A systematic review of acupuncture for sleep quality in people with insomnia

Complementary Therapies in Medicine 26 (2016) 11–20

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Complementary Therapies in Medicine journal homepage: www.elsevierhealth.com/journals/ctim

A systematic review of acupuncture for sleep quality in people with insomnia Johannah Linda Shergis a , Xiaojia Ni a,b,c , Melinda L. Jackson a,d , Anthony Lin Zhang a , Xinfeng Guo b,c , Yan Li b,c , Chuanjian Lu b,c,∗∗ , Charlie Changli Xue a,b,c,∗ a

School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Science, Guangzhou, China c The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China d Institute for Breathing and Sleep, Austin Health, Melbourne, VIC, Australia b

a r t i c l e

i n f o

Article history: Received 12 November 2015 Received in revised form 22 January 2016 Accepted 15 February 2016 Available online 18 February 2016 Keywords: Insomnia Acupuncture Systematic review Meta-analysis Randomized controlled trial

a b s t r a c t Objective: Acupuncture is widely used in Asia and increasingly in Western countries. We performed a systematic review and meta-analysis to examine the effects of acupuncture for insomnia. Methods: We identified randomized controlled trials from English and Chinese databases. Data were extracted using a predefined form and analysed using RevMan 5.2. We included studies that compared acupuncture to sham/placebo, standard pharmacotherapy or cognitive behavioral therapy. Risk of bias was assessed using the Cochrane risk of bias tool. The primary outcome was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI). Results: A total of 30 studies involving 2363 participants were included. Acupuncture point combinations included the use of at least one of the recommended points for insomnia, HT7, GV20, SP6. Pharmacotherapy control was used in 27 studies and sham/placebo in three studies. Cognitive behavioral therapy was not used in any of the studies. Pharmacotherapies in all studies were benzodiazepine receptor agonists, except for one that used an antidepressant. Acupuncture was superior to sham/placebo in terms of PSQI (MD −0.79, 95% CI −1.38, −0.19, I2 = 49%). Acupuncture was also more effective than pharmacotherapy (MD −2.76, 95% CI −3.67, −1.85, I2 = 94%). Most studies were at risk of bias. Some mild adverse events were reported but they were not causally related to the acupuncture treatments. Conclusions: Acupuncture compared to sham/placebo and pharmacotherapy showed statistically significant results. However, the evidence is limited by bias in the included studies and heterogeneity. Well-designed studies are needed to confirm the results identified in this review. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.1. Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.2. Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.3. Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.4. Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Abbreviations: AIS, Athens Insomnia Scale; ANZCTR, Australian New Zealand Clinical Trial Registry; CBT, cognitive behavioral therapy; CCMD, Chinese classification of mental disorders; ChiCTR, Chinese Clinical Trial Registry; CI, confidence interval; CNS, central nervous system; DSM, diagnostic and statistical manual of mental disorders; EU-CTR, EU Clinical Trials Register; GABA, gamma-amino butyric acid; ICD, International Classification of Diseases; ICSD, International Classification of Sleep Disorders; ICTRP, International Clinical Trials Registry Platform; ISI, Insomnia Severity Index; MD, mean difference; PSQI, Pittsburgh Sleep Quality Index; RevMan, review manager; RR, risk ratio; WHO, World Health Organization. ∗ Corresponding author at: School of Health and Biomedical Sciences, RMIT University, PO BOX 71, Bundoora, VIC 3083, Australia. Fax: +61 3 99256539. ∗∗ Corresponding author at: Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China. E-mail addresses: [email protected] (C. Lu), [email protected] (C.C. Xue). http://dx.doi.org/10.1016/j.ctim.2016.02.007 0965-2299/© 2016 Elsevier Ltd. All rights reserved.

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Search methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2.5. 2.6. Data collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2.7. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2.8. Assessment of risk of bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.1. Description of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.2. Risk of bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.3. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.4. PSQI results from meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.5. Subgroup analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.6. Other outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.7. Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Grants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

1. Introduction Insomnia, characterized by trouble falling asleep, staying asleep or early wakening, affects between 5–10% of the population.1–3 Insomnia dramatically impacts quality of life and day time activities,4 and chronic insomnia increases the risk of psychopathology and negative health outcomes.5–7 There are a number of behavioral, psychological and pharmacological options for the treatment of insomnia, however the efficacy of each can vary considerably. Attention has focused on treating insomnia with benzodiazepine receptor agonists, however they are mostly effective in the short-term management and the risk of rebound insomnia and other side-effects are high.8,9 Many individuals prefer non-pharmacological treatments,10 such as cognitive behavioral therapy (CBT), however such treatments can be costly and difficult to access for some patients. Given the high prevalence of insomnia in the community, there is a continuing need to broaden and improve treatment options.11,12 Complementary and alternative medicines, such as acupuncture, are used by as many as one out of four people with insomnia.13 Acupuncture is a promising treatment because it is safe and widely available.14,15 Insomnia can be treated with many different acupuncture points, however a combination of points around the head, on the arms and legs is recommended.16 The Evidence-Based Guideline of Chinese Medicine for Insomnia recommends three main points, HT7 (Shenmen), GV20 (Baihui) and SP6 (Sanyinjiao).16 The exact actions of these points is not fully understood, however, when used together and with other points they have a demonstrated effect on biological responses.17,18 There are a number of possible mechanisms of acupuncture for improving sleep. Acupuncture is reported to interact with the gamma-amino butyric acid (GABA) pathways and suppress central nervous system (CNS) activity.18 GABA has an inhibitory effect on the brain, and is the main neurotransmitter along with several neuropeptides involved in sleep.19 An increase in GABA will suppress the CNS and benzodiazepine and non-benzodiazepine hypnotics are known to act on this pathway.20 In mice stimulated at acupuncture point HT7, with or without competitive GABAa receptor blockers, acupuncture was shown to work though GABA pathways.18 Acupuncture on the head also increased the amount of GABA in multiple brain areas of mice.17 In a clinical study of 48 people, acupuncture on HT7 and SP6 increased the amount of GABA in cerebrospinal fluid compared with alprazolam.21 Acupuncture has also been shown to increase melatonin levels.22 In a non-controlled

study, 18 participants with insomnia and anxiety were given five weeks of acupuncture treatment. After treatment, nocturnal urinary melatonin secretion increased. Polysomnography showed that sleep onset latency was reduced and total sleep time and sleep efficiency increased.22 Acupuncture can also control autonomic nervous system function including reducing blood pressure, heart rate variability and sympathetic nerve activity,23 which is often dysregulated in patients with insomnia.24,25 The efficacy of acupuncture for people with insomnia has been evaluated in previous systematic reviews and authors concluded that despite some methodological limitations acupuncture improved sleep quality and self-reported sleep duration.26,27 The current review assesses the efficacy of acupuncture using recommended acupuncture points from clinical acupuncture guidelines. Inclusion of studies with recommended acupuncture points means that findings have clinical relevance and translatability into clinical practice. This review also expands on previous reviews by examining a larger number of studies and an up-to-date search of English and Chinese databases. 2. Methods 2.1. Studies Included studies are published randomized controlled trials with parallel design. 2.2. Participants Participants include those with a primary complaint of insomnia. Participants diagnosed by standard diagnostic criteria including the Diagnostic and Statistical Manual of Mental Disorders (DSM);4,28 International Classification of Sleep Disorders (ICSD);29 International Classification of Diseases (ICD);30 or the Chinese Classification of Mental Disorders (CCMD).31 Studies that included participants with comorbid disorders or those with insomnia as a secondary complaint were excluded. 2.3. Interventions Interventions included needle acupuncture at one or more of the recommend insomnia points, these points are HT7 (Shenmen), GV20 (Baihui) and SP6 (Sanyinjiao). Studies that evaluated needle acupuncture with other acupuncture interventions such as

J.L. Shergis et al. / Complementary Therapies in Medicine 26 (2016) 11–20

Records idenfied through Chinese database searching (n=41,961)

13

Addional records idenfied through other sources (n=37)

Records idenfied through English database searching (n=6,857)

Records aer duplicates removed (n=19,548)

Records excluded

Records screened (n=19,548)

(n=19,282)

Full-text arcles excluded, with reasons (n =236) Full-text arcles assessed for eligibility (n=266)

1. Duplicate arcle (n=20) 2. No diagnosc criteria for insomnia (n=22) 3. No relevant outcomes reported (n=23) 4. Not an RCT (n=23) 5. Review arcle (n=18) 6. Intervenon does not include relevant acupuncture points (n=64) 7. Not acupuncture treatment (n=52) 8. Not primary insomnia (n=11) 9. Not relevant control (n=3)

Studies included in qualitave synthesis (n=30)

Full-text arcles excluded, with reasons (n =4) Studies included in quantave synthesis (metaanalysis) (n=26)

1. Incomplete reporng of results; could not be entered into meta-analysis (n=2) 2. Reported results were pre/post difference not end of treatment difference (n=2)

Fig. 1. Flow diagram of study selection.

ear acupressure were also included. Studies using non-penetrating acupuncture alone, such as laser acupuncture were excluded because their pathophysiological effects may differ to skin penetrating acupuncture. Comparitor interventions were sham or placebo acupuncture; drugs routinely used to treat insomnia such as benzodiazepine receptor agonists and non-benzodiazepine hypnotics; or cognitive behavioral therapy. Sham acupuncture was defined as needles puncturing a non-acupuncture or non-specific point. Placebo acupuncture was defined as needles placed on the skin but not penetrating.

groups at the end of treatment was considered to be important in this review. Secondary outcomes included validated insomnia scales such as the Insomnia Severity Index (ISI)36 and the Athens Insomnia Scale (AIS).37 Any statistically significant improvement on the AIS, and a reduction of six points or more on the ISI were considered to be clinically meaningful.38 Sleep parameters measured by actigraphy, polysomnography or sleep diary were also evaluated. Parameters included total sleep duration, sleep onset latency, wake after sleep onset, and sleep efficiency (sleep time to time spent in bed).

2.5. Search methods 2.4. Outcomes The primary outcome was the global score of the Pittsburgh Sleep Quality Index (PSQI). The PSQI is validated in both English and Chinese language and commonly used to measure the quality and patterns of sleep.32,33 There are limited studies that evaluate the minimal clinically important difference (MCID) for PSQI. Reports suggest a change 1.54 to three points.34,35 Due to a lack of universal acceptance of a MCID, any statistically significant effect between

Nine major English and Chinese databases were searched from inception to January 2016. English databases included PubMed, Embase, CINAHL, CENTRAL, and AMED. Chinese databases included CBM, CNKI, CQVIP and Wanfang. In addition, reference lists of published reviews and included studies were searched as were clinical trial registries. Search terms included insomnia, acupuncture and randomized controlled trials and their synonyms (Supplement Table 1).

Fig. 2. Forest plot comparing acupuncture to sham or placebo acupuncture in terms of PSQI.

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2.6. Data collection Two independent reviewers (English articles: Johannah Shergis and Xiaojia Ni and Chinese articles: Xioajia Ni and Fuchang Lu) retrieved, selected and performed data extraction. Extracted data included; study design, location, setting, diagnostic criteria, duration of insomnia, sample size, age, gender of participants, intervention, control, treatment duration, follow-up duration, outcomes, and adverse events. Incomplete data or queries were followed up with the original authors via phone and email. 2.7. Data analysis All studies meeting the inclusion criteria were evaluated in qualitative analysis (study demographics). Studies providing the mean and standard deviation for outcomes at end of treatment were included in the quantitative analysis (meta-analysis). Analysis was performed in Review Manager (RevMan) Version 5.2 (The Cochrane Collaboration, Copenhagen, Denmark). Continuous data are reported as mean difference (MD) with 95% confidence intervals (CI) and dichotomous data as risk ratio (RR) with 95% CI. Statistical heterogeneity was assessed with reference to I2 . An 2 I greater than 50% was considered to indicate substantial heterogeneity and a random effects model used, otherwise a fixed effect model was used. To deal with missing data we planned to contact the original authors. Unfortunately we did not receive a response therefore we assumed data was missing at random. We analysed available data only and missing data were not imputed. Planned subgroup analyses evaluated study quality (random sequence generation), acupuncture treatment with other therapies such as electroacupuncture, ear acupressure, duration of insomnia (<24 months or >24 months), and duration of treatment (short term ≤ 4 weeks and long term > 4 weeks). Publication bias for meta-analysis with ten or more studies was visually assed with funnel plots. Egger’s test was used if visual symmetry was unclear.39 2.8. Assessment of risk of bias Risk of bias was assessed using the Cochrane Collaboration’s risk of bias tool.40 Risk of bias was evaluated against the seven domains; sequence generation, allocation concealment, blinding of participants, blinding of personnel, blinding of outcome assessors, incomplete outcome data, and selective reporting. Other bias was assessed with reference to baseline balance and source of funding. Note that blinding of personnel is not possible because acupuncture needs to be performed by a qualified professional. Blinding of personnel was judged at high risk of bias if it was not performed but this should be interpreted with the knowledge that blinding is not feasible in acupuncture studies. Risk of bias was assessment by two independent researchers (English articles: Johannah Shergis and Xioajia Ni and Chinese articles: Xiaojia Ni and La Zhang). Disagreements were resolved by discussion and consultation with a third person (Xinfeng Guo).

Table 1 describes the study characteristics. Acupuncture alone was used in 22 studies, acupuncture plus ear acupressure in three, electroacupuncture in three, and one study each for acupuncture plus ear acupressure plus warm needling, and acupuncture plus moxa. Acupuncture point HT7 was used in 22 studies, GV20 in 21 and SP6 in 19 (Table 1). All studies used different combinations of points except three studies that used GV20, HT7, SP6, GV24, and Sishencong.41,42,62 A total of 58 distinct points were used and point combinations included an average of 9.3 points (standard deviation 5.68; range 3–24 points). Sham acupuncture was used as control in two studies; one used non-insomnia specific points (LI14, LI11, LU10, GB31) and the other used non-acupuncture points.42,56 Placebo with Streitberger needles was used in one study.64 Twenty-six studies used pharmacotherapy as control. Pharmacotherapies included estazolam (18 studies), zolpidem (3), diazepam (2), alprazolam (1), zopiclone (1), clonazepam (1), and trazodone (1). Cognitive behavioral therapy was not used in any of the studies. Treatment duration ranged from 10 days to 6 weeks, median 25.6 days and mode 4 weeks. Six studies had a follow up period between one and three months. All studies used the PSQI, 26 presented end of treatment between-group difference and the data were used in the quantitative analysis. The PSQI data from four studies could not be used in meta-analysis because two presented change from baseline, and two did not provide useable data. Follow up data was available for PSQI in three studies (Table 2). Secondary outcomes, ISI and sleep parameters measured by polysomnography, actigraphy and sleep diaries, were not able to be pooled, however AIS was pooled (Table 3). 3.2. Risk of bias Risk of bias assessment showed sequence generation in 16 studies was at low risk of bias, 11 did not provide enough information and three studies used inappropriate methods, such as odd or even numbers of admission and gender.46,58,69 Allocation was concealed by envelopes in four studies and the remainder did not provide enough information to make a clear judgment. Blinding of participants and personal was not described in any of the studies, except three that used sham or placebo acupuncture as control, they were judged at low risk of bias.42,56,64 Blinding of outcome assessors was described in two studies at low risk of bias,42,64 the others were at high risk of bias because details were not provided and outcomes were patient reported. Twenty-nine studies were judged at low risk of bias for incomplete outcome data. Selective reporting was judged as unclear because protocols were not available and there was insufficient information to permit judgment, except in two studies at high risk of bias that did not provide PSQI outcome data suitable for metaanalysis.59,68 Other bias including baseline balance was at low risk of bias in all studies. The majority of studies did not report funding source and were judged at unclear risk of bias, only seven studies adequately reported funding or conflicts of interest.42,47,54,58–60,64 Risk of bias is presented in Table 4.

3. Results 3.3. Publication bias 3.1. Description of studies We reviewed 266 full-text references of which 30 RCTs with 2363 participants were included (Fig. 1).41–69 Chinese Classification of Mental Disorders (CCMD) was most commonly used for insomnia diagnosis (21 studies), followed by ICD (six studies), and DSM (three studies). Participants had insomnia for between one month and 30 years, their age ranged from 17 to 75 years and 1225 were female and 955 male (183 gender not stated).

Meta-analysis of acupuncture compared with pharmacotherapy included 23 studies. Publication bias was not detected, Egger’s test t = −0.89, 95% CI −5.16, 2.06, p = 0.383 (Supplement Fig. 1). 3.4. PSQI results from meta-analyses Two meta-analyses based on comparator were produced (Figs. 2 and 3). Acupuncture compared with sham or placebo

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Table 1 Characteristics of the 30 included studies. Author, year

No. of participants I/C

Intervention

Acupuncture points

Control

No. of treatments/duration

Outcomes

Guo J 2008 Guo JW 2013 He FL 2010

30/30 60/60 80/38

Acupuncture Acupuncture Acupuncture

Estazolam Sham+ estazolam Estazolam

28/28 days 21/6 weeks NS/14-28 days

PSQI PSQI PSQI; AIS

He T 2010

30/30

Acupuncture

Estazolam

28/28 days

PSQI

Lai Y 2011

20/20

Acupuncture + ear acupressure

Estazolam

12/4 weeks

PSQI

Li PF 2013

50/50

Acupuncture

Estazolam

24/4 weeks

PSQI

Li XY 2010 Liu JY 2013 Liu WH 2009

30/30 45/45 30/30

Acupuncture Electroacupuncture Acupuncture

Estazolam Diazepam Clonazepam

20/20 days 10/10 days 18/3 weeks

PSQI; PSG PSQI PSQI

Lu YY 2008

25/25

Acupuncture

Diazepam

24/4 weeks

PSQI

Luo WZ 2006 Song Q 2007 Su D 2011

35/35 60/60 39/37

Acupuncture Acupuncture Acupuncture

Trazodone Zopiclone Estazolam

36/6 weeks 20/4 weeks 28/28 days

PSQI PSQI PSQI

Su J 2014

23/23

Acupuncture

Estazolam

12/2 weeks

PSQI

Sun ZY 2010 Tan Y 2012 Tao HX 2009 Tu JH 2012 Wang LL 2012

40/40 50/50 58/56 19/14 30/30

Acupuncture Acupuncture Acupuncture Acupuncture Acupuncture

Estazolam Sham + estazolam Estazolam Zolpidem Estazolam

28/28 days 14/14 days 28/28 days 4/4 weeks 30/30 days

PSQI PSQI PSQI PSQI PSQI

Xia XF 2012

42/40

Acupuncture

Estazolam

20/4 weeks

PSQI

Xiong JW 2011

38/25

Acupuncture

Alprazolam

12/4 weeks

PSQI

Xuan YB 2007 Yao W 2014

24/22 30/30

Acupuncture Electroacupuncture

Estazolam Estazolam

20/4 weeks 10/10 days

PSQI PSQI; AIS

Yeung WF 2009

30/30

Electroacupuncture

Placebo

9/3 weeks

You L 2010

40/40

GV20, HT7, SP6, GV24, Sishencong GV20, HT7, SP6, GV24, Sishencong GV20, HT7, SP6, BL62, KI6, KI9, PC6, GB35, Anmian GV20, HT7, SP6, ST36, PC6, GB19, LR3, GV17 GV20, HT7, SP6, PC6, CV4, CV6, CV10, CV12, Sishencong, Yintang; Ear points: heart, kidney, liver, shenmen, spleen, subcortex, sympathetic GV20, GV11, GV14, GV16, GV17, GV18, GV24 GV20, HT7, GB20, Anmian, Sishencong SP6, ST36, Sishencong, Taiyang SP6, BL62, KI6, PC6, Dingshen, Sishencong GV20, HT7, BL23, KI3, PC6, GV11, GV16, GV24 GV20, HT7, LI4, LR3. Yintang GV20, Sishencong HT7, SP6, ST36, HT5, BL15, BL20 or BL15, BL19, PC7 or KI1, KI3, LR3 HT7, SP6, ST36, BL23, BL60, BL62, KI3, KI6, PC6, Sishencong SP6, KI1, KI3 HT7, SP6, Anmian SP6, PC6, Sishencong, Taiyang, Yintang HT7, ST36 GV20, HT7, SP6, ST25, ST36, BL15, BL18, BL19, BL20, BL21, BL23, BL24, BL26, BL40, BL57, PC6, LR3, GV4, GV14, GV24, CV4, CV6, CV12, Anmian GV20, BL15, BL23, GV4, GV9, GV10, GV11, GV14, GV16, GV17, GV24, GV26, CV6, CV12, CV14, CV15, CV17, CV24, Yintang GV20, HT7, SP6, LI10, ST36, BL2, PC6, TE17 GV20, HT7, SP6, GV24, Sishencong GV20, HT7, SP6, BL62, KI6, PC6, LR3, Anmian, Sishencong, Taiyang, Yintang GV20, Anmian, Sishencong, Yintang; Ear points: shenmen GV20, HT7, SP6, LI10, ST36, BL2, PC6, TE17; Ear points: heart, kidney, shenmen, spleen, sympathetic

Zolpidem

30/30 days

Yu DS 2012

30/30

Estazolam

24/4 weeks

PSQI

Yu F 2010

36/35

Zolpidem

20/20 days

PSQI

Zhang HY 2013 Zhu MM 2012

35/35 90/90

Estazolam Estazolam

24/4 weeks 20/20 days

PSQI PSQI

Wang YY 2015

30/30

Acupuncture + ear acupressure + warm needle Acupuncture + moxa HT7, BL15, BL23, KI1, KI3, PC6; moxa: KI1 Acupuncture + ear GV20, HT7, SP6, BL62, KI6, PC6, acupressure Anmian, Sishencong, Yintang; Ear points: heart, kidney, liver, shenmen, spleen, subcortex, sympathetic Acupuncture GV20, HT7, PC6, Sishencong Acupuncture + ear GV20, HT7, CV4, CV6, CV10, CV12, acupressure Yintang; Ear points: shenmen, sympathetic, occiput, braina , hypothysisa Acupuncture GV20, HT7, SP6, PC6, BL13, BL15, BL18, BL20, BL23, BL24, BL26, BL62, Yintang, ST25, KI6

PSQI; actigraphy; ISI; diary PSQI

Estazolam

24/4 weeks

PSQI

AIS: Athens Insomnia Scale; C: control; I: intervention; ISI: Insomnia Severity Index; PSQI: Pittsburgh Sleep Quality Index; PSG: polysomnography. Note: Acupuncture points are referenced to the ‘WHO Standard Acupuncture Nomenclature, 2nd edition’ (WHO 1993). Ear acupuncture points are referenced to ‘Microacupuncture in practice’ (Wang 2009) and non-meridian acupuncture points are referenced to ‘A Manual of Acupuncture’ (Deadman 2007). a Points are not listed under the standard acupuncture point guidelines or nomenclature.

acupuncture showed a statistically significant result in metaanalysis of three studies,42,56,64 mean difference (MD) −0.79 and 95% confidence interval (CI) −1.38, −0.19, p = 0.009, I2 = 49% (Fig. 2). Treatment duration was two, three, and six weeks; one study

administered 21 acupuncture treatments,42 one administered 14 treatments56 and the other nine treatments.64 Compared with pharmacotherapy, acupuncture showed a small reduction in PSQI total score in 23 studies,41,44–55,57,58,60,61,63,65–67,69,70 MD −2.79 (95% CI −3.67,

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Table 2 Analysis of PSQI at end of follow-up and in subgroups. Analysis

1. Acupuncture versus sham or placebo • End of follow-up • Low risk of bias for random sequence generation • Insomnia < 24 months • Insomnia > 24 months • Treatment duration ≤ 4 weeks • Treatment duration > 4 weeks 2. Acupuncture versus pharmacotherapy • End of follow-up • Low risk of bias for random sequence generation • Insomnia < 24 months • Insomnia > 24 months • Treatment duration ≤ 4 weeks • Treatment duration > 4 weeks 3. Acupuncture plus ear acupressure versus pharmacotherapy 4. Electroacupuncture versus pharmacotherapy

No. of studies

No. of patients

PSQI score Mean difference (95% confidence interval)

I2 %

1 0 1 1 2 0

98 0 98 60 158 0

−0.16 (−1.49, 1.17) NA −0.16 (−1.49, 1.17) 0.20 (−1.28, 1.68) 0.00 (−0.99, 0.99) NA

NA NA NA NA 0% NA

2 12 8 11 14 9 3 2

130 812 551 816 1097 599 291 150

2.51 (−8.54, 13.57) −2.71 (−4.08, −1.35)* −2.52 (−4.53, −0.50)* −3.17 (−4.41, −1.92)* −2.50 (−3.46, −1.55)* −3.19 (−5.45, −0.94)* −4.89 (−5.93, −3.85)* −2.10 (−2.73, −1.47)*

100% 95% 95% 93% 92% 95% 54% 0%

NA: Not applicable; PSQI: Pittsburgh Sleep Quality Index. * Significant difference, p < 0.05. Table 3 Analysis of secondary outcomes at end of treatment. Outcomes

Intervention and contol

No. of studies

No. of patients

PSQI score: mean difference (95% confidence interval)

I2 %

Athens Insomnia Scale (AIS) Insomnia Severity Index (ISI) PSG—sleep latency time (min) PSG—total sleep duration (hour) PSG—total awakening time (min) PSG—sleep efficiency (%) PSG—S3 + S4 time/total sleep duration (%) Actigraphy—sleep onset latency (min) Actigraphy—total sleep time (min) Actigraphy—wake after sleep onset (min) Actigraphy—sleep efficiency (%) Sleep diary—total sleep time (min) Sleep diary—sleep efficiency (%)

Acupuncture versus pharmacotherapy Acupuncture vs sham or placebo acupuncture Acupuncture versus pharmacotherapy Acupuncture versus pharmacotherapy Acupuncture versus pharmacotherapy Acupuncture versus pharmacotherapy Acupuncture versus pharmacotherapy Acupuncture vs sham or placebo acupuncture Acupuncture vs sham or placebo acupuncture Acupuncture vs sham or placebo acupuncture Acupuncture vs sham or placebo acupuncture Acupuncture vs sham or placebo acupuncture Acupuncture vs sham or placebo acupuncture

2 1 1 1 1 1 1 1 1 1 1 1 1

168 60 60 60 60 60 60 60 60 60 60 60 60

0.12 (−3.55, 3.97) −0.90 (−3.26, 1.46) 0.70 (−6.14, 7.54) −0.78 (−1.14, −0.42)* −0.60 (−5.00, 3.80) 1.46 (−1.51, 4.43) 4.16 (2.89, 5.43)* −1.90 (−8.88, 5.08) −5.50 (−30.98, 19.98) −2.70 (−12.57, 7.17) 0.80 (−2.09, 3.69) −3.00 (−31.99, 25.99) 7.50 (1.56, 13.44)*

95% NA NA NA NA NA NA NA NA NA NA NA NA

NA: Not applicable; PSQI: Pittsburgh Sleep Quality Index; PSG: polysomnography. * Significant difference, p < 0.05.

−1.85), p < 0.00001. Meta-analysis showed considerable heterogeneity, I2 = 94%. The PSQI includes one domain on sleeping medication; participants in the pharmacotherapy control groups would score this item up to three points higher than individuals in the acupuncture groups. Seven out of 23 studies removed the sleep medication domain47,48,51,52,54,57,58 and meta-analysis showed a similar and statistically significant result MD −1.04 (95% CI −1.89, −0.19), p = 0.02, I2 = 82% (Fig. 3). 3.5. Subgroup analysis None of the a priori hypothesis (method of sequence generation, acupuncture treatment, duration of insomnia and duration of treatment) explained heterogeneity (Table 2). A subgroup of 12 studies reporting appropriate randomization methods showed acupuncture was significantly more effective than pharmacotherapy, MD −2.71 (95% CI −4.08, −1.35), p < 0.00001, yet studies were heterogeneous, I2 = 95%. Acupuncture compared with sham or placebo could not be subgrouped because only three studies were included in the primary pool. Studies that evaluated acupuncture compared with pharmacotherapy were subgrouped. Analysis by acupuncture treatment produced the best pool. Three studies compared acupuncture plus

ear acupressure with pharmacotherapy and showed a statistically superior effect, MD −4.89 (95% CI −5.93, −3.85), p < 0.00001, I2 = 54%. Electroacupuncture compared with pharmacotherapy also showed a small but statistically significant effect in two studies, MD −2.10 (95% CI −2.73, −1.47), p < 0.00001, I2 = 0% (Table 2). When studies were grouped by duration of insomnia and treatment duration and the results were similar to the primary pool (Table 2). Heterogeneity remained high and results did not improve greater than the primary pool. When acupuncture was compared with sham or placebo, follow-up data in one study after four weeks showed no statistical difference between groups. When acupuncture was compared with pharmacotherapy follow-up data in two studies after 1–3 months showed no statistically significant difference between groups, MD 2.51 (95% CI −8.54, 13.57), I2 = 100% (Table 2). 3.6. Other outcomes Secondary outcomes including ISI, AIS, and sleep parameters (actigraphy and polysomnography) were seldom reported and pooling was only possible for the AIS in two studies comparing acupuncture to pharmacotherapy.43,63 Acupuncture was not statistically superior, MD 0.21 (95% CI −3.55, 3.97), I2 = 95%. The ISI,

J.L. Shergis et al. / Complementary Therapies in Medicine 26 (2016) 11–20

17

Fig. 3. Forest plot comparing acupuncture to pharmacotherapy in terms of PSQI.

polysomnography, actigraphy, and sleep diaries were only used in one study each. Statistically significant results for acupuncture included total sleep duration and sleep efficiency (Table 3).

3.7. Adverse events Seven studies reported adverse events (AEs) and 23 did not mention AEs. From the seven studies a total of 103 events were reported, 39 in the intervention groups and 64 in the control groups. All events were considered to be mild. Types of events in the intervention groups were; bruise after acupuncture (18 cases), headache (9), dizziness (5), fatigue (2), muscle convulsion (2), fainting during acupuncture treatment (1), hand numbness (1), and pain after acupuncture (1). Types of events in the control groups were similar in nature to the intervention groups, they included; bruise after sham acupuncture (21 cases), headache (14), dizziness (10), muscle convulsion (6), fatigue (2), nausea (2), pain after sham acupuncture (2), sleepiness (2), dry mouth (1), constipation (1), hand numbness (1), loss of appetite (1), and worsening of insomnia (1). A causal relationship was not linked to any of the AEs.

4. Discussion The findings of this review suggest that acupuncture may be superior to sham/placebo and pharmacotherapy for improving subjective sleep quality in patients with insomnia, however the results were heterogeneous.

Results from this review agree with previously published reports. Cheuk et al. included 33 studies in their review and showed PSQI improved after acupressure in five studies (MD −3.87, 95% CI −5.14, −2.60, I2 = 72%) and electroacupuncture in one study (MD −3.43, 95% CI −5.57, −1.29), compared to no treatment.27 The authors identified heterogeneity and risk of bias in the included studies and overall the evidence did to support or disprove acupuncture effects for improving sleep quality in people with insomnia.27 Other reviews by Kalavapalli et al., Yeung et al., Huang et al. and Cao et al. also reported positive effects of acupuncture therapies for insomnia in terms of PSQI.26,71–73 This update provides a larger number of studies and acupuncture treatments included at least one of the three recommended points, that is, GV20, HT7, SP6. This update provides stronger evidence for acupuncture plus ear acupressure compared to previous reports. It also examined the potential effect of insomnia duration and treatment duration as factors in acupuncture effects—although the result did not show any clear difference in the subgroups. Acupuncture was superior to sham or placebo acupuncture, but the difference was only small. Using a sham or placebo can produce a more methodologically sound study, however, these controls are not inert and placebo responses may include the Hawthorne effect, expectancy and other nonspecific factors.74 This small result is significant and not unexpected because placebo effects are commonly observed in both insomnia and acupuncture clinical trials.75,76 Participants may be affected by the close contact with practitioners and skin penetration (sham) and skin pressure (placebo) may produce biological and psychological effects. Therefore the true effect

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Table 4 Risk of bias of the 30 included studies. Author, year

Sequence generation

Allocation concealment

Blinding of participants

Blinding of personnel

Blinding of outcome assessment

Incomplete outcome data

Selective outcome reporting

Other: baseline Other: funding or balance conflict of interest

Guo J 2008 Guo JW 2013 He FL 2010 He T 2010 Lai Y 2011 Li PF 2013 Li XY 2010 Liu JY 2013 Liu WH 2009 Lu YY 2008 Luo WZ 2006 Song Q 2007 Su D 2011 Su J 2014 Sun ZY 2010 Tan Y 2012 Tao HX 2009 Tu JH 2012 Wang LL 2012 Xia FX 2012 Xiong JW 2011 Xuan YB 2007 Yao W 2014 Yeung WF 2009 You L 2010 Yu DS 2012 Yu F 2010 Zhang HY 2013 Zhu MM 2012 Wang YY 2015

U L U L U H U L L L L L U L U U U H L L U L L U L L L U H L

L L U U U U U U U U U U U U U U U U U U U L L U U U U U U U

H L H H H H H H H H H H H H H L H H H H H H H L H H H H H H

H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

H L H H H H H H H H H H H H H H H H H H H H H L H H H H H H

L L L L L L U L L L L L L L L L L L L L L L L L L L L L L L

U U U U U U U U U U U U U U U U U U H U U U U U U U U H U L

L L L L L L L L L L L L U L L L L L L L L L L L L L L L L L

U L U U U U L U U U U U U L U U U L L L U U U L U U U U U U

Risk of Bias assessments: L: Low risk, U: Unclear risk, H: High risk.

of acupuncture may be underestimated when compared to sham or placebo acupuncture.74,77,78 Unfortunately, the included studies had a short duration and most studies did not follow up for long enough to asses any lasting effects of acupuncture. In an attempt to address heterogeneity we performed subgroup analysis. Generally, subgrouping did not explain heterogeneity. This may be due to differences in insomnia populations within and across studies and many authors did not provide in-depth detail about participants in terms of primary and comorbid insomnia and acute and chronic insomnia. Despite limiting to studies that included at least one of the recommended points for insomnia there was still variability in terms of treatment duration, acupuncture points and number of acupuncture sessions. Other systematic reviews noted similar issues with heterogeneity particularly for the already heterogeneous insomnia population and variable acupuncture treatments.72,73 After grouping, the best evidence was from pooled studies comparing acupuncture plus ear acupressure to pharmacotherapy. The additional benefit of acupuncture plus ear acupressure over acupuncture alone may be due to the continued stimulation of the ear points and participants ability to press these areas as they go to sleep. A recent systematic review found that ear acupressure alone or combined with routine care can improve insomnia.79 Taken together, these previous results and results from our review suggest acupuncture plus ear acupressure may be beneficial for people with insomnia. Interpretation of PSQI was limited because most studies did not specify if they included or excluded the insomnia medication domain score. This biased the results because patients in the control group will have taken insomnia medications and most, if not all patients in the acupuncture group would not be using insomnia medications. Therefore participants in the pharmacotherapy control groups would score up to three points higher on the domain and

appear worse than acupuncture treated patients. Only two studies reported data on objective endpoints, that is, polysomnography and actigraphy. Longer-term assessment of sleep using objective measures will be informative in future studies. Acupuncture appeared to be safe and AEs were mild. The most common AE was bruising after acupuncture and sham acupuncture treatments. Certain AEs that should be monitored according to the Guideline on Medicinal Products for the Treatment of Insomnia,80 such as hangover, increased alertness, dependence, central nervous system reactions, hematological, cardiovascular or endocrinological events were not identified in the included studies. The mechanism of action of acupuncture for insomnia is not fully understood. However acupuncture may modulate GABA pathways.18 This mechanism may provide one plausible explanation for its effects in clinical studies. Acupuncture has also been found to have positive effects on the autonomic nervous system.23 Acupuncture may also increase melatonin, a naturally synthesized hormone, that regulates the sleep-wake cycle.22 Future studies evaluating these mechanisms will help to improve knowledge of acupuncture effects. There are some limitations of this systematic review. Included randomized controlled trials that compared acupuncture to pharmacotherapy were low quality and meta-analyses had heterogeneity. Duration of treatment differed, as did the number of treatment sessions potentially contributing to heterogeneity. Despite all studies including participants with a diagnosis of insomnia, populations may have varied. Insomnia phenotypes are increasingly recognized and response to treatment may differ. It is likely that insomnia phenotypes respond differently to acupuncture depending on the mechanism believed to be driving improvements in sleep. For example increasing melatonin may be beneficial for those with sleep-onset issues or acupuncture may effect autonomic nervous system regulation and assist those

J.L. Shergis et al. / Complementary Therapies in Medicine 26 (2016) 11–20

with hyperarousal. Future studies should assess the mechanisms of acupuncture on sleep. 5. Conclusions Based on PSQI outcomes, evidence shows small but statistically significant effects of acupuncture compared to sham/placebo and pharmacotherapy. Although there were statistically significant results a robust conclusion of effectiveness cannot be drawn from current evidence because of bias and heterogeneity across studies. Conflicts of interest The authors have no conflicts of interest. Authors’ contributions JS conceived and designed the study. JS, XN selected studies and analyzed data. AZ, XG, LY, CL and CX oversaw the conduct of the study and contributed to the overall design, analysis, data interpretation and write-up. MJ assisted with the interpretation of the data and write-up of the manuscript. All authors read, critically reviewed and approved the final manuscript. Grants The project is jointly supported by the China-Australia International Research Centre for Chinese Medicine (CAIRCCM)—a joint initiative of RMIT University, Australia and the Guangdong Provincial Academy of Chinese Medical Sciences, China with additional funding support from the Ministry of Science & Technology of China (International Cooperation Project, Grant Number 2012DFA31760). Acknowledgements We acknowledge Fuchang Lu and Chen Zhou for their assistance with data collection and data sorting. We also acknowledge La Zhang for her independent assessment of risk of bias for the Chinese articles. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ctim.2016.02. 007. References 1. Hillman DR, Lack LC. Public health implications of sleep loss: the community burden. Med J Austr. 2013;199:S7–10. 2. Ohayon MM. Prevalence of DSM-IV diagnostic criteria of insomnia: distinguishing insomnia related to mental disorders from sleep disorders. J Psychiatr Res. 1997;31:333–346. 3. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6:97–111. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-V). 5th ed. Arlington, VA: American Psychiatric Association; 2013. 5. Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord. 2011;135:10–19. 6. Jackson ML, Sztendur EM, Diamond NT, Byles JE, Bruck D. Sleep difficulties and the development of depression and anxiety: a longitudinal study of young Australian women. Arch Womens Ment Health. 2014;17:189–198. 7. Leineweber C, Kecklund G, Janszky I, Åkerstedt T, Orth-Gomér K. Poor sleep increases the prospective risk for recurrent events in middle-aged women with coronary disease: the Stockholm female coronary risk study. J Psychosom Res. 2003;54:121–127. 8. Winkler A, Auer C, Doering BK, Rief W. Drug treatment of primary insomnia: a meta-analysis of polysomnographic randomized controlled trials. CNS Drugs. 2014.

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