Silymarin vs Hesperidin/Diosmin in Fibromyalgia (SHD-FM)

The Effect of Silymarin Versus Hesperidin/Diosmin Combination on Patients With Fibromyalgia

Fibromyalgia is a chronic disease, characterized by chronic widespread pain, physical exhaustion, sleep problems, and unexplained pain in both joints and muscles. Fibromyalgia's causes still unknown, but there are various risk factors that can cause fibromyalgia such as genetic causes, physical shock, and infections. Fibromyalgia typically presents in young or middle aged females, it occurs in females more than males, and it is characterized with widespread pain throughout the whole body in both sides such as arms, shoulders, head, and abdominal areas. The etiology of fibromyalgia still unclear, but there are several factors such as alterations in the sleep pattern, changes in the neuroendocrine transmitters such as cortisol, growth hormones and serotonin, dysfunction of central and autonomic nervous systems, psychiatric aspects and external stressors . The pain seems to result from neurochemical imbalances in the central nervous system that lead to a "central amplification" of pain perception characterized by allodynia (a heightened sensitivity to stimuli that are not normally painful) and hyperalgesia (an increased response to painful stimuli). this interventional study aims to study effect of silymarin and hesperidin/diosmin combination on fibromyalgia patients and compare their effect with control patients on the following

1. Management of pain.
2. Inflammatory biomarkers.
3. Quality of life.

Study Overview

• Status: Recruiting
• Conditions: Fibromyalgia (FM)
• Intervention / Treatment: Drug: Silymarin (LEGALON); Drug: Diosmin / Hesperidin (Daflon); Other: no intervention (control group)

Detailed Description

Fibromyalgia is a chronic disease characterized by chronic widespread pain, physical exhaustion, sleep problems, and unexplained pain in joints and muscles. Although the exact causes remain unknown, several risk factors have been implicated, including genetic predisposition, physical or emotional stress, and infections. Fibromyalgia occurs predominantly in females and is associated with widespread pain in multiple body regions such as the arms, shoulders, head, and abdomen. The etiology involves alterations in sleep patterns, changes in neuroendocrine transmitters such as cortisol, growth hormone, and serotonin, along with dysfunction of the central and autonomic nervous systems. Pain is believed to result from neurochemical imbalances that lead to central amplification of pain perception, characterized by allodynia and hyperalgesia.

Diagnosis of fibromyalgia is challenging, as no specific laboratory tests or imaging confirm the condition. The 1990 ACR criteria relied on tender points and widespread pain for at least three months. More recently, the ACR proposed new diagnostic criteria incorporating the Widespread Pain Index (WPI) and Symptom Severity (SS) scale, which evaluate pain in 19 body regions and rate associated symptoms such as fatigue, cognitive difficulties, headache, and dizziness.

Management of fibromyalgia includes several approaches. FDA-approved medications include pregabalin, duloxetine, and milnacipran, although these may be costly and associated with side effects. Anticonvulsants, amitriptyline, and fluoxetine may also be used to improve pain and sleep. Non-pharmacological therapies include biofeedback, cognitive behavioral therapy, physiotherapy, exercise, and electromyogram-guided interventions. Alternative therapies such as acupuncture, chiropractic care, deep tissue massage, neuromuscular massage, meditation, and certain herbal supplements (e.g., echinacea purpurea, black cohosh, lavender, Silybum marianum) have shown varying degrees of benefit.

Inflammatory mediators, particularly IL-6 and IL-8, are commonly elevated in fibromyalgia and correlate with functional impairment, fatigue, and sleep disturbance. Silymarin, extracted from Silybum marianum, possesses hepatoprotective, antioxidant, anti-inflammatory, immunomodulatory, and cardioprotective activities. It has demonstrated reductions in inflammatory cytokines such as TNF-α and IL-6 and showed significant reduction of IL-1α and IL-8 in clinical studies. Diosmin/hesperidin, a flavonoid combination derived from citrus fruits, also exhibits antioxidant and anti-inflammatory activity and has produced antihyperalgesic effects in neuropathic pain models through the reduction of TNF-α, IL-1β, and IL-6.

Based on these findings, the current study hypothesizes that administering silymarin or diosmin/hesperidin in addition to standard fibromyalgia therapy may reduce inflammation and improve pain outcomes in patients with fibromyalgia. The study will compare the effects of silymarin versus diosmin/hesperidin on clinical symptoms, inflammatory biomarkers, and quality of life over a four-month period, as well as evaluate their safety and tolerability.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: menna s teaching assistant of clinical pharmacy/ master's student; Phone Number: 01064897439; Email: mssalama@msa.edu.eg

Study Locations

• Egypt
  • Cairo, Egypt
    • Recruiting
    • Outpatients clinic of department of Internal medicine- Rheumatology unit Ain shams hospitals.
    • Contact: mennaallah sayed s teaching assistant of clinical pharmacy/ master's student, master's; Phone Number: 01000132431 01064897439; Email: mssalama@msa.edu.eg
    • Contact: nagwa ali A Professor of clinical pharmacy; Phone Number: 01223411984; Email: nagwa.sabri@pharma.asu.edu.eg
    • Principal Investigator: minna sayed

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed written consent.
• Participant must meet the American College of Rheumatology 2016 revised classification criteria for Fibromyalgia: Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥ 5, or WPI 3 to 6 and SS scale score ≥ 9
• Age >18 years old (males and females)
• Diagnosis of FM confirmed by a rheumatologist.
• Persistent pain syndrome on conventional therapy.
• Not taking Daflon or Legalon for 6 months.

Exclusion Criteria:

• Pain due to other conditions (e.g. diabetic peripheral neuropathic pain or post-herpetic neuralgia) that would confound assessment or self-evaluation of the pain associated with FM.
• Patients with pain due to any widespread inflammatory musculoskeletal disorder (e.g. rheumatoid arthritis, lupus) or widespread rheumatic disease other than FM.
• Allergy to silymarin or diosmin or hesperidin.
• Cognitive deficits that could impair understanding of the study, completion of questionnaires, or adherence to therapy.
• Pregnant or planning pregnancy women and breastfeeding women.
• Major comorbidities like renal impairment, severe liver disease, chronic hepatitis C, history of alcohol or drug addiction.
• Current severe or uncontrolled major depressive disorder or anxiety disorders.
• Patients will be excluded if there is no compliance to the medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Silymarin group; this group of patients will receive silymarin (LEGALON) 140 mg three times daily with the standard treatment	Drug: Silymarin (LEGALON); oral silymarin (legalon) 140 mg will be taken 3 times daily for 12 weeks with the standard treatment
Experimental: Diosmin/hisperedin group; this group will receive hesperidin/diosmin (daflon) 500 once daily for 12 weeks with the standard treatment	Drug: Diosmin / Hesperidin (Daflon); Diosmin / Hesperidin (Daflon) 500 mg will be taken once daily for 12 weeks with the standard treatment
Active Comparator: Standard care group; participants will receive standard treatment only	Other: no intervention (control group); this group will receive no intervention (only the standard treatment)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pain assessment through Fibromyalgia impact questionnaire (FIQ)	Change in Fibromyalgia impact questionnaire (FIQ) score will be assessed by the end of the study, the score ranges from 0 to 100 higher score means worse condition	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Erythrocyte sedimentation rate (ESR)	ESR will be measured at baseline and after four months of treatment	4 months
C-reactive protein level (CRP)	CRP will be measured at baseline and after four months of treatment	4 months
Health-related quality-of-life through Short Form 12 health survey SF-12	quality of life will be assessed through Short Form 12 health survey SF-12 (Questionnaire of health) at baseline and after 4 months the score ranges from 0 to 100 higher scores indicate better health	4 months
pain assessment through visual analogue scale (VAS)	visual analogue scale (VAS) score will be assessed at baseline and after four months of treatment, the score ranges from 0 to 10 cm higher score means worse condition	4 months
laboratory evaluation of interleukin- 8 (IL-8) level	serum IL8 concentration will be measured at baseline and after four months of treatment.	4 months

Collaborators and Investigators

• Sponsor: Ain Shams University

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2024
• Primary Completion (Estimated): January 15, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 25, 2025
• First Submitted That Met QC Criteria: December 7, 2025
• First Posted (Actual): December 19, 2025

Study Record Updates

• Last Update Posted (Actual): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 7, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: fibromyalgia; silymarin; hesperidin; diosmin
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Rheumatic Diseases; Fibromyalgia; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Epidemiologic Research Design; Epidemiologic Methods; Research Design; Methods; Pyrans; Carbohydrates; Glycosides; Benzopyrans; Flavonoids; Chromones; Flavonolignans; Flavanones; Flavones; Silymarin; Control Groups; Hesperidin; Diosmin
• Other Study ID Numbers: FM

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No