Assessments of Morbid Soreness Symptoms in Fibromyalgia Help With Phenotype Classification and Predicting Therapeutic Responses: Prospective Observational Analysis

doi:10.21203/rs.3.rs-1431193/v1

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Assessments of Morbid Soreness Symptoms in Fibromyalgia Help With Phenotype Classification and Predicting Therapeutic Responses: Prospective Observational Analysis

https://doi.org/10.21203/rs.3.rs-1431193/v1

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Background: Muscle soreness occurs after exercise and also under morbid conditions, such as fibromyalgia (FM). However, how the morbid soreness manifests in FM and how it affects the disease remain unknown. Also, whether the non-exertional soreness in FM differs from exercise-induced soreness phenotypically is unclear.

Methods: Fifty-one newly diagnosed FM patients from 166 consecutive cases of chronic musculoskeletal pain and 41 healthy controls were prospectively recruited. Musculoskeletal symptoms and metabolomics data were analyzed before the initiation of pharmacotherapy. Clinical manifestations and therapeutic responses were recorded with a follow-up of 4 weeks.

Results: Soreness complaints were common in FM (92.2%). Soreness had clinical impacts different from pain, and affected stiffness and restless conditions. In terms of manifestations and metabolomic features, phenotypes diverged between cases with prominent soreness (FM-PS) and those without symptoms (FM-P). Conventional treatment did not ameliorate soreness severity despite its efficacy on pain. Moreover, despite the salient therapeutic efficacy on pain relief, current treatment did not improve the general disease severity in FM-PS versus FM-P. Metabolomics analyses suggested oxidative metabolism dysregulation in FM. Also, high malondialdehyde level indicated excessive oxidative stress in FM individuals (p=0.008). Contrary to exercise-induced soreness, lactate levels were significantly lower in FM individuals than controls, especially in FM-PS. Moreover, FM-PS cases exclusively featured increased malondialdehyde level (p=0.008) and its correlation with soreness intensity (r=0.337, p=0.086).

Conclusion: Morbid soreness symptoms were prevalent in FM, with presentation distinct from exercise-induced soreness. Assessments of non-exertional soreness in FM may provide valid approaches for phenotype classification and therapeutic prediction.

delayed onset muscle soreness

fibromyalgia

metabolomics

oxidative stress

pain

soreness

Soreness is a familiar unpleasant sensation in the musculoskeletal regions and negatively interferes with daily activities[1]. In most cases, soreness occurs after intense exercise along with myalgia. Acute-onset soreness after exercise is associated with acute lactate accumulation, and musculoskeletal micro-injury results in delayed onset muscle soreness (DOMS)[1–5]. Despite its common occurrence after physical activity, muscle soreness is not exclusive to exertion but also occurs in disease conditions not related to exercise or tissue inflammation, such as in fibromyalgia (FM)[2]. Currently, the prevalence and manifestations of morbid soreness symptoms in FM remains little surveyed[2]. Also, its underlying mechanism is largely unknown.

FM is a prevalent musculoskeletal disorder characterized by chronic widespread pain[6, 7]. Unlike other pain disorders (e.g., low back pain and DOMS), the pathogenesis of FM does not involve muscular tissue injury or overexertion [6]. Also, the widespread nature of musculoskeletal discomforts in FM defines the illness and differentiates it from other localized pain disorders[6–8]. Apart from myalgia, FM patients also have generalized morbid soreness without exercise or workout[2]. The non-exertional soreness may interfere with quality of life and result in intolerance to rehabilitation or physical activity[2, 9, 10]. Despite our comprehensive understanding of pain symptoms in FM, the soreness nosography in fibromyalgia is less understood. Furthermore, the clinical impact on the disease conditions remains to be investigated.

In this study, we aimed to investigate the soreness nosography of FM and compare it with pain symptoms. We also evaluated the clinical impact of soreness symptoms on disease severity and determined its response to current treatment. Additionally, we used metabolomics to explore the neurobiology of this morbid phenomenon and compared the metabolomic expression between FM individuals with different soreness phenotypes. Understanding the nosography of non-exertional soreness in FM could help advance our understanding of the disease and design better therapeutic strategies.

Study participants

This prospective investigation was carried out in accordance with the Declaration of Helsinki and was approved by the institutional review board of Kaohsiung Medical University Hospital (KMUH) [KMUHIRB-(I)-20170012; ClinicalTrials.gov ID: NCT04832100]. Adults with complaints of chronic diffused pain at the outpatient department of KMUH were consecutively enrolled over a 2-year period from July 2017 to June 2019 (Fig. S1). Participants were interviewed by experienced neurologists (CHH or KWL) and we recruited those who fulfilled the 2011 American College of Rheumatology criteria for FM[11]. To investigate the manifestations and metabolomic phenotypes without pharmacological intervention, we recruited only patients with newly diagnosed primary FM before initiation of pharmacotherapy. None of the participants were under treatment with antidepressants, anti-epileptic or antipsychotic drugs. Also, to avoid the metabolomic interference resulting from the other medical conditions, we only recruited patients with primary fibromyalgia for an adequate comparison. All participants underwent routine laboratory examination to exclude disorders that would otherwise explain the pain, including testing for erythrocyte sedimentation rate, antinuclear antibody, rheumatoid factor, thyroid hormone, thyroid-stimulating hormone, alanine and aspartate aminotransferase, creatinine kinase, cortisol, and electrolytes. All participants with a final diagnosis of primary FM were followed for at least 6 months by outpatient services to ensure that no other etiology was identified. We prospectively recruited age- and sex-matched subjects without pain and soreness as healthy controls (HCs). Participants were asked to report their recent physical exertional events (such as intense labor or exercise) in the last 2 weeks. Exclusion criteria for both groups were the presence of systemic rheumatological or immune disorders (e.g., systemic lupus erythematosus, inflammatory myositis), systemic use of corticosteroids, current statin treatment, pregnancy, chronic diseases under poor control (e.g., diabetes mellitus, hypertension or chronic renal failure) and malignancies.

Study design

The demographic and clinical data for patients and controls were obtained by questionnaires and interviews with the same specialist throughout the study. Patients were asked to assess their muscular discomforts in terms of pain and soreness separately. The intensity and diffuseness of pain symptoms were assessed with a numeric rating scale for pain (NRS-P; 0–10) and widespread pain index (WPI; based on the American College of Rheumatology criteria). By analogy to the NRS-P and WPI, participants were asked to rate their soreness severity and report the distribution of soreness symptoms with the NRS for soreness (NRS-S) and widespread soreness index (WSI) to evaluate soreness symptoms of fibromyalgia [12]. The WSI questionnaire is based on the WPI design and comprises a list of 19 areas for soreness assessment, and patients mark the number of body parts where they have experienced soreness symptoms during the last week (Fig. S2). Participants were asked to report their soreness and pain symptoms respectively. Patients were also asked about the relieving and aggravating factors of somatic symptoms. To investigate the impact of soreness and pain symptoms on functional capacity in daily life activities, we used the Revised Fibromyalgia Impact Questionnaire (FIQR) [13]. The severity of comorbid symptoms was assessed by the symptom severity scale for the American College of Rheumatology criteria [14].

Patients underwent three evaluations were conducted to assess clinical manifestations and therapeutic responses, including the initial interview and two scheduled follow-ups at 2 and 4 weeks (Fig. S1). At the first visit, a comprehensive interview and the FIQR were administered, and laboratory tests were performed. Pharmacotherapy was adjusted with a stepwise approach according to the individual conditions. Monotherapy with imipramine was used initially for all patients at the first visit. The first follow-up was arranged 2 weeks later, and therapeutic responses were assessed and reported by patients. Monotherapy with imipramine was retained for patients who reported satisfying control of symptoms. For patients who reported poor therapeutic response but refused the dosage increase because of drug intolerance, pregabalin was added as combination therapy. The second follow-up was arranged 2 weeks later, and therapeutic responses of patients were recorded again. No nonsteroidal anti-inflammatory drugs, morphine or opioid-analogue drugs were used for pain control during follow-up.

Statistical analysis

Clinical data: Data are expressed as mean ± standard deviation (SD). Sample size was calculated with use of G* Power v3.1.9.2, with α = 0.05 significance level and 80% power (β = 0.20). The determination of effect size was referred to previous literature [15]. Differences between groups were assessed with Student t test or one-way ANOVA as appropriate. The changes before and after treatment were compared by ANOVA. The resulting p values for the comparison of clinical outcomes were adjusted by the Bonferroni correction. Pearson correlation was used to assess the correlation between parameters. Cluster analysis was used to identify distinct groups of FM patients based on symptom severity of pain and soreness. The k-means clustering algorithm was used with the NRS-P and NRS-S scales and WPI and WSI by using SPSS v20, and patients with similar manifestations were grouped into two meaningful subgroups according to pain and soreness manifestations. ANOVA was used to compare pain and soreness manifestations in the defined subgroups. Principal component analysis (PCA) was used to identify the intrinsic clustering and relevant subgroups of patients from unlabeled data. Two-tailed p < 0.05 was considered statistically significant in all tests. SPSS v20 (SPSS Inc., USA) was used for analysis.

Non-exertional soreness is prevalent in FM

We enrolled 51 patients with newly diagnosed FM and 41 HCs for the final analysis (Fig. S1). Demographic data and symptom assessments are summarized in Table S1. Soreness complaints were highly prevalent (92.2%) in FM individuals, along with pain (100%) (Fig. 1A). Of note, no FM patient had experienced recent (within 2 weeks) physical exertional events. FM patients were intolerant of daily activities as assessed by the FIQR (Table S1). The distribution of pain and soreness symptoms did not differ among body regions in general (Fig. 1B). Notably, the distribution of pain symptoms was not related to that of soreness (Fig. 1C; Table S2). The soreness intensity score (NRS-S) was moderately correlated with soreness diffuseness (WSI; r = 0.576, p < 0.001), with no correlation between pain intensity score (NRS-P) and pain diffuseness (WPI) (Fig. 1D). We also found a modest correlation between pain and soreness intensity (r = 0.302, p = 0.031) but not diffuseness (r = 0.061, p = 0.670) (Fig. 1E).

Next, we evaluated the clinical correlation of pain/soreness intensity (NRS-P and NRS-S scores) and FIQR (disease severity) scores (Table S3). Pain intensity was significantly correlated with FIQR score (r = 0.434, p = 0.001) but not soreness intensity (r = 0.216, p = 0.128). Participants with high pain intensity reported high disease impact on their life (domain 2) and complained of worse FM symptoms (domain 3). They also reported worse conditions of fatigue, skin allodynia and insomnia. In comparison, high soreness intensity was correlated with intolerance to static activity (sitting for 45 min; r = 0.425, p = 0.002) and high stiffness levels (r = 0.317, p = 0.023). Scores of NRS-P and WPI were effectively reduced by conventional therapies, with no significant improvement in NRS-S and WSI after treatment (Table S4). Also, the treatment effectively relieved the disease severity as assessed by the FIQR.

Assessments of non-exertional soreness allow for characterizing phenotypes in FM

To explore any phenotypic differences among patients in terms of pain and soreness manifestations, we performed a cluster analysis of patients based on manifestations of pain and soreness severity (NRS-P, NRS-S, WPI and WSI) with k-means analysis. Patients with similar manifestations were classified into two meaningful subgroups. Unsupervised principal component analysis (PCA) revealed intrinsic clusters of two subgroups (Fig. 1F). Patients of cluster 1 (n = 24) had similar pain manifestations (NRS-P and WPI) as those of cluster 2 (n = 27), whereas patients of cluster 2 reported significantly higher soreness severity (WSI and NRS-S) than those of cluster 1 (Fig. 1G and H). Thus, patients of cluster 1 were designated FM with pain dominant symptoms (FM-P) and those of cluster 2 as FM with mixed pain and soreness symptoms (FM-PS).

The mean age was lower for FM-PS than FM-P patients, with no difference in sex ratio (Table S5). Somatic symptoms were relieved by limb stretching and massage in FM-PS but not FM-P. Symptom severity and FIQR scores did not significantly differ between the groups. The two groups had comparable distribution of pain symptoms, but soreness symptoms were significantly greater in FM-PS than FM-P in all body regions (Table S6). The correlation of pain and soreness distribution in the body regions was in general unremarkable in both groups (Table S7 and S8). In the FM-PS group, WPI and WSI scores were significantly correlated, as were NRS-S and NRS-P scores, with no correlation among scores in the FM-P group (Fig. S3).

For FM-P patients, high pain intensity was positively correlated with high levels of fatigue, insomnia, allodynia and overall domain 3 scores (Table S9). Similarly, high pain intensity was positively correlated with high overall FIQR scores in FM-PS. Notably, in both groups, patients with high soreness severity tended to manifest restless conditions (intolerance of sitting for 45 min).

Pharmacotherapies effectively alleviated pain symptoms in both groups (Fig. 1I). For soreness, the current treatment timely reduced soreness intensity (NRS-S) in FM-P within 2 weeks, but no therapeutic response was noticed in FM-PS until 4 weeks after treatment (Fig. 1J). Although conventional pharmacotherapies successfully reduced both soreness intensity and diffuseness in the FM-PS group 4 weeks later, NRS-S and WSI scores remained significantly higher in the FM-PS than FM-P group (5.59 ± 2.72 and 8.26 ± 4.44 vs 2.83 ± 2.32 and 2.54 ± 2.41) even after 4 weeks of treatment (Fig. 1J). Moreover, current treatment significantly improved overall SS and disease impacts for FM-P patients but not FM-PS patents (Table S10).

Metabolomic differentials among FM patients with and without prominent soreness

To probe the metabolic features of FM, we used untargeted metabolomics analysis of plasma samples from participants with use of MetaboAnalyst[16]. Unsupervised PCA revealed no clear separation between FM and HC groups (Fig. S4A). Another score plot was constructed to explore any metabolic differences between FM cases with and without prominent non-exertional soreness but still showed no distinct separation between the FM subgroups (Fig. S4B).

Next, we used fold-change analysis to compare the peak intensity expression of metabolites between FM and HC groups. Metabolites with significant dysregulation in FM versus HCs are listed in Table S11. To probe any metabolomic phenotypes in FM cases, we further compared the expression of the identified metabolites in FM-P and FM-PS groups (Fig. 2A-B). Except for N6-acetyl-l-lysine, the levels of upregulated metabolites were prominently higher in the FM-PS but not FM-P group than HCs (Fig. 2A). Also, we observed incremental expression gradients for all metabolites among HC, FM-P and FM-PS groups in that order. Likewise, for downregulated metabolites, the peak intensity was significantly lower for FM-PS patients than HCs (Fig. 2B). We observed decreased expression gradients for metabolites among HC, FM-P and FM-PS groups in a similar order.

Next, we used supervised sparse partial least squares discriminant analysis (sPLS-DA) to identify the discriminative metabolites for FM (Fig. S5A). Most of the top 10 discriminative features selected by the sPLS-DA model based on loading values for component 1 were also the dysregulated metabolites recognized by the fold-change analysis, which correspondingly underpinned the selection by sPLS-DA as consistent markers. Next, we repeated sPLS-DA for FM-P, FM-PS and HC groups (Fig. S5B). Similarly, the top discriminative features selected by the sPLS-DA model based on component 1 loading values were mostly the altered metabolites recognized by the fold-change analysis. Of note, the top 10 selected features identically predicted FM-PS or HC groups but not the FM-P group, which suggested metabolomic differentials predominantly existed between FM-PS and HC but not FM-P and HC groups. To visualize the potential discrepancy among the groups, we constructed a heatmap of the 11 significantly dysregulated metabolites with hierarchical clustering. (Fig. 2C). FM-PS and HC groups had an almost opposite expression of the selected metabolites except for N6-acetyl-l-lysine, whereas the FM-P group showed intermediate expression between FM-PS and HC groups (Fig. 2D).

Next, we used pathway analysis to identify the biologically meaningful pathways relevant to FM. To identify the most biologically meaningful patterns, only metabolites with incremental changes > 2 or decremental changes < 0.5 were used for further analysis. The impact value calculated from topology analysis and -log(p) were used to evaluate the importance of the pathways related to FM. The threshold of impact value was set at 0.05, and pathways with statistical significance and values above the threshold were filtered out as potential pathway targets (Fig. 3A; Table S12). We identified three biologically significant pathways related to FM (taurine metabolism, purine metabolism and arginine biosynthesis), and five metabolites involved in the pathways (taurine, L-arginine, 2-oxoglutarate, hypoxanthine, and AMP) (Fig. S6).

Mounting evidence indicates that the pathophysiology of FM is associated with oxidative stress[17–21]. Previous reports indicated that higher oxidative status for FM individuals than controls, and the oxidative stress loading of FM individuals could be correlated with disease severity[19, 22]. In our study, two of the three identified pathways from pathway analysis are known to be associated with cellular oxidative metabolism, including purine metabolism and arginine biosynthesis. To explore whether excessive oxidative stress exists in FM, we evaluated oxidative stress by assessing plasma levels of lipid peroxidation as determined by malondialdehyde (MDA) level[19, 22]. The significantly higher MDA level in FM patients than HCs suggested higher oxidative stress loading in FM individuals (Fig. 3B). Of note, MDA level was significantly higher in the FM-PS than HC group, with no significant difference between the FM-P and HC groups (Fig. 3B), which suggests excessive oxidative stress with FM-PS but not FM-P. To probe the FM soreness mechanism and make a comparison with exercise-related soreness, we used correlation analyses of plasma lactate expression and soreness intensity between groups, but findings were negative (Fig. 3C and D). Given that FM-PS patients had prominent soreness symptoms with simultaneously higher oxidative stress, we next explored the correlation between soreness intensity and MDA level in FM subgroups (Fig. 3E and F). We identified a correlative trend, although statistically non-significant, in FM-PS versus FM-P groups, which suggest that oxidative stress or other oxidized metabolites might modulate the non-exertional soreness phenotype in FM.

Our investigations revealed that morbid soreness symptoms were prevalent in FM. As compared with exercise-related soreness, several characteristics of the non-exertional soreness in FM were identified in terms of clinical manifestations, distribution, and metabolomic features[5, 23] (Table 1). Additionally, phenotypes, therapeutic responses and metabotypes distinctly differed between FM patients with different severity of soreness symptoms (Table 2). Of note, the morbid soreness phenotypes in FM did not involve lactate accumulation but might be associated with excessive oxidative stress.

Muscle soreness results in intolerance to daily activity and thus prevents individuals from participating in daily activities or rehabilitation[5]. In research of soreness, post-exercise soreness is mostly investigated, including acute post-exercise soreness and DOMS[5]. The morbid soreness in FM shows several similarities as post-exercise conditions. First, both conditions show significant correlations of soreness and pain intensity[1, 24]. Moreover, post-exercise soreness limits range of motion and results in stiffness[25–27]. Similarly, soreness intensity and stiffness severity were positively correlated in FM. Additionally, limb stretch and massage help relieve symptoms in both conditions[1, 5, 27, 28]. However, several divergences exist too. Unlike in DOMS, the symptoms of FM do not involve tissue inflammation or mechanical insults[1, 7, 29]. Also, post-exercise soreness is a transient physiological response to exercise, whereas FM is a chronic pain condition resulting from aberrant central sensitization[1, 4, 7]. Additionally, we found no spatial correlation of pain and soreness symptoms in the affection regions of FM (Fig. 1C), which is quite different from the concordant manifestations of pain and soreness in the post-exercise conditions[5, 29]. In this sense, the investigations of non-exertional soreness in FM may provide a unique approach to probe the soreness nosography that previous DOMS research did not provide[1, 3, 29, 30]. A comparison of non-exertional and exertional soreness is summarized in Table 2.

Lactate accumulation in muscles is commonly thought to be associated with acute soreness after exercise[29, 31]. However, our investigation did not suggest upregulated lactate expression in FM individuals as compared with HCs. On the contrary, lactate expression was even lower in FM individuals with prominent soreness symptoms (FM-PS). Thus, the morbid soreness in FM may not involve lactate production, and the soreness mechanisms might differ from those in exercise conditions. Of note, oxidative status was significantly increased in FM-PS patients (Fig. 3B). In this context, the soreness symptoms in FM may not result from lactate accumulation but might involve other factors related to oxidative stress, such as oxidized products of lipids (e.g., lysophosphatidylcholine) or proteins (e.g., protein carbonyls)[32, 33]. Notably, for exertional soreness, antioxidants have been proposed to treat post-exercise soreness by reducing free radical generation during exercise[23, 34]. However, a recent systematic review did not strongly support the therapeutic efficacy on exertional soreness[35]. Because of the excessive oxidative stress in FM and its correlation with soreness, antioxidants might be of potential therapeutic use to relieve the non-exertional soreness of FM, especially considering that current treatment cannot ameliorate soreness symptoms effectively in FM.

Patients with higher soreness intensity had more difficulty sitting still for 45 min (Tables S3 and S8). The restless conditions are reminiscent of the core feature of restless leg syndrome (RLS), another common comorbidity of FM[36, 37]. Up to one-third of patients with FM reported comorbid RLS symptoms. Coincidentally, soreness sensation is also a prevalent descriptor of RLS discomforts (40.4%)[38]. Like RLS, limb stretching also helps to alleviate the discomforts of FM, especially in FM-PS[39, 40]. So far, the clinical or pathophysiological associations among non-exertional soreness, RLS and FM remains undetermined. Future study is warranted to investigate the prevalence and clinicoetiologic correlates of these two disorders with focus on soreness manifestations.

FM features various symptomatic discrepancies of pain and soreness. For example, soreness diffuseness was fairly correlated with its intensity, but this correlation was not observed in pain conditions. Also, conventional therapies could effectively reduce WPI but not WSI (Table S4). Furthermore, soreness and pain had different clinical impacts on FM symptoms and disease severity. For example, pain symptoms were significantly associated with skin allodynia, sleep disturbance and fatigue, which suggests that coexisting pain symptoms might worse these comorbidities (Table S3). By comparison, soreness symptoms involved stiffness rather than the above conditions. These differences between soreness and pain may result from the potential differences in their somatosensory mechanisms[2, 7, 29].

FM is considered a heterogenous condition[7]. We found distinct phenotypic differences between FM-P and FM-PS in terms of clinical presentation, therapeutic responses, metabolomic expression and oxidative stress status (Table 2). We found significant positive correlations between pain and soreness symptoms in FM-PS, with no similar findings for FM-P (Fig. S3A and 3B). Also, the impact of pain symptoms on the FM comorbidities was evident in FM-P but not FM-PS (Table S9). Moreover, we found remarkable differences in therapeutic responses in pain and soreness symptoms between the two groups (Fig. 1I and 1J). Notably, in FM-PS, conventional treatment successfully alleviated pain intensity but did not improve symptom severity or FIQR scores as compared with FM-P (Table S10). Such a discrepancy of therapeutic responses might result from the ineffective relief of soreness symptoms in FM-PS under current treatment. Accordingly, tailored therapeutic trials focusing on non-exertional soreness (e.g., antioxidants or non-steroidal anti-inflammatory drugs) are indicated, especially for patients with prominent soreness complaints[29].

We identified metabolomic differences between FM-P and FM-PS. The fold change analyses (Fig. 1A-B), sPLS-DA (Fig. S5B) and metabolomic heatmap (Fig. 2C-D) findings all suggest a more distinct metabolomic expression in FM-PS than FM-P versus HCs. Along with the findings of clinical manifestations, the evaluation of soreness in FM provides an easy approach to identify FM phenotypes, thereby benefiting patient classification and better therapeutic strategies.

Besides lactate, several metabolites are dysregulated in FM. Among the five metabolites identified by the pathway analysis, hypoxanthine, L-arginine and 2-oxoglutarate participate in oxidative stress generation and were downregulated concordantly. All three substances can function as source materials to produce endogenous oxidative and nitrosative stress. Hypoxanthine is the breakdown product of purine metabolism and functions as a material for a conversion that produces superoxide (O2⁻•) and hydrogen peroxide in the presence of xanthine oxidase[41, 42]. Also, L-arginine is converted by nitic oxide synthase into citrulline and nitric oxide, which induces nitrative and oxidative stress[32, 43]. Furthermore, ROS can be generated from 2-oxoglutarate via 2-oxoglutarate dehydrogenase catalyzation in the Krebs cycle[44–46]. From these perspectives, the decreased levels of these metabolites might be associated with material consumption for ROS generation, which suggests increased oxidative stress in organisms. This assumption was further validated by the elevated plasma MDA level in FM, as numerous studies previously reported[18, 19, 32]. Of note, the expression of altered metabolites and MDA level was significantly increased in FM-PS, which implies that the oxidative status might participate in modulating the soreness phenotype in FM. Further research is needed to clarify the potential relation and underlying mechanisms.

Despites its undetermined etiology, mounting evidence has suggested that FM is associated with aberrant central amplification of nociceptive signaling. Although the investigation of central mechanisms is beyond the scope of this work, our study pointed out a potential link between morbid soreness and central sensitization based on the findings of our current metabolomic profiling and previous translational research [21]. Our prior translational study found that excessive oxidized lipids (e.g., lysophosphatidylcholine) resulting from excessive oxidative stress induces a psychological stress-induced fibromyalgia-like pain by activating acid-sensing ion channel 3 in the muscular tissue, which thus causes central sensitization and results in pain chronification. In this sense, the oxidized metabolites likely function as a nociceptive ligand and subsequently trigger central sensitization to cause FM symptoms. Likewise, this clinical investigation revealed excessive oxidative stress and lipid oxidization in FM individuals, especially in FM-PS. Additionally, it identified a correlative trend between MDA levels and soreness severity. In this content, the development of morbid soreness in FM might also relate to oxidative stress and involve a similar process of central sensitization as the development of pain.

This study has several limitations. First, the sample size may not adequately represent the general population. Also, combining pharmacotherapies of imipramine and pregabalin with individual adjustment were used to relieve symptoms. Ideally, monotherapy would be better for evaluation of therapeutic effects. However, the therapeutic approach of monotherapy is intrinsically limited by its analgesic efficacy or dose-limiting side effects, or both. Additionally, the need for individual drug adjustment would be an intrinsic limitation in the study. Moreover, the observational duration of therapeutic responses for 4 weeks might be not long enough for appropriate assessment. Further studies with a monotherapy design and longer follow-up are needed for better evaluating therapeutic responses and prognosis.

Our study demonstrates the nosography of soreness symptoms in FM and highlights their clinical importance in the disease. These findings indicate the FM heterogeneity between cases with and without prominent soreness manifestations in terms of clinical and metabolomic presentations. Thus, the soreness assessment may provide a valid strategy to easily recognize disease phenotypes of FM, thereby benefitting clinical practice and further pathological investigations.

DOMS, delayed onset muscle soreness; FIQR, Revised Fibromyalgia Impact Questionnaire; FM, fibromyalgia; FM-P, fibromyalgia with pain dominant symptoms; FM-PS, fibromyalgia with mixed pain and soreness symptoms; HCs, healthy controls; MDA, malondialdehyde; NRS-P, numeric rating scale for pain; NRS-S, numeric rating scale for soreness; PCA, principle component analysis; RLS, restless leg syndrome; ROS, reactive oxygen species; sPLS-DA, sparse partial least squares discriminant analysis; SS, symptom severity; TBARS, thiobarbituric acid reactive substances; WPI, widespread pain index; WSI, widespread soreness index.

Acknowledgments

We thank the Metabolomics Core Laboratory at the Center of Genomic Medicine of National Taiwan University and National Pingtung University of Science and Technology for metabolomics experiments.

Conflicts of interest

None declared.

Funding

This work was supported by intramural funding from the Ministry of Science and Technology (Taiwan) and Kaohsiung Medical University Hospital (MOST 109-2628-B–037–008–, MOST 110-2628–B–037–016–, NPUST–KMU–110–P009, KMUH109–9R71 and KMUH110-0R64 to CHH; MOST 110–2321–B-001–010– to CCC).

Author contributions

CHH, CLL, and CCC designed research; CHH and CCC processed funding acquisition; CHH, KWL and FYO contributed to patient recruitment; CHH, DSH, MHT and PSW contributed to methodology and data for metabolomics analysis; CLL, and CHL contributed to critical revision of manuscript; FWL contributed to statistical methods.

Competing interests

None declared.

Data Availability

Raw and analyzed data will be shared upon written request to the corresponding author from any qualified investigator.

Consent for publication

Not applicable.

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Table 1

A comparison between non-exertional and exertional soreness
	Non-exertional soreness	Exertional soreness
Condition	FM	Acute onset	DOMS
Previous exertional events	No	Yes	Yes
Onset	Chronic⁶	Immediate⁵	Subacute^{1. 5}
Duration	> 3 months⁶	Hours⁵	5–7 days^{1. 5}
Inflammation or tissue insults	No^{6. 7}	Yes⁵	Yes^{1. 5}
Distribution	Widespread^{6. 7}	Localized to exertion sites⁵	Localized to exertion sites^{1. 5}
Correlation with myalgia
Intensity	Yes	Yes^{5. 20}	Yes^{5. 20}
Localization	No	Yes⁵	Yes^{1. 5}
Muscle fatigue	Yes⁶	Yes⁵	Yes^{1. 5}
Clinical impact
Stiffness	Yes	Yes^{5. 21}	Yes^{1. 5. 21}
Restless condition	Yes	Undetermined	Undetermined
Metabolic changes
Lactate levels	Decreased (versus HC)	Increased⁵	non-increased^{1. 5}
Oxidative status	Increased^13–17	Increased^{5. 30}	Uncertained^{1. 5. 19}
Therapeutic efficacy
Stretching	Yes	Yes^{5. 23}	Yes^{1. 5}
Massage	Yes	Yes⁵	Yes^{1. 5 .24}
Pharmacotherapy	Unavailable	NSAID⁵	NSAID^{1. 5}
FM, fibromyalgia. DOMS, delayed-onset muscle soreness. HC, healthy control. NSAID, non-steroid anti-inflammatory drug.

Table 2

Phenotypic characteristics of FM with pain dominant symptoms (FM-P) and FM with mixed pain and soreness symptoms (FM-PS)
	FM-P	FM-PS
Number (percentage)	24 (47.1%)	27 (52.9%)
Manifestation
Correlation of NRS-P and NRS-S	No	Yes
Correlation of WPI and WSI	No	Yes
Therapeutic response
NRS-P	Yes	Yes
NRS-S	Yes	Delayed response
Symptom severity score	Yes	No
FIQR score	Yes	No
Metabolic expression (vs HCs)
Metabolomic phenotype	Less distinct	More distinct
Increased MDA level	Nonsignificant	Significant
FIQR, Revised Fibromyalgia Impact Questionnaire. NRS-P, numeric rating score for pain. NRS-S, numeric rating score for soreness. WPI, widespread pain index. WSI, widespread soreness index. MDA, malondialdehyde. HCs, healthy controls.

No competing interests reported.

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Assessments of Morbid Soreness Symptoms in Fibromyalgia Help With Phenotype Classification and Predicting Therapeutic Responses: Prospective Observational Analysis

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