Effects of Physical-Agent Pain Relief Modalities for Fibromyalgia Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Purpose We conducted a systematic review and meta-analysis to investigate the effects of the following physical-agent modalities for pain relief in fibromyalgia (FM) patients. Methods We identified randomized controlled studies of adults with FM in the MEDLINE, CINAHL, and PEDro databases. The primary outcome measure was pain relief measured by a visual analogue scale (VAS), and the secondary outcome measures of interest were subjective improvements in the number of tender points, Fibromyalgia Impact Questionnaire (FIQ), and quality of life (QOL) scores. Results Eleven studies were included in our review. The studies' physical-agent modalities were low-level laser therapy (LLLT), thermal therapy, electromagnetic field therapy, and transcutaneous electrical nerve stimulation (TENS). LLLT did not reduce VAS scores, but it significantly reduced both the number of tender points and FIQ score. Thermal therapy was associated with significantly reduced VAS scores, tender points, and FIQ scores. Electromagnetic field therapy was associated with significantly reduced VAS score and FIQ score. TENS significantly reduced VAS scores. Conclusion Our analyses revealed that thermal therapy and LLLT had a partial effect on pain relief in FM patients, and this beneficial effect may have a positive influence on FM patients' health status.


Introduction
Fibromyalgia (FM) is an idiopathic, common, and complex syndrome, defined as long-lasting, widespread, and symmetrical nonarticular musculoskeletal pain with generalized tender points at specific anatomical sites [1,2]. e pain that individuals with FM experience interferes with their performance of activities of daily life (ADLs) and results in a decreased quality of life (QOL) [2][3][4][5].
ere are many possible treatments for FM that can be classified as pharmacological and nonpharmacological therapies [6][7][8].
e authors of a 2014 meta-analysis reported that very few drugs in well-designed clinical trials have demonstrated significant relief for multiple FM symptom domains, whereas nonpharmacologic treatments with weaker study designs have demonstrated multidimensional effects [8]. Nonpharmacological therapies such as physical exercise including strength training, aerobic training, and yoga [9,10] and multicomponent therapy interventions [11,12] have been used for FM. Physical-agent modalities are defined as passive treatments such as thermotherapy, cryotherapy, massage, electrotherapy, laser treatment, and others are nonpharmacological interventions used for FM patients [10]. Even though several placebo-controlled trials assessing the effects of physical-agent modalities on pain, ADLs, and QOL in patients with FM have been published in recent years, some studies had small sample sizes and have presented controversial results. A further elucidation of the effects of each physical-agent modality for FM is needed. We conducted the present study to systematically review the effects of physical-agent modalities for the treatment of FM, especially for the improvement of pain, ADLs, and QOL.

Study Criteria and Selection.
Studies were included if (1) the participants were fibromyalgia patients; (2) the design was a randomized controlled trial (RCT) including crossover designs, published in peer-reviewed journals; (3) treatment using physical-agent modalities was compared with a pure control or placebo; and (4) the full text was available. Five independent reviewers screened the titles and abstracts of all retrieved citations for eligibility. Full-text articles were retrieved for review when they showed potential inclusion criteria or when there was insufficient information in the abstract and title to make a decision. Disagreements regarding selected articles were discussed between reviewers until a consensus was achieved, or a fifth reviewer was included to reach a majority decision. is systematic review is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Outcome Measures.
e primary outcome measure was pain relief. e criterion that we used for the study's measurement of pain intensity was that the pain intensity had to be measured by a visual analogue scale (VAS) at the baseline and again after treatment. e secondary outcome measures of interest were subjective improvements in the number of tender points, the score on a Fibromyalgia Impact Questionnaire (FIQ), and the score for quality of life (QOL). e  FIQ measures physical functioning, work status, depression,  anxiety, sleep, pain, stiffness, fatigue, and well being.  e  studies' patients' QOL had to be measured by the Short Form  36 Health Survey (SF-36), Health Assessment Questionnaire (HAQ), or Arthritis Impact Measurement Scale (AIMS).

Data Extraction.
e goal of our data extraction was to determine the differences between the studies' treatment groups regarding the mean outcome differences before and after treatment, and the standard error of these differences. e data were extracted independently by five investigators. e following data were extracted from each included study: participant demographics, the study design, the interventions, and the evaluation methods used for each group.
In studies in which multiple periods of treatment for pain were set, we analyzed the data for the longest period. In studies in which pain (as measured by a VAS) was treated in multiple body parts, the data for the part that had the strongest pain were analyzed. For the study's analysis, we required the mean difference between the baseline and the final data and the standard deviation of that difference for each group of subjects. When the required data were not described in studies, we calculated the mean difference and standard deviation using the study's data as described [13,14]. Studies in which the required data could not be calculated were excluded.

Evaluation of the Studies' Methodological Quality.
Two independent reviewers performed a quality assessment of each study by using the PEDro scale (Physiotherapy Evidence Database, 1999).
is scale has shown good reliability for scoring RCTs [15]. e PEDro scale consists of 11 items related to scientific rigor. e scale's items 2 to 11 contribute to internal validity, and the study is given 1 point for each of these items that is met. e first item relates to external validity and is not included in the final score. e quality assessment was performed independently by the two reviewers, and any disagreement was discussed until consensus was reached.

Data Synthesis and Analyses.
We performed the metaanalysis using Review Manager software, ver. 5.0 (Copenhagen, e Nordic Cochrane Centre, the Cochrane Collaboration, 2008) to determine whether the treatments using physical-agent modalities decreased the FM patients' pain. Outcomes were analyzed as continuous outcomes using a fixed-effect model to calculate the weighted mean difference and 95% confidence interval (95% CI). A p value ≤ 0.05 indicated significance for an overall effect. Heterogeneity was investigated using the chi-square test, and a pvalue ≤ 0.05 was accepted as significant. Subgroup analyses were also performed according to the physical-agent modalities. e initial search of the three electronic databases identified 227 titles and abstracts, of which 30 were retrieved for full-text review. When the exclusion criteria were applied, 11 studies satisfied the criteria to be included in this review [16][17][18][19][20][21][22][23][24][25][26]. e main reasons for exclusion were as follows: (1) outcomes of the pain scale were not reported or (2) the interventions and the comparison groups did not include a control group.

Quality Assessment of the Included Studies.
A detailed description of the 11 studies' PEDro scores is shown in Table 1. Seven studies [17, 18, 21-23, 25, 26] showed a PEDro score >5, two studies [16,17] scored 5, and the remaining two studies [19,24] scored 4. e most frequent omissions in the studies were the lack of blinding of therapists (10 studies). e allocation of patients was not described in sufficient detail to ascertain whether the allocation was concealed in the randomization method (eight studies), and an "intention to treat" analysis was applied for least one key outcome (eight studies).

Characteristics of the Studies' Participants.
e characteristics of the participants of the 11 studies are summarized in Table 2. e total number of participants was 498. Because two studies [23,26] had a double treatment design, 28 subjects were excluded in this meta-analysis. e total number of participants included in the meta-analysis was thus 470. e treatment groups comprised a total of 236 FM patients and the control groups were a total of 234 participants. Detailed demographic data were not reported in all studies, but the majority of the participants were adults; one study [22] did not report the ages of the participants. e male: female ratio varied among the five studies [19][20][21][22][23], and the other six studies included only female participants [16][17][18][24][25][26]. All participants (including the control group subjects) were patients with FM.

Characteristics of the Studies' Interventions and Physical-Agent Modalities.
e interventions (i.e., the physical-agent modalities) applied in the 11 studies are summarized in Table 2. e most common intervention was low-level laser therapy, used in five studies [16,21,22,24,26]. ermal therapy (which included balneotherapy, mudpack, and thermal bath) was used in four studies [16,[18][19][20]. TENS [23] and pulsed electromagnetic field therapy [25] were used in one study each. e intervention protocols varied among the studies. e amplitude and irradiation density of the LLLT [16,21,22,24,26] were, respectively, applied to the tender point and the trigger point from 28 sec to 3 min. In thermal therapy [16,[18][19][20], the temperature ranged from 30°C to 45°C, and the adaptation time was from 10 to 30 min; several studies used 20 min. e TENS [23] was applied for 20 min, 2×/day for 7 days, and the intervention conditions were 200 μsec, 2 and 100 Hz, and 60 mA. Pulsed electromagnetic field therapy [25] was applied for 30 min, 2×/day for 7 days, and the intervention condition was 40 µT, 0.1-64 Hz.

Pain (as Measured by VAS).
Six of the 11 studies evaluated the participants' pain by means of a VAS and were included in the meta-analysis. Figure 2 illustrates the mean difference and 95% CI values for pain relief as measured by VAS in these six studies for the physical-agent modalities LLLT, thermal therapies, TENS, and electromagnetic field therapy. e five studies' LLLT was not associated with the reduction of pain compared with the control group (mean difference: −4.00; 95% CI, −23.4 to 15.4, p � 0.69). In contrast, the TENS (−23.00; 95% CI, −43.28 to −2.72, p � 0.03), the electromagnetic field therapy (−30.30; 95% CI, −35.19 to −25.41, p < 0.00001), and thermal therapy (−29.74; 95% CI, −37.29 to −22.19, I 2 � 75%, p � 0.02) were associated with a significant reduction of VAS score compared with the respective control group.

e Number of Tender Points.
Six studies evaluated pain by evaluating the number of tender points and were included in the meta-analysis. As illustrated in Figure 3, the LLLT (−2.21; 95% CI, −3.51 to −0.92, I 2 � 42%, p � 0.0008) and thermal therapy (−5.71; 95% CI, −7.26 to −4.51, I 2 � 0%, p < 0.00001) were both associated with a significant reduction of the number of tender points compared with the control group.

e Fibromyalgia Impact Questionnaire (FIQ) Score.
Ten studies evaluated the FIQ score and were included in the meta-analysis. As shown in Figure 4

Discussion
Fibromyalgia is defined as chronic pain, tenderness, and pain amplification [1,27]. Increased levels of inflammatory cytokines and changes in neurotropic growth factors in the central nervous system and peripherally may influence the development and maintenance of central pain hypersensitivity by affecting adaptation and neuroplasticity [28][29][30].
e chronic painful lesions of fibromyalgia lead to limitations of activities of daily life and have been very difficult to treat effectively.

Pain Research and Management 3
Fibromyalgia is characterized by a clinical syndrome whose primary symptoms include chronic widespread pain [1], and nonpharmacological options for fibromyalgiainduced pain may be as important as pharmacological treatment. Our meta-analysis revealed that TENS, electromagnetic therapy, and thermal therapy had positive effects on fibromyalgia-induced pain.
ese positive effects of nonpharmacological treatment may be due to physiological and biochemical changes in fibromyalgia patients. In two studies [23,31], one of which was part of the present metaanalysis, the application of a TENS device improved pain relief in FM patients, and the effectiveness was suggested to be derived from a reduction in leukocyte migration, local action at peripheral opioids, and a decrease in local inflammatory reaction in the painful muscles. Low-frequency pulsed electromagnetic field therapy may improve pain in fibromyalgia patients, and several factors might mediate the therapeutic effects, such as alteration in pain perception, increases in the pain threshold and hormone levels, the inhibition of inflammatory edema, and vascular changes [25,32]. Notably, only one RCT for TENS and one RCT for electromagnetic field therapy were identified. A further accumulation of RCT data regarding the effects of TENS and electromagnetic field therapy on fibromyalgia is needed. Ardic et al. [16] indicated that balneotherapy can effectively treat patients with fibromyalgia by relieving their clinical chronic pain, and they proposed that the suppression of inflammatory mediators with balneotherapy is related to its beneficial effect. Studies that examined hyperthermia showed that balneotherapy with mudpack and hot-pool   Pain Research and Management treatments described a pain-relieving effect, which may be explained by a mitigation of muscle tone, increase in the pain threshold in the nerve endings, and/or peripheral vasodilatation [19,20,33]. Tender points were defined by the American College of Rheumatology criteria, which is the standard method for evaluating tenderness in fibromyalgia patients [34]. Our meta-analysis showed that the LLLT and thermal therapy were effective treatments for tenderness in fibromyalgia patients. at is, although Armagan et al. indicated that the numbers of tender points in their LLLT and placebo groups were not significantly different [17], the other two studies showed that the patients' tender point numbers decreased after LLLT [21,24]. Our meta-analysis showed favors plot in LLLT group and that LLLT was thus an effective therapeutic method to reduce the number of tender points in FM patients. However, our meta-analysis indicated that LLLT did not effectively reduce the patients' VAS pain scores. On the other hand, three of the 11 studies in our meta-analysis that evaluated balneotherapy showed tender points' count was significantly different between the treatment group and nontreatment group, in addition to decrease in pain intensity [16,19,20]. is difference between physical-agent modalities may be derived from effective area of each modality. Many thermal therapies influence the body surface widely compared with the LLLT in the same therapeutic time; thermal therapy can treat multiple pain locations at a session. is has an advantage for treatment widespread pain of fibromyalgia patients. erefore, thermal therapy reduces both pain intensity and the number of tender points. By contrast, LLLT may be ruled unfit to widespread pain of fibromyalgia patients because of narrow range of effective irradiated area. In the case of short-term treatment, LLLT may fail to decrease pain intensity in some painful areas, and then VAS in the patients remain persistently high. For this reason, LLLT may be more effective for decreasing the number of tender points than reducing the pain intensity. e therapeutic mechanism underlying LLLT remains to be elucidated in further studies.
e Fibromyalgia Impact Questionnaire (FIQ) comprised ten items in a self-administered instrument that measure physical functioning, work status, anxiety, pain, fatigue, sleep, depression, stiffness, well being, and evaluates activities of daily living (ADLs) in fibromyalgia patients [35]. EULAR guidelines emphasized that the goals of treatment are to improve the quality of life, maintain function (functional ability in everyday situations), and reduce symptoms [36]. In our meta-analysis, electromagnetic field therapy, LLLT, and thermal therapy were all associated with a significant reduction of the FIQ score. ree RCTs indicated that thermal therapy, including balneotherapy, mud baths, and mudpacks, had a positive effect on the FM patients' FIQ score, suggesting that thermal therapy ameliorated fibromyalgia-induced pain, and the improvement of fibromyalgia symptoms thus had a positive effect on the FIQ total score [10,11,13]. On the other hand, three of the five RCTs of LLLT reported that LLLT did not effectively reduce the FIQ score. Fibromyalgia-induced pain was not significantly changed in our meta-analysis, and this noneffectiveness may have led to the unchanged FIQ score. In addition, Bennett et al. suggested that a 14% change in the FIQ total score is clinically relevant [37]. In the results of LLLT, change in the FIQ total score is small compared with the clinically relevant value. erefore, the positive effect of LLLT for fibromyalgia patients is smaller compared with thermal therapy and may be definite for the treatment of fibromyalgia.
Regarding the quality of the studies' evidence, although the PEDro score in nine studies was >5 (max. score � 9, min. score � 4), all nine studies were small-scale (the largest treatment group consisted of 40 participants). e intervention period in all nine studies was short (max. treatment period of 4 weeks).
e quality of evidence according to Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) for all outcomes of efficacy, tolerability, and safety was low, downgraded for the reasons given in the following description of study limitations. e limitations are as follows. First, our review used only the MEDLINE, CINAHL, and PEDro databases for the search for studies, and we selected only English-language publications for the meta-analysis. We also selected only studies that included a pure control group or placebo groups (i.e., no other intervention). ere are few reports on each physical-agent modality for fibromyalgia, and the heterogeneity analysis revealed a high score in the meta-analysis.
Our meta-analysis did not evaluate the total effect of all of the physical-agent modalities since we searched for each modality's effect. Finally, the RCTs did not provide much data regarding the patients' QOL, and our search was thus unable to reveal adequate findings about posttreatment QOL in fibromyalgia patients. ese restrictions are tasks to address in future studies.

Conclusions
In summary, our findings suggest that thermal therapy has a positive effect on fibromyalgia-induced pain, tender point, and FIQ. ermal therapy is a more effective physical-agent modality for fibromyalgia patient treatment. Effect of electromagnetic therapy and TENS for the treatment of FM on pain intensity was observed. However, there are few reports on these physical-agent modalities. We speculate that this effectiveness has underlying mechanisms involving both the central nervous system and the peripheral nervous system. Clinically, nonpharmacological treatment for peripheral organization in fibromyalgia patients is important, and physicians need to consider both central and peripheral tissue as therapeutic targets.  Pain Research and Management 7