Commercial Chinese polyherbal preparation Zao Ren An Shen prescription for primary insomnia: a systematic review with meta-analysis and trial sequential analysis

Background: Natural products are widely used for primary insomnia (PI). This systematic review with trial sequential analysis (TSA) aimed to summarize evidence pertaining to the effectiveness and safety of Zao Ren An Shen (ZRAS) prescription, a commercial Chinese polyherbal preparation, for treating PI. Methods: Controlled clinical trials appraising ZRAS compared to controls or as an add-on treatment were systematically searched across seven databases until January 2024. Cochrane ROB 2.0 and ROBINS-I tools were adopted to determine risk of bias. Quality of evidence was assessed using the GRADE framework. Results: We analyzed 22 studies, involving 2,142 participants. The effect of ZRAS in reducing Pittsburgh Sleep Quality Index scores was found to be comparable to benzodiazepines [MD = 0.39, 95%CI (−0.12, 0.91), p = 0.13] and superior to Z-drugs [MD = −1.31, 95%CI (−2.37, −0.24), p = 0.02]. The addition of ZRAS to hypnotics more significantly reduced polysomnographically-recorded sleep onset latency [MD = −4.44 min, 95%CI (−7.98, −0.91), p = 0.01] and number of awakenings [MD = −0.89 times, 95%CI (−1.67, −0.10), p = 0.03], and increased total sleep time [MD = 40.72 min, 95%CI (25.14, 56.30), p < 0.01], with fewer adverse events than hypnotics alone. TSA validated the robustness of these quantitative synthesis results. However, the quality of evidence ranged from very low to low. The limited data available for follow-up did not support meta-synthesis. Conclusion: While ZRAS prescription shows promising effectiveness in treating PI, the overall quality of evidence is limited. Rigorously-designed randomized control trials are warranted to confirm the short-term efficacy of ZRAS and explore its medium-to-long-term efficacy. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=471497), identifier (CRD42023471497).

The medicinal formula involves reflux extraction of three botanical drugs, namely Ziziphi spinosae semen, Schisandrae chinensis fructus, and Salviae miltiorrhizae radix et rhizoma, in 75% ethanol for 2 hours.The filtrate is then collected and set aside.The residue is subjected to a second reflux with 60% ethanol for 1 hour, filtered, and combined with the previous filtrate.The ethanol is reclaimed from the combined filtrate and concentrated to a thick paste with a relative density of 1.30 (60°C).The residue undergoes further decoction with water, lasting 2 hours for the first time and 1 hour for the second.The resulting filtrates are combined, concentrated to a thick paste with a relative density of 1.30 (60°C), added to the previous paste, further concentrated to a relative density of 1.40 (60°C), and then mixed with an appropriate amount of starch.The mixture is formed into granules, dried, encapsulated, resulting in 1000 capsules.
The medicinal formula involves the decoction of three botanical drugs, namely Ziziphi spinosae semen, Schisandrae chinensis fructus, and Salviae miltiorrhizae radix et rhizoma, in water for two times, each lasting 2 hours.The decoction liquids are combined, filtered, and the filtrate is concentrated to a clear paste with a relative density ranging from 1.05 to 1.20.An appropriate amount of pregelatinized starch is added, mixed thoroughly, and the resulting mixture is formed into granules, dried, yielding a total of 1000g.

Characteristics
The product is presented in the form of hard capsules containing granules and powder ranging in color from yellowish-brown to brown.It possesses a fragrant odor, with a sour and slightly bitter taste.
The product is presented in the form of granules ranging in color from yellowish-brown to brown.
It possesses a fragrant odor, with a sour and slightly bitter taste.

Therapeutic functions
Nourishing Blood and calming the mind.Indicated for insomnia, forgetfulness, restlessness, and dizziness caused by deficient Blood in the Heart; also applicable for neuroasthenic symptoms.
Nourishing Blood and calming the mind.Indicated for insomnia, forgetfulness, restlessness, and dizziness caused by deficient Blood in the Heart; also applicable for neuroasthenic symptoms.

Dosage and administration
Oral administration.Take 5 capsules at a time, once daily, before bedtime.
To be taken by dissolving in hot water.Consume 1 sachet at a time, once daily, before bedtime.

Precautions
Caution should be exercised in pregnant women.Caution should be exercised in pregnant women.

Storage
Seal tightly.Seal tightly.

Excluded studies with specific reasons References Reasons for exclusion
Feng JW.Effectiveness and safety of Zao Ren An Shen capsule in the treatment of insomnia [article in Chinese].Journal of North Pharmacy, 2021; Chen FZ.Efficacy of Zao Ren An Shen capsule in the treatment of senile insomnia [article in Chinese].World Latest Medicine Information, Clinical study of compound Zao Ren An Shen capsule combined with Zopiclone in the treatment of insomnia with Heart-Kidney imbalance syndrome and its effect on serum 5-HT, IL-1β and PGD2 [article in Chinese].Master thesis, 2019; Anhui University of Chinese Medicine.Shi ZG, Sun Y. Efficacy of Zao Ren An Shen Capsule in the treatment of 32 cases of insomnia with deficiency of both Heart and Spleen Clinical study of compound Zao Ren An Shen capsule in the treatment of insomnia with Heart-Liver blood deficiency syndrome [article in Chinese].Master thesis, 2017; Anhui University of Chinese Medicine.
题名或关键词=枣仁安神 AND 题名或关键词=失眠+ 不寐 + 睡眠障碍 AND 题名或关键词=随 机对照试验 + 随机对照实验 + 随机对照研究 China biomedical literature service system (SinoMed) "枣仁安神"[中文标题:智能] AND "失眠"[核心字段:智能] OR "原发性失眠"[核心字段:智能] OR "睡眠障碍"[核心字段:智能] OR "不寐"[常用字段:智能] AND "临床试验"[常用字段:智能] OR " 随机对照试验"[常用字段:智能] OR "试验"[常用字段:智能] US ClinicalTrials.gov(ZaoRen An Shen OR Zaoren Anshen) AND (insomnia sleep OR Initiation and maintenance disorders OR sleep disorder OR sleep wake disorders OR dyssomnias OR sleep disorder) AND (randomized clinical trials OR randomized controlled clinical trial OR randomized controlled trials OR randomized experiment OR rct) WHO International clinical trials registry platform search portal (Zao Ren An Shen OR Zaoren Anshen) AND (insomnia sleep OR Initiation and maintenance disorders OR sleep disorder OR sleep wake disorders OR dyssomnias OR sleep disorder) AND (randomized clinical trials OR randomized controlled clinical trial OR randomized controlled trials OR randomized experiment OR rct) Appendix 3 mismatch of ingredients in proprietary Chinese medicine Ma YD, Li RH, Tao YJ, Sun LR, Hu GZ, Liu YF.Therapeutic effect of compound Zao Ren An Shen capsule in the treatment of insomnia and pharmacological research [article in Chinese].Journal of Integrated Traditional Chinese and Western Medicine, 1989; (2):85-87, 68-69.withoutinternationally recognized, validated scales/questionnaires for quantifying insomnia Pan ZY.Clinical study of Zao Ren An Shen capsule combined with Estazolam in the treatment of sleep disorders [article in Chinese].World Journal of Sleep Medicine, 2021; 8(12):2098-2100.depression-relatedinsomnia Qin GX, Jin HL, Lu GF.A controlled study of Zao Ren An Shen capsule in the treatment of insomnia [article in Chinese].Zhejiang Journal of Integrated Ren YJ, Ni F. Efficacy of Zaoren Anshen capsule in the treatment of senile insomnia [article in Chinese].Journal of Guizhou University of Traditional Chinese Medicine, 2007; (5):23-24.withoutinternationally recognized, validated scales/questionnaires for quantifying insomnia Shao MX, Bao XY, Yao Y, Yan DJ, Wu SF, Zhu XY. 124 cases of senior insomnia patients treated with Zao Ren An Shen capsule [article in Chinese].insomnia Wu YF, Lv BJ, Teng JB.Clinical study of Zao Ren An Shen capsule combined with Estazolam tablets in the treatment of sleep disorders [article in Use of non-standard diagnostic guideline for syndrome [article in Chinese].China Pharmaceuticals, 2007; (19):58.without internationally recognized, validated scales/questionnaires for quantifying insomnia Zhang YW.Effect of Zao Ren An Shen capsule in the treatment of insomnia [article in Chinese].Contemporary Medical Symposium, 2019; 17(16):167-168.without internationally recognized, validated scales/questionnaires for quantifying insomnia Zhao B. Efficacy of Zao Ren An Shen liquid combined with Zopiclone in the treatment of insomnia [article in Chinese].China Health Care & Nutrition,

criteria of clinical efficacy rate used in the included studies
Notes ISI decline rate = (pre-post ISI global scores difference)/pre-ISI global scores × 100%; PSQI decline rate = (pre-post PSQI global scores difference)/pre-PSQI global scores × 100%.
Notes "Ø" for where the adverse events were not measured.Appendix 6

Trial sequential analysis of PSQI global scores (ZRAS Vs. Hypnotic)
is larger, and the heterogeneity could not be completely explained by conducting subgroup analysis, sensitivity analysis, or meta-regression; The GRADE approach classifies bodies of randomized controlled trials as initially starting at high certainty and bodies of non-randomized studies at initially starting at low certainty.
①The design of the trial has a large bias in randomization, allocation concealment, blinding or other factors; ② the confidence interval overlaps less, the heterogeneity test p is very small, the I 2 ③ the confidence interval is not narrow enough; ④ funnel graph asymmetry].