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Table 1 Summary of study characteristics

From: Efficacy and safety of Z-substances in the management of insomnia in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing

Authors and publication year

Study design

Aim

Sample size and number/percentage of patients > 65 years

Study duration or follow-up

Outcome

Sponsor

Ancoli-Israel et al. 2010 (66)

Randomized, placebo-controlled, double-blind study

To evaluate the efficacy and safety of 12 weeks of nightly eszopiclone in elderly outpatients with insomnia

n = 194 Eszopiclone 2 mg

n = 194 placebo

2-week single-blind placebo assessment period

12-week treatment

2-week single-blind placebo run-out

2-week no drug follow-up

Sleep parameters

Daytime function parameters

Insomnia severity index (ISI)

ADE

Sepracor INC., Marlborough, MA

Ancoli-Israel et al. 1999 (67)

Multicenter, randomized, placebo-controlled double-blind study

To evaluate the efficacy and safety of Zaleplon 5/10 mg in elderly outpatients with insomnia in comparison to Zolpidem 5 mg and placebo

n = 166 Zaleplon 5 mg

n = 165 Zaleplon 10 mg

n = 111 Zolpidem 5 mg

n = 107 placebo

1-week single-blind placebo baseline period

2-week double-blind treatment

1-week single-blind placebo run-out

Sleep parameters

Rebound insomnia

ADE

Routine physical examination (vital signs, ECG)

Wyeth-Ayerst Research, Radnor, Pa. and Zaleplon clinical study group

Avidan et al. 2010 (83)

Retrospective cohort analysis

To examine the risk of accidental events in older adults newly prescribed Benzodiazepine-like medication (BDLM) or selective melatonin receptor agonist (MRA)

n = 156,987 Benzodiazepine-like medication (Zolpidem, Zaleplon, Eszopiclone)

n = 988 Selective melatonin receptor agonist (Ramelteon)

30 days of insomnia therapy and 3-month period after treatment initiation

Accidental events identified using External Causes of Injury Codes (ICD) and ICD-9-CM Codes in claims files

Takeda pharmaceutical company, Ltd

Berry et al. 2013 (74)

Case-crossover study

To estimate the association between BDLM use (Zolpidem, Eszopiclone, Zaleplon) and the risk for hip fractures among a nationwide sample of long-stay nursing home residents

n = 927 with discordant Exposure to BDLM in hazard and control periods

Dispensing of BDLM (Zolpidem, Eszopiclone, Zaleplon) 30 days before fracture (hazard period) or 60–90 days and 120–149 days before fracture (control periods)

Hip fracture defined as ICD-9: 820.xx or 733.14

National Institute on Aging and Friends of Hebrew Senior Life

Chang et al. 2011 (75)

Case-control study

To examine the association between medical conditions and medications and falls in older people in hospital

n = 19 Zolpidem

n = 8 controls

Medications used within 24 h of falls

Falls reported in the hospital

Department of Health, Taiwan

Dehlin et al. 1995 (68)

Multicenter, randomized, double-blind study

To compare the efficacy and safety of Zopiclone 5 mg and Flunitrazepam 1 mg in elderly patients

n = 50 Zopiclone 5 mg

n = 52 Flunitrazepam 1 mg

3-day single-blind placebo baseline period

2-week double-blind treatment

1-week single-blind placebo run-out

Sleep parameters

Daytime function parameters

ADE

Rhone-Poulenc Rorer, Box 33, Helsingborg Sweden

Elie et al. 1990 (69)

Randomized, placebo controlled, double-blind study

To evaluate and compare the efficacy and safety of Zopiclone 5/7.5 mg and Triazolam 0.125/0.25 mg in elderly patients with insomnia in comparison with placebo

n = 15 Zopiclone 5 mg for 1 week then increase to 7.5 mg for 2 weeks

n = 14 Triazolam 0.125 mg for 1 week then increase to 0.25 mg for 2 weeks

n = 15 placebo

3-day single-blind wash-out period

3-week double-blind treatment period

4-day single-blind wash-out period

Sleep parameters

Hang-over

Routine physical examination (ECG, routine lab test)

ADE

Rhone-Poulenc Pharma Inc., Montreal, CA

Kang et al. 2012 (76)

Case-crossover study

To evaluate the risk of fractures related with Zolpidem in elderly insomnia patients

n = 1508 with discordant exposure to BDLM in hazard and control periods

Prescription of Zolpidem 1 day before fracture (hazard period) or 1 day before 5/10/15 and 20 weeks before fracture (control periods)

Diagnosis of fracture ICD-10: S02, S12, S22, S32, S42, S52, S62, S72, S82, S92, T02

No information

Klimm et al. 1987 (70)

Randomized double-blind study

To evaluate the efficacy and safety of Zopiclone 7.5 mg in elderly patients with insomnia in comparison to Nitrazepam 5 mg

n = 36 Zopiclone 7.5 mg

n = 36 Nitrazepam 5 mg

1-week single-blind placebo wash-out period

1-week double-blind treatment

Sleep parameters

Spiegel Sleep Questionnaire

ADE

General evaluation

No information

Lai et al. 2015 (77)

Case-control study

To investigate the correlation between zopiclone use and risk of hip fracture in elderly adults

Cases:

n = 170 Zopiclone last 7 days

n = 780 Zopiclone before

n = 10,046 non-users

Controls:

n = 37 Zopiclone last 7 days

n = 586 late users

n = 8458 non-users

Prescription of Zopiclone:

− 7 days prior to fall

-any time before

-never

First episode of hip fracture according to ICD 9

Taiwan Ministry of Health and Welfare

Clinical Trial Research Center of Excellence, China Medical University Hospital

Academia Sinica of the Taiwan Biobank

Stroke Biosignature Project of the National Research Program for Biopharmaceuticals Stroke Clinical Trial Consortium, Taiwan

Tseng-Lien Lin Foundation, Taiwan

Tai- wan Brain Disease Foundation, Taiwan

Katsuzo and Kiyo Aoshima Memorial Funds, Japan

Leppik et al. 1997 (71)

Randomized, placebo-controlled double-blind study

To evaluate the efficacy and safety of Zolpidem 5 mg, Triazolam 0.125 mg and Temazepam 15 mg in elderly patients with insomnia in comparison with placebo

n = 76 Zolpidem 5 mg

n = 71 Triazolam 0.125 mg

n = 74 Temazepam 15 mg

n = 74 placebo

1-week single-blind placebo wash-out period

4-week double-blind treatment

Sleep parameters

Daytime function parameters

Global Impression of Therapy score

ADE

Routine physical examination (ECG, laboratory evaluation)

Lorex Pharmaceuticals, Skokie, IL

Pierfitte et al. 2001 (78)

Case-control study

To determine whether benzodiazepines are associated with an increased risk of hip fracture

Cases:

Zolpidem n = 15

Zopiclone n = 14

Controls:

Zolpidem n = 35

Zopiclone n = 48

Drug use 24 h before fracture determined from questionnaires, medical records, or blood samples

Acute hip fracture resulting from a fall, not associated with cancer, a traffic accident, or aggression, ascertained from x-ray films and orthopedic consultation

Agence du médicament, Paris

Department of Pharmacology, Victor Segalen University, Bordeaux, France

Roger et al. 1993 (72)

Randomized placebo- controlled double-blind multicenter study

To compare the efficacy and safety of Zolpidem with a reference benzodiazepine in elderly insomniac patients

n = 70 Zolpidem 5 mg

n = 74 Zolpidem 10 mg

n = 77 Triazolam 0.25 mg

3-day placebo wash-out period

3-week double-blind treatment period

7-day placebo withdrawal period

Sleep parameters

Use of rescue hypnotic medication

ADE

No information

Scharf et al. 2005 (73)

Randomized placebo- controlled double-blind multicenter study

To evaluate the efficacy of Eszopiclone and primary insomnia

n = 72 Eszopiclone 1 mg

n = 79 Eszopiclone 2 mg

n = 80 placebo

2-week double-blind treatment period

Sleep parameters

Daytime function parameters

Q-LES-Q

ADE

Routine physical examination (ECG, vital signs, neurological examination, lab measures)

Sepracor, Inc., Marlborough, Mass., US

Tang et al. 2015 (79)

Case-crossover study

To clarify the risk of acute effects of Zolpidem on all-sites of fracture in the elderly

n = 6010 with discordant exposure to BDLM in hazard and control periods

1 day prior to fracture (hazard period) or 1 day 5/10/15/20 weeks prior to fracture (control periods)

ICD-9 CM: 820, 812, 813, 814, 805, 806, 800–829

Tri-Service-General-Hospital

Ministry of Science and Technology of Taiwan

National Chiao Tung University

Ministry of Education of Taiwan

Tom et al. 2016 (80)

Case-crossover study

To test the hypothesis that use of Zolpidem, Eszopiclone, and Zaleplon would be associated with increased risk of traumatic brain injury (TBI) and hip fracture

TBI:

BDLM users n = 491

non-BDLM users n = 14,540

Hip fracture: BDLM users n = 1192

non-BDLM users n = 36,641

30 days before fracture (hazard period) or 3/6/9/12 months before fracture (control periods)

ICD-9 CM: 800.xx, 801.xx, 803.xx, 804.xx, 850.xx-854.1x, 950.1–950.3, 959.01; 820.xx

National Institute of Health

Wang et al. 2001 (81)

Case-control study

To identify hazardous regimens (for insomnia) that should be avoided and safer regimens that may be used preferentially by older people

n = 20 Zolpidem

n = 35 controls

Index date and 6 months prior

Hospitalization for surgical repair of hip fracture

National Institute of Drug Abuse

National Institute on Aging

Zint et al. 2010 (82)

Case-control study

To determine how concomitant use of potentially interacting drugs, drug dosage, and duration of therapy modify the risk of hip fracture associated with use of BDLM in older adults

Cases:

Zaleplon n = 21

Zolpidem n = 456

Controls:

Zaleplon n = 62

Zolpidem n = 1608

14 days before fracture

First hip fracture leading to hospitalization

Graduiertenkolleg 793

National Institute on Aging of the National Institutes of Health

Federal Ministry of Education and Research