Topical curcumin for knee osteoarthritis: A randomized controlled trial

In adults with knee osteoarthritis (KOA), a four-week course of topical curcumin gel produces a modest but statistically significant reduction in knee pain while maintaining a favorable safety profile.

Osteoarthritis (OA) is the most common joint disease worldwide, and the knee is the most frequently affected joint, accounting for the large majority of OA cases. It causes cartilage breakdown, bone remodeling, and joint inflammation, leading to chronic pain, reduced mobility, and lower quality of life. Standard treatments — acetaminophen, oral or topical non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroid injections — offer only modest relief, and many patients cannot tolerate them or have coexisting conditions that rule them out.

Curcumin, a naturally occurring polyphenolic compound extracted from turmeric (Curcuma longa), possesses anti-inflammatory, antioxidant, and analgesic properties. Multiple clinical trials and meta-analyses have illustrated that oral curcumin can alleviate pain in KOA sufferers. However, its clinical utility is limited by poor oral bioavailability, and high doses may be associated with gastrointestinal discomfort or potential liver toxicity.

Topical or transdermal delivery could avoid these issues, but very little clinical research has tested this route. VAS-101 is an investigational topical curcumin gel using a proprietary transdermal delivery platform intended to bypass liver metabolism and improve absorption. Preclinical work showed measurable blood curcumin levels and reduced pain sensitivity after transdermal application, providing the rationale for testing it in humans with KOA.

Objective

This study aimed to evaluate the clinical efficacy, tolerability, and safety of a four-week course of topically applied VAS-101 vs. placebo gel for knee pain and related symptoms in adults with KOA.

(a) Study design

A 4-week, two-arm, parallel-group, randomized, double-blind, placebo-controlled trial was conducted. Randomization was performed in a 1:1 ratio via a computerized randomization calculator.

(b) Recruitment and study location

Recruitment took place between February and June 2025. The study was carried out at Clinical Research Australia, Perth, Western Australia.

(c) Inclusion criteria

• Healthy male or female adults aged 45–75 years
• KOA per National Institute for Health and Care Excellence (NICE) clinical criteria (age ≥45, activity-related knee pain, morning stiffness ≤30 minutes)
• Body mass index (BMI) between 18 and 32 kg/m²
• Documented prior knee OA diagnosis
• Average walking knee pain score of 4–7 on a 10-point NRS over the past week at screening
• Knee pain on more than 50% of days in the previous month
• No plans to start new treatments during the study period

(d) Exclusion criteria

• Recently diagnosed or unmanaged conditions (e.g., cardiovascular, diabetes, gastrointestinal, endocrine, neurological, cancer) or any condition judged to threaten safety or data validity
• Hip arthritis or chronic back pain significantly affecting function
• Intra-articular corticosteroid or hyaluronic acid injection in the target knee within 6 months
• Target knee surgery performed within the last 6 months or surgery planned while the study was ongoing
• Clinically relevant infection, injury, or illness within 28 days of screening
• Planned heavy exercise (e.g., marathon, heavy squats) during the study
• Known allergy to curcumin-containing products
• Knee injury within 3 months prior to screening
• Current use of curcumin-containing products
• New or changed prescription medication, herbal product, or supplement within 4 weeks of screening
• More than 14 standard alcoholic drinks per week
• Regular illicit drug use in the past 12 months
• Pregnant, breastfeeding, or planning pregnancy within 2 months

(e) Sample size

A total of 60 participants were randomized (30 per group). The sample size was determined by a power calculation providing 80% power to detect a 15-point difference on a 100-point outcome scale (standard deviation 19), while allowing for a 10% dropout rate.

(f) Intervention and follow-up

• Participants applied 0.1 mL (two clicks) of either VAS-101 (providing 8 mg of 50% curcuminoids per dose) or a matching yellow placebo gel to the peripatellar area and kneecap of the target knee every second day.
• The gel was rubbed into the skin using a supplied toothbrush for at least 1 minute, covered with a knee sleeve, left in place for approximately 10–12 hours, and then washed off.
• Participants received 28 days of treatment, with clinic visits on day 0, day 14, and day 28, and online questionnaires on days 7 and 21.

(h) Outcomes

• Primary: Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale from day 0 to day 28.
• Secondary: Other KOOS subscales (symptoms/stiffness, daily living, sports/recreation, quality of life); daily Numeric Pain Rating Scale (NPRS) while walking; performance-based tests (30-second Chair Stand, 40-metre Fast-Paced Walk, Timed Up and Go, Six-Minute Walk); Patient Global Impression of Change (PGIC); rescue pain medication use; Patient Global Assessment of Tolerability to Therapy (PGATT); treatment-expectancy score like Clinical Trials Treatment Expectancies Scale (CTTES).

(i) Statistical analysis

Generalised linear mixed models (GLMM) compared groups on the full analysis set (FAS) and per protocol set (PPS), adjusting for baseline score, age, sex, BMI, and treatment-expectancy score, with sequential Bonferroni correction for multiple comparisons and a hierarchical testing order for secondary endpoints. Minimal clinically important difference (MCID), threshold 15.4 points) was analyzed with chi-square testing. Non-normally distributed medication-use data were analysed with Mann-Whitney U tests; safety data used repeated-measures ANOVA. Significance was defined as p ≤ 0.05 (two-sided).

A total of 101 individuals were screened, of whom 60 participants met the eligibility criteria and were randomized. Thirty participants were assigned to the VAS-101 topical curcumin group and thirty to the placebo group. Two participants from the VAS-101 group discontinued the trial for reasons unrelated to treatment (Figure 1).

(a) Pain scores

• VAS-101 produced better improvement in the primary endpoint, the KOOS pain score, than placebo after 28 days (β=5.12; Cohen's d=0.62; p=0.041).
• Mean KOOS pain scores improved by 9.09 points (14.9% improvement) with VAS-101 compared with 3.97 points (6.5% improvement) with placebo. Similar findings were observed in the per-protocol analysis.
• Daily NPRS scores also favored VAS-101, showing a significant time-by-treatment interaction (F=4.42; d=0.55; p=0.005). Pain dropped by 0.65 points from week 1 to week 4 in the VAS-101 group (p<0.001), whereas placebo exhibited no significant reduction (0.14 points; p=0.983).
• Clinically meaningful pain improvement (KOOS pain MCID >15.4) was attained by 32.1% of subjects receiving VAS-101 vs. 13.3% receiving placebo, although this difference did not attain statistical significance (p=0.086).

(b) Other KOOS subscales

Participants treated with VAS-101 exhibited greater improvement in the KOOS sports and recreation subscale than placebo (12.9 vs. 6.5 points; β=6.41; d=0.57; p=0.046). However, this result did not satisfy the predefined hierarchical criteria for statistical significance. No prominent differences emerged for symptoms/stiffness, daily living, or quality-of-life subscales.

(c) Performance-based tests

No significant group differences were found on the Chair-Stand, Paced Walk, Timed Up-and-Go, or Six-Minute Walk tests.

(d) Rescue medication

• Rescue medication-free days were similar between groups (83.3% for VAS-101 vs. 78.0% for placebo; p=0.518).
• Participants receiving VAS-101 consumed fewer rescue medication tablets on average (11.9 vs. 21.4 tablets over 28 days), although the difference was not clinically meaningful (p=0.409).

(e) PGIC

On day 28, significantly more VAS-101 participants reported feeling "much" or "very much" improved (39.3% vs. 13.3%, p = 0.019). The key findings are summarized in Table 1:

(f) Blinding Assessment

Participant blinding was successfully maintained, as most participants either incorrectly identified their treatment assignment or remained unsure (57.1% in the VAS-101 group and 60% in the placebo group). Only one volunteer correctly identified therapeutic allocation based on gel color.

(g) Safety and Tolerability

• No serious adverse events, treatment-related adverse events, skin irritation, or allergic reactions were reported. Temporary yellow discoloration of the skin occurred in some participants but resolved within 2-3 days after treatment discontinuation.
• Among those who completed treatment, 92.9% rated VAS-101 tolerability as good or excellent, while 7.1% reported moderate tolerability.
• No vital changes in BMI, blood pressure, or resting pulse were noted between groups.
• Two participants discontinued the VAS-101 arm, but neither withdrawal was related to treatment.

The findings indicate that a low, conservative dose of topical curcumin gel applied every second day for four weeks produces measurable, self-reported pain relief in knee OA — consistent across two independent pain measures (KOOS pain subscale and daily NPRS). The effect size (d = 0.62) on the primary endpoint compares favorably with pooled effect sizes reported for topical NSAIDs (around 0.37) in prior meta-analyses. This suggests that topical curcumin may offer comparable short-term analgesic benefit, though direct comparison is limited by differences in trial duration and dosing schedules across studies.

Only one other trial has examined topical curcumin for knee OA, using a higher dose (1.5 mL twice daily for 6 weeks) and a non-colour-matched placebo, raising blinding concerns; the current study strengthens this evidence base with confirmed blinding and multiple validated outcome measures. Comparing this topical formulation with an earlier oral curcumin trial by the same investigative group, both showed remarkable KOOS pain improvements, with a numerically larger effect size for the topical route (0.62 vs. 0.39), though population differences make direct comparison difficult.

Despite the significant pain-score improvement, only about one-third of VAS-101 users achieved a clinically meaningful reduction (MCID), and no functional/performance gains were observed, suggesting the treatment provides modest, not universal, benefit. Exploratory findings — such as a correlation between negative treatment expectations and greater rescue medication use — point to psychological factors that may influence outcomes and warrant further study.