolerance, withdrawal symptoms or rebound
insomnia
-most frequent AEs (duration up to 10 nights; up to 10 mg)
-drowsiness, dizziness, diarrhea
-most frequent AEs (duration 28-35 nights; up to 10 mg)
-dizziness, drugged feelings
-CNS AEs(headache, dizziness, drowsiness) appear to be dose
related
-GI AEs (nausea, dyspepsia) appear to be related to
discontinuation
Zolpidem extended release (CR)
-6.25 and 12.5 mg
-elimination half life similar to regular release
-indicated for sleep onset or sleep maintenance insomnia
-preliminary trials do not show an advantage of CR over regular
Zaleplon
-fast onset of action (~half hour)
-shortest duration of action (2-4 hours)
-indicated for use at any time during the night (if ≥4 hours sleep
time remaining)
-no studies evaluating during the night use in elderly subjects
-effective in primary insomnia for short term management
-no significant withdrawal or rebound effect except in elderly
subjects
-significant rebound effect on discontinuation in elderly
subjects
-most frequent AEs do not occur more frequently at 5mg vs 10
mg vs placebo
-headache, dizziness, nausea, somnolence
Summary (continued)
Nonbenzodiazepine sedative-hypnotics (continued)
Eszopiclone
-shares some pharmacologic properties of benzodiazepines
-no clinical significant withdrawal symptoms after 6 or 12
months of nightly use
-no published reports of the potential for abuse, dependence
or withdrawal in the elderly
-rapid onset (~1 hour)
-mean elimination half life = 6 hours
-not affected by drug-drug interactions caused by protein
binding
-extensively metabolized via oxidation and demethylation
-has distinctive behavioral pharmacologic effects (eg
anxiolytic effects)
-decreases sleep latency and improves sleep maintenance in
elderly subjects with primary insomnia
-2 mg dose associated with
-daytime alertness
-fewer naps taken
-AEs in elderly similar at 1 mg vs 2 mg vs placebo
-headache
-unpleasant taste (bitterness) (most common reason for
discontinuation)
-somnolence
-dyspepsia
Meta-analyses of benzodiazepine and nonbenzodiazepine
sedative hypnotics
Nowell 1997
-efficacy of benzodiazepines or zolpidem for chronic insomnia
in adults aged <65 (studies 1978 to 1996; N = 1894)
-22 double blind placebo controlled RCTs
-Median treatment duration = 7 days (range 4-35 days)
-Active treatment moderately more effective that placebo
-Clinically meaningful results (vs placebo)
-fell asleep faster than 71% of placebo subjects
-slept longer than 76%
-woke less often than 74%
-reported better sleep quality than 73%
-largest effect sizes for sleep latency
-temazepam (0.78)
-zolpidem (0.77)
-smallest effect sizes (flurazepam and estazolam)
-largest effect sizes for total sleep time
-flurazepam (0.84)
-temazepam (0.71)
-estazolam (0.67)
-smallest effect for total sleep time
-zolpidem (0.39)
Page 3 Bain 2006
Summary (continued)
Meta-analyses of benzodiazepine and nonbenzodiazepine
sedative hypnotics (continued)
Holbrook 2000
-effect of benzodiazepines, other active drugs and placebo for
primary insomnia
-45 RCTs; N = 2672 subjects; age range 29 to 82
-15 studies included subjects aged ≥65
-4 studies involved elderly subjects exclusively
-mean study duration 12.2 days; median 7.5 days; range 1
day to 6 weeks
-improved sleep latency favored benzodiazepines by -4.2
minutes (patient estimated improvement -14.3 minutes)
-mean TST favored benzodiazepines by 61.8 minutes
-more AE reports in benzodiazepine groups (OR 1.8)
-daytime drowsiness (OR 2.4)
-dizziness/lightheadedness (OR 2.6)
-BZ vs zopiclone (N = 3 studies)
-no significant difference in sleep latency
-BZ groups had significantly greater TST (mean difference
23.1 minutes)
-BZ groups reported numerically more AEs (OR 1.5)
-no significant differences in sleep outcomes for BZ vs
antihistamines (diphenhydramine or promethazine)
Glass 2005
-24 RCTs; subjects aged ≥60
-any pharmacologic treatment for insomnia >5 nights
-INCLUDED: OTC medications (antihistamines),
benzodiazepine sedative hypnotics, nonbenzodiazepine
sedative hypnotics
-EXCLUDED barbiturates and chloral hydrate
-3 studies (339 subjects) no significant difference in sleep
quality between benzodiazepines vs Zdrugs (zolpidem,
zaleplon, zopiclone); mean effect size 0.04)
-6 studies (648 subjects) no significant difference between BZ
and nonBZ sedative hypnotics for AEs (OR 1.11)
-NNT to achieve a significant improvement in sleep quality
for sedative hypnotics vs placebo = 13; NNH for any AE = 6
-NNT and NNH indicated that an AE was more than twice
as likely to occur as enhanced sleep quality
-conclusion that sedative hypnotics may benefit older patients
less than younger adults and that older people have similar or
greater risk for AEs (but no direct comparisons of
younger/older adults were available)
-there also was a possible publication bias favoring positive
results for sedative hypnotics on measures of sleep quality and
TST
Summary (continued)
Melatonin agonists
Secretion of endogenous melatonin declines with age
Melatonin is available as an OTC dietary supplement
Trials of OTC melatonin are difficult to interpret due to
-dose ranges from 0.1 to 2000 mg
-diverse populations
-characteristics of melatonin
-binding to multiple melatonin receptors
-unfavorable pharmacokinetic properties when administered
orally
-short elimination half-life (20-50 min)
-poor absorption / poor absolute bioavailability
-reports of AEs for 1-5 mg (fatigue, headache, dizziness,
irritability)
Ramelteon
-highly selective MT1/MT2 receptor agonist (affinity for receptors 3
to 6 times higher than endogenous melatonin)
-no potential for dependence (not a controlled substance)
-early studies showed promise for chronic primary insomnia
-1 RCT melatonin 16 mg and 64 mg vs placebo
-increase in TST (425.4 vs 411.3 min)
-16 mg = shorter sleep latency (22.2 vs 31.2 min) (no
difference for 64 mg)
- no comparison of 16 mg vs 64 mg
-64 mg produced more AEs
-most common AEs (all groups; no comparison between
groups)
-somnolence
-fatigue
-dizziness
-product information reported trials with elderly subjects (n = 654
age >65; n = 199 age >75)
-not published
-dose range = 4 to 16 mg vs placebo
-improvements in sleep latency, sleep maintenance, TST
-RCT (n = 829; mean age 72.4 (range 64 to 93)
-chronic primary insomnia
-4 mg vs 8 mg vs placebo; 5 weeks
-84% completed study
-significant improvements in sleep vs placebo
-TST in week one (not reported at weeks 3 or 5)
-AEs high in all groups (4mg = 54.8%; 8mg = 58%; placebo
= 51.5%)
-studies needed comparing ramelteon with exogenous melatonin
Comments
Untreated or unresponsive insomnia in the elderly associated
with
-increased risk of falls
-decreases quality of life
Medications currently used for the management of insomnia
have been associated with adverse outcomes in the elderly
-physical disability (mobility, ADLs)
-falls
-motor vehicle accidents
Short acting benzodiazepines do not appear to confer any
safety benefit vs long acting in elderly patients
Collectively, findings suggest that the use of any
benzodiazepine may place elderly people at risk for ≥1
adverse outcome beyond the known adverse effects of these
drugs.
Limited direct comparative data on the use benzodiazepine vs
nonbenzodiazepine sedative hypnotics specifically in the
elderly
-findings of available studies do not show significant clinical
advantages for nonbenzodiazepine sedative hypnotics
None of the currently available agents meet all of the criteria
for an ideal sedative hypnotic
-clinicians must weight the shortcomings and benefits of each
agent and determine best option for an individual patient
Older adults are more likely to develop chronic insomnia and
experience excessive daytime sleepiness than younger adults
Improvement of sleep onset and sleep maintenance are
particularly important in elderly patients
Nonpharmacologic interventions (CBT) may be of greater
importance in this age group
Conclusion: Long term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse effects
as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long term
use of these agents remain to be determined. Although they are among the groups with the greatest need for treatment, elderly patients with chronic insomnia are often viewed as difficult to treat.
More research is needed to determine the long term effects of pharmacotherapy and the most appropriate management strategy for elderly persons with chronic insomnia.