Prescription of Chinese Herbal Medicine and Selection of Acupoints in Pattern-Based Traditional Chinese Medicine Treatment for Insomnia: A Systematic Review

Traditional Chinese medicine (TCM) treatments are often prescribed based on individuals' pattern diagnoses. A systematic review of Chinese and English literatures on TCM pattern differentiation, treatment principle, and pattern-based treatment for insomnia has therefore been conducted. A total of 227 studies, 17916 subjects, and 87 TCM patterns were analyzed. There was a limited consistency in pattern-based TCM treatment of insomnia across practitioners. Except for Gui Pi Tang, An Shen Ding Zhi Wan, and Wen Dan Tang which were used more commonly for deficiency of both the heart and spleen, internal disturbance of phlegm-heat, and qi deficiency of the heart and gallbladder, respectively, the selection of herbal formula for other patterns and pattern-based prescription of individual herbs and acupoints were not consistent. Suanzaoren (Semen Z. spinosae), Fuling (Poria), Yejiaoteng (Caulis P. multiflori), Gancao (Radix Glycyrrhizae), Baishao (Radix P. alba), Shenmen (HT7), Yintang (EX-HN3), Sanyinjiao (SP6), Baihui (GV20), Anmian (EX-HN22), and Sishencong (EX-HN1) were commonly used, but nonspecifically for many patterns. Treatment principles underlying herb and acupoint selection were seldom reported. Although many studies were reviewed, the study quality and diagnostic process were inadequate. More high quality studies are needed to examine the additional benefits of pattern differentiation and pattern-based TCM treatment.


Introduction
Insomnia is a frequent clinical complaint. Nearly one-third of the general population worldwide presents with insomnia symptoms, and the prevalence of insomnia symptoms accompanied by daytime consequences is approximately 9-15% [1]. Insomnia is a risk factor of a number of negative health consequences, including major depression, suicide, anxiety disorders, and alcohol and substance abuse or dependence [2]. Effective pharmacological treatments for insomnia are available. However, their uses are limited due to concerns about long-term efficacy and potential for dependence, abuse, and adverse effects [3]. Although psychological and behavioral therapies have empirical evidence for insomnia [4], they have remained underused because of the time-intensive nature and treatment nonadherence. Since the currently available treatments have their limitation, complementary and alternative medicine has been sought to treat insomnia. According to a national survey, over 1.6 million adults in the United States used complementary and alternative medicine to treat insomnia in the year 2002 [5].
Traditional Chinese medicine (TCM), a form of complementary and alternative medicine, is one of the oldest medical systems in the world. The use of TCM for insomnia can be traced more than 2000 years ago in Chinese medical texts [6,7]. In clinical practice, TCM treatments are individualized according to the TCM pattern diagnosis. TCM pattern, in terms of TCM theory, is defined as a diagnostic conclusion 2 Evidence-Based Complementary and Alternative Medicine of the pathological changes of a disease state based on an individual's symptoms and signs, including pulse form and tongue appearance [8]. The patterns of bodily disharmony can be described in terms of eight major parameters: yin and yang, external and internal, hot and cold, and excess and deficiency. Additional systems, such as qi, blood and bodyfluid differentiation, and zang fu (organ) differentiation are also used [9]. For a given disease there may be different presentations of various symptoms and signs; hence, many TCM pattern diagnoses are possible and this forms the rationale that different TCM treatments can be given for the same disease. On the other hand, different diseases may be treated with the same TCM treatment if they share the same pattern. The TCM patterns used today and the selection of herbal formulas and acupoints for specific TCM patterns are developed based on clinical experience, ancient medical texts, and some recently published TCM textbooks. It has to be acknowledged that most TCM concepts and therapies have not yet been proven by scientific method.
Although it is believed that pattern-based TCM treatment will provide better efficacy, previous studies regarding the additional benefit of TCM pattern differentiation are scarce. One randomized controlled trial (RCT) found that the therapeutic effect of Chinese herbal treatment according to TCM pattern was more sustainable than the standard formula in treating irritable bowel syndrome [10]. It has also been reported in rheumatoid arthritic patients that TCM pattern diagnoses can guide the use of Western medicine [11]. However, other RCTs found that the efficacy of pattern-based individualized acupuncture was not superior to standardized acupuncture for chronic shoulder pain [12], chronic back pain [13], and hypertension [14].
A previous survey in a Chinese medicine clinic in Taiwan has summarized the commonly prescribed single Chinese herbs and herbal formulas for insomnia [15]. Another study has reviewed the randomized controlled trials of acupuncture for insomnia and determined the most frequently used acupoints [16]. To the best of our knowledge, there has been no systematic review on the TCM patterns for insomnia. Information regarding pattern-based TCM treatments for insomnia is also lacking. Given the high prevalence of insomnia in the general population and its frequent presentation to TCM practitioners, it is important to review the current application of syndrome differentiation in TCM treatments for insomnia. The objectives of this paper were (1) to summarize the commonly diagnosed TCM patterns in patients with insomnia and (2) to find out the current practice of pattern-based TCM treatments for insomnia.

Method
The present study was part of our systematic review on TCM treatments for insomnia. Chinese herbal medicine, traditional needle acupuncture, and variants of acupuncture, including acupressure, moxibustion, transcutaneous electrical nerve stimulation, auricular acupressure, and reflexology were reviewed [17]. We searched the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, and Allied and Complementary Medicine from inception to May 2010 using the grouped terms (insomnia * or wakeful * or sleepless * or sleep * ) and ((acupuncture * or acupoints * or acupressure * or meridian * or transcutaneous electrical nerve stimulation or TENS or moxibustion or tuina) or (herb * or herbal medicine * or traditional Chinese medicine * or TCM)).

Selection Criteria.
Studies included in this paper were case series or clinical trials that described TCM patterns of subjects who received TCM treatment for their chief complaint of insomnia. In order to obtain a full coverage of the topic, we had not set any specification for sampling procedure, treatment method, outcome measure, and study quality. In addition, to derive a general picture of TCM pattern utilization, studies were excluded if they (1) had less than 30 subjects; (2) examined male or female only; (3) focused on subjects aged below 18 or above 70 years; (4) focused on a specific medical and psychiatric condition, a particular life transition period, or a specific TCM pattern; (5) had no statistical information regarding the frequency of individual TCM pattern; or (6) were duplicated publications. A sample size of 30 is considered as the minimum to examine the TCM pattern diagnosis in individuals with insomnia.

Data Extraction Process.
Two authors (W. Yeung and M. Poon) searched the databases and selected the relevant publications independently. If there were any disagreements about the eligibility of a study, the two authors would check the study against the inclusion and exclusion criteria, discuss its eligibility, and come to a further decision. One author (M. Poon) extracted the data and the other (W. Yeung) checked the extracted data. For each study, the following variables were extracted: study design, sample size, mode of recruitment, sampling and diagnostic procedure, inclusion and exclusion criteria, and participants' characteristics including age, gender, and duration of insomnia. TCM patterns, treatment principles, treatment regimen, and outcome of TCM treatments were obtained. In a majority of the reviewed studies, effective rate was the only outcome measure. The definition of effective rate was not standardized, but it was most often defined as the proportion of subjects who had at least some improvement of sleep or at least 30% reduction in the severity of insomnia by rating scales. We calculated the mean, standard deviation, and 95% confidence interval of dichotomous outcome measure. All Chinese to English translations were deduced primarily from the World Health Evidence-Based Complementary and Alternative Medicine 3 Organization (WHO) International Standard Terminologies on Traditional Medicine in the Western Pacific Region [8], and additionally from Traditional Chinese Internal Medicine [18], a commonly used English-language TCM textbook in China.

Quality Assessment.
For RCTs of Chinese herbal medicine, methodological quality will be assessed using Jadad scale. The Jadad scale evaluates a study in terms of the description of randomization, blinding, and dropouts. Points are awarded if the study is described as randomized, 1 point; has appropriate randomization method, 1 point; is described as double-blind, 1 point; uses appropriate blinding method, 1 point; has description of withdrawals and dropouts, 1 point. For RCTs involving acupuncture, a modified Jadad scale will be used. The modified Jadad scale takes into consideration the difficulty in blinding the acupuncturist to the treatment process. Points are awarded if the study is described as randomized, 1 point; has appropriate randomization method, 1 point; subjects blinded to intervention, 1 point; evaluator blinded to intervention, 1 point; has description of withdrawals and dropouts, 1 point [19,20]. Both the Jadad scale and modified Jadad scale scores range from 1 to 5; RCTs with a score from 3 to 5 are regarded as better quality trials.

Statistical Analysis.
We used SPSS version 16.0 for statistical analysis. Effective rate was summarized using mean (SD) and 95% confidence intervals (CIs).

Results
The search yielded 14045 potential titles for review, of which 4924 were duplicate records and 6249 were excluded for reasons of irrelevance. The full text of 2872 articles was retrieved for detailed assessment, of which 2645 were excluded for various reasons ( Figure 1). Of the 227 studies which fulfilled the inclusion and exclusion criteria, 89 were on Chinese herbal medicine, 64 on acupuncture, 40 on a combination of two acupuncture treatments, 24 on a combination of Chinese herbal medicine and acupuncture, and 10 on other TCM treatments. Sample size of the 227 studies ranged from 30 to 400. TCM diagnosis was available in 17916 subjects. A total of 87 different TCM diagnoses were examined in the 227 studies. The most common pattern was deficiency of both the heart and spleen, which was diagnosed in 4056 subjects or 22.6% of the 17916 subjects; it was followed by hyperactivity of fire due to yin deficiency (N = 2926, 16.3%), liver-qi stagnation transforming into fire (N = 1817, 10.1%), heart-kidney noninteraction (N = 1157, 6.5%), internal disturbance of phlegm heat (N = 904, 5.0%), qi deficiency of the heart and gallbladder (N = 838, 4.7%), liver fire flaming upward (N = 456, 2.5%), heart deficiency with timidity (N = 356, 2.0%), disharmony between spleen and stomach (N = 325, 1.8%), and stomach disharmony (N = 162, 0.9%). The top 10 TCM patterns accounted for 72.5% of the 17916 subjects ( Table 1).
The criteria used for diagnosis of TCM pattern varied between studies. Twenty-one of the 227 studies (9.3%) were based on TCM textbooks, 17 (7.5%) studies used the Clinical Research Guidelines of New Chinese Herbal Medicine [21], 16 (7.0%) used the Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes in TCM [22], 6 (2.6%) used some self-defined criteria, 3 (1.3%) adopted the criteria used by other TCM experts, and 1 used a combination of the Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes in TCM and a textbook. One hundred and sixtythree studies (71.8%) did not report the diagnostic criteria used.

TCM Pattern and Chinese Herbal
Medicine. Eightynine of the 227 included studies examined Chinese herbal medicine for insomnia: 54 of the 89 studies (60.7%) were case series, 8 (9.0%) were controlled studies, and 27 (30.3%) were RCTs. Of the 27 RCTs, 15 (55.6%) compared Chinese herbal medicine with Western medication, 9 (33.3%) with another Chinese herbal medicine, and 3 (11.1%) with Western medication and another Chinese herbal medicine. Twenty-six (96.3%) of the 27 RCTs were described as randomized but the randomization method, blinding, and dropouts were not presented; hence, these 26 RCTs had a Jadad score of 1. Only 1 (3.7%) of the 27 RCTs had appropriate randomization and double-blind design and obtained a Jadad score of 3.
Gui Pi Tang or its modification was the most frequently used Chinese herbal formula for the treatment of insomnia in patients diagnosed with deficiency of both the heart and spleen ( Table 2); for hyperactivity of fire due to yin deficiency, Huang Lian E Jiao Tang was the most frequently used formula. Modified Long Dan Xie Gan Tang and Dan Zhi Xiao Yao San were the most often used herbal formula for liver-qi stagnation transforming into fire. For internal disturbance of phlegm heat, the most frequently used formula was modified to Wen Dan Tang; lastly, for qi deficiency of the heart and gallbladder, modified An Shen Ding Zhi Wan was the most frequently used. There was a great variation in Chinese herbal treatment among patients diagnosed with heartkidney noninteraction and heart deficiency with timidity, with no single formula being studied twice. Studies on liver fire flaming upward, disharmony between spleen and stomach, and stomach disharmony were so limited that reliable information was not possible ( Table 2).
The TCM treatment principles and ingredients of the Chinese herbal formulas for treating insomnia are presented in Table 2. Due to a wide variation in the composition of herbal formulas, we only listed those individual herbs that were used in at least 20% of the studies on the TCM pattern. Suanzaoren (Semen Z.         ), and Baizhu (Rhizoma A. macrocephalae) were more often used and the most frequently used TCM treatment principle was to soothe liver and purge fire. There was no single herb being used in more than 50% of the studies on heart-kidney noninteraction, indicating that the selection of Chinese herbs varied greatly among practitioners. Suanzaoren (Semen Z. spinosae), Fuling (Poria), Yejiaoteng (Caulis P. multiflori), Gancao (Radix Glycyrrhizae), and Baishao (Radix P. alba) were the most commonly used individual herbs, but they were also the most nonspecific and were used in most of the TCM patterns. The effective rate of pattern-based Chinese herbal medicine treatment for insomnia was provided in 38 of the 89 studies on Chinese herbal medicine (Table 3). Based on the findings from RCTs, the mean effective rates were similar across TCM patterns, with the highest mean effective rate of 95.0% for liver-qi stagnation transforming into fire and the lowest at 79.4% for heart deficiency with timidity. When the case series were examined, the mean effective rates in liverqi stagnation transforming into fire and heart deficiency with timidity were very similar (79.1% and 77.8%, resp.).
The effective rate of pattern-based acupuncture-related treatments for insomnia was provided in 24 of the 64 studies on acupuncture-related treatments ( Table 3). As there were few RCTs available for comparison, based on the case series findings, the mean effective rates of acupuncture for the different TCM patterns were similar, with the highest mean effective rate of 98.1% for disharmony between spleen and stomach and the lowest at 75.0% for qi deficiency of the heart and gallbladder.

Chinese Herbal Medicine Plus Acupuncture-Related
Therapies. Twenty-four studies examined Chinese herbal medicine plus acupuncture-related treatments for insomnia. Thirteen (54.2%) of the 24 studies were case series, 1 (4.2%) was a controlled study, and 10 (41.7%) were RCTs. Of the 10 RCTs, 5 (50.0%) used Chinese herbal medicine for comparison, 3 (30.0%) used Western medication, and 2 (20.0%) compared with usual care. All 10 RCTs had a modified Jadad score of 1 as they were only described as randomized, but the randomization method, blinding, and dropouts were not presented.
We only presented the results of Chinese herbal medicine plus traditional needle acupuncture in deficiency of both the heart and spleen, hyperactivity of fire due to yin deficiency, and liver-qi stagnation transforming into fire, because studies on other TCM patterns and other forms of acupuncture were too few to give reliable information (Table 5). For deficiency of both the heart and spleen, the commonly used herbal ingredients for insomnia were Suanzaoren       Only the studies that examined traditional needle acupuncture plus auricular acupressure are presented, because studies on other combinations are too few to give reliable information (Table 6). For deficiency of both the heart and spleen, the commonly used acupoints were Baihui (GV20), Sanyinjiao (SP6), Shenmen (HT7), Sishencong (EX-HN1), Neiguan (PC6), Xinshu (BL15), Zusanli (ST36), Pishu (BL20), Anmian (EX-HN22), Fengchi (GB20); while the commonly used auricular points were shenmen, subcortex, heart, spleen, sympathesis, kidney, brain, endocrine, neurasthenia point, stomach, liver, and occiput. The selection of acupoints and auricular points for other TCM patterns is shown in Table 6. Sanyinjiao (SP6), Baihui (GV20), Shenmen (HT7), Sishencong (EX-HN1), and Neiguan (PC6) and shenmen, subcortex, heart, kidney, sympathesis, spleen, and liver were the commonly used acupoints and auricular points, respectively, in the combined traditional needle acupuncture and auricular acupressure for insomnia.

Discussion
This study is the first systematic review of English and Chinese literature, involving 227 studies and 17916 subjects on the classification and treatment of insomnia using the TCM diagnostic system. We found that the TCM pattern diagnoses for insomnia were diverse, with a total of 87 different TCM patterns identified. Deficiency of both the heart and spleen was the most commonly used TCM pattern in subjects with insomnia, followed by hyperactivity of fire due to yin deficiency, liver-qi stagnation transforming into fire, heartkidney noninteraction, internal disturbance of phlegm-heat, qi deficiency of the heart and gallbladder, liver fire flaming upward, stomach disharmony, heart deficiency with timidity, and disharmony between spleen and stomach. Pattern-based TCM treatment was more common in deficiency of both the heart and spleen, internal disturbance of phlegm heat, and Qi deficiency of the heart and gallbladder, but limited to the use of Chinese herbal medicine formula. Gui Pi Tang was the most frequently used herbal formula in Deficiency of both the heart and spleen; for Internal disturbance of phlegm heat and qi deficiency of the heart and gallbladder, it was Wen Dan Tang and An Shen Ding Zhi Wan, respectively. For other TCM patterns, no single formula could be regarded as commonly used across TCM practitioners.
We could not identify certain combinations of herbal agents or acupoints being used for particular TCM patterns. Suanzaoren (Semen Z. spinosae), Fuling (Poria), Yejiaoteng (Caulis P. multiflori), Gancao (Radix Glycyrrhizae), and Baishao (Radix P. alba) and Shenmen (HT7), Yintang (EX-HN3), Sanyinjiao (SP6), Baihui (GV20), Anmian (EX-HN22), and Sishencong (EX-HN1) were the commonly used Chinese herbs and acupoints, respectively, and they were being used nonspecifically for treating insomnia in many different TCM patterns. Treatment principles underlying the selection of herbal combinations were seldomy reported and it was more obvious with pattern-based acupuncture studies. One explanation for the variability in pattern-based TCM treatment may be the variability in treatment principle. It is important that treatment principles should be included in future pattern-based TCM treatment studies. Further research on the link between TCM pattern, treatment principle, and treatment is warranted.
The effective rates of TCM treatments were quite similar across different TCM patterns. However, the effective rate summarized in this paper was based on case-series and clinical trials with inadequate study quality. Further studies with better methodological design should be performed to compare the efficacy of TCM treatment in different TCM patterns.
The present paper found that some Chinese herbs, such as Suanzaoren (Semen Z. spinosae), Fuling (Poria), Yejiaoteng (Caulis P. multiflori), Gancao (Radix Glycyrrhizae), and Baishao (Radix P. alba) were frequently used to treat insomnia regardless of the TCM pattern. In TCM theory, a standard Chinese herbal formula is consisted of "Sovereign," "Minister," "Assistant," and "Courier" herbs. The Sovereign is used for treating the principal diseases; the Minister has synergistic effects with Sovereign herbs and helps to alleviate other accompanying symptoms; the Assistant is for enhancing the therapeutic effects and modulating the adverse effects of Sovereign and Minister herbs; while the Courier is used for harmonizing the actions of the others [23]. Suanzaoren (Semen Z. spinosae) and Yejiaoteng (Caulis P. multiflori) are classified as Anshen (mind tranquilizing) herbs and can act as Sovereign or Minister herbs in the treatment of insomnia. Fuling (Poria),