A traditional Chinese medicine composition for improving fibromyalgia syndrome with pain and fatigue, and a traditional Chinese medicine preparation and application thereof

Abstract

The present application relates to the technical field of traditional Chinese medicine. More particularly, it relates to a traditional Chinese medicine composition for improving fibromyalgia syndrome with pain and fatigue, and a traditional Chinese medicine preparation and application thereof. The traditional Chinese medicine composition comprises the following raw medicinal materials: Fructus Corni, Radix Bupleuri, Radix Paeoniae Alba, Rhizoma Corydalis, Flos Chrysanthemi, Cortex Albiziae, Radix Angelicae Sinensis, Poria, Rhizoma Pinelliae, Pericarpium Citri Reticulatae, and Radix Glycyrrhizae. The composition of the present application is targeted at the pathogenesis characteristics of fibromyalgia syndrome, i.e. deficiency of liver-kidney yin and blood, and contraction of tendons and vessels, and can relieve pain and improve fatigue at the same time, thus achieving the overall regulation effect of treating the symptoms and the root cause. Moreover, the traditional Chinese medicine compound of the present application is safe, and is suitable for long-term treatment of fibromyalgia syndrome patients with pain and fatigue as the main symptoms, and has good clinical application value.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine. More specifically, it relates to a traditional Chinese medicine composition for improving fibromyalgia syndrome with pain accompanied by fatigue, as well as the traditional Chinese medicine preparation and application thereof. Background Art

[0002] Fibromyalgia syndrome is a refractory disease with chronic widespread pain as the core symptom, accompanied by manifestations such as fatigue, sleep disorders, cognitive impairment and impaired physical function, which seriously affects the quality of life of patients and brings heavy social and economic burdens. Among them, fatigue is an important indicator reflecting the severity of the disease and the therapeutic effect, and is assessed using the Multidimensional Fatigue Inventory (MFI). The American Working Group for Outcomes in Rheumatology Clinical Trials emphasizes that the efficacy evaluation of fibromyalgia syndrome needs to focus on the improvement of pain, fatigue and other aspects at the same time. The incidence of fatigue in patients with fibromyalgia syndrome in China exceeds 90%, of which moderate to severe fatigue accounts for more than 70%. Therefore, intervention measures that take into account both pain relief and fatigue improvement have become an important direction in the treatment of fibromyalgia syndrome, but there are still no therapeutic drugs targeting the fatigue symptom at present.

[0003] Traditional Chinese medicine has the advantages of holistic regulation and multi-target intervention in the treatment of fibromyalgia syndrome, and this disease has been included in the catalogue of dominant diseases of traditional Chinese medicine. The traditional Chinese medicine disease name of this disease is "muscle impediment". The liver is "the root of stopping fatigue", governing the muscles and storing blood, and the muscles rely on blood for nourishment to manage movement; the kidney stores essence, and essence and blood share the same origin, which is the foundation for nourishing the tendons and vessels. This disease is mostly a chronic and protracted syndrome. Long-term illness easily consumes and damages yin blood. In addition, factors such as long-term stress and emotional depression can not only lead to deficiency of yin blood, but also cause the liver to fail in governing free flow, leading to qi stagnation. The liver and kidney share the same origin of essence and blood. Over time, the disease spreads from the liver to the kidney, eventually leading to deficiency of both the liver and kidney; while unsmooth qi movement obstructs the operation of qi and blood, resulting in the failure of tendons and vessels to be nourished. The two interact, eventually leading to the coexistence of malnourished tendons and vessels and adverse qi movement, which not only causes spasm and pain, but also manifests as physical function decline such as limb weakness and reduced exercise tolerance.

[0004] A survey on the distribution rule of traditional Chinese medicine syndromes of fibromyalgia syndrome in China shows that 85~100% of the patients' traditional Chinese medicine syndrome types are related to the liver. The liver depression and qi stagnation syndrome is one of the most common single syndromes, accounting for about 15.2%, mainly manifested as migratory distending pain in muscles, chest and hypochondrium distension and fullness, irritability and other symptoms; the liver and kidney deficiency syndrome also accounts for a significant proportion (about 16.4%), which is more common especially in elderly patients or those with symptoms such as insomnia, soreness and weakness of the waist and knees, and fatigue and lack of strength. Among the compound syndromes, the liver depression and qi stagnation combined with liver and kidney deficiency syndrome accounts for about 7.3%, suggesting that the two often appear in combination.

[0005] Pregabalin, duloxetine, and mirtazapine, as early FDA-approved medications for fibromyalgia, can improve pain symptoms in about 30% of cases. However, their efficacy on accompanying symptoms such as fatigue, sleep disturbances, and physical dysfunction is limited, and the incidence of adverse reactions is high, with 51.5%–64.6% of patients discontinuing the medication within one year due to intolerance of these side effects. Furthermore, when single-drug therapy is ineffective, clinical practice often involves combination therapy with antidepressants and sedative-hypnotics. This multi-drug combination not only increases the burden of medication for patients but also easily leads to adverse reactions such as dizziness, drowsiness, and weight gain.

[0006] In traditional Chinese medicine treatment, formulas containing Bupleurum, such as Xiao Chai Hu Tang and Chai Hu Shu Gan San, have achieved certain efficacy in relieving pain and are widely used in clinical practice. However, their regulatory effect on fatigue still needs improvement. Especially for patients with prolonged illness and concurrent liver and kidney deficiency, simply soothing the liver may deplete qi and damage yin.

[0007] Based on the aforementioned shortcomings of existing technologies, there is an urgent clinical need for a traditional Chinese medicine compound that addresses the core pathogenesis of fibromyalgia syndrome, namely "deficiency of liver and kidney yin and blood, and tension of tendons and ligaments," and can simultaneously improve pain and fatigue. Summary of the Invention

[0008] For patients with fibromyalgia syndrome whose main symptoms are pain and fatigue, one objective of this invention is to provide a traditional Chinese medicine composition for improving fibromyalgia syndrome with pain and fatigue, aiming to fill the gap in the existing treatments that do not adequately address the synergistic improvement of pain relief and fatigue.

[0009] Another objective of this invention is to provide a traditional Chinese medicine preparation for improving fibromyalgia syndrome with pain and fatigue.

[0010] Another object of the present invention is to provide the use of the above-mentioned traditional Chinese medicine composition and its preparation in the preparation of a medicament for improving pain and fatigue in fibromyalgia syndrome.

[0011] To achieve the first objective mentioned above, the present invention adopts the following technical solution: This invention discloses a traditional Chinese medicine composition for improving fibromyalgia syndrome with pain and fatigue, characterized in that the traditional Chinese medicine composition comprises the following raw materials: Cornus officinalis, Bupleurum chinense, stir-fried Paeonia lactiflora, vinegar-processed Corydalis yanhusuo, lily bulb, Albizia julibrissin bark, Angelica sinensis, Poria cocos, processed Pinellia ternata, tangerine peel, and prepared licorice root.

[0012] This formula, based on the previously developed "Soothing Muscles Formula," has been further optimized through long-term clinical practice and in accordance with the theory of "Yi and Gui sharing the same origin." This formula nourishes Yin and blood, relaxes muscles and relieves pain, and is suitable for patients with fibromyalgia syndrome exhibiting a pattern of liver and kidney Yin deficiency combined with liver Qi stagnation. The formula focuses on tonifying the kidneys, as the saying goes, "strengthening the source of water is essential for the flourishing of wood," which better aligns with the clinical characteristics of fibromyalgia's chronic course, characterized by a mixture of deficiency and excess, complex symptoms, and recurring relapses. Therefore, it exerts a holistic regulatory effect, addressing both the root cause and symptoms, and targeting multiple points, demonstrating significant clinical application value.

[0013] The formula uses Cornus officinalis and Bupleurum chinense as the chief herbs. Cornus officinalis is sour and astringent, slightly warm in nature, and enters the liver and kidney meridians. Wang Ang's *Compendium of Materia Medica* states that "Cornus officinalis consolidates essence and preserves qi, strengthens yin and assists yang, soothes the five internal organs, and opens the nine orifices." It not only nourishes the yin and blood of the liver and kidneys but also consolidates essence and qi, allowing yin and blood to recover and essence and qi to be restrained, making it a key herb for treating the root cause. Bupleurum chinense is pungent, bitter, and slightly cold, entering the liver and gallbladder meridians. It excels at soothing the liver, relieving stagnation, and regulating qi. As the chief herb, Bupleurum chinense allows stagnant qi to be released, serving as the initiating force of the entire formula. It also guides other tonifying herbs into the liver meridian, directing the tonifying power to the affected organ. In a body deficient in essence and blood, if tonification is merely applied without soothing, stagnation easily occurs; if soothing is merely applied without tonification, yin and blood are further damaged. The combination of Cornus officinalis and Bupleurum chinense ensures that essence and blood are replenished without stagnation, and that qi flows smoothly without dissipation, serving as the guiding principle of the formula.

[0014] The main ingredients are white peony root, corydalis rhizome, lily bulb, and albizia bark. White peony root is sour and astringent, nourishing blood and softening the liver. It enters the liver meridian to relieve spasms and pain. When combined with bupleurum root, it softens the liver and harmonizes its function, without the liver-yin-draining effect of bupleurum root, making it a common method for regulating the liver. Corydalis rhizome is pungent and bitter, entering the liver meridian. It is good at promoting qi and blood circulation and relieving pain. Qi stagnation causes pain, and qi stagnation easily leads to blood stasis, which also causes pain. Corydalis rhizome, following the dispersing effect of bupleurum root, specifically targets the painful area, allowing qi and blood to flow, thus reducing pain. Lily bulb is sweet and cold, nourishing yin and moistening dryness, clearing the heart and calming the mind. Prolonged stagnation can transform into heat, disturbing the mind, or insufficient yin and blood can cause restlessness and insomnia. Lily bulb nourishes heart yin and moistens the heart and lungs, nourishing the mind and enhancing its calming effect. Albizia bark is sweet and neutral, entering the heart and liver meridians. It is good at relieving depression and calming the mind. Emotional stagnation leads to malnourishment of the mind, resulting in recurring irritability, depression, and insomnia. Albizia bark enters the liver to relieve depression and enters the heart to calm the mind; when used together with Bupleurum, its effect in relieving depression is enhanced.

[0015] The adjuvant herbs are Angelica sinensis, Poria cocos, Pinellia ternata, and Citrus reticulata peel. Angelica sinensis is sweet and warm in nature, and can both nourish and invigorate blood. The *Rihuazi Materia Medica* states that it "treats all wind-related ailments, all blood-related ailments, and replenishes all fatigue." It nourishes blood and harmonizes the body, relieves spasms and pain, allows qi to be carried by blood, and nourishes the liver, thus assisting the principal herbs in enhancing the effects of nourishing blood and relieving pain. Poria cocos and Pinellia ternata work together with Lilium brownii to calm the mind. Poria cocos is sweet, bland, and mild, calming the mind and spirit. Pinellia ternata harmonizes the stomach and descends rebellious qi; when stomach qi is harmonious and descends, the mind and spirit are at peace. Poria cocos, Pinellia ternata, and Citrus reticulata peel embody the principles of the Er Chen Tang formula. When wood element is stagnant and suppresses earth element, the spleen loses its ability to function properly, leading to dampness and phlegm accumulation; phlegm and qi combine, disturbing the clear orifices and aggravating emotional and pain symptoms. Poria cocos strengthens the spleen and eliminates dampness, Pinellia ternata dries dampness and resolves phlegm, and Citrus reticulata peel regulates qi and invigorates the spleen. These three herbs work together to strengthen the spleen to benefit muscles, aid digestion to eliminate phlegm and dampness, and promote the smooth flow of qi in the middle jiao, alleviating symptoms such as constipation, diarrhea, and abdominal pain. When qi flows smoothly, blood flows smoothly; when phlegm is resolved, the mind is clear. Furthermore, a healthy spleen and stomach ensure a source for the generation of qi and blood, replenishing depleted yin and blood. The guiding herb is licorice root, which is sweet and warm, tonifying the middle jiao and harmonizing the effects of the other herbs. Overall, the combined effects of these herbs are to benefit the kidneys, soothe the liver, calm the mind, and strengthen the spleen.

[0016] Furthermore, by weight, the traditional Chinese medicine composition includes the following active pharmaceutical ingredients: Cornus officinalis 9-18 parts, Bupleurum chinense 6-12 parts, stir-fried Paeonia lactiflora 15-30 parts, vinegar-processed Corydalis yanhusuo 9-18 parts, lily bulb 12-24 parts, Albizia julibrissin bark 9-18 parts, Angelica sinensis 6-12 parts, Poria cocos 15-30 parts, processed Pinellia ternata 6-9 parts, Citrus reticulata peel 6-9 parts, prepared Glycyrrhiza uralensis 5-10 parts.

[0017] Furthermore, by weight, the traditional Chinese medicine composition includes the following active pharmaceutical ingredients: Cornus officinalis 9 parts, Bupleurum chinense 6 parts, stir-fried Paeonia lactiflora 15 parts, vinegar-processed Corydalis yanhusuo 9 parts, lily bulb 12 parts, Albizia julibrissin bark 9 parts, Angelica sinensis 6 parts, Poria cocos 15 parts, processed Pinellia ternata 6 parts, tangerine peel 6 parts, and prepared licorice root 5 parts.

[0018] Furthermore, by weight, the traditional Chinese medicine composition includes the following active pharmaceutical ingredients: Cornus officinalis 12 parts, Bupleurum chinense 8 parts, stir-fried Paeonia lactiflora 20 parts, vinegar-processed Corydalis yanhusuo 12 parts, Lilium brownii 16 parts, Albizia julibrissin bark 12 parts, Angelica sinensis 8 parts, Poria cocos 20 parts, processed Pinellia ternata 8 parts, Citrus reticulata peel 8 parts, and prepared Glycyrrhiza uralensis 7 parts.

[0019] Furthermore, by weight, the traditional Chinese medicine composition includes the following active pharmaceutical ingredients: Cornus officinalis 18 parts, Bupleurum chinense 12 parts, stir-fried Paeonia lactiflora 30 parts, vinegar-processed Corydalis yanhusuo 18 parts, lily bulb 24 parts, Albizia julibrissin bark 18 parts, Angelica sinensis 12 parts, Poria cocos 30 parts, processed Pinellia ternata 12 parts, Citrus reticulata peel 12 parts, and prepared Glycyrrhiza uralensis 10 parts.

[0020] The basic formula of the above-mentioned traditional Chinese medicine composition of the present invention can be adjusted according to clinical symptoms in specific embodiments to achieve the purpose of treating fibromyalgia syndrome and improving certain specific clinical symptoms, further enhancing the adaptability of the composition of the present invention and improving the therapeutic effect. These adjustments made based on the basic formula of the present invention are also within the scope of protection of this application.

[0021] To achieve the second objective mentioned above, the present invention adopts the following technical solution: This invention discloses a traditional Chinese medicine preparation for improving fibromyalgia syndrome with pain and fatigue, wherein the raw materials of the traditional Chinese medicine preparation include the traditional Chinese medicine composition as described above.

[0022] In use, the traditional Chinese medicine composition of this invention can be prepared into a decoction according to traditional prescription methods, such as decocting with water and then taking the decoction. Alternatively, the active ingredients of the prescription can be refined with water or other suitable solvents and then prepared into various dosage forms, such as granules, tablets, capsules, pills, powders, and oral liquids, according to conventional pharmaceutical processes. Experimental verification has shown that all the above preparation and usage methods can achieve the therapeutic effect of the drug.

[0023] Furthermore, the raw materials of the traditional Chinese medicine preparation also include pharmaceutically acceptable excipients.

[0024] To achieve the third objective mentioned above, the present invention adopts the following technical solution: This invention discloses the use of the traditional Chinese medicine composition or preparation described above in the preparation of a medicament for improving pain and fatigue associated with fibromyalgia syndrome.

[0025] In addition, unless otherwise specified, all raw materials of the traditional Chinese medicine composition of the present invention can be obtained commercially available. Any traditional Chinese medicine composition of any range described in the present invention, including the end value and any value between the end values ​​and any sub-range formed by the end value or any value between the end values, can achieve the purpose of treating fibromyalgia syndrome.

[0026] Beneficial effects of the present invention The formulation of this invention targets the pathogenesis of fibromyalgia syndrome characterized by "deficiency of liver and kidney yin and blood, and stiffness of tendons and ligaments." While relieving pain symptoms, it can also synergistically improve fatigue, achieving a holistic regulatory effect that addresses both the symptoms and the root cause. Furthermore, the traditional Chinese medicine compound of this invention has good safety and is suitable for the long-term treatment of patients with fibromyalgia syndrome whose main symptoms are pain accompanied by fatigue, thus possessing good clinical application value. Attached Figure Description

[0027] Figure 1 This is a flowchart of a clinical trial research process.

[0028] Figure 2This is a trend graph of the total BPI score at various assessment time points in the clinical trial study. Compared to the placebo group, # P <0.05, ## P <0.01.

[0029] Figure 3 This is a trend graph of BPI pain intensity scores at various assessment time points in the clinical trial study. Compared with the placebo group, # P <0.05.

[0030] Figure 4 This is a trend chart of the impact of BPI on pain scores at various assessment time points in the clinical trial study. Compared with the placebo group, # P <0.05.

[0031] Figure 5 This is a trend chart of WPI scores at various assessment time points in the clinical trial study.

[0032] Figure 6 This is a trend chart of MFI scores at various assessment time points in the clinical trial study, where compared with the placebo group, # P <0.05, ## P <0.01.

[0033] Figure 7 This is a trend chart of the total FIQR score at various assessment time points in the clinical trial study, where, compared with the placebo group, ## P <0.01.

[0034] Figure 8 This is a trend chart of FIQR functional dimension scores at various assessment time points in clinical trials.

[0035] Figure 9 This is a trend chart showing the impact of FIQR on the scoring dimensions at various assessment time points in clinical trials.

[0036] Figure 10 This is a trend chart of FIQR symptom dimensions scores at various assessment time points in the clinical trial study. Compared to the placebo group, # P <0.05, ## P <0.01.

[0037] Figure 11 This is a trend chart of PSQI scores at various assessment time points in the clinical trial study, where compared with the placebo group, # P <0.05.

[0038] Figure 12 This is a trend chart of PSS scores at various assessment time points in the clinical trial study.

[0039] Figure 13 This is a trend chart of SF-36 PCS scores at various assessment time points in the clinical trial study. The comparison with the placebo group is shown below. # P <0.05, ## P <0.01.

[0040] Figure 14 This is a trend chart of SF-36 MCS scores at various assessment time points in the clinical trial study.

[0041] Figure 15 To investigate the effect of the kidney-tonifying and muscle-relaxing formula on the mechanical pain threshold of rats, the graph shows that the horizontal axis represents time (in weeks) and the vertical axis represents the mechanical pain threshold of rats (in grams). The color of the line graph indicates the grouping. The graph compares the FM-FMT+YYRJF group with the FM-FMT group. P < 0.01.

[0042] Figure 16 To investigate the effect of the kidney-tonifying and muscle-relaxing formula on heat-induced pain sensitivity in rats, the graph shows that the horizontal axis represents time (in weeks), and the vertical axis represents the rat's response time to heat stimulation (in grams). The color of the line graph indicates the grouping. The graph compares the FM-FMT+YYRJF group with the FM-FMT group. P < 0.05. Detailed Implementation

[0043] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0044] Example 1 Kidney-tonifying and muscle-relaxing formula: Cornus officinalis 9g, Bupleurum chinense 6g, stir-fried Paeonia lactiflora 15g, vinegar-processed Corydalis yanhusuo 9g, lily bulb 12g, Albizia julibrissin bark 9g, Angelica sinensis 6g, Poria cocos 15g, processed Pinellia ternata 6g, Citrus reticulata peel 6g, prepared Glycyrrhiza uralensis 5g. Decocted and taken orally.

[0045] 1. Clinical Trial: A randomized, double-blind, placebo-controlled study of this traditional Chinese medicine compound for the treatment of fibromyalgia syndrome. 1.1 Design Type Through an exploratory clinical trial with randomized, double-blind, placebo-parallel controlled design, patients with fibromyalgia syndrome who met the 2016 American College of Rheumatology classification criteria and were differentiated in traditional Chinese medicine as the syndrome of yin deficiency of liver and kidney combined with liver depression and qi stagnation were enrolled. The patients were randomly divided into a Yishen Shujin Formula group and a placebo group. The Yishen Shujin Formula group was administered the traditional Chinese medicine compound of Example 1, and the placebo group was administered a placebo, with a treatment course of 12 weeks. The evaluation time points were week 0, week 2, week 4, week 8, and week 12. The internationally recognized evaluation indicator for this disease - the Brief Pain Inventory - was used as the primary efficacy evaluation indicator, and the secondary efficacy evaluation indicators included the Widespread Pain Index, the Multidimensional Fatigue Inventory, the Revised Fibromyalgia Impact Questionnaire, the Pittsburgh Sleep Quality Index, the Perceived Stress Scale, and the Short Form Health Survey, to assess the changes of the indicators in patients before and after treatment. Meanwhile, the blood routine, liver and kidney functions, urine routine, and electrocardiogram of the patients at week 0 and week 12 were monitored to evaluate the safety.

[0046] 1.2 Clinical study results A total of 48 patients were enrolled in this study. After 12 weeks of intervention, 42 patients actually completed the study, with 6 cases of shedding (14.3%). In the Yishen Shujin Formula group, 22 cases completed the trial and 2 cases shed (8.3%); in the placebo group, 20 cases completed the trial and 4 cases shed (16.7%). The details are as Figure 1 shown.

[0047] 1.3 Baseline comparison 1.3.1 General conditions In the Yishen Shujin Formula group, there were 24 patients, with an average age of 46.46±12.30 years, the oldest being 67 years old and the youngest 19 years old; there were 2 male patients and 22 female patients; the average body mass index was 23.25±2.88kg / m 2 , the highest being 27.39kg / m 2 , the lowest being 18.29kg / m 2 ; the average disease course was 65.46±75.52 months, the longest being 360 months and the shortest 4 months.

[0048] In the placebo group, there were 24 patients, with an average age of 43.54±11.48 years, the oldest being 67 years old and the youngest 26 years old; there were 3 male patients and 21 female patients; the average body mass index was 23.06±2.85kg / m 2 , the highest being 30.08kg / m 2 , the lowest being 18.59kg / m 2 ; the average disease course was 57.58±50.79 months, the longest being 240 months and the shortest 6 months.

[0049] As shown in Table 1, there were no statistically significant differences in the data of age, gender, disease course, BMI, etc. between the two groups of patients (P>0.05), indicating comparability. The patients in both groups were mainly middle-aged and elderly women, which was consistent with the epidemiological characteristics of FM.

[0050] Table 1 General Information Table

[0051] 1.3.2 Comparison of various efficacy indicators at baseline As shown in Table 2, there were no statistically significant differences in the total BPI score, BPI pain intensity score, BPI pain impact score, WPI, MFI score, FIQR score, PSQI score, PSS score, SF-36 PCS score, and SF-36 MCS score between the two groups before treatment, indicating that they were comparable.

[0052] Table 2 Comparison of baseline assessment indicators between the two groups of patients

[0053] 1.4 Results of the analysis of therapeutic indicators 1.4.1 Main therapeutic indicators Comparison of BPI total scores at different assessment points as follows: Figure 2 As shown in Table 3. ① Intra-group comparison: The total BPI score of the Yishen Shujin Fang group at 4, 8, and 12 weeks of treatment was significantly different from the baseline. P <0.05). There were no statistically significant differences in the total BPI score at any evaluation time point compared to baseline in the placebo group. P >0.05). ② Intergroup comparison: After 8 and 12 weeks of treatment, the improvement in total BPI score from baseline was statistically significant in both groups. P <0.05).

[0054] Table 3 Comparison of BPI total scores at different assessment points

[0055] Note: Compared with before treatment, P <0.05, P <0.01.

[0056] Trends in BPI pain intensity scores at each assessment time point are as follows: Figure 3 As shown in Table 4. ① Intra-group comparison: The BPI pain intensity scores at each evaluation time point in the Yishen Shujin Fang group showed statistically significant differences compared with baseline. P <0.05). There were no statistically significant differences in BPI pain intensity scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the difference in BPI pain intensity scores between the two groups was statistically significant ( P<0.05). After 8 and 12 weeks of treatment, the improvement in BPI pain intensity scores from baseline was statistically significant in both groups. P <0.05).

[0057] Table 4 Comparison of BPI pain intensity scores at different assessment time points

[0058] Note: Compared with before treatment, P <0.05, P <0.01.

[0059] Comparison of BPI pain scores at different assessment time points Figure 4 As shown in Table 5. ① Intra-group comparison: The effects of the Yishen Shujin Fang formula on BPI pain at 4, 8, and 12 weeks of treatment showed statistically significant differences compared to baseline. P <0.05). There were no statistically significant differences in the impact of BPI on pain at any evaluation time point in the placebo group compared to baseline. P >0.05). ② Intergroup comparison: At each evaluation time point, there was no statistically significant difference in the BPI pain impact scores between the two groups ( P >0.05). After 12 weeks of treatment, the improvement in BPI pain impact scores from baseline was statistically significant between the two groups. P <0.05).

[0060] Table 5 Comparison of BPI pain scores at different assessment time points

[0061] Note: Compared with before treatment, P <0.05, P <0.01.

[0062] 1.5 secondary efficacy indicators 1.5.1 WPI Score Comparison of WPI scores at different assessment points Figure 5 As shown in Table 6. ① Intra-group comparison: The WPI scores of the Yishen Shujin Fang group at 4, 8, and 12 weeks of treatment were all statistically significant compared with baseline. P <0.05). There were no statistically significant differences in WPI scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: At each assessment time point, there were no statistically significant differences in WPI scores and improvements from baseline between the two groups (>0.05).P >0.05).

[0063] Table 6 Comparison of WPI scores at different assessment points

[0064] Note: Compared with before treatment, P <0.05, P <0.01.

[0065] 1.5.2 MFI Score Comparison of MFI scores at different evaluation points Figure 6 As shown in Table 7. ① Intra-group comparison: The MFI scores of the Yishen Shujin Fang group at 8 and 12 weeks of treatment were statistically significant compared with baseline. P <0.01). There were no statistically significant differences in MFI scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the difference in MFI scores between the two groups was statistically significant ( P <0.05). After 8 and 12 weeks of treatment, the improvement in MFI scores from baseline was statistically significant in both groups. P <0.05).

[0066] Table 7 Comparison of MFI scores at different assessment points

[0067] Note: Compared with before treatment, P <0.01.

[0068] 1.5.3 FIQR Score Comparison of FIQR total scores at different assessment points as follows: Figure 7 As shown in Table 8. ① Intra-group comparison: The total FIQR score of the Yishen Shujin Fang group at 4, 8, and 12 weeks of treatment was significantly different from the baseline. P <0.01). There were no statistically significant differences in the total FIQR score at any evaluation time point in the placebo group compared to baseline. P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the improvement in FIQR total score and baseline value between the two groups was statistically significant (>0.05). P <0.01).

[0069] Table 8 Comparison of FIQR total scores at different assessment points

[0070] Note: Compared with before treatment, P <0.01.

[0071] Comparison of FIQR functional dimensions scores at different assessment points: Figure 8 As shown in Table 9. ① Intra-group comparison: The FIQR functional dimension scores of the Yishen Shujin Fang group at 12 weeks of treatment were statistically significant compared with baseline. P <0.05). There were no statistically significant differences in FIQR functional dimension scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the difference in FIQR functional dimension scores between the two groups was statistically significant ( P <0.05). At each assessment time point, there was no statistically significant difference in the improvement values ​​of the two groups' FIQR functional dimension scores compared to baseline. P >0.05).

[0072] Table 9 Comparison of FIQR functional dimensions scores at different evaluation points

[0073] Note: Compared with before treatment, P <0.05.

[0074] Comparison of the impact of FIQR on the scores of different evaluation points. Figure 9 As shown in Table 10. ① Intra-group comparison: The FIQR impact dimension scores of the Yishen Shujin Fang group at 8 and 12 weeks of treatment were statistically significant compared with baseline. P <0.01). At 8 weeks of treatment, the FIQR impact dimension scores in the placebo group showed a statistically significant difference compared to baseline. P <0.05). ② Intergroup comparison: After 12 weeks of treatment, the difference in FIQR impact dimension scores between the two groups was statistically significant ( P <0.05). At each assessment time point, there was no statistically significant difference in the improvement values ​​of the two groups' FIQR impact dimension scores compared to baseline. P >0.05).

[0075] Table 10 Comparison of FIQR Influence Dimension Scores at Different Assessment Points

[0076] Note: Compared with before treatment, P <0.01.

[0077] Comparison of FIQR symptom dimension scores at different assessment points, as follows: Figure 10As shown in Table 11. ① Intra-group comparison: The FIQR symptom scores at each evaluation time point in the Yishen Shujin Fang group were statistically significant compared with baseline. P <0.05). There were no statistically significant differences in FIQR symptom scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 8 and 12 weeks of treatment, the improvement values ​​of FIQR symptom dimensions and baseline values ​​in both groups were statistically significant (>0.05). P <0.05).

[0078] Table 11 Comparison of FIQR symptom dimension scores at different assessment time points

[0079] Note: Compared with before treatment, P < 0.05.

[0080] 1.5.4 PSQI Score Comparison of PSQI scores at different evaluation points Figure 11 As shown in Table 12. ① Intra-group comparison: The PSQI scores of the Yishen Shujin Fang group at 8 and 12 weeks of treatment were statistically significant compared with baseline. P <0.01). There were no statistically significant differences in PSQI scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the improvement in PSQI scores from baseline was statistically significant between the two groups ( P <0.05).

[0081] Table 12 Comparison of PSQI scores at different assessment points

[0082] Note: Compared with before treatment, P <0.01.

[0083] 1.5.5 PSS rating Comparison of PSS scores at different evaluation points Figure 12 As shown in Table 13. ① Intra-group comparison: The PSS scores of the Yishen Shujin Fang group at 8 and 12 weeks of treatment were statistically significant compared with baseline. P <0.05). There were no statistically significant differences in PSS scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the difference in PSS scores between the two groups was statistically significant ( P <0.05). At each assessment time point, there was no statistically significant difference in the improvement of PSS scores from baseline between the two groups (P >0.05).

[0084] Table 13 Comparison of PSS scores at different evaluation points

[0085] Note: Compared with before treatment, P <0.05, P <0.01.

[0086] 1.5.6 SF-36 rating Comparison of SF-36 PCS scores at different testing points: Figure 13 As shown in Table 14. ① Intra-group comparison: The SF-36 PCS scores at each evaluation time point in the Yishen Shujin Fang group showed statistically significant differences compared to baseline. P <0.05). There were no statistically significant differences in SF-36 PCS scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: After 12 weeks of treatment, the difference in SF-36 PCS scores between the two groups was statistically significant ( P <0.05). After 8 and 12 weeks of treatment, the improvement in SF-36 PCS scores from baseline was statistically significant in both groups. P <0.05).

[0087] Table 14 Comparison of SF-36 PCS scores at different evaluation points

[0088] Note: Compared with before treatment, P <0.05, P <0.01.

[0089] Comparison of SF-36 MCS scores at different testing points Figure 14 As shown in Table 15. ① Intra-group comparison: The SF-36 MCS score of the Yishen Shujin Fang group after 8 weeks of treatment was significantly different from the baseline. P <0.05). There were no statistically significant differences in SF-36 MCS scores at any evaluation time point compared to baseline in the placebo group ( P >0.05). ② Intergroup comparison: At each assessment time point, there were no statistically significant differences in the SF-36 MCS scores and improvements from baseline between the two groups (>0.05). P >0.05).

[0090] Table 15 Comparison of SF-36 MCS scores at different evaluation points

[0091] Note: Compared with before treatment, P <0.05.

[0092] 1.5.7 PGIC Assessment The PGIC assessment results are shown in Table 16. Patients in the Yishen Shujin Fang group reported significantly greater overall improvement than those in the placebo group (Z=3.95). P <0.01), of which 22.7% of patients in the Yishen Shujin Fang group reported significant improvement, while 0% in the placebo group, and the difference between the groups was statistically significant. P <0.05).

[0093] Table 16 PGIC Assessment Results [Example (%)]

[0094] Note: Compared with the placebo group # P <0.05, ## P <0.01.

[0095] 1.6 Security Analysis In this study, 42 patients completed the trial. Complete blood counts, urinalysis, liver function tests (ALT, AST), and kidney function tests (BUN, Cr) were performed at weeks 0 and 12 of treatment, and no abnormalities were found. Two patients reported adverse events during the trial. One patient reported elevated liver function indicators, which was assessed as possibly related to the patient's self-selection of lipid-lowering medication and definitely unrelated to the study drug. For safety reasons, this patient discontinued medication and withdrew from the trial. The other patient experienced mild nausea after medication administration; after persuasion, the patient agreed to continue medication, and the trial could not be continued. Details are shown in Table 17 below.

[0096] Table 17 List of Adverse Events

[0097] 1.7 Compliance Analysis A total of 6 patients dropped out of this study, including 2 in the Yishen Shujin Fang group and 4 in the placebo group. The 2 dropouts in the Yishen Shujin Fang group were due to loss to follow-up and failure to complete the trial. Of the 4 dropouts in the placebo group, 2 failed to complete the trial due to lack of efficacy, 1 withdrew due to unwillingness to continue participation, and 1 withdrew due to an adverse event.

[0098] 2. Animal Experiments: A study was conducted on the effects of this traditional Chinese medicine compound on pain behavior in a rat model of fibromyalgia syndrome. A fibromyalgia-like pain animal model is established via human-mice fecal microbiota transplantation technology. Male SD rats are randomly divided into the HC-FMT group (receiving gut microbiota transplantation from healthy individuals), the FM-FMT group (receiving gut microbiota transplantation from fibromyalgia patients), and the FM-FMT+YSSJF group (intervened with the traditional Chinese medicine compound of Example 1). All groups of rats are treated with broad-spectrum antibiotics for one week to establish a pseudo-aseptic state, and then are gavaged with fecal microbiota suspensions from healthy individuals or FM patients respectively for 6 consecutive weeks. In the previous pre-experiment of the research group, the effects of different doses of Yishen Shujin Formula on pain behavior of FM rats were observed. The rat doses were converted according to the body surface area method, and a low-dose group (4.41 g / kg), a medium-dose group (8.82 g / kg) and a high-dose group (17.64 g / kg) were set. The results showed that the medium-dose group of the traditional Chinese medicine compound had the best curative effect, so the medium dose was selected for intervention in this study. For the administration method, the FM-FMT+YSSJF group was subjected to gavage starting from the 4th week of fecal microbiota transplantation, once a day for 2 consecutive weeks, and the HC-FMT group and the FM-FMT group were gavaged with an equal volume of distilled water at the same period. The Von Frey filament test and hot plate test are used to evaluate the mechanical pain threshold and thermal pain threshold of rats, the differences in mechanical pain threshold and thermal pain threshold among groups of rats are compared, so as to reveal the effect of this traditional Chinese medicine compound on the pain behavior of fibromyalgia syndrome model rats.

[0099] The effect of Yishen Shujin Formula on the mechanical pain threshold of rats is shown in Figure 15 , at the 4th week of fecal microbiota transplantation, the mechanical pain thresholds of the FM-FMT group and the FM-FMT+YSSJF group are significantly lower than that of the HC-FMT group. After the intervention of Yishen Shujin Formula, the mechanical paw withdrawal threshold of rats begins to rise. At the 6th week of fecal microbiota transplantation, the mechanical paw withdrawal threshold of the FM-FMT+YSSJF group is significantly higher than that of the FM-FMT group (p<0.05), but still lower than the level of the HC-FMT group.

[0100] The effect of Yishen Shujin Formula on thermal hyperalgesia in rats is shown in Figure 16 , at the 4th week of fecal microbiota transplantation, the thermal pain thresholds of the FM-FMT group and the FM-FMT+YSSJF group are significantly lower than that of the HC-FMT group. After the intervention of Yishen Shujin Formula, the thermal pain threshold of rats is significantly higher than that of the FM-FMT group, and returns to the level of the HC-FMT group.

[0101] Apparently, the above-mentioned examples of the present invention are only used to clearly illustrate the present invention, and are not intended to limit the implementation manners of the present invention. For those of ordinary skill in the art, other variations or modifications of different forms can be made on the basis of the above description. It is impossible to exhaust all the implementation manners here. All obvious variations or modifications derived from the technical solutions of the present invention still fall within the protection scope of the present invention.

Claims

1. A traditional Chinese medicine composition for relieving fibromyalgia syndrome with pain and fatigue, characterized in that, The traditional Chinese medicine composition includes the following raw materials: Cornus officinalis, Bupleurum chinense, stir-fried Paeonia lactiflora, vinegar-processed Corydalis yanhusuo, lily bulb, Albizia julibrissin bark, Angelica sinensis, Poria cocos, processed Pinellia ternata, tangerine peel, and prepared licorice root.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following active pharmaceutical ingredients in parts by weight: Cornus officinalis 9-18 parts, Bupleurum chinense 6-12 parts, stir-fried Paeonia lactiflora 15-30 parts, vinegar-processed Corydalis yanhusuo 9-18 parts, lily bulb 12-24 parts, Albizia julibrissin bark 9-18 parts, Angelica sinensis 6-12 parts, Poria cocos 15-30 parts, processed Pinellia ternata 6-9 parts, Citrus reticulata peel 6-9 parts, prepared Glycyrrhiza uralensis 5-10 parts.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following active pharmaceutical ingredients in parts by weight: Cornus officinalis 9 parts, Bupleurum chinense 6 parts, stir-fried Paeonia lactiflora 15 parts, vinegar-processed Corydalis yanhusuo 9 parts, lily bulb 12 parts, Albizia julibrissin bark 9 parts, Angelica sinensis 6 parts, Poria cocos 15 parts, processed Pinellia ternata 6 parts, tangerine peel 6 parts, and prepared licorice root 5 parts.

4. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following active pharmaceutical ingredients in parts by weight: Cornus officinalis 12 parts, Bupleurum chinense 8 parts, stir-fried Paeonia lactiflora 20 parts, vinegar-processed Corydalis yanhusuo 12 parts, Lilium brownii 16 parts, Albizia julibrissin bark 12 parts, Angelica sinensis 8 parts, Poria cocos 20 parts, processed Pinellia ternata 8 parts, Citrus reticulata peel 8 parts, and prepared Glycyrrhiza uralensis 7 parts.

5. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises the following active pharmaceutical ingredients in parts by weight: Cornus officinalis 18 parts, Bupleurum chinense 12 parts, stir-fried Paeonia lactiflora 30 parts, vinegar-processed Corydalis yanhusuo 18 parts, lily bulb 24 parts, Albizia julibrissin bark 18 parts, Angelica sinensis 12 parts, Poria cocos 30 parts, processed Pinellia ternata 12 parts, Citrus reticulata peel 12 parts, and prepared Glycyrrhiza uralensis 10 parts.

6. A traditional Chinese medicine preparation for improving fibromyalgia syndrome with pain and fatigue, characterized in that, The raw materials for the traditional Chinese medicine preparation include the traditional Chinese medicine composition according to any one of claims 1-5.

7. The traditional Chinese medicine preparation according to claim 6, characterized in that, The dosage forms of the traditional Chinese medicine preparations include decoctions, granules, capsules, tablets, powders, pills, or oral liquids.

8. The traditional Chinese medicine preparation according to claim 6, characterized in that, The raw materials for the traditional Chinese medicine preparations also include pharmaceutically acceptable excipients.

9. The use of the traditional Chinese medicine composition according to any one of claims 1-5 or the traditional Chinese medicine preparation according to any one of claims 6-8 in the preparation of a medicament for improving pain and fatigue in fibromyalgia syndrome.

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