Complementary Therapies in Medicine (2014) 22, 826—833
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Traditional Chinese medicine for chronic fatigue syndrome: A systematic review of randomized clinical trials Yu-Yi Wang a, Xin-Xue Li b, Jian-Ping Liu a,∗, Hui Luo c, Li-Xin Ma d, Terje Alraek e,∗∗ a
Center for Evidence-Based Medicine, Beijing University of Chinese Medicine, Beijing, China Department of Academic Exchange, World Federation of Chinese Medicine Societies, Beijing, China c Institute for Tibetan Medicine, China Tibetology Research Center, Beijing, China d School of Public Health, Hebei University, Baoding, Hebei, China e The National Research Center in Complementary and Alternative Medicine, NAFKAM, Department of Community Medicine, Faculty of Health Science, UiT The Arctic University of Norway, 9037 Tromsø, Norway Available online 30 June 2014 b
KEYWORDS Chronic fatigue syndrome; Traditional Chinese medicine; Systematic review; Randomized clinical trials
Summary Background: There is no curative treatment for chronic fatigue syndrome (CFS). Traditional Chinese medicine (TCM) is widely used in the treatment of CFS in China. Objective: To evaluate the effectiveness and safety of TCM for CFS. Methods: The protocol of this review is registered at PROSPERO. We searched six main databases for randomized clinical trials (RCTs) on TCM for CFS from their inception to September 2013. The Cochrane risk of bias tool was used to assess the methodological quality. We used RevMan 5.1 to synthesize the results. Results: 23 RCTs involving 1776 participants were identified. The risk of bias of the included studies was high. The types of TCM interventions varied, including Chinese herbal medicine, acupuncture, qigong, moxibustion, and acupoint application. The results of meta-analyses and several individual studies showed that TCM alone or in combination with other interventions significantly alleviated fatigue symptoms as measured by Chalder’s fatigue scale, fatigue severity scale, fatigue assessment instrument by Joseph E. Schwartz, Bell’s fatigue scale, and guiding principle of clinical research on new drugs of TCM for fatigue symptom. There was no enough evidence that TCM could improve the quality of life for CFS patients. The included studies did not report serious adverse events.
∗ Corresponding author at: Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Chaoyang District, Beijing 100029, China. Tel.: +86 1064286760; fax: +86 10 64286760. ∗∗ Corresponding author at: Department of Community Medicine, Faculty of Health Science, UiT The Arctic University of Norway, 9037 Tromsø, Norway. E-mail addresses: [email protected], Jianping [email protected] (J.-P. Liu), [email protected] (T. Alraek).
http://dx.doi.org/10.1016/j.ctim.2014.06.004 0965-2299/© 2014 Elsevier Ltd. All rights reserved.
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Conclusions: TCM appears to be effective to alleviate the fatigue symptom for people with CFS. However, due to the high risk of bias of the included studies, larger, well-designed studies are needed to confirm the potential benefit in the future. © 2014 Elsevier Ltd. All rights reserved.
Introduction Chronic fatigue syndrome (CFS) is a disorder characterized by unexplained and persistent fatigue, impaired memory or concentration, post exercise malaise/tiredness, sleep disturbances, musculoskeletal pain, and several other somatic complaints.1 US Centers for Disease Control and Prevention (CDC) is offering a clinical definition (1994) of CFS, which was based on Holmes and Fukuda scoring and evaluating systems.1 The pathogenesis of CFS is still not clear, but studies showed that multifactorial disease pathways might be contributing factors of its complex symptoms and mechanisms.2 Studies reported that the prevalence rate of CFS in western countries ranged from 0.2% to 2.6%.3,4 Similarly, the rates were 1.9% in Beijing and 3% in Hong Kong, China.5 Currently, no curative treatments are available for CFS. There are some encouraging evidences showing that CFS patients might benefit from graded exercise therapy,6 cognitive behavior therapy7 and rehabilitation programs.8 Patients with CFS in China can be referred to TCM therapies. A Cochrane systematic review in 20099 evaluated the effectiveness of traditional Chinese herbal medicine (CHM) in treating idiopathic chronic fatigue and chronic fatigue syndrome. However, this systematic review set strict inclusion criteria which required control groups applying placebo or conventional standard of care, and finally no studies fulfilled the criteria. Besides herbal medicine, TCM covers a broad range of medical therapies which are customized and tailored according to TCM theories, and related to the symptoms and signs of individual patient.10 These therapies include CHM, acupuncture, moxibustion, massage (tuina), Qigong, cupping, Tai Chi. The objective of this review is to evaluate the effectiveness and adverse events from available studies of TCM therapies on treating and managing patients with CFS.
Materials and methods Standard protocol registrations This systematic review was registered in PROSPERO, and the registration identifier of the protocol is CRD42013005965.11
Search strategy and study selection The following six online databases were searched for relevant studies from their inception to September 2013: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Chinese Biomedical Database (Sino-Med), and Wanfang Database. The following searching terms as abstract
terms and MeSH terms were used individually or combined including ‘‘traditional Chinese medicine’’, ‘‘’herbal medicine’’, ‘‘acupuncture’’, ‘‘tuina’’, ‘‘qigong’’, ‘‘tai chi’’, ‘‘massage’’, ‘‘chronic fatigue syndrome’’, ‘‘CFS’’, ‘‘randomly’’, ‘‘trial’’, ‘‘randomised’’ and ‘‘randomized’’. The search strategy for PubMed can be found in Appendix S1, and other search strategies can be available through contacting corresponding author. No language restriction was applied. Two authors (YYW and XXL) identified studies which met the inclusion criteria. Any disagreements on studies to be included were resolved by discussion or a third author (JPL) was consulted.
Inclusion and exclusion criteria Type of study We included all relevant randomized controlled trials, irrespective of blinding, publication status or language. Quasi-randomized trials were excluded. Type of participants Participants met the diagnostic criteria of the US CDC definition (1994)1 for CFS. There were no limitations on gender, age, the disease course and severity. Type of intervention We included any kind of TCM therapies used alone or in combination that was compared with placebo or no intervention, conventional medicine, or general non-specific treatments such as vitamins, adenosine triphosphate (ATP). Co-intervention was allowed if they were applied in both arms. We excluded studies that applied TCM in both intervention and control groups. In this review, TCM is defined as a broad range of medical practice sharing common theoretical concepts and tradition in China, such as herbs, acupuncture and other acupoint stimulation, moxibustion, massage or qigong.10 Type of outcomes Primary outcomes. Fatigue was reported by a validated tool (e.g. Chalder’s fatigue scale). The fatigue scores of post-treatment were compared between the intervention and control groups. Secondary outcomes. (a) Quality of life measured by validated instruments; (b) Adverse events. Data extraction. Data were extracted independently by two authors (XXL and HL) using a self-developed data extraction form. Disagreement was resolved by discussion. The following information was extracted: study population, participant demographics and baseline characteristics; details
828 of the intervention and control; study methodology; outcome measures and main results. Methodological quality assessment. The methodological quality of included studies was assessed independently by two authors (YYW and XXL) using the Cochrane risk of bias tool.12 The tool included six items: random sequence generation (selection bias), allocation concealment (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other bias. The risk of bias was categorized as low/unclear/high risk of bias. Trials which met all criteria were judged as having a low risk of bias, trials which met none of the criteria were judged as having a high risk of bias, and trials with insufficient information to judge were classified as unclear risk of bias. Disagreements between the authors over the risk of bias in specific studies were resolved by discussion and consensus, with involvement of a third author when necessary. Strategy for data synthesis. All data synthesis was performed by RevMan 5.1 software. Dichotomous data were presented as relative risk (RR) and continuous outcomes as mean difference (MD), both with 95% confidence intervals (CI). If necessary data could not be available, we contacted corresponding authors of the studies. Subgroup analyses were performed according to different outcome measures and different types of TCM interventions. We used fixed effects model unless there was evidence of heterogeneity (defined as heterogeneity test p < 0.1). Funnel plots were used to detect potential publication bias where sufficient numbers of studies were available.
Results Description of studies The search process and study selection are presented by a flow chart (Fig. S1). Finally 23 RCTs13—35 involving 1776 participants with CFS were included. The detailed characteristics of the included studies are listed in Table S1. All studies used CDC 1994 for CFS as their diagnostic criteria. Among the 23 RCTs, 18 studies13—17,19—23,25,28,24 performed in mainland China, four studies18,24,26,35 in Hong Kong, and one study27 in Taiwan. 22 of 23 studies (included three unpublished dissertations)13—34 published in Chinese, and only one35 published in English. The number of participants randomized ranged from 60 to 240, but only one study35 reported sample size calculation. The mean disease duration varied from 6 months to 32.68 months, and the duration of treatment ranged from 1.5 weeks to 16 weeks. The types of comparisons were variable: herbal medicine versus non-specific treatment,13—21 acupuncture versus sham-acupuncture,24—28,30 electroacupuncture versus shamelectroacupuncture,29 moxibustion versus conventional medicine,31 moxibustion versus non-specific treatment,32,33 acupoint application versus placebo,34 qigong versus no treatment.35
Y.-Y. Wang et al.
Methodological quality assessment The overall methodological quality of included trials was poor in terms of risk of bias (Figs. S2 and S3). Twelve of 23 studies13—15,18,19,21,23,24,29,31—33 described ‘‘randomization’’ without reporting the specific method for random sequence generation. For allocation concealment, only two13,25 used sealed, opaque envelops, and one28 used a center controlled method. Blinding of participants and personnel were not mentioned in all studies, and five studies24—26,28,30 used blinding of the assessors. Sixteen studies13—23,27,31—34 did not describe the information about dropouts. For selective outcome reporting, only one study35 gave the clinical trial identifier number, and we were able to find the protocol for comparison and assessment. We could not conduct a funnel plot to detect publication bias due to significant clinical heterogeneity of the included trials.
Effects of interventions The effect estimates of TCM for CFS are shown in Table S2. Fatigue The severity of fatigue symptom was assessed by several different fatigue scales including Chalder’s fatigue scale, fatigue assessment instrument by Joseph E. Schwartz (FAI), fatigue severity scale (FSS), guiding principle of clinical research on new drugs of TCM for fatigue symptom (GPFS), and Bell’s fatigue scale (BFS). Chalder’s fatigue scale is consisting of 14 items for evaluating two dimensions of chronic fatigue: physical fatigue (8 items) and mental fatigue (6 items). Generally, Chalder’s fatigue scale was measured by a five-point Likert scale (none, better than usual, no more than usual, worse than usual, much worse than usual) scored from 0 to 4, however, several studies in China used a twopoint scale (no or yes) scored from 0 to 1. In order to distinguish them, we marked them as CFS1 (0—1) and CFS2 (0—4). In addition, FAI consisted 29 items for evaluating four dimensions of fatigue: severity, situation-specificity, psychological consequence, and response to rest/sleep. Chinese herbal medicine. Compared with non-specific treatment, a meta-analysis of five studies13—17 favored Chinese herbal medicine as measured by GPFS (MD −5.93 [−7.51, −4.34]). Two individual studies19,20 both showed better effect of Chinese herbal medicine as measured by CFS1 total FS score (MD −1.51 [−2.40, −0.62], MD −3.90 [−5.05, −2.75] respectively), however due to high heterogeneity, a meta-analysis could not be conducted. One study18 which was measured by CFS2 plus auxiliary symptom score also favored Chinese herbal medicine (MD −29.76 [−35.55, −23.97]); one study21 favored Chinese herbal medicine on three dimensions of FAI (S, SS, PC), but not on the dimension of RTR/S (MD 0.52 [−0.25, 1.29]). Acupuncture. The results from two meta-analyses (four studies and two studies) and three individual studies all found significant better effects in acupuncture group. Only two individual studies24,25 showed no significant difference between acupuncture group and sham-acupuncture group which were measured by CFS1-mental FS score and CFS2physical FS score respectively. We conducted a summary of finding table to present these findings (Table 1).
summary of finding table of acupuncture for CFS.
Acupuncture compared to sham-acupuncture for CFS Patient or population: patients with CFS Settings: Intervention: acupuncture Comparison: sham-acupuncture Outcomes
Illustrative comparative risksa (95% CI)
Assumed risk
Corresponding risk
Sham-acupuncture
Acupuncture
CFS1-total FS score CFS1.b Scale from: 0 to 14. CFS1-physical FS score CFS1. Scale from: 0 to 8.
The mean CFS1-total FS score ranged across control groups from 7.5 to 9.92 points The mean CFS 1-physical FS score ranged across control groups from 5 to 5.61 points
CFS1-mental FS score CFS1. Scale from: 0 to 6. CFS2-physical FS score CFS2.g Scale from: 0 to 32.
See comment
The mean CFS1-total FS score in the intervention groups was 2.61 lower (3.56—1.65 lower) The mean CFS 1-physical FS score in the intervention groups was 0.9 lower (2.44 lower to 0.65 higher) See comment
CFS 2-mental FS score CFS2.g Scale from: 0 to 24.
The mean CFS 2-mental FS score in the control groups was 14.92 points
The mean CFS 2-physical FS score in the control groups was 23.7 points
The mean CFS 2-physical FS score in the intervention groups was 1.41 lower (3.97 lower to 1.15 higher) The mean CFS 2-mental FS score in the intervention groups was 1.17 lower (3.03 lower to 0.69 higher)
Relative effect (95% CI)
Not estimable
No of participants (studies)
Quality of the evidence (GRADE)
261 (4 studies)
− ⊕⊕ − lowc,d,e
141 (2 studies)
⊕⊕⊕ − moderatec
141 (2 studies)
⊕⊕⊕ − moderatec
99 (1 study)
⊕⊕ − − lowc,f
99 (1 study)
− ⊕⊕ − lowc,f
Comments
Traditional Chinese medicine for chronic fatigue syndrome
Table 1
Two studies could not synthesize into a meta-analysis due to statistical heterogeneity
829
830
Table 1 (Continued ) Outcomes
Illustrative comparative risksa (95% CI)
Relative effect (95% CI)
No of participants (studies)
Quality of the evidence (GRADE)
Comments
Three studies reported QOL using three different measurement tools showing inconsistent results. Three of 23 studies reported safety, and no serious adverse events reported.
Assumed risk
Corresponding risk
Sham-acupuncture
Acupuncture
SF 12 SF 12.h Scale from: 12 to 56
The mean SF 12 score in the control groups was 38.72 points
The mean FS 12 score in the intervention groups was 2.64 higher (0.99 lower to 6.27 higher)
99 (1 study)
− ⊕⊕ − lowc,f
Safety reporting
See comment
See comment
485 (7 studies)
⊕⊕⊕ − moderatec
CI: Confidence interval. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). b CFS1 was measured by a five-point Likert scale (none, better than usual, no more than usual, worse than usual, much worse than usual) scored from 0 to 4. c The main problems were that insufficient information was given to assess. d Statistical heterogeneity was substantial. e All results were positive, which might have some publication bias. f Only one study included. Total sample size was relatively small, and the 95% confidence interval was wide. g CFS2 was measured by a two-point scale (no, yes) scored from 0 to 1. h SF 12, the 12-item short form health survey.
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Traditional Chinese medicine for chronic fatigue syndrome Electroacupuncture. One study29 compared electroacupuncture to sham-electroacupuncture, and demonstrated a significant effect favoring electroacupuncture as measured by FSS (MD −12.87 [−15.86, −9.88]). Moxibustion. One study31 compared moxibustion with Fluoxetine favoring moxibustion as measured by GPFS (MD −3.18 [−6.21, −0.15]). Another study32 also favored moxibustion as measured by BFS (MD 9.43 [4.64, 14.22]) when compared to hydrocortisone. Acupoint application. One study34 compared Chinese medicinal ointment applying externally on acupoints with placebo, and the result favored treatment group as measured by GPFS (MD −14.87 [−16.78, −12.96]). Qigong. One study35 compared Qigong with no treatment, and showed a significant effect favoring Qigong as measure by CFS2-total FS score (MD −10.50 [−15.01, −5.99]), CFS2physical FS score (MD −7.40 [−10.17, −4.63]), and CFS2mental FS score (MD −3.10 [−5.08, −1.12]). Combined treatment. One study22 showed that a combination of Chinese herbal medicine and paroxetine was better than paroxetine alone as measured by CFS1-total FS score (MD −2.22 [−2.53, −1.91]), CFS1-physical FS score (MD −1.69 [−1.84, −1.54]) and CFS1-mental FS score (MD −1.65 [−1.81, −1.49]). Another study23 also favored combined treatment (Modulated medium frequency electrotherapy plus Chinese herb Ciwujia injection) as measured by CFS1total FS score (MD −5.84 [−7.08, −4.60]), CFS1-physical FS score (MD −3.31 [−3.99, −2.23]) and CFS1-mental FS score (MD −2.47 [−2.92, −2.02] when compared to non-specific treatment. Quality of life Totally, four trials24,26,28,33 reported Quality of Life (QOL) which was measured by three different tools including SF 12, SF 36 and WHOQOL-BREF. Acupuncture. Compared with sham-acupuncture, one study26 showed better effect of acupuncture when measured by WHOQOL-BREF, but two studies24,28 using SF 12 and SF 36 found no significant difference between the two treatments (Table 1). Moxibustion. One study33 found better improvement of moxibustion for QOL as measured by SF 36 (MD 163.60 [140.48, 186.72]) compared with non-specific treatment. Adverse events Among the 23 studies, 16 studies (69.6%)14,15,17—19,21,23,26,27,29—35 did not report any information on adverse events. Of the seven studies13,16,20,22,24,25,28 that did mention safety outcomes, four studies13,16,24,25 found no adverse events neither in the intervention nor in the control group. The remaining three studies20,22,28 reported detailed adverse events which were mild and transient, e.g. nausea, thirst or bleeding due to acupuncture.
Discussion In this review, various types of TCM interventions were identified and evaluated for the effectiveness and safety for CFS. Several TCM interventions used alone or in combinations showed potential positive effect for alleviating fatigue symptoms. However, we should be cautious about these
831 positive findings which were based on the low quality of included studies. In addition, whether TCM could improve the QOL of patients is still inconclusive. Because four studies18,26,28,33 that evaluated QOL outcomes showed inconsistent results, and we could not conduct a meta-analysis due to different intervention comparisons and measurements. Though no serious adverse events were reported, we could not draw a firm conclusion about the safety of TCM because 16 studies (70%) did not provide any information on safety. A number of limitations were identified. Firstly, several studies were excluded because they did not meet inclusion criteria. Therefore, it was not possible to reach a global and complete summary of all evidence. For example, we excluded 80 studies due to TCM interventions in both intervention and control group. Since effectiveness of TCM was inconclusive and the purpose of this review was to evaluate the effectiveness of TCM, we thought it was inappropriate to include studies which applied one TCM intervention versus another TCM intervention. In addition, we also excluded 27 studies that did not report the outcomes of fatigue symptoms that we needed as primary outcome. Secondly, the way of reporting and measuring outcomes varied, which prevented us conducting meta-analyses. For fatigue symptom, five different scales were used. Even for the same measurement, there were various methods to report. For example, Chalder’s fatigue scale was an international scale measured on a five-point Likert scale (none, better than usual, no more than usual, much worse than usual), but some studies in China just measured on a two-point scale (no or yes). Hence, we could not synthesize data from these two kinds of outcomes into one meta-analysis. Thirdly, the methodological quality of included studies was not satisfactory. The main problem was that insufficient information was provided to assess risk of bias. More specifically, about half of included studies did not describe how they generate random sequence clearly, and allocation concealment was only mentioned in three studies.13,25,28 Therefore, we doubt that whether the randomization was conducted properly. In additional, only five studies24—26,28,30 reported the blinding of outcome assessment. We could not explain the reason why no studies claimed blinding to the participants and personnel. At least eight studies,24—30,34 which used controls of sham-acupuncture or placebo, were available to apply double-blind. Moreover, of 23 studies, only one study35 registered the protocol, which we could compare the protocol with the publication to assess selective outcome reporting bias, and other bias. We did not conduct funnel plot analysis due to insufficient number of studies included in the meta-analysis. However, almost all studies included reported positive findings, indicating existence of potential publication bias. Though the strength of the results of the review may be weakened due to the above limitations, this systematic review is still meaningful since TCM interventions for treatment of CFS are increasing popular as well as lack of evidence. On the other hand, we can also achieve important implications from this review for future clinical trials in order to get high-qualified evidence. At least following aspects should be noticed for a rigorous trial on TCM interventions for CFS in the future.
832 Firstly, clinical trials should be prospectively registered in international trial registry. In this way, reviewers can recognize whether the trials have selective reporting and/or incomplete outcome reporting. And protocol registration is also a method to avoid publication bias that negative results were generally not published in the past. Secondly, the appropriate control group and blinding are especially crucial for future trials. We recommend that it is better to use placebo or no treatment as control treatments when applicable since no curative treatments were available. Another reason to use placebo or no treatment is that CFS is a chronic disease, and generally it has no serious safety issue for using placebo. For Chinese herbal medicine, currently no placebo was used except one34 for point application (pasting the medicinal ointment on the acupoints). The placebo ointment was made by flour, milk powder, ink and honey which was in according with the color and appearance of medicinal ointment. This placebo ointment can be used to blind participants because it was pasted on the acupoints. However, placebo of decoction of Chinese herbal medicine is still not easy to made, because Chinese patients are familiar with the smell and taste of real decoction of herbal medicine. Thirdly, outcomes which are clearly defined, clinical relevant and internationally validated are required in the future trials. Currently, the outcomes on fatigue included Chalder’s fatigue scale, fatigue severity scale, etc. Finally, to ensure the quality of the future trials on TCM for CFS, other methodological items should also be clearly reported. The complete procedure of randomization, including random sequence generation and allocation concealment, is crucial, which can avoid potential performance bias and keep a balance between two groups on the baseline data. In addition ITT analysis is needed when there are noncompliance and missing outcomes.
Conclusions In total, this review shows that TCM may have some beneficial effects on alleviating the fatigue symptom for people with CFS. However, the findings should be interpreted with cautions since most results were not concluded from the meta-analyses but individual studies, and the methodological quality of the included studies was poor. Therefore, large, well-designed studies are needed to confirm these findings in the future.
Ethical approval Not applicable.
Source of funding This research was supported by the Program for Innovative Research Team (2011-CXTD-09) of Beijing University of Chinese Medicine, the grant number 201207007 from the State Administration of Traditional Chinese Medicine in China, and the postgraduate program (532/0100604225) from Beijing University of Chinese Medicine. The study was also
Y.-Y. Wang et al. supported with a grant from the Norwegian Directorate of Health.
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.2014.06.004.
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Traditional Chinese medicine for chronic fatigue syndrome: A systematic review of randomized clinical trials Yu-Yi Wang a, Xin-Xue Li b, Jian-Ping Liu a,∗, Hui Luo c, Li-Xin Ma d, Terje Alraek e,∗∗ a
Center for Evidence-Based Medicine, Beijing University of Chinese Medicine, Beijing, China Department of Academic Exchange, World Federation of Chinese Medicine Societies, Beijing, China c Institute for Tibetan Medicine, China Tibetology Research Center, Beijing, China d School of Public Health, Hebei University, Baoding, Hebei, China e The National Research Center in Complementary and Alternative Medicine, NAFKAM, Department of Community Medicine, Faculty of Health Science, UiT The Arctic University of Norway, 9037 Tromsø, Norway Available online 30 June 2014 b
KEYWORDS Chronic fatigue syndrome; Traditional Chinese medicine; Systematic review; Randomized clinical trials
Summary Background: There is no curative treatment for chronic fatigue syndrome (CFS). Traditional Chinese medicine (TCM) is widely used in the treatment of CFS in China. Objective: To evaluate the effectiveness and safety of TCM for CFS. Methods: The protocol of this review is registered at PROSPERO. We searched six main databases for randomized clinical trials (RCTs) on TCM for CFS from their inception to September 2013. The Cochrane risk of bias tool was used to assess the methodological quality. We used RevMan 5.1 to synthesize the results. Results: 23 RCTs involving 1776 participants were identified. The risk of bias of the included studies was high. The types of TCM interventions varied, including Chinese herbal medicine, acupuncture, qigong, moxibustion, and acupoint application. The results of meta-analyses and several individual studies showed that TCM alone or in combination with other interventions significantly alleviated fatigue symptoms as measured by Chalder’s fatigue scale, fatigue severity scale, fatigue assessment instrument by Joseph E. Schwartz, Bell’s fatigue scale, and guiding principle of clinical research on new drugs of TCM for fatigue symptom. There was no enough evidence that TCM could improve the quality of life for CFS patients. The included studies did not report serious adverse events.
∗ Corresponding author at: Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Chaoyang District, Beijing 100029, China. Tel.: +86 1064286760; fax: +86 10 64286760. ∗∗ Corresponding author at: Department of Community Medicine, Faculty of Health Science, UiT The Arctic University of Norway, 9037 Tromsø, Norway. E-mail addresses: [email protected], Jianping [email protected] (J.-P. Liu), [email protected] (T. Alraek).
http://dx.doi.org/10.1016/j.ctim.2014.06.004 0965-2299/© 2014 Elsevier Ltd. All rights reserved.
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Conclusions: TCM appears to be effective to alleviate the fatigue symptom for people with CFS. However, due to the high risk of bias of the included studies, larger, well-designed studies are needed to confirm the potential benefit in the future. © 2014 Elsevier Ltd. All rights reserved.
Introduction Chronic fatigue syndrome (CFS) is a disorder characterized by unexplained and persistent fatigue, impaired memory or concentration, post exercise malaise/tiredness, sleep disturbances, musculoskeletal pain, and several other somatic complaints.1 US Centers for Disease Control and Prevention (CDC) is offering a clinical definition (1994) of CFS, which was based on Holmes and Fukuda scoring and evaluating systems.1 The pathogenesis of CFS is still not clear, but studies showed that multifactorial disease pathways might be contributing factors of its complex symptoms and mechanisms.2 Studies reported that the prevalence rate of CFS in western countries ranged from 0.2% to 2.6%.3,4 Similarly, the rates were 1.9% in Beijing and 3% in Hong Kong, China.5 Currently, no curative treatments are available for CFS. There are some encouraging evidences showing that CFS patients might benefit from graded exercise therapy,6 cognitive behavior therapy7 and rehabilitation programs.8 Patients with CFS in China can be referred to TCM therapies. A Cochrane systematic review in 20099 evaluated the effectiveness of traditional Chinese herbal medicine (CHM) in treating idiopathic chronic fatigue and chronic fatigue syndrome. However, this systematic review set strict inclusion criteria which required control groups applying placebo or conventional standard of care, and finally no studies fulfilled the criteria. Besides herbal medicine, TCM covers a broad range of medical therapies which are customized and tailored according to TCM theories, and related to the symptoms and signs of individual patient.10 These therapies include CHM, acupuncture, moxibustion, massage (tuina), Qigong, cupping, Tai Chi. The objective of this review is to evaluate the effectiveness and adverse events from available studies of TCM therapies on treating and managing patients with CFS.
Materials and methods Standard protocol registrations This systematic review was registered in PROSPERO, and the registration identifier of the protocol is CRD42013005965.11
Search strategy and study selection The following six online databases were searched for relevant studies from their inception to September 2013: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Chinese Biomedical Database (Sino-Med), and Wanfang Database. The following searching terms as abstract
terms and MeSH terms were used individually or combined including ‘‘traditional Chinese medicine’’, ‘‘’herbal medicine’’, ‘‘acupuncture’’, ‘‘tuina’’, ‘‘qigong’’, ‘‘tai chi’’, ‘‘massage’’, ‘‘chronic fatigue syndrome’’, ‘‘CFS’’, ‘‘randomly’’, ‘‘trial’’, ‘‘randomised’’ and ‘‘randomized’’. The search strategy for PubMed can be found in Appendix S1, and other search strategies can be available through contacting corresponding author. No language restriction was applied. Two authors (YYW and XXL) identified studies which met the inclusion criteria. Any disagreements on studies to be included were resolved by discussion or a third author (JPL) was consulted.
Inclusion and exclusion criteria Type of study We included all relevant randomized controlled trials, irrespective of blinding, publication status or language. Quasi-randomized trials were excluded. Type of participants Participants met the diagnostic criteria of the US CDC definition (1994)1 for CFS. There were no limitations on gender, age, the disease course and severity. Type of intervention We included any kind of TCM therapies used alone or in combination that was compared with placebo or no intervention, conventional medicine, or general non-specific treatments such as vitamins, adenosine triphosphate (ATP). Co-intervention was allowed if they were applied in both arms. We excluded studies that applied TCM in both intervention and control groups. In this review, TCM is defined as a broad range of medical practice sharing common theoretical concepts and tradition in China, such as herbs, acupuncture and other acupoint stimulation, moxibustion, massage or qigong.10 Type of outcomes Primary outcomes. Fatigue was reported by a validated tool (e.g. Chalder’s fatigue scale). The fatigue scores of post-treatment were compared between the intervention and control groups. Secondary outcomes. (a) Quality of life measured by validated instruments; (b) Adverse events. Data extraction. Data were extracted independently by two authors (XXL and HL) using a self-developed data extraction form. Disagreement was resolved by discussion. The following information was extracted: study population, participant demographics and baseline characteristics; details
828 of the intervention and control; study methodology; outcome measures and main results. Methodological quality assessment. The methodological quality of included studies was assessed independently by two authors (YYW and XXL) using the Cochrane risk of bias tool.12 The tool included six items: random sequence generation (selection bias), allocation concealment (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other bias. The risk of bias was categorized as low/unclear/high risk of bias. Trials which met all criteria were judged as having a low risk of bias, trials which met none of the criteria were judged as having a high risk of bias, and trials with insufficient information to judge were classified as unclear risk of bias. Disagreements between the authors over the risk of bias in specific studies were resolved by discussion and consensus, with involvement of a third author when necessary. Strategy for data synthesis. All data synthesis was performed by RevMan 5.1 software. Dichotomous data were presented as relative risk (RR) and continuous outcomes as mean difference (MD), both with 95% confidence intervals (CI). If necessary data could not be available, we contacted corresponding authors of the studies. Subgroup analyses were performed according to different outcome measures and different types of TCM interventions. We used fixed effects model unless there was evidence of heterogeneity (defined as heterogeneity test p < 0.1). Funnel plots were used to detect potential publication bias where sufficient numbers of studies were available.
Results Description of studies The search process and study selection are presented by a flow chart (Fig. S1). Finally 23 RCTs13—35 involving 1776 participants with CFS were included. The detailed characteristics of the included studies are listed in Table S1. All studies used CDC 1994 for CFS as their diagnostic criteria. Among the 23 RCTs, 18 studies13—17,19—23,25,28,24 performed in mainland China, four studies18,24,26,35 in Hong Kong, and one study27 in Taiwan. 22 of 23 studies (included three unpublished dissertations)13—34 published in Chinese, and only one35 published in English. The number of participants randomized ranged from 60 to 240, but only one study35 reported sample size calculation. The mean disease duration varied from 6 months to 32.68 months, and the duration of treatment ranged from 1.5 weeks to 16 weeks. The types of comparisons were variable: herbal medicine versus non-specific treatment,13—21 acupuncture versus sham-acupuncture,24—28,30 electroacupuncture versus shamelectroacupuncture,29 moxibustion versus conventional medicine,31 moxibustion versus non-specific treatment,32,33 acupoint application versus placebo,34 qigong versus no treatment.35
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Methodological quality assessment The overall methodological quality of included trials was poor in terms of risk of bias (Figs. S2 and S3). Twelve of 23 studies13—15,18,19,21,23,24,29,31—33 described ‘‘randomization’’ without reporting the specific method for random sequence generation. For allocation concealment, only two13,25 used sealed, opaque envelops, and one28 used a center controlled method. Blinding of participants and personnel were not mentioned in all studies, and five studies24—26,28,30 used blinding of the assessors. Sixteen studies13—23,27,31—34 did not describe the information about dropouts. For selective outcome reporting, only one study35 gave the clinical trial identifier number, and we were able to find the protocol for comparison and assessment. We could not conduct a funnel plot to detect publication bias due to significant clinical heterogeneity of the included trials.
Effects of interventions The effect estimates of TCM for CFS are shown in Table S2. Fatigue The severity of fatigue symptom was assessed by several different fatigue scales including Chalder’s fatigue scale, fatigue assessment instrument by Joseph E. Schwartz (FAI), fatigue severity scale (FSS), guiding principle of clinical research on new drugs of TCM for fatigue symptom (GPFS), and Bell’s fatigue scale (BFS). Chalder’s fatigue scale is consisting of 14 items for evaluating two dimensions of chronic fatigue: physical fatigue (8 items) and mental fatigue (6 items). Generally, Chalder’s fatigue scale was measured by a five-point Likert scale (none, better than usual, no more than usual, worse than usual, much worse than usual) scored from 0 to 4, however, several studies in China used a twopoint scale (no or yes) scored from 0 to 1. In order to distinguish them, we marked them as CFS1 (0—1) and CFS2 (0—4). In addition, FAI consisted 29 items for evaluating four dimensions of fatigue: severity, situation-specificity, psychological consequence, and response to rest/sleep. Chinese herbal medicine. Compared with non-specific treatment, a meta-analysis of five studies13—17 favored Chinese herbal medicine as measured by GPFS (MD −5.93 [−7.51, −4.34]). Two individual studies19,20 both showed better effect of Chinese herbal medicine as measured by CFS1 total FS score (MD −1.51 [−2.40, −0.62], MD −3.90 [−5.05, −2.75] respectively), however due to high heterogeneity, a meta-analysis could not be conducted. One study18 which was measured by CFS2 plus auxiliary symptom score also favored Chinese herbal medicine (MD −29.76 [−35.55, −23.97]); one study21 favored Chinese herbal medicine on three dimensions of FAI (S, SS, PC), but not on the dimension of RTR/S (MD 0.52 [−0.25, 1.29]). Acupuncture. The results from two meta-analyses (four studies and two studies) and three individual studies all found significant better effects in acupuncture group. Only two individual studies24,25 showed no significant difference between acupuncture group and sham-acupuncture group which were measured by CFS1-mental FS score and CFS2physical FS score respectively. We conducted a summary of finding table to present these findings (Table 1).
summary of finding table of acupuncture for CFS.
Acupuncture compared to sham-acupuncture for CFS Patient or population: patients with CFS Settings: Intervention: acupuncture Comparison: sham-acupuncture Outcomes
Illustrative comparative risksa (95% CI)
Assumed risk
Corresponding risk
Sham-acupuncture
Acupuncture
CFS1-total FS score CFS1.b Scale from: 0 to 14. CFS1-physical FS score CFS1. Scale from: 0 to 8.
The mean CFS1-total FS score ranged across control groups from 7.5 to 9.92 points The mean CFS 1-physical FS score ranged across control groups from 5 to 5.61 points
CFS1-mental FS score CFS1. Scale from: 0 to 6. CFS2-physical FS score CFS2.g Scale from: 0 to 32.
See comment
The mean CFS1-total FS score in the intervention groups was 2.61 lower (3.56—1.65 lower) The mean CFS 1-physical FS score in the intervention groups was 0.9 lower (2.44 lower to 0.65 higher) See comment
CFS 2-mental FS score CFS2.g Scale from: 0 to 24.
The mean CFS 2-mental FS score in the control groups was 14.92 points
The mean CFS 2-physical FS score in the control groups was 23.7 points
The mean CFS 2-physical FS score in the intervention groups was 1.41 lower (3.97 lower to 1.15 higher) The mean CFS 2-mental FS score in the intervention groups was 1.17 lower (3.03 lower to 0.69 higher)
Relative effect (95% CI)
Not estimable
No of participants (studies)
Quality of the evidence (GRADE)
261 (4 studies)
− ⊕⊕ − lowc,d,e
141 (2 studies)
⊕⊕⊕ − moderatec
141 (2 studies)
⊕⊕⊕ − moderatec
99 (1 study)
⊕⊕ − − lowc,f
99 (1 study)
− ⊕⊕ − lowc,f
Comments
Traditional Chinese medicine for chronic fatigue syndrome
Table 1
Two studies could not synthesize into a meta-analysis due to statistical heterogeneity
829
830
Table 1 (Continued ) Outcomes
Illustrative comparative risksa (95% CI)
Relative effect (95% CI)
No of participants (studies)
Quality of the evidence (GRADE)
Comments
Three studies reported QOL using three different measurement tools showing inconsistent results. Three of 23 studies reported safety, and no serious adverse events reported.
Assumed risk
Corresponding risk
Sham-acupuncture
Acupuncture
SF 12 SF 12.h Scale from: 12 to 56
The mean SF 12 score in the control groups was 38.72 points
The mean FS 12 score in the intervention groups was 2.64 higher (0.99 lower to 6.27 higher)
99 (1 study)
− ⊕⊕ − lowc,f
Safety reporting
See comment
See comment
485 (7 studies)
⊕⊕⊕ − moderatec
CI: Confidence interval. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). b CFS1 was measured by a five-point Likert scale (none, better than usual, no more than usual, worse than usual, much worse than usual) scored from 0 to 4. c The main problems were that insufficient information was given to assess. d Statistical heterogeneity was substantial. e All results were positive, which might have some publication bias. f Only one study included. Total sample size was relatively small, and the 95% confidence interval was wide. g CFS2 was measured by a two-point scale (no, yes) scored from 0 to 1. h SF 12, the 12-item short form health survey.
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Traditional Chinese medicine for chronic fatigue syndrome Electroacupuncture. One study29 compared electroacupuncture to sham-electroacupuncture, and demonstrated a significant effect favoring electroacupuncture as measured by FSS (MD −12.87 [−15.86, −9.88]). Moxibustion. One study31 compared moxibustion with Fluoxetine favoring moxibustion as measured by GPFS (MD −3.18 [−6.21, −0.15]). Another study32 also favored moxibustion as measured by BFS (MD 9.43 [4.64, 14.22]) when compared to hydrocortisone. Acupoint application. One study34 compared Chinese medicinal ointment applying externally on acupoints with placebo, and the result favored treatment group as measured by GPFS (MD −14.87 [−16.78, −12.96]). Qigong. One study35 compared Qigong with no treatment, and showed a significant effect favoring Qigong as measure by CFS2-total FS score (MD −10.50 [−15.01, −5.99]), CFS2physical FS score (MD −7.40 [−10.17, −4.63]), and CFS2mental FS score (MD −3.10 [−5.08, −1.12]). Combined treatment. One study22 showed that a combination of Chinese herbal medicine and paroxetine was better than paroxetine alone as measured by CFS1-total FS score (MD −2.22 [−2.53, −1.91]), CFS1-physical FS score (MD −1.69 [−1.84, −1.54]) and CFS1-mental FS score (MD −1.65 [−1.81, −1.49]). Another study23 also favored combined treatment (Modulated medium frequency electrotherapy plus Chinese herb Ciwujia injection) as measured by CFS1total FS score (MD −5.84 [−7.08, −4.60]), CFS1-physical FS score (MD −3.31 [−3.99, −2.23]) and CFS1-mental FS score (MD −2.47 [−2.92, −2.02] when compared to non-specific treatment. Quality of life Totally, four trials24,26,28,33 reported Quality of Life (QOL) which was measured by three different tools including SF 12, SF 36 and WHOQOL-BREF. Acupuncture. Compared with sham-acupuncture, one study26 showed better effect of acupuncture when measured by WHOQOL-BREF, but two studies24,28 using SF 12 and SF 36 found no significant difference between the two treatments (Table 1). Moxibustion. One study33 found better improvement of moxibustion for QOL as measured by SF 36 (MD 163.60 [140.48, 186.72]) compared with non-specific treatment. Adverse events Among the 23 studies, 16 studies (69.6%)14,15,17—19,21,23,26,27,29—35 did not report any information on adverse events. Of the seven studies13,16,20,22,24,25,28 that did mention safety outcomes, four studies13,16,24,25 found no adverse events neither in the intervention nor in the control group. The remaining three studies20,22,28 reported detailed adverse events which were mild and transient, e.g. nausea, thirst or bleeding due to acupuncture.
Discussion In this review, various types of TCM interventions were identified and evaluated for the effectiveness and safety for CFS. Several TCM interventions used alone or in combinations showed potential positive effect for alleviating fatigue symptoms. However, we should be cautious about these
831 positive findings which were based on the low quality of included studies. In addition, whether TCM could improve the QOL of patients is still inconclusive. Because four studies18,26,28,33 that evaluated QOL outcomes showed inconsistent results, and we could not conduct a meta-analysis due to different intervention comparisons and measurements. Though no serious adverse events were reported, we could not draw a firm conclusion about the safety of TCM because 16 studies (70%) did not provide any information on safety. A number of limitations were identified. Firstly, several studies were excluded because they did not meet inclusion criteria. Therefore, it was not possible to reach a global and complete summary of all evidence. For example, we excluded 80 studies due to TCM interventions in both intervention and control group. Since effectiveness of TCM was inconclusive and the purpose of this review was to evaluate the effectiveness of TCM, we thought it was inappropriate to include studies which applied one TCM intervention versus another TCM intervention. In addition, we also excluded 27 studies that did not report the outcomes of fatigue symptoms that we needed as primary outcome. Secondly, the way of reporting and measuring outcomes varied, which prevented us conducting meta-analyses. For fatigue symptom, five different scales were used. Even for the same measurement, there were various methods to report. For example, Chalder’s fatigue scale was an international scale measured on a five-point Likert scale (none, better than usual, no more than usual, much worse than usual), but some studies in China just measured on a two-point scale (no or yes). Hence, we could not synthesize data from these two kinds of outcomes into one meta-analysis. Thirdly, the methodological quality of included studies was not satisfactory. The main problem was that insufficient information was provided to assess risk of bias. More specifically, about half of included studies did not describe how they generate random sequence clearly, and allocation concealment was only mentioned in three studies.13,25,28 Therefore, we doubt that whether the randomization was conducted properly. In additional, only five studies24—26,28,30 reported the blinding of outcome assessment. We could not explain the reason why no studies claimed blinding to the participants and personnel. At least eight studies,24—30,34 which used controls of sham-acupuncture or placebo, were available to apply double-blind. Moreover, of 23 studies, only one study35 registered the protocol, which we could compare the protocol with the publication to assess selective outcome reporting bias, and other bias. We did not conduct funnel plot analysis due to insufficient number of studies included in the meta-analysis. However, almost all studies included reported positive findings, indicating existence of potential publication bias. Though the strength of the results of the review may be weakened due to the above limitations, this systematic review is still meaningful since TCM interventions for treatment of CFS are increasing popular as well as lack of evidence. On the other hand, we can also achieve important implications from this review for future clinical trials in order to get high-qualified evidence. At least following aspects should be noticed for a rigorous trial on TCM interventions for CFS in the future.
832 Firstly, clinical trials should be prospectively registered in international trial registry. In this way, reviewers can recognize whether the trials have selective reporting and/or incomplete outcome reporting. And protocol registration is also a method to avoid publication bias that negative results were generally not published in the past. Secondly, the appropriate control group and blinding are especially crucial for future trials. We recommend that it is better to use placebo or no treatment as control treatments when applicable since no curative treatments were available. Another reason to use placebo or no treatment is that CFS is a chronic disease, and generally it has no serious safety issue for using placebo. For Chinese herbal medicine, currently no placebo was used except one34 for point application (pasting the medicinal ointment on the acupoints). The placebo ointment was made by flour, milk powder, ink and honey which was in according with the color and appearance of medicinal ointment. This placebo ointment can be used to blind participants because it was pasted on the acupoints. However, placebo of decoction of Chinese herbal medicine is still not easy to made, because Chinese patients are familiar with the smell and taste of real decoction of herbal medicine. Thirdly, outcomes which are clearly defined, clinical relevant and internationally validated are required in the future trials. Currently, the outcomes on fatigue included Chalder’s fatigue scale, fatigue severity scale, etc. Finally, to ensure the quality of the future trials on TCM for CFS, other methodological items should also be clearly reported. The complete procedure of randomization, including random sequence generation and allocation concealment, is crucial, which can avoid potential performance bias and keep a balance between two groups on the baseline data. In addition ITT analysis is needed when there are noncompliance and missing outcomes.
Conclusions In total, this review shows that TCM may have some beneficial effects on alleviating the fatigue symptom for people with CFS. However, the findings should be interpreted with cautions since most results were not concluded from the meta-analyses but individual studies, and the methodological quality of the included studies was poor. Therefore, large, well-designed studies are needed to confirm these findings in the future.
Ethical approval Not applicable.
Source of funding This research was supported by the Program for Innovative Research Team (2011-CXTD-09) of Beijing University of Chinese Medicine, the grant number 201207007 from the State Administration of Traditional Chinese Medicine in China, and the postgraduate program (532/0100604225) from Beijing University of Chinese Medicine. The study was also
Y.-Y. Wang et al. supported with a grant from the Norwegian Directorate of Health.
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.2014.06.004.
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