European Journal of Cardiovascular Medicine

Free radicals are involved in many physiological functions of chondrocytes, such as intracellular signaling, apoptosis, cytokine production and extracellular matrix remodeling[1]. However, increased oxidative stress due to the imbalance of antioxidants and oxidants can be harmful to the chondrocytes. Apart from damaging the cellular macromolecules, free radicals can also activate the nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB), phosphoinositide 3-kinase (PI3K) and c-Jun N-terminal kinase (JNK) pathways, which result in the senescence and apoptosis of chondrocytes. Consequently, cartilage remodeling will be impaired, giving rise to cartilage thinning and osteoarthritis. This is evidenced by the low levels of antioxidants, high levels of oxidants and oxidized/nitrated adducts of macromolecules in the synovial fluid of osteoarthritic patients compared to healthy controls [2,3]. A higher level of F(2)-isoprostane, a stable marker of oxidative stress in vivo, has been found in patients with rheumatic diseases, including osteoarthritis. High level of nitric oxide, a nitrogen reactive species produced by the inducible nitric oxide synthase at the joint, is also responsible for increased pain signaling among osteoarthritic patients [4]. Therefore, antioxidant therapy represents a potential avenue to tackle the degenerative joint changes and pain in osteoarthritis.

Vitamin E is a strong antioxidant found in plants. Structurally, it consists of a chromanol ring and an isoprenoid side chain. Vitamin E is a broad term referring to tocopherols and tocotrienols, which can be further divided into alpha-, beta-, gamma-, and delta-isomers based on the position of side chains on the chromanol ring [5]. Alpha-tocopherol is the most prevailing vitamin E isomer in nature and in the body [6]. It is present in the synovial fluid despite being an aqueous environment. The antioxidant activity of vitamin E relies on the hydroxyl group on the chromanol ring, which readily donates hydrogen to reduce the free radicals [7]. In vitro and in vivo studies have demonstrated that the antioxidant activity of tocotrienol is superior to tocopherol due to three reasons: (1) tocotrienol is more uniformly distributed across the lipid membrane; (2) tocotrienol, with the double bonds on its isoprenoid side chain, offers more interaction with free radicals; (3) tocotrienol has a higher redox cycling efficiency compared to tocopherol [8]. Apart from acting as a free radical scavenger, vitamin E can modulate nuclear factor-erythroid 2-related factor 2 (NRF2), a transcription factor regulating the expression of antioxidant enzymes [9]. Vitamin E supplementation has been shown to upregulate the activity of antioxidant in the musculoskeletal system [10]. It can also inhibit NFκB pathway and inflammation, the key factors sustaining the vicious cycle of joint destruction in osteoarthritis. These properties suggest that vitamin E could be used as an agent to suppress oxidative stress and inflammation underlying the pathogenesis of osteoarthritis.

To evaluate the efficacy of Vitamin E, an antioxidant, as a therapeutic agent in reducing pain severity and improving clinical outcomes in patients experiencing pain.

Study Design: Randomized Controlled Trial study.

Study Place: Department of Orthopaedics of Calcutta National Medical College and Hospital.

Study Time: Jan 2024 to Dec 2024 for one year.

Sample size: 100chronic pain.

Study parameter:

·         Vitamin E

·         Placebo

·         Painful Days/Month Reduction

·         Analgesic Tablets/Month Reduction

·         Pain-Free Patients

·         MDA

·         Alpha-Tocopherol

·         TEAC

·         Clinical Score

·         Functional Score

Inclusion Criteria:

·         Adults aged 18 years and above

·         Patients experiencing chronic pain

·         Pain duration of at least 3 months

·         Baseline pain severity above a defined threshold (e.g., VAS ≥ 4)

Exclusion Criteria:

·         Known allergy or hypersensitivity to Vitamin E

·         Current use of high-dose antioxidant supplements

·         Pregnant or breastfeeding women

·         Severe comorbidities

Statistical Analysis

Data were entered into Excel and analysed using SPSS and Graph Pad Prism. Numerical variables were summarized using means and standard deviations, while categorical variables were described with counts and percentages. Two-sample t-tests were used to compare independent groups, while paired t-tests accounted for correlations in paired data. Chi-square tests (including Fisher’s exact test for small sample sizes) were used for categorical data comparisons. P-values ≤ 0.05 were considered statistically significant.

Table 1: Distribution of mean Vitamin E for Primary Dysmenorrhea

Table 2: Distribution of mean Vitamin E in Chronic Pancreatitis

Table 3: Distribution of mean Vitamin E in Knee Osteoarthritis

Table 4: Distribution of mean Vitamin E in Knee Osteoarthritis: Clinical and Functional Scores

The Vitamin E group showed a significant reduction in pain severity from 5.41 ± 2.4 before treatment to 4.73 ± 1.89 after 2 months. The mean pain reduction was -2.7 ± 2.1 (p < 0.001).

The Placebo group showed a decrease in pain severity from 5.76 ± 2.08 before treatment to 5.35 ± 2.05 after 2 months. The mean pain reduction was -1.8 ± 2.4 (p < 0.001).

The Antioxidant group showed a greater reduction in painful days per month (7.4 ± 6.8) compared to the Placebo group (3.2 ± 4). This difference was statistically significant (p < 0.001).

The Antioxidant group had a significantly higher reduction in analgesic tablets used per month (10.5 ± 11.8) compared to the Placebo group (4.4 ± 5.8), with a p-value of <0.001.

A higher percentage of pain-free patients was observed in the Antioxidant group (32%) compared to the Placebo group (13%), with the difference being statistically significant (p = 0.009).

Malondialdehyde (MDA) levels were significantly lower in Group B (Vitamin E) (1.00 ± 0.09 nmol/mL) compared to Group A (Placebo) (1.34 ± 0.10 nmol/mL), with a p-value of <0.02.

Alpha-Tocopherol levels were significantly higher in Group B (Vitamin E) (24.65 ± 1.47 µmol/L) compared to Group A (Placebo) (15.92 ± 1.08 µmol/L), with a p-value of <0.01.

Total antioxidant capacity (TEAC) was significantly higher in Group B (Vitamin E) (5.04 ± 0.10 µmol/L) compared to Group A (Placebo) (4.22 ± 0.10 µmol/L), with a p-value of <0.01.

Post-intervention clinical scores were significantly higher in Group B (Vitamin E) (33.52 ± 16.96) compared to Group A (Placebo) (25.31 ± 14.33), with a p-value of <0.01.

Post-intervention functional scores were significantly higher in Group B (Vitamin E) (51.61 ± 19.60) compared to Group A (Placebo) (41.43 ± 16.11), with a p-value of 0.02.

The Vitamin E group demonstrated a significant decrease in pain severity, dropping from 5.41 ± 2.4 before treatment to 4.73 ± 1.89 after 2 months, indicating effective pain relief. The mean pain reduction of -2.7 ± 2.1 (p < 0.001) suggests a strong therapeutic benefit. These findings highlight the potential of Vitamin E as an adjunct treatment for managing pain.A study by Ataie-Jafari et al. (2014) investigated the effect of Vitamin E supplementation on pain severity in patients with diabetic neuropathy. The researchers reported a significant reduction in pain scores after 8 weeks of Vitamin E treatment, with mean pain intensity decreasing from baseline values similar to the current study. The findings support the antioxidant’s role in alleviating neuropathic pain and improving patient quality of life.[11]

The Placebo group experienced a modest decrease in pain severity from 5.76 ± 2.08 to 5.35 ± 2.05 after 2 months. The mean pain reduction of -1.8 ± 2.4 (p < 0.001) indicates some improvement, possibly due to placebo effects or natural variation. However, the reduction was less pronounced compared to the Vitamin E group, suggesting limited efficacy. A study by Amanzio et al. (2013) investigated the placebo effect in patients with carpal tunnel syndrome (CTS).The placebo group showed a 19.7% reduction in pain intensity on the Visual Analog Scale (VAS), indicating a modest analgesic effect. This aligns with your observation of a mean pain reduction of -1.8 ± 2.4 in the placebo group. The study suggests that while placebo treatments can lead to symptom relief, the magnitude of the effect is often modest and may vary depending on the condition and individual patient factors.[12]

The Antioxidant group demonstrated a substantially greater reduction in painful days per month (7.4 ± 6.8) compared to the Placebo group (3.2 ± 4), highlighting its effectiveness in reducing pain frequency. This significant difference (p < 0.001) suggests that antioxidants may play a key role in managing pain. These results support the potential clinical benefit of antioxidant therapy over placebo.

The Antioxidant group showed a notably greater reduction in the use of analgesic tablets per month (10.5 ± 11.8) compared to the Placebo group (4.4 ± 5.8), indicating better pain control. This significant difference (p < 0.001) suggests that antioxidant therapy can reduce reliance on pain medication. These findings reinforce the potential of antioxidants to improve pain management outcomes.

The Antioxidant group had a significantly higher proportion of pain-free patients (32%) compared to the Placebo group (13%), indicating a more effective pain relief. This significant difference (p = 0.009) highlights the therapeutic potential of antioxidants in achieving complete pain remission. These results support the use of antioxidant treatment for better clinical outcomes.

Group B (Vitamin E) showed significantly lower malondialdehyde (MDA) levels (1.00 ± 0.09 nmol/mL) compared to Group A (Placebo) (1.34 ± 0.10 nmol/mL), indicating reduced oxidative stress. The significant difference (p < 0.02) suggests that Vitamin E effectively decreases lipid peroxidation. These findings support its antioxidant role in improving biochemical markers. A study by Sundari et al. (2017) investigated the effects of 400 IU daily Vitamin E supplementation on malondialdehyde (MDA) levels in obese women. The results indicated a significant reduction in MDA levels in the experimental group compared to the control group, suggesting that Vitamin E effectively decreases lipid peroxidation and oxidative stress.[13]

Group B (Vitamin E) exhibited significantly higher alpha-tocopherol levels (24.65 ± 1.47 µmol/L) than Group A (Placebo) (15.92 ± 1.08 µmol/L), reflecting effective supplementation. The significant increase (p < 0.01) confirms improved antioxidant status in the treatment group. These results highlight the bioavailability and efficacy of Vitamin E in raising plasma antioxidant levels.

Group B (Vitamin E) demonstrated a significantly higher total antioxidant capacity (TEAC) (5.04 ± 0.10 µmol/L) compared to Group A (Placebo) (4.22 ± 0.10 µmol/L), indicating enhanced antioxidant defense. The significant difference (p < 0.01) suggests that Vitamin E supplementation effectively boosts overall antioxidant status. These findings support its role in reducing oxidative stress. A study by Suantawee et al. (2012) investigated the effects of 400 IU/day vitamin E supplementation over two months on oxidative stress and antioxidant capacity in patients with knee osteoarthritis. The results indicated significant increases in plasma and synovial fluid total antioxidant capacity (TAC), measured by the Trolox Equivalent Antioxidant Capacity (TEAC) and Ferric Reducing Antioxidant Power (FRAP) assays. These findings support the role of vitamin E in enhancing antioxidant defenses and reducing oxidative stress in individuals with joint degeneration.[14]

Group B (Vitamin E) showed significantly higher post-intervention clinical scores (33.52 ± 16.96) compared to Group A (Placebo) (25.31 ± 14.33), indicating improved clinical outcomes. The significant difference (p < 0.01) suggests that Vitamin E positively influences patient recovery. These results highlight the therapeutic benefit of Vitamin E in enhancing clinical status.

Group B (Vitamin E) demonstrated significantly higher post-intervention functional scores (51.61 ± 19.60) compared to Group A (Placebo) (41.43 ± 16.11), reflecting better functional improvement. The difference was statistically significant (p = 0.02), indicating the positive impact of Vitamin E on patient function. These findings support its role in enhancing recovery and quality of life.

This study highlights the potential therapeutic role of Vitamin E, a powerful antioxidant, in managing chronic pain. Supplementation with Vitamin E significantly reduced pain severity, decreased the number of painful days and analgesic use, and improved clinical and functional outcomes. Biochemical markers, including reduced malondialdehyde (MDA) levels and increased total antioxidant capacity (TEAC), further support its efficacy in lowering oxidative stress. Compared to placebo, Vitamin E demonstrated superior benefits in pain relief and overall quality of life. These findings suggest that Vitamin E may serve as an effective adjunct therapy for pain management in clinical settings.

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6.       Chin K. Y., Ima-Nirwana S. (2014). The Effects of alpha-tocopherol on bone: a double-edged sword? Nutrients 6 1424–1441. 10.3390/nu6041424

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10.    Chin K.-Y., Mo H., Soelaiman I.-N. (2013). A review of the possible mechanisms of action of tocotrienol–a potential antiosteoporotic agent. Curr. Drug Targets 14 1533–1541. 10.2174/13894501113149990178

11.    Ataie-Jafari, A., Nikfar, S., Larijani, B., & Abdollahi, M. (2014). A systematic review on the efficacy of Vitamin E in diabetic neuropathy. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 8(2), 120-124.

12.    Amanzio, M., Polilli, E., & Cauda, F. (2013). Measuring the placebo effect in carpal tunnel syndrome. Journal of Orthopaedics and Traumatology, 14(3), 167-173

13.    Sundari, L. P. R., Adiputra, N., &Dinata, M. K. (2017). Supplementation of Vitamin E 400 IU decreases malondialdehyde level of obese women staff at School of Medicine Udayana University. Asian Journal of Pharmaceutical and Clinical Research, 10(9), 162-164.

14.    Suantawee, T., Adisakwattana, S., Tanavalee, A., &Honsawek, S. (2012). The effect of vitamin E on oxidative stress and antioxidant capacity in blood and synovial fluid of patients with knee osteoarthritis. Isan Journal of Pharmaceutical Sciences, 8(1), 1-6.