TITLE: Treatment of Older Adults with Insomnia, Agitation, or Delirium with Benzodiazepines: A Review of the Clinical Effectiveness and Guidelines

DATE: 14 January 2016

CONTEXT AND POLICY ISSUES

Insomnia is a common sleep complaint, with up to 40% of older adults reporting difficulty getting to sleep, early awakening, or feeling unrefreshed upon waking.1 Risk factors for insomnia include medical and psychiatric disorders, psychological factors, stress, daytime napping, hyperarousal, and advancing age.1 Management of insomnia includes treatment for any medical or psychiatric illness that may be contributing to insomnia, behavioral therapy (e.g., sleep hygiene, relaxation, or cognitive therapy), and/or medication. Available medications used to treat insomnia include benzodiazepines, non-benzodiazepine sedatives (e.g. zopiclone, zolpidem), melatonin agonists, and antidepressants (e.g. doxepin).2 Benzodiazepines may also be used to manage patients with delirium and agitation.3 Older adults, however, may be at increased risk of adverse events from sedative drugs. In particular, those with reduced renal or hepatic function may experience excessive sedation due to reduced drug elimination and drug accumulation.2

The objective of this report is to evaluate the clinical efficacy and safety, and guidelines for use of sedative hypnotic agents in older adults with insomnia, agitation or delirium. This report is an update to a previous Rapid Response Summary of Abstracts on the treatment of older adults with insomnia, agitation or delirium with benzodiazepines.4

RESEARCH QUESTIONS

1. What is the clinical effectiveness of the treatment of older adults with insomnia, agitation, or delirium with benzodiazepines or other sedative hypnotic agents?

2. What are the evidence-based guidelines for the treatment of older adults with insomnia, agitation, or delirium with benzodiazepines or other sedative hypnotic agents?

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner.

Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

KEY FINDINGS

In older adults, low dose doxepin (up to 6 mg daily) appears to be more effective than placebo for the short-term treatment of insomnia. The short-term incidence of adverse effects with doxepin and placebo appears to be similar; however no conclusions can be drawn due to limitations in the evidence available. No studies or evidence-based guidelines were identified on the use of benzodiazepines or other sedative hypnotics in older adults.

METHODS

Literature Search Methods

This report makes use of a literature search conducted for a previous CADTH report.4 The original literature search was conducted in March 2015 on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and guidelines. Where possible, retrieval was limited to the human population. The initial search was also limited to English-language documents published between January 1, 2010 and March 30, 2015. For the current report, database searches were rerun on December 4, 2015 to capture any articles published since the initial search date. The search of major health technology agencies was also updated to include documents published since March 2015.

Rapid Response reports are organized so that the evidence for each research question is presented separately.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

Population Older adults with insomnia, agitation, or delirium Subgroup: end stage kidney disease patients who have chosen conservative management (i.e., no dialysis or transplant) Intervention Benzodiazepines Other sedative hypnotics Comparator Other treatments No benzodiazepines or other sedatives Outcomes Clinical effectiveness (benefits and harms [e.g. fractures, falls, deaths, hospitalizations]) Guidelines and recommendations Study Designs Systematic reviews, health technology assessments, meta-analyses, randomized controlled trials (RCTs), guidelines

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Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, were published prior to 2010, or examined drugs that have not been approved for use in Canada. Systematic reviews and clinical guidelines were excluded if they did not meet accepted standards for methodological rigor.

Critical Appraisal of Individual Studies

The included systematic review was critically appraised using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist.5 Summary scores were not calculated; rather, a review of the strengths and limitations of the study was described.

SUMMARY OF EVIDENCE

Quantity of Research Available

A total of 22 citations were identified in the update to the literature search. Following screening of titles and abstracts, 20 citations were excluded and two potentially relevant reports from the electronic search were retrieved for full-text review. Eight potentially relevant publications were retrieved from the previous Summary of Abstracts report. No relevant articles were identified in the updated grey literature search. Of these potentially relevant articles, nine publications were excluded for various reasons, while one systematic review met the inclusion criteria and was included in this report.6 Appendix 1 describes the PRISMA flowchart of the study selection.

None of the studies included in the previous Rapid Response Report met the inclusion criteria when the full text reports were examined. One systematic review and three RCTs were for drugs that have not been approved for use in Canada (ramelteon, eszopiclone and EVT-201).7- 10 These studies have been listed in the Appendix 5. One guideline did not include the interventions of interest for the treatment of delirium.11 Two other systematic reviews and one guideline were excluded due to methodological limitations.1,12,13 The key limitations of the systematic reviews included no duplicate selection of articles or extraction of data,1,12 no quality assessment of individual studies,1,12 and inappropriate methods to analyze and summarize data.12 For the guideline, only a summary was available, and from this it was unclear if the recommendations were based on a systematic review of the literature, and if the internal and external review process was robust.13

Summary of Study Characteristics

A summary of the characteristics of the included systematic review is presented in Appendix 2.

Study Design

The systematic review (Yeung 20156) included nine double-blind RCTs, however this report will focus on the three RCTs that enrolled older patients. These three trials were industry sponsored studies published between 2008 and 2012. Two trials used a parallel design and one was a cross-over study. Yeung et al,6 summarized the studies narratively due to differences in study design and doxepin dosage.

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Country of Origin

The systematic review was conducted in Hong Kong.6

Patient Population

The three trials in older adults restricted enrollment to patients greater or equal to 65 years of age. The mean age per study ranged from 71.0 to 72.4 years, and 61% to 65% were female.6 The total number of patients enrolled ranged from 76 to 254. In all trials, patients had to meet Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) or DSM-IV text revision criteria for insomnia.

No information was available on patients with end-stage renal disease, which was a subgroup of interest in this report.

Interventions and Comparators

One parallel design study in older adults compared 12 weeks of doxepin 1 mg or 3 mg to placebo, and a second study compared doxepin 6 mg to placebo for four weeks.6 The crossover study compared two days of treatment with doxepin 1 mg, 3 mg, and 6 mg to placebo (washout period between treatments not reported). In all three trials, patients underwent a single-blind placebo run-in period of two to seven days prior to being randomized to the study treatments.6

Outcomes

Three trials used patient-reported subjective measures (e.g., morning questionnaire) and two trials used polysomnography to assess sleep-related outcomes such as time to sleep onset, total sleep time, wake time after sleep onset, number of awakenings, and sleep quality or efficiency.6 Two trials also reported data for the Insomnia Severity Index, a patient-reported questionnaire that includes seven sleep-related domains on the nature, severity and impact of insomnia. Each domain was scored on a zero to four Likert scale and the total score ranged from 0 to 28 points with higher values indicating more severe insomnia and insomnia impacts.14 Standardized mean differences (i.e. effect size or d value) were calculated by dividing the between-group difference in post-treatment means by the pooled standard deviation.6 By convention, an effect size of 0.2, 0.5 and 0.8 may be interpreted as a small, medium and large treatment effect.15

All trials reported on short-term adverse events; however no data were reported on fractures, falls or hospitalizations.6

Summary of Critical Appraisal

A summary of the critical appraisal of the included systematic review is presented in Appendix 3.

The systematic review by Yeung et al.6 used accepted methods to search for the literature, select and extract data (i.e., comprehensive literature search, duplicate screening and extraction); however it was unclear if methods and inclusion criteria were defined prior to initiating the review. The authors provided a summary of the included studies but did not list the excluded trials. The quality of individual studies was assessed using the Cochrane risk of bias

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instrument and the quality of the studies was used appropriately in formulating conclusions. None of the RCTs in older adults were rated by Yeung et al. as high risk of bias.6 Due to heterogeneity amongst the trials, Yeung et al. summarized the findings narratively. Yeung et al. reported no conflicts of interest in the conduct of the systematic review. The authors did not assess the risk of publication bias.6

Summary of Findings

A summary of the results of the included systematic review is presented in Appendix 4.

What is the clinical effectiveness of the treatment of older adults with insomnia, agitation, or delirium with benzodiazepines or other sedative hypnotic agents?

Based on three RCTs in older adults, doxepin 1 mg, 3 mg and 6 mg showed statistically significant differences over placebo (across different time points from night one to night 85) in sleep-related measures including: • wake time after sleep onset (effect size [d] range: -0.37 to -0.78) • total sleep time (d range: 0.33 to 0.97) • sleep efficiency (d range: 0.41 to 0.98) • sleep quality (d: 0.5)6 For the above outcomes, the differences for doxepin 6 mg versus placebo were statistically significant after one week of treatment, but not four weeks. In a second trial, the differences between doxepin 3 mg and placebo were statistically significant on night 1, 28 and 85, but the differences between doxepin 1 mg and placebo were statistically significant on night 1 only.6

Two trials showed statistically significant reductions in the Insomnia Severity Index scores for doxepin 3 mg and 6 mg versus placebo (d range: -0.26 to -0.50). The differences between doxepin and placebo were not statistically significantly different for the number of awakenings or the time from lights out to sleep onset, based on data from two trials.6

The incidence of adverse events ranged from 31% to 40% for doxepin 1 mg to 6 mg compared with 27% to 52% for placebo, in the four and 12 week studies. In the two-day crossover study, the incidence of adverse events was 7% to 12% for doxepin and 10% for placebo.6

No serious adverse events occurred during the four week trial, and in the crossover study, one patient, who had received doxepin 1 mg, experienced chest pain that required hospitalization.6 The most common adverse events reported in the doxepin groups were somnolence, headache, hypertension, dizziness, dry mouth, and upper respiratory tract infection.

What are the evidence-based guidelines for the treatment of older adults with insomnia, agitation, or delirium with benzodiazepines or other sedative hypnotic agents?

No evidence-based guidelines that met the inclusion criteria were identified in the literature search for this report.

Treatment of Older Adults with Insomnia, Agitation, or Delirium with Benzodiazepines 5

Limitations

From the literature search, one systematic review,6 that compared doxepin to placebo for the treatment of insomnia, met the inclusion criteria for this report. From this systematic review, the evidence in older adults was limited to three RCTs. No data were available for the use of benzodiazepines or other sedative hypnotics in older adults, nor were any evidence-based guidelines identified in the literature search.

Yeung et al.6 identified some key limitations to the RCTs of low dose doxepin. All three trials had a placebo run-in period, which may have excluded placebo responders and biased the findings in favor of doxepin. Yeung et al.6 stated that the studies did not monitor patients’ vital signs or laboratory findings, and that drug-drug interactions, suicidality, precipitation of manic episodes, and withdrawal effects were not examined. Yeung et al.6 stated that due to the limitations in how adverse events were assessed, the risks associated with low dose doxepin are unclear and further evidence is needed.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

In older adults, low dose doxepin (up to 6 mg daily) appears to be more effective than placebo for the short-term treatment of insomnia, based on three double-blind RCTs. Doxepin showed small to medium effect sizes compared to placebo for sleep duration, sleep maintenance and sleep efficiency. No substantial impact on sleep initiation was observed with doxepin.

The short-term incidence of adverse effects with doxepin and placebo appears to be similar; however no conclusions can be drawn due to limitations in the evidence available.

No studies or evidence-based guidelines were identified on the use of benzodiazepines or other sedative hypnotics in older adults.

PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

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REFERENCES

1. Alessi C, Vitiello MV. Insomnia (primary) in older people. BMJ Clin Evid [Internet]. 2011 [cited 2015 Dec 4];2011. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275108

2. Bonnet MH, Arand DL. Treatment of insomnia. 2015 Nov 23 [cited 2015 Dec 22]. In: UpToDate [Internet]. Waltham (MA): UpToDate; 1992 - . Available from: www.uptodate.com Subscription required.

3. Francis J, Jr. Delirium and acute confusional states: Prevention, treatment, and prognosis. 2014 Aug 13 [cited 2015 Dec 22]. In: UpToDate [Internet]. Waltham (MA): UpToDate; 1992 - . Available from: www.uptodate.com Subscription required.

4. Treatment of older adults with insomnia, agitation, or delirium with benzodiazepines: clinical effectiveness and guidelines [Internet]. Ottawa: CADTH; 2015 Apr 17. (Rapid response report: summary of abstracts). [cited 2016 Jan 4]. Available from: https://www.cadth.ca/sites/default/files/pdf/htis/apr- 2015/RB0838%20Treatment%20of%20Insomnia%20Agitation%20or%20Delirium%20with %20Benzodiaepines%20Final.pdf

5. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2016 Jan 14];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

6. Yeung WF, Chung KF, Yung KP, Ng TH. Doxepin for insomnia: a systematic review of randomized placebo-controlled trials. Sleep Med Rev. 2015 Feb;19:75-83.

7. Liu J, Wang LN. Ramelteon in the treatment of chronic insomnia: systematic review and meta-analysis. Int J Clin Pract. 2012 Sep;66(9):867-73.

8. Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep [Internet]. 2010 Feb [cited 2015 Dec 4];33(2):225-34. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817909

9. Gooneratne NS, Gehrman P, Gurubhagavatula I, Al-Shehabi E, Marie E, Schwab R. Effectiveness of ramelteon for insomnia symptoms in older adults with obstructive sleep apnea: a randomized placebo-controlled pilot study. J Clin Sleep Med [Internet]. 2010 Dec 15 [cited 2015 Dec 4];6(6):572-80. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014244

10. Walsh JK, Salkeld L, Knowles LJ, Tasker T, Hunneyball IM. Treatment of elderly primary insomnia patients with EVT 201 improves sleep initiation, sleep maintenance, and daytime sleepiness. Sleep Med [Internet]. 2010 Jan [cited 2015 Dec 4];11(1):23-30. Available from: http://www.sleep-journal.com/article/S1389-9457(09)00297-4/pdf

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11. Gage L, Hogan DB. 2014 CCSMH guideline update: the assessment and treatment of delirium [Internet]. Toronto: Canadian Coalition for Seniors' Mental Health; 2014. [cited 2015 Dec 4]. Available from: http://www.ccsmh.ca/pdf/guidelines/2014-ccsmh-Guideline- Update-Delirium.pdf

12. Sithamparanathan K, Sadera A, Leung L. Adverse effects of benzodiazepine use in elderly people: a meta-analysis. Asian J Gerontol Geriatr [Internet]. 2012 [cited 2015 Dec 4];7:107-11. Available from: http://www.ajgg.org/AJGG/V7N2/2011-110.pdf

13. National Guideline Clearinghouse [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); [1997] -. Guideline summary: Clinical guideline for the treatment of primary insomnia in middle-aged and older adults; 2014 May [cited 2015 Dec 4]. Available from: http://www.guideline.gov/content.aspx?id=48218

14. Morin CM, Belleville G, Belanger L, Ivers H. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep [Internet]. 2011 May [cited 2015 Dec 22];34(5):601-8. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079939

15. Cohen J. A power primer. Psychol Bull. 1992;112(1):155-9.

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APPENDIX 1: Selection of Included Studies

22 citations identified from electronic literature search and screened

20 citations excluded

2 potentially relevant articles retrieved for scrutiny (full text, if available)

8 potentially relevant reports retrieved from other sources (grey literature, hand search)

10 potentially relevant reports

9 reports excluded: -irrelevant intervention (6) -not a systematic review or evidence-based guideline (3)

1 report included in review

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APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses First Author, Types and Population Intervention Comparator Clinical Outcomes, Publication numbers of Characteristics Length of Follow- Year, primary Up Country studies included Yeung 9 RCTs Patients with Doxepin Placebo Sleep variables 2015,6 (3 RCTs in chief (low dose (based on sleep older adults) complaint of <10 mg/day; diaries or Hong Kong insomnia moderate questionnaires, or Published dose 25 mg polysomnography) between to 300 1974 to 2012; mg/day) Harms 1 unpublished Follow-up: 1 day RCT to 12 weeks RCT = randomized controlled trial

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APPENDIX 3: Critical Appraisal of Included Publications

Table A2: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR5 Strengths Limitations Yeung 20156 • A comprehensive literature search was • It is unclear whether an “a priori” performed with no language restrictions. Key design was used. search terms and a flow diagram for the search • A list of the excluded studies was not results were provided. provided. • Two authors screened studies and extracted • The likelihood of publication bias was data independently. not assessed. • A list of the included studies and their characteristics were provided. • Study quality assessed using the Cochrane risk of bias tool and the quality of the included studies was used appropriately in formulating conclusions. • Appropriate methods were used to summarize the studies. • No conflicts of interest were declared

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APPENDIX 4: Main Study Findings and Author’s Conclusions

Table A3: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Yeung 20156 One DB parallel RCT (N=240) compared doxepin 1 mg or 3 mg once “We concluded that low- daily to placebo for 12 weeks in patients ≥ 65 years with primary dose doxepin for 1-2 insomnia (DSM-IV-TR criteria). nights appeared to be safe and effective in • Doxepin 3 mg showed statistically significant differences versus improving sleep. placebo on night 1, 29 and 85 in the following outcomes, However, a clear measured using PSG: conclusion on its short- o wake time after sleep onset (effect size [d] range: -0.42 to term benefits and risks -0.75) as well as withdrawal o total sleep time (d range: 0.33 to 0.87) effects was not possible o sleep efficiency in last quarter of night (d range: 0.50 to due to the small number 0.69) of studies.” • Doxepin 3 mg showed statistically significant reductions in the Insomnia Severity Index score relative to placebo on night 14, 28 and 85 (d range: -0.34 to -0.50). • Doxepin 3 mg showed no statistically significant difference versus placebo in the number of awakenings or the time from lights out to first 10 minutes of sleep based on PSG. • The differences between doxepin 1 mg and placebo were inconsistent. Some subjective measures showed statistically significant differences between treatments. When measured using PSG, statistically significant differences were observed for some measure on night 1, but on night 29 or 85, few significant differences were reported.

• No significant difference in adverse events was observed: placebo (52%), doxepin 1 mg (40%), 3 mg (38%). • Common adverse events in the doxepin 1 mg and 3 mg groups were headache (3% and 6%), somnolence (5% and 2%) and hypertension (1% and 4%), respectively. One DB parallel RCT (N=254) compared doxepin 6 mg once daily to placebo for 4 weeks in patients ≥ 65 years with primary insomnia (DSM-IV-TR criteria) for at least 3 months.

• At week 1 doxepin 6 mg statistically significantly improved the following outcomes (based on patient reported sleep questionnaires), relative to placebo: o wake time after sleep onset (d: -0.37) o total sleep time (d: 0.31) o sleep quality (d: 0.50) • The above sleep-related measures were not statistically significant at week 4.

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Table A3: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions Yeung 20156 • At week 2 and 4 doxepin 6 mg statistically significantly improved Insomnia Severity Index score (d range: -0.26 to -0.38), relative to placebo.

• No significant difference in adverse events: placebo (27%), doxepin 6 mg (31%) • Common adverse events for doxepin 6 mg were somnolence (9%), dizziness (2%), dry mouth (2%), and upper respiratory tract infection (2%). • No serious adverse events were reported. One DB cross-over RCT (N=76) compared 2 day treatment of doxepin 1 mg, 3 mg or 6 mg to placebo in patients ≥ 65 years with primary insomnia (DSM-IV criteria) for at least 3 months.

• Doxepin 1 mg, 3 mg and 6 mg showed statistically significant differences versus placebo for the following outcomes, based on PSG measures averaged over 2 nights: o wake time after sleep onset (d range: -0.45 to -0.78) o total sleep time (d range: 0.41 to 0.97) o sleep efficiency (d range: 0.41 to 0.98) • No significant differences were observed between doxepin and placebo for the number of awakenings or the time from lights out to first 10 minutes of sleep.

• The incidence of adverse events over 2 nights’ treatment with placebo, doxepin 1 mg, 3 mg, or 6 mg was 10%, 12%, 8%, or 7%, respectively. • One serious adverse event (chest pain) was reported in a patient who had received doxepin 1 mg. d = effect size; DB = double blind; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision; PSG = polysomnography; RCT = randomized controlled trial.

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APPENDIX 5: Additional References of Potential Interest

Studies of sedative hypnotic agents not currently approved for use in Canada

• Liu J, Wang LN. Ramelteon in the treatment of chronic insomnia: systematic review and meta-analysis. Int J Clin Pract. 2012 Sep;66(9):867-73.

• Gooneratne NS, Gehrman P, Gurubhagavatula I, Al-Shehabi E, Marie E, Schwab R. Effectiveness of ramelteon for insomnia symptoms in older adults with obstructive sleep apnea: a randomized placebo-controlled pilot study. J Clin Sleep Med [Internet]. 2010 Dec 15 [cited 2015 Dec 4];6(6):572-80. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014244

• Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep [Internet]. 2010 Feb [cited 2015 Dec 4];33(2):225-34. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817909

• Walsh JK, Salkeld L, Knowles LJ, Tasker T, Hunneyball IM. Treatment of elderly primary insomnia patients with EVT 201 improves sleep initiation, sleep maintenance, and daytime sleepiness. Sleep Med [Internet]. 2010 Jan [cited 2015 Dec 4];11(1):23-30. Available from: http://www.sleep-journal.com/article/S1389-9457(09)00297-4/pdf

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