A composition for treating primary fibromyalgia syndrome, its preparation and use

Abstract

The present application belongs to the field of traditional Chinese medicine treatment, and particularly relates to a composition for treating primary fibromyalgia syndrome, a preparation method and application. The raw materials of the composition comprise the following components: Radix Bupleuri, Rhizoma Cyperi, Radix Angelicae Sinensis, Radix Paeoniae Alba, Semen Ziziphi Spinosae, Rhizoma Corydalis, Flos Carthami, Radix Paeoniae Alba, Radix Scrophulariae and Fructus Corni. The composition and the western medicine duloxetine hydrochloride can both relieve pain, and the improvement degree of pain VAS of the composition is obviously superior to that of duloxetine hydrochloride after 12 weeks of treatment. The composition can improve the quality of life, and the effects of improving fatigue and sleep quality are more obvious after 8 weeks and 12 weeks. The effect of improving anxiety and depression of the patient taking the composition for 12 weeks is obviously superior to that of duloxetine for 12 weeks. In terms of clinical symptom relief, the effective rate of the composition is superior to that of the control group. The composition has remarkable treatment effect, wide market prospect and social benefits.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine treatment, specifically relating to a composition, preparation method and application for treating primary fibromyalgia syndrome. Background Technology

[0002] Primary fibromyalgia syndrome refers to fibromyalgia syndrome without other causative factors. It belongs to non-articular rheumatic diseases, and its etiology is still unclear. The main symptoms are widespread pain and stiffness throughout the body, while sleep disorders, fatigue, irritable bowel syndrome, anxiety, and depression are also common symptoms.

[0003] Currently, the treatment of primary fibromyalgia syndrome mainly relies on Western medicine, such as antidepressants, anticonvulsants, analgesics, and sedative-hypnotics.

[0004] Antidepressants include: tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin reuptake inhibitors.

[0005] Anticonvulsant drugs can significantly improve symptoms such as pain, depression, and anxiety in patients. Examples include gabapentin, thiogabenin, topiramate, and pregabalin.

[0006] Analgesics include nonsteroidal anti-inflammatory drugs such as acetaminophen; and opioid central analgesics such as tramadol (Cimaldin), morphine, and methadone.

[0007] Sedative-hypnotics can be effective in treating FMS patients with anxiety and sleep disorders, such as benzodiazepines, which are widely used.

[0008] However, Western medicine treatments often have significant side effects, poor patient compliance, and are not very effective in improving quality of life. Traditional Chinese medicine, with its multiple targets and pathways and relatively fewer side effects, has become an important research direction.

[0009] Therefore, developing a traditional Chinese medicine composition that is effective for patients, significantly improves their quality of life, has a simple manufacturing process, and is easy to use is a persistent pursuit in this field. Summary of the Invention

[0010] In view of the shortcomings of the existing technology, the present invention provides a composition, preparation method and application for treating primary fibromyalgia syndrome.

[0011] To achieve the objectives of this invention, the following technical solution is adopted:

[0012] A composition for treating primary fibromyalgia syndrome, the composition comprising the following components: Bupleurum chinense, Cyperus rotundus, Angelica sinensis, Paeonia lactiflora, Ziziphus jujuba var. spinosa, Corydalis yanhusuo, Carthamus tinctorius, Astragalus membranaceus, Scutellaria baicalensis, and Cornus officinalis.

[0013] In some embodiments, the raw materials of the formulation of the present invention include the following components in parts by weight: Bupleurum chinense 5-15 parts, Cyperus rotundus 5-15 parts, Angelica sinensis 5-15 parts, Paeonia lactiflora 5-15 parts, Ziziphus jujuba var. spinosa 10-25 parts, Corydalis yanhusuo 5-15 parts, Carthamus tinctorius 5-15 parts, Astragalus membranaceus 10-25 parts, Scutellaria baicalensis 5-15 parts, and Cornus officinalis 10-25 parts.

[0014] In some embodiments, the raw materials of the formulation of the present invention include the following components in parts by weight: Bupleurum chinense 10-15 parts, Cyperus rotundus 10-15 parts, Angelica sinensis 10-15 parts, Paeonia lactiflora 10-15 parts, Ziziphus jujuba var. spinosa 15-25 parts, Corydalis yanhusuo 10-15 parts, Carthamus tinctorius 10-15 parts, Astragalus membranaceus 10-20 parts, Scutellaria baicalensis 10-15 parts, and Cornus officinalis 15-25 parts.

[0015] In other embodiments, the raw materials of the composition include the following components in parts by weight: 12 parts Bupleurum chinense, 12 parts Cyperus rotundus, 12 parts Angelica sinensis, 12 parts Paeonia lactiflora, 18 parts Ziziphus jujuba var. spinosa, 10 parts Corydalis yanhusuo, 12 parts Carthamus tinctorius, 15 parts Astragalus membranaceus, 12 parts Scutellaria baicalensis, and 20 parts Cornus officinalis.

[0016] Secondly, the present invention also provides a method for preparing the above composition, comprising the following steps:

[0017] (1) Crush the raw materials separately, sieve them, mix them together to obtain powder;

[0018] (2) Mix the powder with a solvent to obtain the final product.

[0019] In some embodiments, it is sieved.

[0020] In some embodiments, the solvent is water;

[0021] Thirdly, the present invention also provides a pharmaceutical preparation whose raw materials include the above-described composition and pharmaceutically acceptable excipients.

[0022] Fourthly, another object of the present invention is to provide the use of the above composition in the preparation of a medicament for treating primary fibromyalgia syndrome.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] (1) The composition of this invention uses Bupleurum and Cyperus as the principal herbs to soothe the liver and relieve depression. Angelica and Paeonia lactiflora are used as assistant herbs to nourish blood and soften the liver, while Astragalus and Cornus officinalis are used to tonify the liver and kidneys and replenish essence and qi. Scutellaria baicalensis is added as an adjuvant to clear heat and guide the medicine to the liver. On this basis, Carthamus tinctorius and Corydalis yanhusuo are added to further enhance the effects of promoting blood circulation, regulating qi and relieving pain. At the same time, Ziziphus jujuba seed powder is added to improve sleep, nourish qi through sleep, strengthen the spleen and replenish essence and blood. The whole formula works together to nourish blood, soften the liver, soothe the liver and relieve pain.

[0025] (2) The prescription of this invention is simple, and significant effects can be achieved after 12 weeks of intervention, with statistical significance compared with the pretreatment level.

[0026] (3) Both the composition of the present invention and the Western medicine duloxetine hydrochloride can relieve pain. After the 4th week and the 8th week, the improvement of pain VAS of the two is not much different. After the 12th week of treatment, the improvement of pain VAS of the composition of the present invention is significantly better than that of duloxetine hydrochloride.

[0027] (4) Regarding secondary efficacy evaluation indicators: Both the composition of the present invention and duloxetine hydrochloride can improve quality of life. Compared with patients in the control group treated with duloxetine, patients taking the composition of the present invention showed more significant improvement in fatigue and sleep quality after week 8 and week 12 of treatment. Patients taking the composition of the present invention for 12 weeks showed significantly better improvement in anxiety and depression than those taking duloxetine for 12 weeks.

[0028] (5) In terms of clinical symptom relief, the efficacy of the composition of the present invention (observation group) was better than that of the control group; after 8 weeks and 12 weeks of treatment, the efficacy of the composition of the present invention (observation group) was significantly better than that of the control group. Attached Figure Description

[0029] Figure 1 Pain VAS score results;

[0030] Figure 2 The result is the degree of pain improvement (△VAS = pre-treatment pain VAS score - post-treatment pain VAS score);

[0031] Figure 3 The FIQR score for quality of life in fibromyalgia.

[0032] Figure 4 The degree of improvement in quality of life (△FIQR = FIQR score before treatment - FIQR score after treatment);

[0033] Figure 5 Results of the FS-14 fatigue scale;

[0034] Figure 6 The result represents the degree of improvement in fatigue (△FS-14 = FS-14 score before treatment - FS-14 score after treatment);

[0035] Figure 7 Results of the Pittsburgh Sleep Quality Index (PSQI);

[0036] Figure 8 The result represents the degree of improvement in sleep quality (△PSQI = FSQI score before treatment - PSQI score after treatment);

[0037] Figure 9 Results of the Baker Anxiety Scale;

[0038] Figure 10The degree of improvement in anxiety (△Beck Anxiety Scale score = Beck Anxiety Scale score before treatment - Beck Anxiety Scale score after treatment);

[0039] Figure 11 Results of the Baker Self-Rating Depression Scale;

[0040] Figure 12 The result represents the degree of improvement in depression (△Beck Depression Rating Scale score = Beck Depression Rating Scale score before treatment - Beck Depression Rating Scale score after treatment). Detailed Implementation

[0041] The present invention will be further described below with reference to specific embodiments.

[0042] Example 1

[0043] The formulation of this embodiment consists of the following components in parts by weight: Bupleurum chinense 12 parts, Cyperus rotundus 12 parts, Angelica sinensis 12 parts, Paeonia lactiflora 12 parts, Ziziphus jujuba var. spinosa 18 parts, Corydalis yanhusuo 10 parts, Carthamus tinctorius 12 parts, Astragalus membranaceus 15 parts, Scutellaria baicalensis 12 parts, and Cornus officinalis 20 parts.

[0044] The preparation method is as follows: Soak the above-mentioned medicinal materials in 9 times their volume of water for 30 minutes. Heat over high heat until boiling, then simmer over low heat for 30 minutes, concentrating to 3 times the volume of the raw herbs. Add 3 times the volume of water again, heat to boiling, and simmer for another 20 minutes, concentrating to 3 times the volume of the raw herbs. Stir the herbs in the decoction pot during the decoction process. Mix the two decoctions thoroughly, and seal them into two sealed packages.

[0045] Example 2

[0046] The treatment formula in this embodiment consists of the following components in parts by weight: 10 parts Bupleurum, 10 parts Cyperus, 10 parts Angelica sinensis, 10 parts Paeonia lactiflora, 15 parts Ziziphus jujuba var. spinosa, 10 parts Corydalis yanhusuo, 10 parts Carthamus tinctorius, 10 parts Astragalus membranaceus, 10 parts Scutellaria baicalensis, and 15 parts Cornus officinalis.

[0047] The preparation method is as follows: Soak the above-mentioned medicinal materials in 5 times the amount of water for 30 minutes. Heat over high heat until boiling, then simmer over low heat for 30 minutes, concentrating to 3 times the volume of the raw herbs. Add 3 times the amount of water again, heat to boiling, and simmer for another 20 minutes, concentrating to 3 times the volume of the raw herbs. Stir the herbs in the decoction pot during the decoction process. Mix the two decoctions thoroughly, and seal them into two sealed packages.

[0048] Example 3

[0049] The formula in this embodiment consists of the following components in parts by weight: Bupleurum chinense 15 parts, Cyperus rotundus 15 parts, Angelica sinensis 15 parts, Paeonia lactiflora 15 parts, Ziziphus jujuba var. spinosa 25 parts, Corydalis yanhusuo 15 parts, Carthamus tinctorius 15 parts, Astragalus membranaceus 20 parts, Scutellaria baicalensis 15 parts, and Cornus officinalis 25 parts.

[0050] The preparation method is as follows: Soak the above-mentioned medicinal materials in 8 times the amount of water for 30 minutes. Heat over high heat until boiling, then simmer over low heat for 30 minutes, concentrating to twice the volume of the raw herbs. Add 3 times the amount of water again, heat to boiling, and simmer for another 20 minutes, concentrating to twice the volume of the raw herbs. Stir the herbs in the decoction pot during the decoction process. Mix the two decoctions thoroughly, and seal them into two sealed packages.

[0051] The following comparative examples 1-3 are individual prescriptions screened in the early stage of the experiment.

[0052] Comparative Example 1

[0053] This specific formula consists of the following components in parts by weight: Bupleurum chinense 10 parts, Cyperus rotundus 10 parts, Angelica sinensis 10 parts, Paeonia lactiflora 10 parts, Ziziphus jujuba var. spinosa 15 parts, Corydalis yanhusuo 10 parts, Carthamus tinctorius 10 parts, Astragalus membranaceus 10 parts, and Scutellaria baicalensis 25 parts.

[0054] The preparation method is as follows: Soak the above-mentioned medicinal materials in 5 times the amount of water for 30 minutes. Heat over high heat until boiling, then simmer over low heat for 30 minutes, concentrating to 3 times the volume of the raw herbs. Add 3 times the amount of water again, heat to boiling, and simmer for another 20 minutes, concentrating to 3 times the volume of the raw herbs. Stir the herbs in the decoction pot during the decoction process. Mix the two decoctions thoroughly, and seal them into two sealed packages.

[0055] Comparative Example 2

[0056] This prescription consists of the following components in parts by weight: Bupleurum 10 parts, Cyperus rotundus 10 parts, Angelica sinensis 10 parts, Paeonia lactiflora 10 parts, Ziziphus jujuba var. spinosa 15 parts, Corydalis yanhusuo 10 parts, Carthamus tinctorius 10 parts, Astragalus membranaceus 10 parts, and Cornus officinalis 25 parts.

[0057] The preparation method is as follows: Soak the above-mentioned medicinal materials in 5 times the amount of water for 30 minutes. Heat over high heat until boiling, then simmer over low heat for 30 minutes, concentrating to 3 times the volume of the raw herbs. Add 3 times the amount of water again, heat to boiling, and simmer for another 20 minutes, concentrating to 3 times the volume of the raw herbs. Stir the herbs in the decoction pot during the decoction process. Mix the two decoctions thoroughly, and seal them into two sealed packages.

[0058] Comparative Example 3

[0059] This prescription consists of the following components in parts by weight: Bupleurum chinense 12 parts, Cyperus rotundus 12 parts, Angelica sinensis 12 parts, Paeonia lactiflora 12 parts, Albizia julibrissin bark 18 parts, Ligusticum chuanxiong 10 parts, Carthamus tinctorius 12 parts, Codonopsis pilosula 15 parts, Scutellaria baicalensis 12 parts, and Cornus officinalis 20 parts.

[0060] The preparation method is as follows: Soak the above-mentioned medicinal materials in 9 times their volume of water for 30 minutes. Heat over high heat until boiling, then simmer over low heat for 30 minutes, concentrating to 3 times the volume of the raw herbs. Add 3 times the volume of water again, heat to boiling, and simmer for another 20 minutes, concentrating to 3 times the volume of the raw herbs. Stir the herbs in the decoction pot during the decoction process. Mix the two decoctions thoroughly, and seal them into two sealed packages.

[0061] Clinical Trial 1

[0062] Table 1 Comparison of General Data

[0063]

[0064] Enrollment: Forty-one patients with primary FMS (Fluid-Stasis Syndrome) and Liver Qi Stagnation Syndrome were enrolled according to a prospective randomized controlled trial method (study period: May 2022 - May 2025). They were randomly divided into two groups. There were no statistically significant differences between the two groups in terms of gender, disease duration, age, and BMI (P > 0.05), indicating comparability. There were no statistically significant differences between the two groups in VAS pain scores, FIRQ quality of life, FS-14 fatigue, PSQI sleep, Beck anxiety, and Beck depression scores, as detailed below:

[0065] Treatment method: The observation group was treated with the composition prepared in Example 1, taken twice a day, each time equivalent to 135g of raw drug.

[0066] The control group was treated with duloxetine hydrochloride (registered trademark: Xinyoufen, batch number: National Drug Approval Number H20213037, produced by Chongqing Yaoyou Pharmaceutical Co., Ltd.), 40mg / day, 20mg bid.

[0067] The study was conducted for 12 consecutive weeks. The efficacy and safety of the Shugan Dingtong formula in treating patients with primary liver qi stagnation syndrome (FMS) were evaluated using indicators such as the VAS pain score.

[0068] The primary efficacy endpoint was the VAS score for pain; secondary efficacy endpoints included the Fibromyalgia Quality of Life Rating Scale (FIQR), the FS-14 Fatigue Scale, the Pittsburgh Sleep Quality Index (PSQI), the Beck Anxiety Scale, the Beck Self-Rating Depression Scale, and the FMS Traditional Chinese Medicine Syndrome Score for Liver Qi Stagnation, Spleen Deficiency, and Blood Stasis Syndrome.

[0069] Evaluation Methods: Case report form data were entered using EpiData. Data analysis was performed using SPSS 27.0 statistical software. For count and measurement data conforming to a normal distribution, percentages and mean ± standard deviation (x ± s) were used, respectively. For measurement data not conforming to a normal distribution, the median (interquartile range), i.e., P50 (P25, P75), was used. Differences in pain VAS, fibromyalgia quality of life (FIQR) score, fatigue FS-14 score, sleep quality PSQI score, and TCM syndrome score before and after treatment were compared. Within the same group, paired-samples t-tests were used to compare data conforming to a normal distribution and with homogeneous variances. Independent-samples t-tests were used to compare data between the observation and control groups. Non-parametric tests were used when data did not conform to a normal distribution or had unequal variances. A p-value < 0.05 was considered statistically significant.

[0070] Results Analysis: There was no statistically significant difference in pain VAS scores between the two groups before treatment (P>0.05), indicating comparability. Compared with before treatment, pain scores decreased in both groups after 12 weeks of treatment (P<0.001 in the observation group, P<0.05 in the control group). Compared with the control group, the observation group (using the Liver-Soothing and Pain-Relieving Formula of Example 1) showed more significant pain improvement (P<0.05). VAS scores are as follows: Figure 1 As shown. Pain improvement level △VAS as... Figure 2 As shown.

[0071] There was no statistically significant difference in FIQR scores between the two groups before treatment (P>0.05), indicating comparability. Compared with before treatment, the FIQR scores of both groups decreased after 12 weeks of treatment (P<0.05). Compared with the control group, the observation group (using the Shugan Dingtong formula from Example 1) showed a more significant decrease in quality of life scores after 4 and 12 weeks of treatment (P<0.05), indicating that the traditional Chinese medicine group improved quality of life better than the Western medicine group. FIQR scores are as follows: Figure 3 As shown. The degree of improvement in quality of life △FIQR is as follows. Figure 4 As shown.

[0072] There was no statistically significant difference in FS-14 scores between the two groups before treatment (P>0.05), indicating comparability. After 12 weeks of treatment, the FS-14 scores of patients in the observation group (using the liver-soothing and pain-relieving formula from Example 1) were lower (P<0.05), while no significant improvement was observed in the control group before and after treatment (P>0.05). FS-14 scores are as follows: Figure 5 As shown. Fatigue improvement degree △FS-14 as... Figure 6 As shown.

[0073] There was no statistically significant difference in PSQI scores between the two groups before treatment (P > 0.05), indicating comparability. Compared with before treatment, the PSQI sleep score of patients in the observation group (using the Shugan Dingtong formula from Example 1) decreased after 12 weeks of treatment (P < 0.001). Compared with the control group, the improvement in sleep (ΔPSQI) was more significant in the treatment group after 12 weeks of treatment (P < 0.05), demonstrating that the Shugan Dingtong formula can significantly improve sleep. PSQI scores are as follows... Figure 7 As shown. Sleep improvement level △PSQI as... Figure 8 As shown.

[0074] There was no statistically significant difference in Beck Anxiety Scale scores between the two groups before treatment (P>0.05), indicating comparability. Compared with before treatment, the anxiety scores of patients in the observation group (using the Shugan Dingtong formula from Example 1) decreased after 12 weeks of treatment (P<0.001). Compared with the control group, the Shugan Dingtong formula significantly reduced anxiety scale scores after 8 weeks of treatment (P<0.05), indicating that the anxiety relief was more significant in the traditional Chinese medicine treatment group. Beck Anxiety Scale scores are as follows: Figure 9 As shown. The degree of anxiety improvement △ Beck Anxiety Scale score is as follows. Figure 10 As shown.

[0075] There was no statistically significant difference in the Beck Depression Rating Scale scores between the two groups before treatment (P>0.05), indicating comparability. Compared with before treatment, the depression scores of patients in the observation group (using the Shugan Dingtong formula from Example 1) decreased after 12 weeks of treatment (P<0.001). No significant improvement was observed in the control group before and after 12 weeks of treatment (P>0.05). The Beck Depression Rating Scale scores are as follows: Figure 11 As shown. The degree of improvement in depression is indicated by the Beck Depression Scale score. Figure 12 As shown.

[0076] The efficacy was evaluated according to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs" promulgated in 2002. Based on the scoring results of TCM syndromes, the efficacy was divided into clinical cure, significant effect, effective, and ineffective. The TCM syndrome scoring is shown in Table 2.

[0077] Clinical cure: ① A reduction rate of 95% or higher in the total score of TCM syndrome is considered clinical cure;

[0078] Significant effect: ② A reduction rate of 70% to 95% in the total score of TCM syndrome is considered significant effect;

[0079] Effective: ③ A reduction rate of 30% to 70% in the total score of TCM syndrome is considered effective;

[0080] Invalid: ④ If the total score reduction rate of TCM syndrome is less than 30%, it is invalid.

[0081] Calculation formula: Total reduction rate of TCM syndrome = Total reduction rate of TCM syndrome = [(Pre-treatment score - Post-treatment score) / Pre-treatment score] × 100%.

[0082] Table 2 Comparison of total effective rates between the two groups after 12 weeks of treatment.

[0083]

[0084] Note: Statistical analysis showed that the difference in the reduction rate of TCM syndrome scores between the two groups was statistically significant (P < 0.001).

[0085] Clinical Trial 2

[0086] A total of 120 patients with primary FMS (Fluid-Induced Syndrome) and liver qi stagnation syndrome were treated using Examples 1-3 and Comparative Examples 1-3, with 20 patients in each group. The treatment method was the same as in Clinical Trial 1, and the equivalent daily dose of raw herbs was the same in each group. The treatment lasted for 12 weeks, and the VAS (Visual Analogue Scale) for pain before and after treatment was compared. See the table below:

[0087] Table 3. Pain VAS scores before and after 12 weeks of treatment.

[0088]

[0089] Note: Rank-sum test was used for analysis. In the same row, ** indicates extremely significant difference (P < 0.01), and * indicates significant difference (P < 0.05) when comparing before and after treatment.

[0090] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A composition for treating primary fibromyalgia syndrome, characterized in that, The raw materials of the composition are composed of the following components in parts by weight: Bupleurum chinense 5-15 parts, Cyperus rotundus 5-15 parts, Angelica sinensis 5-15 parts, Paeonia lactiflora 5-15 parts, Ziziphus jujuba var. spinosa 10-25 parts, Corydalis yanhusuo 5-15 parts, Carthamus tinctorius 5-15 parts, Astragalus membranaceus 10-25 parts, Scutellaria baicalensis 5-15 parts, and Cornus officinalis 10-25 parts.

2. The composition according to claim 1, characterized in that, The raw materials of the composition are composed of the following components in parts by weight: Bupleurum chinense 10-15 parts, Cyperus rotundus 10-15 parts, Angelica sinensis 10-15 parts, Paeonia lactiflora 10-15 parts, Ziziphus jujuba var. spinosa 15-25 parts, Corydalis yanhusuo 10-15 parts, Carthamus tinctorius 10-15 parts, Astragalus membranaceus 10-20 parts, Scutellaria baicalensis 10-15 parts, and Cornus officinalis 15-25 parts.

3. The composition according to claim 1, characterized in that, The raw materials of the composition are composed of the following components in parts by weight: Bupleurum chinense 12 parts, Cyperus rotundus 12 parts, Angelica sinensis 12 parts, Paeonia lactiflora 12 parts, Ziziphus jujuba var. spinosa 18 parts, Corydalis yanhusuo 10 parts, Carthamus tinctorius 12 parts, Astragalus membranaceus 15 parts, Scutellaria baicalensis 12 parts, and Cornus officinalis 20 parts.

4. A method for preparing the composition according to any one of claims 1-3, characterized in that, This involves soaking the raw materials in water and extracting them to obtain the final product.

5. The preparation method according to claim 4, characterized in that, The mass-to-volume ratio of the raw material to water is 1g:1-10mL; the soaking time is 20-40min.

6. The preparation method according to claim 4, characterized in that, The extraction is performed 1-3 times, with each extraction lasting 20-50 minutes.

7. A pharmaceutical preparation, characterized in that, The raw materials of the pharmaceutical preparation include the composition according to any one of claims 1-3 and pharmaceutically acceptable excipients.

8. Use of the composition according to any one of claims 1-3 in the preparation of a medicament for treating primary fibromyalgia syndrome.

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