Benzodiazepine receptor agonists zolpidem and zopiclone among adults older than 55 years
Näytönastekatsaukset
2.6.2026
Level of evidence: C
Benzodiazepine receptor agonists zolpidem and zopiclone may reduce insomnia symptoms, and adverse effects are mild in short-term use (2-6 weeks) among adults older than 55 years.
Summarizing effect size based on the retrieved studies is inapplicable. In addition, the applicability of the research findings to Finland is somewhat limited because one study included patients with Alzheimer's disease, and some studies used extended-release zolpidem, which is not available on the market in Finland. Data of extended-release zolpidem studies were only gathered for assessing adverse events. There are only few randomized controlled studies on the use of zolpidem and zopiclone in the treatment of insomnia in the elderly, and the studies and outcomes measured are very heterogenous.
| Reference | Study type | Population | Intervention and comparison | Outcomes | Risk of bias [ «Additional comments for included studies»2 Additional comments] |
|---|---|---|---|---|---|
| RCT=randomized controlled trial | |||||
| «Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Cli»1 | RCT | Women ≥55 and men ≥65 years with insomnia disorder (DSM-V) in North America and Europe | Zolpidem extended release 6.25 mg (n=263) Lemborexant 5 mg (n=266), Lemborexant 10 mg (n=269) Placebo (n=208) for 4 weeks | Secondary outcomes: Adverse events | Low |
| «Leppik IE, Roth-Schechter GB, Gray GW ym. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug development research 1997;403:230-8»2 | RCT | 59-85 years, chronic insomnia (DSM III-R) in United States | Zolpidem 5 mg (n=82) Triazolam 0.125 mg (n=85) Temazepam 15 mg (n=84) Placebo (n=84) For 4 weeks | Primary outcome: Morning Questionnaire (sleep latency and sleep duration) Secondary outcomes: Ease of falling asleep, number of awakenings, wake time after sleep onset, quality of sleep, morning sleepiness, ability to concentrate | High |
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | RCT | ≥ 55 years old with insomnia disorder (DSM-IV) in Norway | CBT (n=18) 7.5 mg zopiclone (n=16) Placebo (n=12) for 6 weeks | Primary outcome: Objective (polysomnography) and subjective (sleep diary): Total wake time (summation of sleep oncet latency, wake time after sleep, early morning awakening) total sleep time, sleep efficiency | Low |
| «Walsh JK, Soubrane C, Roth T. Efficacy and safety of zolpidem extended release in elderly primary insomnia patients. Am J Geriatr Psychiatry 2008;16(1):44-57 »4 | RCT | 65-87 years with primary insomnia (DSM-IV) in Argentina, Canada, France, Germany, Mexico, and USA | Zolpidem extended release 6.25 mg (n=99) Placebo (n=106) 3 weeks | Secondary outcome: Adverse events | Low |
| «Louzada LL, Machado FV, Quintas JL, et al. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial. Neuropsycho»5 | RCT | ≥ 65 years, major neurocognitive disorder (DSM-V), probable late-onset Alzheimer's disease, and insomnia disorder (DSM-V) in Brazil | Zolpidem 10 mg (n=21) Zopiclone 7.5 mg (n=21) Placebo (n=20) For 2 weeks | Primary outcomes (actigraphy): Main nocturnal sleep duration Secondary outcomes: Adverse events | High |
| «Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Prim Care Companion J Clin »6 | RCT | ≥ 65 years, insomnia (DSM-IV) in USA | Zaleplon 5 mg (n=166) Zaleplon, 10 mg (m=165) Zolpidem, 5 mg (n=111) Placebo (n=107) for 2 weeks | Primary outcome: Subjective sleep latency, subjective total sleep time, number of awakenings, and sleep quality. Secondary: adverse events | Moderate |
| Reference | Comments |
|---|---|
| «Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Cli»1 | Study subject zolpidem was in the extended release form, which is not in clinical use in Finland. Thus, only adverse events were extracted. A total of 93 participants (45%) in placebo group and 120 (46%) participants in zolpidem group were ≥ 65 years. Study was sponsored by Eisai Inc and Purdue Pharma L.P. |
| «Leppik IE, Roth-Schechter GB, Gray GW ym. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug development research 1997;403:230-8»2 | The study was sponsored by Lornex Pharmaceuticals. A total of 38 patients discontinued of which 18 had adverse events (6 placebo, 2 zolpidem, 5 each triazolam and temazepam). Authors did not report how the missing data were handled. Randomization was not reported in detail. Authors did not report the use of intention-to-treat analysis. Change from baseline was not reported with confidence intervals which complicated the confidence of the results. Objective outcomes were not used. The morning questionnaire is not a validated measure for insomnia but it was developed for the study purposes. |
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | A total of 2 participants discontinued study in zopiclone group and were excluded from ITT-analysis, 1 participant discontinued due to adverse event. Zopiclone was used for 6 weeks which is not considered as a short-term use. |
| «Walsh JK, Soubrane C, Roth T. Efficacy and safety of zolpidem extended release in elderly primary insomnia patients. Am J Geriatr Psychiatry 2008;16(1):44-57 »4 | Study subject, zolpidem was in the extended-release form, which is not in clinical use in Finland, thus, only adverse events were extracted. Randomization code was generated and maintained by the sponsor Sanofi-Aventis Research. |
| «Louzada LL, Machado FV, Quintas JL, et al. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial. Neuropsycho»5 | Indirectness in the certainty of evidence due to the fact, that study patients had Alzheimer's disease. It is not certain that they react similarly to the medication studied. In addition, there may have been underreporting in the adverse effects in the target group. |
| «Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Prim Care Companion J Clin »6 | No baseline values presented for primary outcomes; no confidence intervals; no variation of mean values reported in the results for the weeks 1 and 2. Sponsored by Wyeth-Ayerst Research, Radnor, Pa. |
Results
| Reference | Number of patients | Follow-up time | Intervention: Mean (SD) at baseline Mean (SD) at follow-up | Control: Mean (SD) at baseline Mean (SD) at follow-up | Effect size |
|---|---|---|---|---|---|
| Level of evidence: low The quality of evidence is downgraded due to imprecision. | |||||
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | Zopiclone (n=16) Placebo (n=12) | 6 weeks | 82.3 (8.2) Mean at 6 weeks 81.5 (9.3) | 78.9 (16.2) Mean at 6 weeks 76.2 (11.3) | Intervention: -0.1 (Cohen d) Control: -0.2 (Cohen d) |
| Reference | Number of patients | Follow-up time | Intervention: Mean at baseline Mean at follow-up (SD) | Control: Mean at baseline Mean at follow-up (SD) | Effect size |
|---|---|---|---|---|---|
| Level of evidence: low The quality of evidence is downgraded due to imprecision | |||||
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | Zopiclone (n=16) Placebo (n=12) | 6 weeks | 63.2 (12.5) Mean at 6 weeks 71.3 (14.7) | 65.8 (9.9) Mean at 6 weeks 71.7 (10.0) | Intervention: 0.6 (Cohen d) Control: 0.6 (Cohen d) |
| Reference | Number of patients | Follow-up time | Intervention: Mean at baseline (SD) Mean (SD) change from baseline | Control: Mean at baseline (SD) Mean (SD) change from baseline | Difference between treatment groups after the intervention |
|---|---|---|---|---|---|
| Level of evidence: very low The quality of evidence is downgraded due to study limitations, imprecision, and possible publication bias. | |||||
| «Leppik IE, Roth-Schechter GB, Gray GW ym. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug development research 1997;403:230-8»2 | Zolpidem (n=82) Plasebo (n=84) | 4 weeks | 78.1 (SE 5.2) –39.7 (SE 4.7) (n=77) | 76.9 (SE 5.4) –21.4 (SE 4.6) (n=75) | Mean sleep latency 17 min shorter in the zolpidem group vs. control group after the intervention (calculated based on reported data) |
| «Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Prim Care Companion J Clin »6 | Zolpidem (n=111) Placebo (n=107) | 2 weeks | Baseline NR Follow-up: differs significantly (P<0.01) from placebo but mean NR | Baseline NR Mean at 14 days: 56 min | N/A (practically clinical relevance cannot be deduced based on selective reporting) |
| Reference | Number of patients | Follow-up time | Intervention: Mean (SD) at baseline Mean (SD) at follow-up | Control: Mean (SD) at baseline Mean (SD) at follow-up | Effect size |
|---|---|---|---|---|---|
| Level of evidence: very low The quality of evidence is downgraded due to study limitations, indirectness, and imprecision. | |||||
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | Zopiclone (n=16) Placebo (n=12) | 6 weeks | 388.3 (58.3) Mean at 6 weeks 322.7 (57.2) | 346.0 (59.3) Mean at 6 weeks 322.9 (60.2) | Effect size Intervention: -1.1 (Cohen d) Control: -0.4 (Cohen d) |
| «Louzada LL, Machado FV, Quintas JL, et al. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial. Neuropsycho»5 | Zolpidem (n=21) Zopiclone (n=18) Placebo (n=20) | 2 weeks | Zolpidem: 420.0 (110.4) Mean at 2 weeks 387.9 (102.0) Zopiclone: 420.0 (120.0) Mean at 2 weeks 450.0 (141.6) | 410.5 (108.0) Mean at 2 weeks 370.9 (99.0) | Zolpidem vs. placebo difference at follow-up (SD; CI): 17 min (31.4; -46.4,80.6) Zopiclone vs. placebo difference at follow-up (SD; CI): 81 min (40.0; -0.8, 163.2) |
| Reference | Number of patients | Follow-up time | Intervention: Mean (SD) at baseline Mean (SD) at follow-up | Control: Mean SD) at baseline Mean (SD) at follow-up | Difference between treatment groups after the intervention |
|---|---|---|---|---|---|
| Level of evidence: very low The quality of evidence is downgraded due to study limitations, indirectness, imprecision and possible publication bias. | |||||
| «Leppik IE, Roth-Schechter GB, Gray GW ym. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug development research 1997;403:230-8»2 | Zolpidem (n=82) Plasebo (n=84) | 4 weeks | 294.5 (6.9) +70.0 (7.4) (n=77) | 309.2 (5.8) +51.8 (8.0) (n=75) | Mean sleep duration 3.5 minutes longer in the zolpidem group vs. control group after the intervention (calculated based on reported data) |
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | Zopiclone (n=16) Placebo (n=12) | 6 weeks | 304.9 (67.6) Mean at 6 weeks 339.5 (75.9) | 313.1 (54.1) Mean at 6 weeks 334.2 (44.2) | Effect size Intervention: 0.5 (Cohen d) Control: 0.4 (Cohen d) |
| «Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Prim Care Companion J Clin »6 | Zolpidem (n=111) Placebo (n=107) | 2 weeks | N/A Mean at 14 days: 360 min | N/A Mean at 14 days: 326 min | Mean sleep duration 34 min longer in the zolpidem group vs. the control group after the intervention (authors reported statistically significant) |
| Reference | Number of patients | Follow-up time | Intervention | Control |
|---|---|---|---|---|
| «Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Cli»1 | Zolpidem extended release 6.25 mg (n=263) Placebo (n=209) | 4 weeks | Zolpidem: Severe, not treatment related (n=8), Serious, not treatment related (n=4), Death (n=0), Headache (n=14), Somnolence (n=4), Urinary tract infection (n=2), Nasopharyngitis (n=1), Upper respiratory tract infection (n=2), Dizziness (n=8) | Placebo: Severe, not treatment related (n=3), Serious, not treatment related (n=0) Death (n=0), Headache (n=13), Somnolence (n=4), Urinary tract infection (n=2), Nasopharyngitis (n=3), Upper respiratory tract infection (n=4), Dizziness (n=4) |
| «Leppik IE, Roth-Schechter GB, Gray GW ym. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug development research 1997;403:230-8»2 | Zolpidem (n=82) Plasebo (n=84) | 4 weeks | Zolpidem: Headache (n=15), Myalgia (n=8), Drowsiness (n=4), Nausea (n=6), Upper respiratory infection (n=6), Dyspepsia (n=5), Nervousness (n=2), Arthralgia (n=4), Fatigue (n=1) | Plasebo: Headache (n=16), Myalgia (n=9), Drowsiness (n=3), Nausea (n=6), Upper respiratory infection (n=7), Dyspepsia (n=7), Nervousness (n=4), Arthralgia (n=3), Fatigue (n=1) |
| «Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 »3 | Zopiclone 7.5 mg (n=16) Placebo (n=12) NR | 6 weeks | Zopiclone: Bitter taste (n=6), dry mouth (n=4), daytime drowsiness (n=4), light nausea (n=2), headache (n=2), chest pain (n=1) | Placebo: light nausea and dry mouth (n=1) |
| «Walsh JK, Soubrane C, Roth T. Efficacy and safety of zolpidem extended release in elderly primary insomnia patients. Am J Geriatr Psychiatry 2008;16(1):44-57 »4 | Zolpidem extended release 6.25 mg (n=99) Placebo (n=106) | 16 days | Zolpidem: headache 14%, dizziness 8%, somnolence 6%, nasopharyngitis 6%. No falls. | Placebo: headache 11%, dizziness 3%, somnolence 5%, nasopharyngitis 4%. No falls. |
| «Louzada LL, Machado FV, Quintas JL, et al. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial. Neuropsycho»5 | Zolpidem 10 mg (n=21) Zopiclone 7.5 mg (n=21) Placebo (n=20) | 2 weeks | Zolpidem: agitation and hallucination (n=1), mental confusion and wandering (n=1), morning sleepiness and fall (n=1) Zopiclone: severe daytime sedation (n=2), agitation and wandering (n=1), mild morning sleepiness (n=1) | Placebo: no adverse events. |
| «Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Prim Care Companion J Clin »6 | Zolpidem, 5 mg (n=111), Placebo (n=107) | 14 days | Zolpidem 63% (headache, pain, somnolence, rhinitis). | Placebo 56% (headache, pain, somnolence, rhinitis). |
References
- Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open 2019;2(12):e1918254 «PMID: 31880796»PubMed
- Leppik IE, Roth-Schechter GB, Gray GW ym. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug development research 1997;403:230-8
- Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8 «PMID: 16804151»PubMed
- Walsh JK, Soubrane C, Roth T. Efficacy and safety of zolpidem extended release in elderly primary insomnia patients. Am J Geriatr Psychiatry 2008;16(1):44-57 «PMID: 18165461»PubMed
- Louzada LL, Machado FV, Quintas JL, et al. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial. Neuropsychopharmacology 2022;47(2):570-579 «PMID: 34635802»PubMed
- Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Prim Care Companion J Clin Psychiatry 1999;1(4):114-120 «PMID: 15014684»PubMed