Qigong and Fibromyalgia: Randomized Controlled Trials and Beyond

Introduction. Qigong is currently considered as meditative movement, mindful exercise, or complementary exercise and is being explored for relief of symptoms in fibromyalgia. Aim. This narrative review summarizes randomized controlled trials, as well as additional studies, of qigong published to the end of 2013 and discusses relevant methodological issues. Results. Controlled trials indicate regular qigong practice (daily, 6–8 weeks) produces improvements in core domains for fibromyalgia (pain, sleep, impact, and physical and mental function) that are maintained at 4–6 months compared to wait-list subjects or baselines. Comparisons with active controls show little difference, but compared to baseline there are significant and comparable effects in both groups. Open-label studies provide information that supports benefit but remain exploratory. An extension trial and case studies involving extended practice (daily, 6–12 months) indicate marked benefits but are limited by the number of participants. Benefit appears to be related to amount of practice. Conclusions. There is considerable potential for qigong to be a useful complementary practice for the management of fibromyalgia. However, there are unique methodological challenges, and exploration of its clinical potential will need to focus on pragmatic issues and consider a spectrum of trial designs. Mechanistic considerations need to consider both system-wide and more specific effects.


Introduction
Fibromyalgia (FM) is characterized by widespread pain and multiple somatic symptoms. In the 1990s, the American College of Rheumatology (ACR) provided criteria involving presence of allodynia (tender point examination) and other symptoms including fatigue, sleep disruption, and gastrointestinal symptoms [1]. A recent PubMed search indicated 361 English language articles with "fibromyalgia" as a keyword in the 20-year period prior to the 1990 ACR criteria being published, and 3844 articles in the 20-year period following publication attesting to growing recognition of the condition [2]. In 2010, modified criteria were developed to address the issue of tender points, associated symptoms, and the observation that FM might represent an extreme end of a pain continuum; updated criteria include a chronic widespread pain index and symptom severity scale for cognitive symptoms, sleep disturbance, fatigue, and somatic symptoms [3].
The prevalence of FM is 0.5-5% while that of chronic widespread pain is 10-20% [2,4]. FM is a challenging condition, both for those who experience it and for those who treat it [5,6]. Longitudinal benefits are modest despite use of currently approved drugs [7,8]. Mechanisms involved in FM include central sensitization, altered central pain processing, impaired endogenous pain regulation mechanisms, and disturbances in the hypothalamus-pituitary-adrenal axis, the autonomic nervous system, and peripheral tissues [2,4]. Current treatment guidelines emphasize patient education, pharmacological and nonpharmacological approaches, and treatment of comorbid conditions [5,9,10].
Qigong (Chi Kung, Chi Gong) refers to cultivation (practice, discipline) of qi (life energy, energetic essence) and has a long history in China, extending thousands of years, as a health and wellness practice [11][12][13]. Many forms of qigong have developed, reflecting particular contexts for development (martial arts, health practice, and spiritual 2 Evidence-Based Complementary and Alternative Medicine practice). The modern history of qigong began in China in the 1950s; western interest grew in the 1960s and has further accelerated in recent decades. As a self-practice, internal qigong involves dynamic (movement) and static (quiescent) elements and involves regulation of movement, breath, and awareness. When highly developed by skilled practitioners, qigong can be applied as external qigong, whereby the practitioner directs energy (using hand movements, focused attention) towards an individual to improve the flow of qi. In the past decade, qigong has been characterized as "mindful exercise" [14] or "meditative movement" [15], and these conceptualizations are useful for considering qigong in relation to other practices such as mindfulness, meditation, and conventional exercise.
There have been several recent (published 2012-2013) systematic reviews and meta-analyses of randomized controlled trials (RCTs) of qigong for fibromyalgia. Some consider qigong as a distinct entity [16,17] while others consider it as a "meditative movement therapy" or "complementary and alternative exercise" whereby qigong, tai chi, and yoga are clustered together [18,19]. There also have been reviews of qigong in the even broader context of complementary and alternative therapies [20,21]. These overviews reach different conclusions regarding the potential of qigong for fibromyalgia, ranging from cautious (may be useful, but emphasize the limited quality of trials and methodological challenges) [16,17] to indicating it may be a useful component of multimodal treatment [18,19] and even to proposing a rational usage algorithm (for complementary therapies in general) [21].
In addition to RCTs, there is an increasing recognition of the need for pragmatic or effectiveness trials to provide information for improving the management of chronic pain [22]. Furthermore, multiple diverse trial designs need to be considered for exploring the effectiveness of complementary and alternative medicine (CAM) modalities [23][24][25][26]. Several trial variations are now available and provide additional insight into potential benefits of qigong. The purpose of the present narrative review paper is to describe (1) evidence for efficacy of qigong in FM (RCTs, reviews, and others) published to the end of 2013 and to discuss (2) the relationship between practice and outcomes, (3) methodological issues that require attention, and (4) potential mechanisms of action of qigong.

RCTS of Qigong for Fibromyalgia
There are 7 RCTs of qigong for FM published to the end of 2013 (Table 1). Six of these trials involved adults ( = 367, mean age 45-57 years, and mean FM duration 5-15 years) and one involved children and adolescents ( = 30, mean age 13 years). Three RCTs involved qigong instruction and daily home-practice over 6-8 weeks and monitored adherence to practice [27][28][29]. One trial over 7 weeks did not appear to require home-practice for the qigong group but did for the comparator group [30]. Two RCTs over 8-12 weeks involved weekly group sessions where qigong was part of a multimodal session (with meditation, body awareness, and education) and no home-practice was performed [31,32].
Two RCTs ( = 57, = 100) involving qigong (7-8 weeks, daily home practice) compared outcomes to wait-list subjects and reported significant benefits in pain, impact, sleep, physical and mental function, and quality of life following the intervention and at 4-6 months of follow-up [27,29]. Post-intervention standard mean differences (SMD, or Cohen's d, is the difference between means divided by the pooled standard deviation (M1−M2)/√[ 1 2 + 2 2 ]; values of ≥ 0.2 are small, ≥ 0.5 are medium, and ≥ 0.8 are of large effect sizes) across these domains were 0.44-0.73 [27] and 0.71-1.16 [29] compared to the wait-list group. At follow-up, there was some drift but significant effects were maintained (SMDs 0.2-0.7 in [27]; 0.52-0.72 in [29]). A smaller RCT ( = 14) of qigong (7 weeks, daily home practice) compared qigong to sham exercise and reported significant postintervention benefits in the qigong group but not the sham exercise group (effect sizes 0.99-1.98), but there was no follow-up [28]. One RCT ( = 30) compared qigong (QG) to another movement and body awareness method (Rességuier method, RM) and compared two groups in which these methods were used sequentially for 7 weeks (RM + QG, QG + RM). The first 7 weeks of this trial represents a comparative trial of QG versus RM. In both groups, there were significant and comparable postintervention improvements in pain, impact, mood, and function following the first intervention; addition of the second intervention did not lead to further improvement, but benefits were maintained at 6-7 months [30]. SMDs compared to baseline ranged from 0.7 to 1.5 postintervention and at follow-up.
Two earlier RCTs ( = 128, = 38) of qigong involved weekly sessions (8-12 weeks, but no home practice) in which qigong was part of a multimodal approach; both noted no differences in pain or impact compared to the comparison group (education support, normal daily activity) [31,32]. There were beneficial changes across time in both the intervention and the control groups in one study [31], but few differences in the other [32]. The RCT in children and adolescents ( = 30) compared qigong to aerobic exercise (3 sessions/week) and monitored many aspects of physical function and functional outcomes; benefits were reported in both groups, but the aerobics group performed better on several measures [33].

Other Trials of Qigong for Fibromyalgia
Additional information on the effects of qigong for FM is available from other trials that use heterogeneous approaches (Table 2). Three pilot studies examined qigong (all used different forms) in an open-label manner over 3-9 weeks with follow-up to 3-6 months. Creamer et al. [34] ( = 28) included qigong as one component of a multimodal intervention (weekly for 8 weeks, no home practice) and observed significant improvements in many areas that were maintained over time (4-6 months); however, it is not possible to discern an effect of qigong in this study due to the Evidence-Based Complementary and Alternative Medicine 3 Note: (1) The study addressed both physical fitness and clinical symptoms and monitored multiple outcomes.
(2) Trial is limited by the small sample size and lack of follow-up data.   Evidence-Based Complementary and Alternative Medicine Note: (1) Comparative trial between two active methods considered as "mind-body" practices. Both groups represent potentially active interventions.
(2) Initial 7 weeks is comparison trial; the remainder of study represents a crossover trial but can also be considered an add-on trial.  who completed the 6-month trial. (2) Pre-post SMD values for pain, impact, and physical function were 0.6-0.9 following the intervention and at follow-up.   versus those who did not complete the extension ( = 7), with more favourable health effects reported by completers.
Comments recapitulate quantitative measures but also cover other areas.

Thematic comments:
There was a clear difference in comments on pain, sleep, and quality of life, by those who practiced per protocol versus those who practiced minimally, and these reflect quantitative differences between the two groups. Those who practiced an intermediate amount also had positive comments on experiences, but there was a difference in tone (more moderated) compared to those who practiced per protocol. Evidence-Based Complementary and Alternative Medicine 9 multimodal nature of the intervention (included educational, cognitive/behavioural, and relaxation/meditation elements, all of which potentially contribute to benefit). Chen et al. [36] ( = 13) used external qigong (5-7 sessions over 3 weeks) and observed significant pre-post intervention improvements (SMDs 0.7-1.9) that were maintained at follow-up. Two participants in this study had such marked reductions in symptoms that they were considered "cured" by the intervention, and their end symptomology was minimal. Lynch et al. [37] ( = 23) examined qigong practice over 9 weeks with daily home-practice and follow-up to 6 months; significant improvements in several areas were observed over time. The latter trial informed the conduct of a larger RCT (Table 1(6)). Attrition in the three pilot studies over 3-9 weeks was 23-39%.
Information on the effects of extended practice of qigong is available from case studies and an extension trial (Tables 2(4) and 2 (5)). There are qualitative case reports of individuals ( = 2) who engage in extended qigong practice (≥1 hr/day) over longer periods of time (1-2 years) in a community setting which indicate marked reductions in FM symptoms (pain, sleep disturbance, impact, mood, and quality of life), as well as health improvements in other areas (allergies, vision, skin, and circulation) [38]. There is another case of extended qigong practice in a community setting providing marked health benefits in several areas [41]. Effects of long-term practice of qigong in FM also were addressed in an extension trial in which = 20 who had completed an earlier controlled trial went on to a further 6-month phase (total practice ≥ 1 year) [39].
= 13 completed the extension, and their outcomes indicate that extended qigong practice resulted in significant gains in core FM areas (pain, impact, sleep, and physical function and mental function) in quantitative assessments. In the = 5 subgroup who had previously voluntarily undertaken additional practice prior to the extension and who practiced the most during the extension trial, end symptomology was mild, and qualitative comments indicated additional health benefits (food allergies, chemical sensitivities, asthma, migraines, blood pressure, and vision; some discontinued several medications). The other = 8 who completed the extension phase had similar improvements in pain, impact, sleep, and physical and mental function in quantitative scores, but their end symptomology was higher (as were baselines). In addition, their qualitative comments were clearly more moderate in tone, and there was little mention of health benefits in other areas. It appears that a subgroup of individuals benefits greatly from extended qigong practice, with respect to both FM and other symptoms. The amount of practice undertaken by these individuals would be difficult to study in a prospective manner, and extension trial methodology is a useful and practical consideration for documenting effects. A qualitative post hoc analysis of comments of RCT participants who completed or did not complete the extension trial, and considered in relation to amount of practice, reveals that initial favourable experiences with the practice predispose to continued practice and better outcomes (Table 2(6)).

Methodological Issues
Qigong is a complex practice involving regulation of movement, breath, and attention, and methodological issues related to qigong studies have been considered recently [42]. Some of these relate to general experimental design (e.g., sample size, description of practice, blinding, and controls), while others relate to factors that are specific to qigong (e.g., diversity of interventions, differing doses and duration, and mixture of active factors). Tai chi research issues share many of these features [43,44]. Methodological issues particularly relevant to qigong and FM are summarized in Table 3.
The following considerations relate to studies of qigong for FM summarized in Tables 1 and 2.
(1) Plurality of Forms. Studies are from several geographic locations (United States, Canada, Sweden, and Italy) and reflect different forms that are available locally. There is considerable heterogeneity in the amount of details provided as to the nature of practice in these studies. There are no comparative trials of different forms of qigong for FM, and it is not clear whether all forms of qigong would necessarily produce the same results.
(2) Components of Practice.The recent designation of qigong as "meditative movement" and "mindful exercise" has been useful in terms of identifying core elements (deconstruction), using recognizable language to define instructions (operationalization), and providing relevant comparisons (qigong versus other movements or meditative practices); these facilitate the design, conduct, and interpretation of clinical trials into qigong.
(3) Amount of Practice. Table 1 summarizes RCTs that examined qigong over 6-8 weeks and involve regular/daily home-practice and follow-up to 6 months (Tables 1(4)-1 (7)). These trials uniformly report significant benefits in core FM domains (pain, sleep, impact, physical and mental function, and quality of life) compared to wait-list and/or significant and sustained improvements over time compared to baseline. Trials involving weekly sessions whereby qigong was part of a mixed session noted little difference or ambiguous results and are difficult to interpret specifically in relation to qigong (Tables 1(1) and 1(2)). One trial performed a post hoc analysis in relation to amount of qigong practice and noted significant differences in outcomes between those who practiced daily and those who practiced minimally (Table 1(6)). Table 2 provides further insight, noting case studies and extension trial participants who engage in extensive practice and report markedly improved health outcomes. Collectively, this information indicates that benefit is related to amount of practice. However, with increased practice time comes increased attrition, and the number who engaged in extended practice is limited. The factors that predispose to such extended practice are not clear, but post hoc analysis of the qualitative information from a RCT does indicate that good experiences over the initial 8 weeks of practice predispose to continued practice and better outcomes (Table 2(6)).

Issue Comments
(1) Plurality of forms (i) Qigong has a long history and is part of traditional Chinese medicine; many forms have evolved; different contexts (martial arts, health benefits, and spiritual development) emphasize different elements.
(ii) Qigong is used either generically to refer to collective practices with common elements or specifically to refer to a particular form of practice.
(2) Components of practice (i) Qigong consists of movement, breath instruction, and mental/mind components.
(ii) Qigong is now characterized as "meditative movement" and "mindful exercise, " recognizing a unique form of movement.
(iii) Qigong movements emphasize softness, looseness, flowing, and relaxation; this differs from the emphasis on muscular strength or flexibility or aerobic capacity that is part of other exercise regimens.
(3) Amount of practice (i) Internal qigong involves self-practice, while external qigong involves highly skilled practitioners; most FM studies use self-practice.
(ii) Minimal amounts of practice required (threshold for effect) and relationship of amount of practice to outcomes (practice-response relationship) are important.
(iii) Threshold requirements can be explored in RCTs where the amount of practice is specified, and adherence to practice is monitored.
(iv) The practice-response relationship can be explored in a prospective or retrospective manner within RCTs. However, as the amount of practice increases, there is increased attrition, and retrospective analyses are limited by self-selection.
(v) Observational studies of those who engage in extended practice in a controlled setting, or voluntarily in a community setting, provide important information relating to the health potential of qigong.
(4) Effectiveness of practice Not all practice time is equally effective. Movements can take time to learn, and nuances of execution can matter. With mental instructions, it can be a challenge to determine parameters that reflect effective engagement.
(5) Control/comparator group (i) Some trials strive to isolate an active component of an intervention, to delineate "specific" from "nonspecific" factors.
(ii) With complex interventions, many elements (specific, nonspecific) can be contributive, and isolating specific components can be a challenge.
(6) Multiple trial designs (i) RCTs involve controlled settings, defined inclusion-exclusion criteria, predetermined primary and secondary outcomes, and comparison to placebo or comparator groups, and provide information that is relevant to the regulatory approval process.
(ii) Pragmatic trials provide "in situ" information, include more heterogeneous patient groups, compare outcomes to usual care or standards of care, include long-term follow-ups, and provide information that is relevant to clinical practice. (iii) Qualitative research provides further valuable insights.
(iv) It is impossible to blind qigong practice, and multiple trial designs are needed to explore efficacy.  (ii) Comparisons can be between groups (compared to control or comparator) or within groups (compared to baseline).
(iii) With the latter approach, it is possible to consider outcomes in relation to those considered to be clinically significant, which have been defined by clinicians and patients.
(iv) For a condition with multiple symptoms, an intervention that provides benefits in multiple core domains (pain, sleep, mood, impact, and quality of life) will be of particular relevance for clinical practice.
(4) Effectiveness of Practice. Not all practice time is equally effective with meditative practices, and it can be a challenge to address this component. A meditative movement inventory [45] has been designed but is not validated or widely used. The mindfulness and body awareness literatures face a similar challenge and also are developing measures to address this issue [46,47]. Table 1 use a variety of control groups, and each has its merits and Evidence-Based Complementary and Alternative Medicine 11 limitations. It is important to distinguish between a group where the intent is to utilize a sham (presumed inert) procedure which lacks the active component and a group where the intent is to compare effects of qigong to another active group. With the latter approach, there may not be a difference between qigong and active comparators in betweengroup analyses. However, within-group analysis compared to baseline for both groups can be assessed and considered in relation to benchmark clinical outcomes, and this provides a further valuable perspective.

(5) Control or Comparison Group. RCTs in
(6) Multiple Trial Designs. RCTs and pragmatic trials for chronic pain have unique strengths and limitations and inform different contexts (regulatory processes, clinical care) [22]. Both approaches provide information on qigong for FM (Tables 1 and 2). Mixed-methods research that includes qualitative information is of further value, especially with extended practice.
(7) Participants. The mean age of adult participants in qigong for FM trials ranges from 42 to 57 years and the mean FM duration ranges from 5 to 15 years, and these are typical of FM trials in general. One trial conducted a post hoc analysis of those with FM duration above and below the median of 9 years and observed no differences in pain and impact with qigong [29]. There is the potential to explore subgroups in a prospective manner in relation to factors relevant to self-practice (e.g., locus of control, motivation, and psychological characteristics). Furthermore, with a practice that is less familiar than other practices (exercise, meditation, and yoga), it may be important to determine attitudes towards complementary and alternative therapies and especially in relation to extended practice.
(8) Outcomes. FM outcomes can align with general IMM-PACT guidelines for chronic pain and FM-specific OMER-ACT guidelines [48,49]. Between-group analysis of outcomes provides a statistical measure of effectiveness, but not necessarily a clinical assessment of effectiveness. Effect size analysis (standard mean difference, Cohen's d) provides an indication of whether an effect is small (≥ 0.2), medium (≥ 0.5), or large (≥ 0.8). Changes that constitute clinically important outcomes for pain (30-35% reduction from baseline) [50,51] and impact (14% reduction from baseline) [52] have been determined and provide further benchmarks. These interpreted and benchmark parameters are of particular importance for within-group analyses.

Mechanisms of Qigong
Mechanistic considerations for qigong can be global (systemwide) or specific (focus on cellular, molecular, or chemical mediators). Within a traditional framework, there is a qimatrix which interacts dynamically with physiological systems; qigong practice smooths and strengthens the circulation of qi within this system, and unrestricted qi flow leads to health and longevity [11,12]. Contemporary language for this concept is coherence and resonance within a living system matrix which allows for self-organization in a complex system leading to integrated function [11,53]. Qigong has also been characterized as a complex biopsychosocial activity [12,14,54]. Within this framework, psychological factors (e.g., cognitive/behavioral, social interactions) and physiological factors (e.g., cardiovascular fitness, autonomic nervous system regulation, central neurotransmitter systems, neuroendocrine, and stress hormone systems) contribute to mind/body integration and a state of health. A further conceptualization considers qigong as a complex intervention involving somatic regulatory systems and neurohormonal and neurotransmitter mediators; it considers movements in relation to metabolic expenditure, rhythm, and posture and reflects on interoception, imagery, and neuroplastic changes [42]. The latter acknowledges that a shortcoming of this area of investigation is a lack of taxonomy of components within recognizable categories.
Additional studies examine effects of qigong on specific functional parameters and biomarkers. An analysis of 26 trials published from 1997 to 2006 indicates that qigong has effects on immune function (white blood cells, lymphocytes), cardiovascular function (cardiac kinetics, blood pressure), and respiratory function (capacity, exchange) [55]. Other reviews note effects of qigong on biomarkers of stress, inflammation, and immune function [56,57]. Such studies are limited by the multiple forms of practice in individual studies, variable durations of practice, and variable linkages with clinical outcomes.
Some recent intriguing studies demonstrate that extended qigong practice can lead to changes at a molecular level. Thus, there is a report that extensive qigong practice (1-2 hrs daily, for at least a year) leads to altered expression of 250 genes in neutrophils compared to healthy controls, with changes characterized by enhanced immunity, downregulation of cellular metabolism, and alteration in apoptotic genes in favor of resolution of inflammation [58]. However, that study was small and did not include functional effects. Another report on a therapeutic regimen of qigong (twiceweekly group practice for 5 weeks, daily home-practice for 12 weeks) compared to a wait-list control group reported significant beneficial effects in chronic fatigue syndrome (which exhibits overlap with FM [59,60]) and demonstrated a significant increase in telomerase activity after 4 months of practice [61]. It will be important for future studies of qigong to examine functional outcomes and biomarkers particularly relevant to those conditions. It will also be important to consider the amount of practice time in a systematic manner in relation to these events.

Summary and Perspective
Complementary therapies represent a diverse group of therapies and practices and there are attempts being made to find their place in treatment of FM [20,21]. Evidence-based guidelines from different countries differ in recommendations relating to complementary therapies [62]. The current review focuses on qigong, considers RCTs as well as other studies, and provides an additional perspective beyond a singular focus on RCTs. Certain themes are emerging.
(1) The Magnitude and Duration of Benefit Is Significant. Regular self-practice (particularly daily) for 6-8 weeks leads to effect sizes of 0.5-0.8 and beyond for pain, sleep, impact, and physical and mental function, and benefits are maintained at follow-up at 4-6 months [27][28][29][30]. These effects are manifest when compared to wait-list subjects and/or baselines, and effects are consistently moderate-to-large over a range of core domains for FM. Other body awareness regimens practiced diligently (daily, for 7 weeks) produce similar effects to qigong [30]. While there can be concern over whether effects of qigong are specific or nonspecific, and this is relevant to regulatory and mechanistic considerations, the observation most relevant to clinical care is magnitude of post-intervention effects that are sustained over time. The magnitude of other nonpharmacological approaches can be similar to qigong, while pharmacological effects are generally modest [10,[63][64][65]. This emphasizes the need to more fully explore nonpharmacological modalities for FM.
(2) The Amount of Qigong Practice Matters. There has been limited systematic assessment of the relationship of outcomes to amount of qigong practice, but several observations are relevant. Thus (a) RCTs that utilize limited amounts of qigong practice (weekly session) report more limited and ambiguous outcomes compared to those that engage in regular practice (6-8 weeks, daily practice); (b) outcomes are related to amount of practice within a trial (minimal practice versus daily practice); (c) extended practice (≥1 hr/day, ≥6-12 months) leads to marked health benefits in FM and other areas. Practice time and compliance will be important to consider in future controlled trials and in systematic reviews and meta-analyses of qigong.
(3) There Is a Need for Additional Exploration of Qigong. The literature on qigong for FM is limited by the small number of RCTs and heterogeneity of qigong styles and study designs, but the magnitude, scope, and duration of beneficial effects in core domains of FM with regular qigong practice are intriguing and the practice merits further attention. The benefits of extended qigong practice are particularly notable, but there are few such reports. There is a particular need to further explore extended qigong practice in observational trials, both as extension trials to RCTs, and in those who practice in a community setting. Thus, a recent review of FM guidelines from several countries concluded by noting "FM cannot be cured by any therapy" [62] yet extended qigong practice has produced marked health benefits in FM in a subset of individuals, and their experiences can provide valuable insights. It is impossible to blind qigong practice, so it will be important to examine intact systems of practice. Additional studies need to make direct comparisons to other practices (exercise, other movements, and meditative methods) and with drug regimens, psychological methods (e.g., cognitive/behavioural therapy), and even combinations of such approaches (multimodal therapy). They also need to examine components of practice (deconstruct elements, work towards a more uniform and recognizable taxonomy) and address mechanistic substrates (at systems, cellular and molecular levels). Finally, barriers to the practice of qigong need to be identified (e.g., nature of instruction, conceptualization, language, optimal training regimes, motivating factors, and subgroup factors) as these can impact on our understanding of the health potential of this practice.