Acupoint Stimulation for Fibromyalgia: A Systematic Review of Randomized Controlled Trials

Background. Acupoint stimulation is popular for treatment of fibromyalgia though there is lack of comprehensive evaluation of current clinical evidence for its effect and safety. Objective. To systematically review the beneficial effects and safety of acupoint stimulation for fibromyalgia. Methods. We searched six electronic databases for randomized trials on acupoint stimulation for treatment of fibromyalgia. Two authors extracted data and assessed the trial quality independently. RevMan 5.2 software was used for data analyses with effect estimate presented as (standard) mean difference and a 95% confidence interval. We defined minimum, medium, and large SMD effect sizes as 0.3, 0.5, and 0.75. Results. 16 RCTs with 1081 participants were involved in this review. Only two trials were evaluated as low risk of bias. Meta-analysis showed that acupuncture alone or combined with cupping therapy was superior to conventional medications on reducing pain scores and/or the number of tender points. However, acupuncture showed no better than sham acupuncture on pain reduction. There was no serious adverse event reported to be related to acupoint stimulation. Conclusions. Acupoint stimulation appears to be effective in treating fibromyalgia compared with medications. However, further large, rigorously designed trials are warranted due to insufficient methodological rigor in the included trials.


Background
As nonspecific rheumatism, fibromyalgia (FM) is a disorder in which typical symptoms are chronic widespread muscularskeletal pain and stiffness accompanying with fatigue, anxiety, sleep disorder, and/or irritable bowel syndrome [1]. The well known diagnostic criterion for this disease was developed by the American College of Rheumatology (ACR) in 1990 [2], and the latest version of this diagnostic criterion was updated in 2009 [3]. The main purpose of treatment for FM is to alleviate the pain and improve the quality of life for FM patients [4].
Without the curative medications for the entire scope of symptoms and disabilities associated with FM [4], complementary therapies are commonly used by FM patients, such as acupuncture, herbal medicine, and massage. Systematic reviews were also conducted to summarize the clinical evidence of therapeutic effect of those complementary therapies in treating FM. Mayhew and Ernst [5] collected results from five randomized controlled trials in 2007 and demonstrated that due to the small sample size and low methodological quality of included trials, acupuncture could not be recommended for FM. Three years later, other two systematic reviews [6,7] draw the similar conclusions with three more trials included. Recently, a Cochrane review [8] which is entitled as "Acupuncture for treating fibromyalgia" was published. With nine included trials, it concluded moderate level evidence that acupuncture had no better effect for pain relief compared with sham acupuncture, and there was low to moderate level that evidence showed that acupuncture was better than standard therapy or antidepressant for improving pain. However, all these four reviews only included English articles and mainly observed the comparison between acupuncture and sham acupuncture. In our previous review [9], 12 trials focusing on acupuncture were included, and the result showed that even though acupuncture showed no significant effect compared with sham acupuncture (MD −0.55, 95% CI −1.35 to 0.24, = 0.17, 2 = 69%) on pain reduction, there were significant effect of acupuncture on reducing 2 Evidence-Based Complementary and Alternative Medicine the number of tender points (MD −3.21, 95% CI −4.23 to −2.11, < 0.00001, 2 = 0%), and pain scores (MD −1.78, 95% CI −2.24 to −1.32, < 0.00001, 2 = 0%) compared with conventional medications. We also found that, besides acupuncture, other point stimulation therapies, such as cupping therapy, were commonly used in clinics for treatment of FM.
Acupoint stimulation therapy includes acupuncture, cupping therapy (which involves applying suction by placing a vacuumized, usually by fire, cup or jar on points or affected body surfaces to induce local hyperemia or haemostasis), moxibustion (which involves the controlled burning of material, typically mugwort herb, at certain points or areas of the body surface), point injection (which involves injecting medication into an acupuncture point), point embedding (which involves embedding in the skin over the point with a small needle (s) or medicated catgut), or combination of two or more of those acupoint stimulation.
In traditional Chinese medicine (TCM) theory, stagnation of qi activity leads to the stasis of blood which causes pain [10]. Therefore, the potential mechanism of acupoint stimulation for FM is to regulate the qi and blood, combined with dispelling cold and removing damp. Though acupoint stimulation was popularly employed in treating FM, there is no systematic review that evaluates the clinical evidence of all types of acupoint stimulation. This systematic review aims to update the evidence from RCTs to evaluate the therapeutic effect and safety of different types of acupoint stimulation therapies for FM.

Inclusion Criteria.
We included parallel-group RCTs of any kind of point stimulation therapies including acupuncture, cupping therapy, point injection, point catgut embedding, or moxibustion, compared with no treatment, placebo, or conventional medication in patients with FM. We also included combined therapy with acupoint stimulation and other interventions compared with other interventions in RCTs, or combined therapy of two kinds of point stimulation therapies compared with medication or other interventions. FM should be diagnosed according to recognized criteria. Primary outcome was change of pain intensity, and secondary outcomes included improvement of relevant symptoms, such as depression or quality of life and adverse events. There was no limitation on language and publication type. , and all the searches ended at May 2013. The search terms included "fibromyalgia, " "fibrosis, " "fibrositis, " "myofascitis, " or "myofibrositis" combined with "acupuncture, " "electroacupuncture, " "auricular therapy, " "acupoint, " "point embedding, " "point injenction, " "cupping, " "moxibustion, " or "meridian. " Two authors (Huijuan Cao and Mei Han) selected studies for eligibility and checked against the inclusion criteria independently.

Data Extraction and Quality Assessment.
Two authors (Huijuan Cao and Mei Han) extracted the data from the included trials independently. Selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias were assessed according to the criteria from the Cochrane Handbook for Systematic Reviews of Intervention [11]. There were three potential bias judgments: low risk, high risk, and unclear risk. A judgment of low risk was made when all the seven items met the criteria as "low risk, " a judgment of high risk of bias was made when at least one of the seven items was assessed as "high risk. " 2.4. Data Analysis. Data were summarized using risk ratio (RR) with 95% confidence intervals (CI) for binary outcomes or mean difference (MD)/standard mean difference (SMD) with 95% CI for continuous outcomes. For pain reduction, at least 30% difference of VAS scores are needed to be detected after treatment to achieve the minimum clinical therapeutic effect [12]. Thus, we defined minimum, medium, and large SMD effect sizes as 0.3, 0.5, and 0.75. We used Revman5.2 software from the Cochrane Collaboration for data analyses. Meta-analysis was used if the trials had an acceptable homogeneity on study design, participants, interventions, control, and outcome measures. Statistical heterogeneity was tested by examining 2 [13], meaning that an larger than 50% indicates the possibility of statistical heterogeneity. Both fixed effect model and random effects model were used if there was possibility of statistical heterogeneity among trials. If 2 was less than 50%, only a fixed effect model was used for meta-analysis. Publication bias was explored by funnel plot analysis. Subgroup analyses were conducted to determine the evidence for the different point choice or the different treatment duration if data were sufficient. Sensitivity analyses were in order to determine whether the conclusions were differed if (1) eligibility was restricted to studies without high risk of bias; (2) a fixed effect/random effect model had been applied.

Methodological
Quality. According to our predefined quality assessment criteria, two [19,20] out of the 16 trials (12.5%) were evaluated as low risk of bias, ten trials were evaluated as high risk of bias, while the other four included trials [14,18,27,29] as unclear risk of bias ( Figure 2 Methodological quality summary: review authors' judgments about each methodological quality item for each included study).
Evidence-Based Complementary and Alternative Medicine 9
One trial [26] observed the comparison between moxibustion and medication (amitriptyline 10-30 mg daily) for treating FM.
Three trials [15,21,24] tested therapeutic effect of combination therapies of acupoint stimulation for fibromyalgia. Two trials [15,21] compared acupuncture and cupping therapy plus medication with medication only (amitriptyline 25 mg daily), one trial [21] compared acupuncture and cupping therapy with medications, and one trial [24] compared acupuncture plus point injection with amitriptyline (25-50 mg daily).
Due to the insufficient number of the included trials in one meta-analysis, we could not perform a meaningful funnel plot analysis. Results of meta-analysis were listed in Table 2 (estimate effect of included trials in meta-analyses), while results of each individual trials which could not be synthesized in a meta-analyses were concluded in Table 3 (characteristics of randomized controlled trial outside of meta-analysis).
Meta-analysis showed that acupuncture was better than antidepression drugs (amitriptyline or fluoxetine) for improving depression (SMD −0.67, 95% CI −1.10 to −0.25, 2 = 0%, fixed model, = 0.02, 2 trials). Two trials also demonstrated that combination of acupuncture and cupping therapy plus medications was better than medications alone for treating FM related depression ( < 0.01); however, meta-analysis could not be conducted due to the significant statistical heterogeneity between trials.

Adverse Events.
Only three trials described adverse events [14,21,29], all of which were related to acupuncture or medications. The adverse events of acupuncture included bruising, nausea (3%), fainting (0.3-5%), discomfort at the sites of needle insertion or simulated needle insertion (37%), and a small amount of bleeding (0.02%). One trial [14] reported that patients assigned to simulated acupuncture (29%) had significantly less discomfort than those assigned to real acupuncture (61%), acupuncture for an unrelated condition (70%), or sham needling (64%). Few patients (up to 8.3%) with palpitations, fainting, dry mouth, fatigue, and constipation were reported from control medications. The remaining thirteen trials did not report related information about adverse events during the treatment.    Acupuncture versus sham laser acupuncture There was significant difference between acupuncture and sham treatment in pain reduction measured for all 3 methods by end of treatment. At follow up of 3 months after the last treatment, no significant changes were observed ( > 0.05).
Sprott 1998 [27] Acupuncture versus sham laser acupuncture The data for pain reduction by tender points were not completely reported, but the results showed that the number of tender points was not significantly decreased after acupuncture treatment in comparison to sham treatment ( > 0.05). The intensity of pain, measured by the VAS, also showed no significant reduction, neither immediately at the end of treatment or 2 months after the treatment ( > 0.05). Acupuncture versus no treatment Sprott 1998 [27] Acupuncture versus no treatment The number of tender points was significantly decreased after acupuncture treatment in comparison to no treatment ( > 0.05). Acupuncture plus standard cares versus standard cares alone Targino 2008 [28] Acupuncture plus tricyclic antidepressants and exercise with tricyclic antidepressants and exercise Patients in acupuncture group were significantly better than the control group in terms of VAS scores ( < 0.001), pressure pain threshold (PPT) ( < 0.001), the number of tender points below 4 kg/cm 2 ( < 0.001), and in 5 subscales of the SF-36 ( < 0.05).
No serious adverse event was reported in all included trials.

Discussions
Our review with 16 included trials demonstrates that acupuncture or combination of acupuncture and cupping therapy was significantly more effective than conventional medications (anti-depression drugs or analgesic antipyretic) on reducing pain and improving the FM related symptoms (such as depression or fatigue), and however, the therapeutic effects of other types of acupoint stimulation are uncertain due to the limited numbers of clinical trials.
There are several limitations of this review. The quality of the included studies is generally poor, which indicates high or unclear risk of bias due to insufficient reporting of methodological components from the trials. There was unclear description of randomization procedure and lack of blinding in half of the trials which may create potential performance bias and detection bias as patients and researchers might be aware of the therapeutic interventions. Intentionto-treat analysis was not applied in most of the included trials. We were limited in our ability to perform meta-analysis due to the incomplete outcome data reporting in three included trials [14,25,28]. Outcomes such as cure, markedly effective, effective, or ineffective were used in six trials, these are not validated, and the finding will be hard to interpret. Consequently, the interpretation of these positive findings needs to be cautious, and the study methodology needs to be improved for future confirmatory studies.
Though we could not perform a meaningful funnel plot due to the insufficient number of included trials in meta-analysis, there was potential publication bias among included trials. All the nine English publications reported no significant statistical difference between groups, but five out of seven Chinese publications showed significant advantages of acupoint stimulation compared with control. One of the potential reasons is all but one trial [18] conducted outside China employed the comparison between acupuncture and sham acupuncture, but sham acupuncture may not be appropriate as a placebo against which to evaluate the therapeutic effect of real acupuncture [34]. Due to the sociocultural background, Chinese participants may have a preference for acupuncture treatment compared to a pharmacological intervention, which may create potential performance bias and affect the results of assessment with patients report outcome. Besides, no trial used syndrome differentiation for acupuncture point selection.
Comparing to previous systematic reviews [6][7][8] which assessed acupuncture, our review included two more English publications and four more trials conducted in China. Results of the comparison between acupuncture and sham acupuncture were similar to other reviews due to the same data source; however, regardless of the poor methodological quality of included trials, we found that acupuncture compared to medications showed significant therapeutic effects on improving FM related symptoms (including pain, fatigue, depression, or insomnia). We also assessed trials focusing on the effect of other acupoint stimulation, but no confirmed conclusions could be drawn due to the insufficient number of relevant trials.
Considering the small sample sizes and unclear or high risk of bias of the current included trials, we suggest that trials with rigorous designing should be conducted to further confirm the effectiveness of acupoint stimulation in treating FM. Although there is not ideal placebo for acupoint stimulation and blinding of the patients and practitioners might be very difficult for acupuncture or herbal medicine, blinding of outcome assessors should be attempted as far as possible to minimize performance and assessment biases. Choosing outcome measures should be based on international consensus and include continuous data and daily average pain scores from baseline to study completion. Using appropriate methods (such as intention to treat analysis) to deal with missing data is vital as is the application of welldefined diagnostic criteria, such as ACR 2009. Reporting of trials should follow the Consolidated Standards of Reporting Trials (CONSORT) [35] or Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) [36] to explicitly explain the processes involved transparently. Our preliminary conclusions suggest that patients with FM might benefit from acupoint stimulation, especially acupuncture or combination of acupuncture and cupping therapy. However, more high quality clinical evidence is needed to further testify this conclusion.

Key Message.
There is low level evidence showing that acupuncture or a combination of acupuncture and cupping therapy was significantly more effective than conventional medications (antidepression drugs or analgesic antipyretic) on reducing pain and improving the FM related symptoms (such as depression or fatigue).
Acupuncture seems to have no better effect than sham acupuncture with regard to pain relieve in patients with fibromyalgia according to the current moderate level clinical evidence.
The therapeutic effects of other types of acupoint stimulation are uncertain due to limited numbers of clinical trials.