Complementary and alternative medicine treatments in the ...

Orient Pharm Exp Med (2013) 13:85–93 DOI 10.1007/s13596-012-0096-9

REVIEW

Complementary and alternative medicine treatments in the management of chronic fatigue syndrome: a systematic review of randomized controlled trials Koh-Woon Kim & Won-Suk Chung & Mi-Yeon Song & Seok-Hee Chung

Received: 7 August 2012 / Accepted: 30 October 2012 / Published online: 15 November 2012 # Institute of Oriental Medicine, Kyung Hee University 2012

Abstract Chronic fatigue greatly deteriorates the quality of life and is a frequent reason for consulting a physician. Since conventional medicine usually provides limited help, patients with chronic fatigue syndrome (CFS) tend to use complementary and alternative medicines (CAM). The objective of this review was to summarize the evidence of the effectiveness of CAM treatments in the management of CFS. Electronic databases were systematically searched up to December 2010. All randomized controlled trials (RCTs) of CAM used in patients with CFS were considered for inclusion if they included placebo controls or were controlled against a comparator intervention. Methodology quality was assessed using modified Jadad score and the Cochrane criteria for allocation concealment. A total of 414 possibly relevant articles were identified, of which eight RCTs met our inclusion criteria: three dietary interventions, two herbal medicines, one distant healing, one homeopathic medicine, and one massage. The methodology quality of the trials varied, and on average, was moderate (mean Jadad score, 3.625; range, 0–5). Details on allocation concealment were reported for seven of the trials, of which six were classified as adequate. Of the eight included RCTs, three reported significant differences between the treatment and placebo groups in the primary outcome measures. However, the total number of RCTs included in the analysis was too small to provide definite evidence for the effectiveness of The research was supported by the 2nd grant in 2010 for excellent research articles from Graduate School of Korean Medicine, College of Korean Medicine, Kyung Hee University. K.-W. Kim : W.-S. Chung : M.-Y. Song : S.-H. Chung (*) Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea e-mail: [email protected]

CAM in treating CFS. More RCTs on the effectiveness of CAM in the management of CFS should be conducted with larger patient samples, longer treatment periods, and appropriate methodology. Keywords Complementary and alternative medicine . Chronic fatigue syndrome . Randomized controlled trials . Systematic review

Introduction Chronic fatigue syndrome (CFS) is an illness characterized by a subjective feeling of tiredness or lack of energy lasting for longer than 6 months and associated with symptoms such as memory and concentration difficulties, muscle aches, sleep disturbances, and headache, for which no definite cause has been identified. The syndrome is diagnosed by exclusion of other explanatory diseases (Fukuda et al. 1994). Diagnostic criteria for CFS commonly used in research and clinical practice are the Oxford criteria (Sharpe et al. 1991) and the Centers for Disease Control and Prevention (CDC) criteria (Fukuda et al. 1994) (Table 1). The point prevalence of CFS, according to the Oxford criteria, is estimated to be 0.5 % for a population aged 18–45 years without comorbid psychological disorders (Wessely et al. 1997). A review of CFS treatments concluded that cognitive behavioral therapy (CBT) and graded exercise therapy proved somewhat beneficial, but evidence for benefits from pharmacological therapies is weak (Whiting et al. 2001). When conventional medicine fails, patients often turn to complementary and alternative therapies. There are indications that patients seeking treatment for CFS might seek help from complementary and alternative medicines (CAM) (O’Dowd et al. 2006). Several unconventional

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Table 1 Oxford and Centers for Disease Control and Prevention (CDC) Criteria for Chronic Fatigue Syndrome (CFS) case definition Oxford criteria

CDC criteria

Severe disabling fatigue affecting physical and mental functioning that Severe disabling fatigue with substantial functional impairment, which is present for at least 50 % of the time and has been present for at least has been present for at least 6 months. 6 months. Cognitive or neuropsychiatric symptoms may be present. The condition is of definite onset and to reach a diagnosis, known Four other symptoms are required: impaired memory or concentration, physical causes of chronic fatigue should be excluded. The presence sore throat, tender cervical or axillary lymph nodes, muscle pain, of psychosis, bipolar depression, eating disorders, or organic brain multijoint pain, new headaches, unrefreshing sleep or post exertion disease precludes the diagnosis of CFS. malaise.

therapies and herbal remedies have been evaluated for their efficacy in ameliorating chronic fatigue (Hartz et al. 2004; Lijue 2005). However, a few systematic reviews of randomized controlled trials (RCTs) tried to assess the effectiveness of CAM treatments in the management of CFS, which concluded that although studies examining the use of acupuncture, moxibustion and herbal medicines for chronic fatigue were located, methodologic limitations resulted in the exclusion of all studies (Wang et al. 2008; Wang et al. 2009c; Adams et al. 2009). The aim of the present review was to summarize and critically evaluate the evidence from RCTs related to the effectiveness of CAM treatments in the management of CFS.

Methods Data sources The National Centre for Complementary and Alternative Medicine defines CAM as “a group of diverse medical systems, practices and products that are not presently considered to be part of conventional medicine” (NCCAM 2007). Another definition of CAM is “it is a holistic approach to patients and involves both individual physical and spiritual dimensions” (Hardy-Pickering 2007). The selection of potential CAM topics followed mostly the CAM definition of the National Institute of Health (NIH). Some techniques that were considered CAM in the past have become mainstream (for example, patient support groups and CBT), for which CBT and graded exercise therapy were not included in the analysis (O’Dowd et al. 2006; Fulcher and White 1997; Moss-Morris et al. 2005; Powell et al. 2001; Stubhaug et al. 2008; Wallman et al. 2004). The following electronic databases were searched from their inception to December 2010 (the first search was completed in October 2009): Cochrane Central Register of Controlled Trials, Medline, EMBASE, CINAHL, Allied and Complementary Medicine Database (AMED), Korean medical databases (which include the National Assembly

Library, KoreaMed, Korean Studies Information Service System, DBpia, and Korea Institute of Science Technology Information and Research Information Service System) and Chinese Journals Fulltext Database (CNKI). The search terms used were (“chronic fatigue syndrome” OR “CFS”) AND (“complementary medicine” OR “alternative medicine” OR “CAM” OR “biologically based” OR “energy medicine” OR “reiki” OR “johrei” OR “qi gong” OR “healing touch” OR “intercessory prayer” OR “therapeutic touch” OR “distant healing” OR “putative energy” OR “manipulation” OR “alexander technique” OR “bowen” OR “chiropractic” OR “craniosacral” OR “feldenkrais” OR “massage” OR “osteopathic” OR “reflexology” OR “rolfing” OR “bodywork” OR “neural therapy” OR “acupressure” OR “acupuncture” OR “electroacupuncture” OR “meridian” OR “acupoint” OR “bee venom” OR “apiotherapy” OR “bee venom therapy” OR “bee venom acupuncture” OR “auricular acupuncture” OR “moxibustion” OR “cupping” OR “cup-moving” OR “mind-body medicine” OR “meditation” OR “imaging” OR “placebo” OR “expectancy” OR “breathing exercise” OR “whole medicine” OR “traditional Chinese medicine” OR “ayurvedic” OR “naturopathy” OR “homeopathy” OR “anthroposophy” OR “herb” OR “phytotherapy” OR “balneo” OR “bath” OR “diet”). The search terms were adopted from a review of RCTs on CAM in fibromyalgia (Baranowsky et al. 2009). Study selection Titles and abstracts of the articles identified were checked for relevance to the CAM field, CFS, and study category (CT). Uncontrolled trials and case studies were excluded. Articles that fulfilled these inclusion criteria were obtained in full for further evaluation without restriction with respect to publication language. Confirmation of diagnosis by the Oxford or CDC criteria and mention of randomization in the study protocol were regarded as final inclusion criteria unless interventions assessed by the study could not be attributed to the CAM field such as patient support groups, CBT, and graded exercise therapy which have become mainstream. Studies assessing the efficacy of acupuncture

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treatments in the management of CFS (Wang et al. 2009a; Wang et al. 2009b; Yiu et al. 2007; Chen et al. 2012) were also excluded when there were already systematic reviews and meta-analyses on randomized controlled trials of acupuncture treatment of chronic fatigue syndrome (Wang et al. 2008; Wang et al. 2009c). Studies that operated with a within subject design were excluded. No restriction was imposed on studies with respect to blinding. Data extraction and quality assessment All articles were read by two independent reviewers (K.W.K. and W.S.C.) who validated and extracted data from the articles according to predefined criteria. The reviewers also evaluated the quality of the methodology, using the modified Jadad scoring system (Table 2) (Jadad et al. 1996). Adequacy of allocation concealment was classified by the Cochrane criteria (Table 3). Indeed, concealment has been found to be more important in preventing bias than other components of allocation, such as the generation of the allocation sequence. Thus, studies can be judged on the method of allocation concealment (Reitsma et al. 2009). The authors communicated by e-mail or telephone, and discrepancies were resolved through discussion with the other two authors (M.Y.S. and S.H.C.). Data analysis

et al. 2002; The et al. 2007; Hobday et al. 2008), one distant healing (Walach et al. 2008), one homeopathic medicine (Weatherley-Jones et al. 2004), one massage (Wang et al. 2009d), and two herbal medicines (Hartz et al. 2004; Cho et al. 2009). Key data of the included RCTs are summarized in Tables 4, 5, 6, 7 and 8. Study quality The methodology quality of the trials varied, and on average was moderate (mean Jadad score, 3.625; range, 0–5). Of the eight included RCTs, the reports of six (Hartz et al. 2004; Brouwers et al. 2002; The et al. 2007; Hobday et al. 2008; Walach et al. 2008; Weatherley-Jones et al. 2004) described the methods of randomization and those of four (Brouwers et al. 2002; The et al. 2007; Weatherley-Jones et al. 2004; Cho et al. 2009) described patient and evaluator blinding. Sufficient details of dropouts and withdrawals were described in six (Hartz et al. 2004; Brouwers et al. 2002; The et al. 2007; Hobday et al. 2008; Walach et al. 2008; Weatherley-Jones et al. 2004) reports. Details on allocation concealment were reported for seven of the trials, of which six (Hartz et al. 2004; Brouwers et al. 2002; The et al. 2007; Hobday et al. 2008; Walach et al. 2008; Weatherley-Jones et al. 2004) were classified as adequate (Table 9). Outcomes

The extracted data from RCTs related to the effectiveness of CAM treatments in the management of CFS were analyzed and divided into five categories: dietary interventions, distant healing, homeopathic medicine, massage, and herbal medicines.

Of the eight included RCTs, the reports of three (WeatherleyJones et al. 2004; Wang et al. 2009d; Cho et al. 2009) showed significant differences between the treatment and placebo groups in the primary outcome measures. –

Results Study description The searches identified 414 potentially relevant articles, of which eight met our inclusion criteria (Fig. 1). Five categories of CAM were assessed: three dietary interventions (Brouwers Table 2 Modified Jadad scale Criteria

Point

Study described as randomized Appropriate randomization method Inappropriate randomization method Patient blinded to intervention Evaluator blinded to intervention Description of withdrawals and dropouts Total

+1 +1 −1 +1 +1 +1 5

Dietary interventions Three (Brouwers et al. 2002; The et al. 2007; Hobday et al. 2008) of the RCTs that compared the effectiveness of dietary interventions with placebo reported no significant differences in any outcome measures. One of the studies (Brouwers et al. 2002) addressed the effect of a polynutrient supplement for 10 weeks on fatigue and physical activity of 53 patients with CFS. No significant differences were found between the placebo and the treated group on any of the outcome measures: Checklist Individual Strength (CIS) fatigue +2.16 (p00.984); CDC symptoms +0.42 (p00.417); Sickness Impact Profile (SIP-8) +182 (p00.297). Another study (The et al. 2007) was on the effect of Acclydine treatment combined with amino acid supplements for 14 weeks in 57 patients with CFS. Treatment with Acclydine did not result in significant differences compared with the placebo group on any of the outcome measures: CIS-fatigue +1.1 (p00.70), SIP-8 +59.1 (p00.65), and IGFBP3/IGF1 ratio −0.5 (p00.63).

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Table 3 Cochrane criteria for allocation concealment Adequate

Unclear

Inadequate

■ Centralized (e.g. allocation by a central office ■ Insufficient information to permit judgement of ■ Alternation unaware of subject characteristics) or pharmacy‘Yes’ or ‘No’. This is usually the case if the • Case record numbers controlled randomization. method of concealment is not described or not • Dates of birth or day of the week ■ Pre-numbered or coded identical containers that described in sufficient detail to allow a definite • Any procedure that is entirely transparent before allocation, such are administered serially to participants judgement – for example if the use of assignment ■ On-site computer system combined with allocations envelopes is described, but it remains unclear as an open list of random numbers kept in a locked unreadable computer file that can be whether envelopes were sequentially. assessed only after the characteristics of an enrolled participant have been entered ■ Sequentially numbered, sealed, opaque envelopes

Reviewers are required to indicate whether allocation concealment was adequate (A), unclear (B), inadequate (C), or that allocation concealment was not used (D) as a criterion to assess validity

The other RCT (Hobday et al. 2008) was conducted with 52 CFS patients randomized to either low sugar low yeast (LSLY) or healthy eating (HE) dietary interventions for 24 weeks. Participants in Fig. 1 Flowchart of the trial selection process. Abbreviations: CFS, Chronic fatigue syndrome; CAM, Complementary and alternative medicine; CT, clinical trial; RCT, randomized controlled trial

HE group were encouraged to increase fiber, fruit and vegetables to at least five portions a day and reduce consumption of fat and refined carbohydrate. Increasing fish intake to twice a week was also

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Table 4 Key data of RCTs on the effect of Complementary and Alternative Medicine (CAM) treatments in the management of Chronic Fatigue Syndrome (CFS)—dietary interventions References

Intervention

Control

Brouwers et al. 2002 Polynutrient supplement Placebo identical containing several in appearance vitamins, minerals and (co)enzymes

No. of subjects, Duration no. of groups 53, 2

The et al. 2007

Acclydine treatment combined with amino acid supplements

Placebo Acclydine 57, 2 and placebo amino acid supplements

Hobday et al. 2008

Low sugar/low yeast diet

Healthy eating diet

–

Results

10 weeks, CIS-fatigue No significant differences 6 month Number of CDC between the treatment follow-up symptoms and placebo groups in any outcome measure SIP-8 Actometer DOF 14 weeks CIS-fatigue No significant differences SIP-8 between the treatment and placebo groups in Actometer any outcome measure DOF IGF1 IGFBP3 IFGBP3/IGF1 ratio 24 weeks Chalder Fatigue No significant differences Scale between the treatment MOS SF-36 and placebo groups in any outcome measure HADS

52, 2

recommended. A high dropout rate occurred with 13 participants not completing the final evaluation (7HE/6LSLY). Intention to treat analysis showed no statistically significant differences on primary outcome measurements: Chalder Fatigue Scale −1.7 (p00.6). Distant Healing One RCT (Walach et al. 2008) on the effectiveness of distant healing for patients with CFS was included. Four hundred nine patients were randomized to either immediate or deferred (waiting for 6 months) distant healing. Half of the patients knew their treatment allocation, while half of them didn’t. There were no differences over 6 months in post-treatment Mental Health Component Summary (MHCS) scores between the treated and

Outcome measures

–

untreated groups. There was a non-significant outcome (p00.11) for healing with Physical Health Component Summary (PHCS) and a significant effect (p00.027) for blinding; patients who knew their treatment allocation became worse during the trial (−1.544). Homeopathic medicine One RCT (Weatherley-Jones et al. 2004) using a triple-blind design (patient and homeopath blinded to group assignment and data analyst blinded to group until the completion of initial analyses to reduce the possibility of bias due to data analyst) randomly assigned 103 CFS patients to homeopathic medicine or identical placebo for 6 months. Seventeen of the 103 patients withdrew from treatment or were lost to follow-up. Patients in the homeopathic medicine group

Table 5 Key data of RCTs on the effect of Complementary and Alternative Medicine (CAM) treatments in the management of Chronic Fatigue Syndrome (CFS)—distant healing References

Intervention

Control

No. of subjects, Duration no. of groups

Walach et al. 2008 Immediate distant Different distant healing 409, 4 healing: knowing (waiting for 6 months): and not knowing knowing and not knowing

Outcome measures

Results

6 months MHCS (SF-36) No significant differences between the treated and PHCS (SF-36) untreated groups in MHCS scores. There was a non-significant outcome (p00.11) for healing with PHCS and a significant effect (p00.027) for blinding.

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Table 6 Key data of RCTs on the effect of Complementary and Alternative Medicine (CAM) ttreatments in the management of Chronic Fatigue Syndrome (CFS)—homeopathic medicine References

Intervention

Control

No. of subjects, no. of groups

Duration

Outcome measures

Results

Weatherley-Jones et al. 2004

Homeopathic medicine

Identical placebo

103, 2

6 months

MFI FIS FLP

Patients in the homeopathic medicine group showed significantly more improvement of the MFI general fatigue subscale (p00.04) and the FLP physical subscale (p00.04)

–

–

showed significantly more improvement on the Multidimensional Fatigue Inventory (MFI) general fatigue subscale (one of the primary outcome measures) and the Functional Limitations Profile (FLP) physical subscale but not on other subscales. More people in the homeopathic medicine group showed clinical improvement on all primary outcomes (relative risk02.75, p0 0.09). Massage One RCT (Wang et al. 2009d) on the effects of the intelligent-turtle massage on the physical symptoms and immune functions in 182 patients with chronic fatigue syndrome has been conducted for five times a week, 10 times as a course, for two courses with a 1-week interval in between. Patients were randomly divided into an experimental group of 91 cases treated by the intelligent-turtle massage, and a control group of 91 cases treated with the conventional massage method. There was a significant difference between the two groups in the accumulated scores for improvement of the symptoms (p