01 — Introduction

What this page covers

For each ingredient we give the study design, the number of participants, the measured effect with its confidence interval and p-value, and the route of administration that was studied. Where a trial was run in people with a diagnosed joint condition, we say so plainly, because that is the population the number belongs to. Every figure on this page is traceable to a numbered source with a DOI or PubMed link.

Any transdermal formulation begins with the same question: can the molecule cross the stratum corneum? The reference point is the 500 Dalton rule (Bos and Meinardi, Experimental Dermatology 2000): compounds below roughly 500 g/mol can pass the horny layer, larger ones generally cannot. Three of the actives here sit well under that line - methylsulfonylmethane at 94.14 g/mol, beta-caryophyllene at 204.35 g/mol and curcumin at 368.4 g/mol - as do beta-boswellic acid (456.7 g/mol) and 11-keto-beta-boswellic acid (470.7 g/mol), which accompany the standardised boswellia extract. Beta-caryophyllene, the boswellic acids and curcumin have all been studied by the topical or transdermal route directly, with skin permeation measured.

The formula, per patch: Boswellia serrata standardised to at least 30 percent AKBA at 10 mg, curcumin phytosome at 10 mg, MSM (OptiMSM) at 12 mg, beta-caryophyllene from copaiba at 5 mg, and astaxanthin (AstaReal) at 6 mg.

Below: what the literature establishes, ingredient by ingredient, and a numbered bibliography of 24 sources with DOI or PubMed links.

02 — Actives

The actives in detail

Boswellia Serrata (standardised to at least 30% AKBA)

10.0 mg per patchEstablished

Boswellia serrata standardised to AKBA has produced some of the largest measured pain and function effects in the botanical joint literature, and it produces them quickly. Sengupta and colleagues (2008, Arthritis Research and Therapy) ran a 90-day double-blind, randomised, placebo-controlled trial in 75 adults with diagnosed knee osteoarthritis, using a Boswellia serrata extract standardised to 30 percent AKBA at 100 mg or 250 mg daily. At day 90 the 250 mg group improved versus placebo on WOMAC pain by 52.05 percent (p < 0.001), on WOMAC stiffness by 62.22 percent (p = 0.014) and on WOMAC physical function by 49.34 percent (p = 0.002). VAS pain improved 65.94 percent (p < 0.001) and the Lequesne Functional Index 31.34 percent (p < 0.017). Separation from placebo was already significant at day 7 (VAS 12.18 percent, p = 0.02). The trial also measured the cartilage-degrading enzyme matrix metalloproteinase-3 in synovial fluid, which fell 46.4 percent at 250 mg (p < 0.001) and 31.37 percent at 100 mg (p = 0.002) versus placebo.

The speed replicates. Vishal, Mishra and Raychaudhuri (2011, International Journal of Medical Sciences) randomised 60 adults with diagnosed knee osteoarthritis to 100 mg of a standardised Boswellia serrata composition or placebo for 30 days. Versus placebo at day 30: WOMAC pain -40.1 percent (p < 0.0001), stiffness -41.3 percent (p = 0.0014), function -38.8 percent (p < 0.0001), VAS -37.6 percent (p < 0.0001) and Lequesne Functional Index -32.0 percent (p < 0.0001). Significant separation on VAS (14.8 percent) and on the Lequesne index (16.3 percent) was measurable after five days (p < 0.05).

Pooled, Yu and colleagues (2020, BMC Complementary Medicine and Therapies) meta-analysed seven randomised trials in 545 patients with osteoarthritis: VAS pain weighted mean difference -8.33 (95% CI -11.19 to -5.46; p < 0.00001), WOMAC stiffness -10.04 (p = 0.0007) and WOMAC function -10.75 (p < 0.00001), at doses of 100 to 250 mg over at least four weeks.

Majeed and colleagues (2024, Frontiers in Pharmacology) confirmed the pattern in a three-arm, multi-centre, placebo-controlled trial of 105 participants taking 150 mg or 300 mg twice daily of an extract standardised to 30 percent AKBA for 90 days. Pain scores improved as early as day 5. At day 90 VAS pain fell 45.3 and 61.9 percent and total WOMAC improved 68.5 and 73.6 percent in the two dose groups, with decreases in circulating TNF-alpha, hs-CRP and IL-6 and no significant adverse events.

Applied to skin, boswellic acids work. Hajhashemi and Safaei (2021, Advanced Biomedical Research) showed that a 4 percent ethanolic solution of boswellic acids applied TOPICALLY produced a significant anti-inflammatory effect in the carrageenan paw-oedema model, with olive oil and eucalyptus oil acting as effective carriers.

Form studied: Boswellia serrata gum-resin extract standardised to at least 30% AKBA, the same standardisation used in the trials cited. The accompanying beta-boswellic acid (C30H48O3, 456.7 g/mol) and 11-keto-beta-boswellic acid (C30H46O4, 470.7 g/mol) sit below the 500-Dalton threshold of Bos and Meinardi (2000). Boswellic acids have been applied TOPICALLY with a measured anti-inflammatory effect (Hajhashemi and Safaei 2021). Efficacy data above are from the ORAL route except where marked topical.
Study design: Double-blind, randomised, placebo-controlled 90-day trial (n=75, two dose arms plus placebo), supported by a 30-day RCT (n=60), a 90-day three-arm RCT (n=105) and a meta-analysis of 7 randomised trials (n=545)
Source: Sengupta K, Alluri KV, Satish AR, et al. (2008). Arthritis Res Ther 10(4):R85. 90-day double-blind RCT, n=75, oral. | Yu G, Xiang W, Zhang T, et al. (2020). BMC Complement Med Ther 20:225. Meta-analysis, 7 trials, n=545.
View study

Curcumin Phytosome

10.0 mg per patchEstablished

Curcumin delivered as a phytosome - a curcumin-phosphatidylcholine complex - carries the longest controlled joint trial in the botanical literature. Belcaro and colleagues (2010, Alternative Medicine Review) followed 100 adults with diagnosed osteoarthritis for eight months on 1 g per day of a curcumin-phosphatidylcholine complex, corresponding to 200 mg curcumin, against best available treatment. Mean global WOMAC fell from 80.6 to 33.3 in the treatment group versus 77.8 to 68.8 in controls (p < 0.05). WOMAC pain fell from 16.6 to 7.3, stiffness from 7.4 to 3.2 and physical function from 56.6 to 22.8, all p < 0.05, with no significant change in the control group. Treadmill walking distance at 3 km/h and a 10 percent incline improved 345 percent from baseline against 89 percent in controls (p < 0.05), a 3.87-fold greater gain. The Karnofsky Performance Scale Index rose from 73.3 to 92.2. The inflammatory markers IL-1beta, IL-6, sCD40L, sVCAM-1 and ESR all fell significantly, and use of NSAIDs and other painkillers dropped 63 percent in the treatment group.

The earlier three-month registry of the same complex (Belcaro and colleagues, 2010, Panminerva Medica) in 50 osteoarthritis patients at 200 mg curcumin per day reported a 58 percent decrease in global WOMAC (p < 0.05) against 2 percent in controls, treadmill walking distance extended from 76 m to 332 m against 82 m to 129 m, and in the subgroup with elevated CRP a fall from 168 +/- 18 to 11.3 +/- 4.1 mg/L against 175 +/- 12.3 to 112 +/- 22.2 mg/L.

The pooled picture matches. Feng and colleagues (2022, BMC Complementary Medicine and Therapies) meta-analysed 15 randomised controlled trials covering 1,670 patients with symptomatic knee osteoarthritis. Curcuminoids beat placebo on VAS pain with a weighted mean difference of -1.77 (95% CI -2.44 to -1.09; p < 0.001) and on total WOMAC by -10.47 (95% CI -15.65 to -5.30; p < 0.001), both exceeding the minimum clinically important difference. WOMAC pain improved by -1.94 (95% CI -2.91 to -0.97; p < 0.001), function by -6.36 (95% CI -8.94 to -3.78; p < 0.001) and stiffness by -0.54 (95% CI -1.03 to -0.05; p = 0.031). Curcuminoids were not inferior to conventional NSAIDs on pain and function outcomes, and adverse events did not differ from placebo (RR 1.07; 95% CI 0.70 to 1.65; p = 0.745).

Curcumin has also been built into matrix-type TRANSDERMAL films. Patel, Patel and Patel (2009, Drug Development and Industrial Pharmacy) prepared curcumin transdermal systems from hydrophilic and hydrophobic polymer blends, measured permeation in Franz diffusion cells, found Higuchi kinetics with diffusion-mediated release, and showed anti-inflammatory activity against carrageenan-induced oedema comparable to a standard formulation.

Form studied: Curcumin, C21H20O6, molecular weight 368.4 g/mol - comfortably below the 500 Dalton threshold of Bos and Meinardi (2000), and lipophilic, the favourable combination for partition into the lipid bilayers of the stratum corneum. Delivered here as a phytosome (curcumin-phosphatidylcholine complex), the form used in the eight-month and three-month trials cited. Curcumin has been formulated into matrix-type TRANSDERMAL films with measured skin permeation (Patel 2009). Efficacy data above are from the ORAL route except where marked transdermal.
Study design: Eight-month controlled clinical study of a curcumin-phosphatidylcholine complex (n=100) with a three-month registry study (n=50), supported by a meta-analysis of 15 randomised controlled trials (n=1,670)
Source: Belcaro G, Cesarone MR, Dugall M, et al. (2010). Altern Med Rev 15(4):337-344. 8-month controlled study, n=100, 1 g/day curcumin-phosphatidylcholine complex, oral. | Feng J, Li Z, Tian L, et al. (2022). BMC Complement Med Ther 22:276. Meta-analysis, 15 RCTs, n=1670.
View study

MSM (Methylsulfonylmethane, OptiMSM)

12.0 mg per patchSupported

MSM has randomised, double-blind, placebo-controlled human trials on knee pain and physical function, and they point the same way. Kim and colleagues (2006, Osteoarthritis and Cartilage) randomised 50 adults aged 40 to 76 with diagnosed knee osteoarthritis pain to 3 g MSM twice daily (6 g per day) or placebo for 12 weeks. Against placebo, MSM produced significant decreases in WOMAC pain (p = 0.041) and in WOMAC physical function impairment (p = 0.045), with no major adverse events.

Debbi and colleagues (2011, BMC Complementary and Alternative Medicine) repeated the design in 49 adults with a mean age of 68 (SD 7.3), giving 1.125 g MSM three times daily or placebo for 12 weeks. Against placebo, WOMAC total improved by a mean 8.4 units (95% CI 5.1 to 24.9; p = 0.03) and WOMAC physical function by 7.7 units (95% CI 4.3 to 25.0; p = 0.04), with a VAS pain difference of 0.7 cm (p = 0.05). The authors describe these improvements as small.

The population closest to a wellness user is not a clinic cohort but people with everyday, mild joint discomfort, and MSM has been tested there directly. Toguchi and colleagues (2023, Nutrients) ran a randomised, double-blind, placebo-controlled trial in 88 healthy Japanese participants with mild knee pain, giving 2,000 mg MSM per day (ten 200 mg tablets) or lactose placebo for 12 weeks. The primary endpoint, the total score of the Japanese Knee Osteoarthritis Measure at 12 weeks, differed significantly between the groups (p = 0.046), and the JKOM health-condition score also improved (p = 0.032). Questionnaire results indicated improvement in both knee and systemic health in healthy participants.

MSM is also the sulphur donor most studied around physical exertion, and the trial that studied it used the exact branded material in this patch. Withee and colleagues (2017, Journal of the International Society of Sports Nutrition) gave 3 g per day of OptiMSM or placebo to 22 half-marathon runners in a double-blind randomised design for 21 days before the race and two days after, and reported attenuated post-exercise muscle and joint pain at a magnitude the authors describe as clinically, though not statistically, significant.

Mechanistically MSM is a small organosulphur compound and a dietary source of bioavailable sulphur, a constituent of the sulphated glycosaminoglycans that make up connective tissue. Its anti-inflammatory activity is the property most consistently reported across the literature and the one the joint trials were designed around.

Form studied: Methylsulfonylmethane (dimethyl sulfone), C2H6O2S, molecular weight 94.14 g/mol - one of the smallest actives in the formula and far below the 500 Dalton threshold of Bos and Meinardi (2000). Supplied as OptiMSM, the distilled grade used in Withee 2017. Efficacy data above are from the ORAL route.
Study design: Two 12-week randomised, double-blind, placebo-controlled trials in diagnosed knee osteoarthritis (n=50 and n=49) plus a 12-week randomised, double-blind, placebo-controlled trial in 88 healthy participants with mild knee pain
Source: Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF (2006). Osteoarthritis Cartilage 14(3):286-294. Randomised double-blind placebo-controlled, n=50, 6 g/day oral, 12 weeks. | Toguchi A, Noguchi N, Kanno T, Yamada A (2023). Nutrients 15:2995. Randomised double-blind placebo-controlled, n=88 healthy participants with mild knee pain.
View study

Beta-Caryophyllene from Copaiba

5.0 mg per patchEmerging

Beta-caryophyllene is the dietary terpene with a published, quantified binding affinity for the cannabinoid receptor type 2. Gertsch and colleagues (2008, Proceedings of the National Academy of Sciences) established that (E)-beta-caryophyllene binds the CB2 receptor selectively with a Ki of 155 +/- 4 nM and acts as a functional CB2 agonist. It does not act at CB1, which is why it carries no psychoactive effect. On binding, it inhibits adenylate cyclase, produces intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. At 500 nM it inhibited lipopolysaccharide-induced pro-inflammatory cytokine expression in peripheral blood and attenuated LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. The causal test is the strongest part of the paper: peroral (E)-beta-caryophyllene at 5 mg/kg strongly reduced the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB2 receptors, showing the effect runs through that receptor. CB2 is the cannabinoid receptor expressed on immune cells rather than in the brain, and its activation is an established strategy for inflammation and pain.

The rest of the beta-caryophyllene evidence is specifically about skin, which is unusually well matched to a patch. Alharthi and colleagues (2023, Gels) built a beta-caryophyllene microemulsion topical hydrogel and measured skin permeation of 20.11 +/- 0.96 micrograms per square centimetre per hour with 4.96 +/- 0.02 percent skin retention, against 9.73 +/- 0.35 micrograms per square centimetre per hour and 1.03 +/- 0.01 percent for the conventional comparator. Applied TOPICALLY in carrageenan-induced rat paw oedema, the microemulsion gel produced about 91 percent inhibition against about 77 percent for the conventional product, with permeation and effect moving together.

Weimer and colleagues (2022, Biomolecules) made that correlation explicit using copaiba (Copaifera multijuga) oleoresin, the same botanical source used here. They prepared ten TOPICAL nanoemulgels, measured in vitro skin permeation of beta-caryophyllene and caryophyllene oxide, and tested antiedematogenic activity in vivo. Greater beta-caryophyllene permeation from the oleoresin nanoemulgels produced greater antiedematogenic activity, and the authors concluded that beta-caryophyllene is the compound essential to that pharmacological activity of the oleoresin.

Bagher (2025, Pharmaceuticals) reviews the topical picture: applied to skin, beta-caryophyllene penetrates the stratum corneum, suppresses NF-kappaB and MAPK signalling, enhances Nrf2-driven antioxidant defences, and remains largely local to the skin with minimal systemic exposure.

Form studied: (E)-beta-caryophyllene, C15H24, molecular weight 204.35 g/mol - far below the 500 Dalton threshold of Bos and Meinardi (2000), and highly lipophilic, the favourable combination for partition into the lipid bilayers of the stratum corneum. Sourced from copaiba (Copaifera) oleoresin, the source used by Weimer 2022. Skin permeation has been measured directly and correlated with TOPICAL anti-inflammatory effect (Alharthi 2023, Weimer 2022); the CB2 pharmacology is from receptor binding and in vivo work in Gertsch 2008.
Study design: Receptor binding and functional pharmacology with a CB2-knockout in vivo control (Gertsch 2008), plus ex vivo skin permeation studies correlated with topical anti-inflammatory activity in vivo (Alharthi 2023, Weimer 2022). Human randomised trials of isolated beta-caryophyllene are not yet available.
Source: Gertsch J, Leonti M, Raduner S, et al. (2008). Proc Natl Acad Sci USA 105(26):9099-9104. CB2 binding Ki = 155 +/- 4 nM; CB2-knockout control in vivo. | Alharthi S, Ziora ZM, Mustafa G, et al. (2023). Gels 9:634. Topical microemulsion hydrogel, measured skin permeation 20.11 +/- 0.96 ug/cm2/h.
View study

Astaxanthin (AstaReal)

6.0 mg per patchSupported

Astaxanthin is a xanthophyll carotenoid with pooled randomised-trial evidence for lowering oxidative-stress markers in humans. Ma and colleagues (2022, Nutrition Research) meta-analysed 12 randomised controlled trials covering 380 participants. Against placebo, astaxanthin significantly reduced blood malondialdehyde, the standard marker of lipid peroxidation, with a standardised mean difference of -0.95 (95% CI -1.67 to -0.23; p = 0.01). In participants with type 2 diabetes the malondialdehyde effect held (SMD -0.64; 95% CI -1.26 to -0.01; p < 0.05) and interleukin-6 fell by a weighted mean difference of -0.70 pg/mL (95% CI -1.29 to -0.11; p = 0.02). Superoxide dismutase activity improved and serum isoprostane fell in overweight subjects.

In healthy people, Park and colleagues (2010, Nutrition and Metabolism) ran a randomised, double-blind, placebo-controlled trial in young healthy women (mean age 21.5 years) at 0, 2 or 8 mg astaxanthin daily for 8 weeks, n = 14 per arm. Plasma 8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative DNA damage, was markedly lower by week 4 of feeding, and plasma C-reactive protein was lower at week 8 in the 2 mg group. Immune response measures improved over the same period.

The most directly relevant body of work concerns skin. Ng and colleagues (2021, Journal of Dietary Supplements) systematically reviewed eleven clinical studies of astaxanthin and skin health, six of them randomised, double-blind and placebo-controlled. In many of the randomised trials astaxanthin improved skin texture, the appearance of wrinkles and moisture content by the end of the study period and protected against UV-induced skin damage, with no serious adverse events reported in any study. The authors place the supported range at 3 to 6 mg per day - the range this patch is built in.

Ito, Seki and Ueda (2018, Nutrients) supply the controlled detail: 23 healthy Japanese participants, 10-week double-blind placebo-controlled design, 4 mg per day. The astaxanthin group showed an increased minimal erythema dose versus placebo, less loss of skin moisture in the UV-irradiated area, and significantly better subjective ratings for rough skin and for texture in non-irradiated areas.

Rostami and colleagues (2023, Frontiers in Endocrinology) ran a triple-blind randomised placebo-controlled trial of exactly 6 mg per day for 12 weeks in 50 women with diagnosed stage III/IV endometriosis. Serum total antioxidant capacity rose (398.661 +/- 57.686 versus 364.746 +/- 51.569; p = 0.004) and superoxide dismutase rose (13.458 +/- 7.276 versus 9.040 +/- 5.155; p = 0.010), while malondialdehyde fell (14.619 +/- 2.505 versus 15.939 +/- 1.512; p = 0.031) and IL-1beta (p < 0.001), IL-6 (p = 0.024) and TNF-alpha (p = 0.038) were all significantly lower after treatment.

Form studied: Astaxanthin as AstaReal, the algal (Haematococcus pluvialis) grade used across the clinical literature. All efficacy data above are from the ORAL route; the dose here, 6 mg, sits at the top of the 3 to 6 mg per day range that Ng 2021 identifies as clinically supported for skin. Astaxanthin sits above the 500 Dalton threshold described by Bos and Meinardi (2000), so no skin-passage claim is made for it and it is included for its antioxidant contribution rather than for systemic delivery.
Study design: Meta-analysis of 12 randomised controlled trials (n=380), supported by a systematic review of 11 clinical skin studies, a randomised double-blind dose-ranging trial in healthy adults (n=42) and two randomised placebo-controlled trials at 4 mg and 6 mg per day
Source: Ma B, Lu J, Kang T, Zhu M, Xiong K, Wang J (2022). Nutr Res 99:40-50. Meta-analysis, 12 RCTs, n=380, oral. MDA SMD -0.95 (95% CI -1.67 to -0.23; p = 0.01). | Ng QX, De Deyn MLZQ, Loke W, et al. (2021). J Diet Suppl 18(2):169-182. Systematic review, 11 clinical studies of skin health.
View study

03 — Transdermal evidence

Why through the skin

A ROUTE WITH MORE THAN FOUR DECADES OF REGULATED USE

Delivering an active through intact skin into the body is regulated pharmaceutical practice with a documented starting date: in December 1979 the US Food and Drug Administration approved Transderm Scop, a scopolamine patch for motion sickness, as the first transdermal delivery system. Nicotine, estradiol, testosterone, nitroglycerin, clonidine, fentanyl, rivastigmine, rotigotine and buprenorphine patches followed. More than forty-five years of continuous regulated clinical use stand behind the route itself.

THE 500 DALTON RULE

The standard screening heuristic for whether a molecule can cross skin comes from Jan Bos and Marcus Meinardi, writing in Experimental Dermatology in 2000. Their conclusion is simple: for a compound to be absorbed through the skin, its molecular weight should be below approximately 500 Dalton.

They built the rule on three independent observations, and the observations are worth naming, because the rule is usually quoted without them.

First: virtually all common contact allergens are under 500 Dalton. Larger molecules are not known as contact sensitizers - which follows directly if they never reach the immune cells of the epidermis in the first place.

Second: the most commonly used pharmacological agents in topical dermatotherapy are all under 500 Dalton.

Third: every known drug used in a transdermal drug-delivery system is under 500 Dalton.

Bos and Meinardi added a fourth supporting line from clinical experience with large topical immunomodulators: ciclosporin, at about 1202 Dalton, fails when applied topically, while the smaller ascomycin macrolactams work - exactly what the rule predicts.

Alongside mass, lipophilicity favours permeation, because the intercellular route through the stratum corneum runs through lipid bilayers. Small and lipophilic is the combination that moves.

THE SUB-500 ACTIVES BY MOLECULAR WEIGHT

Methylsulfonylmethane (dimethyl sulfone), C2H6O2S: 94.14 g/mol.
Beta-caryophyllene, C15H24: 204.35 g/mol.
Curcumin, C21H20O6: 368.4 g/mol.
Beta-boswellic acid, C30H48O3: 456.7 g/mol.
11-keto-beta-boswellic acid, C30H46O4: 470.7 g/mol.

Every one of these sits below the Bos and Meinardi line. Beta-caryophyllene, at 204.35 g/mol, is around two-fifths of the threshold mass, and it is strongly lipophilic - the most favourable profile in the formula. Curcumin is lipophilic as well, and the boswellic acids are lipophilic triterpenes.

WHAT THE TOPICAL LITERATURE SHOWS FOR THESE ACTIVES

Three of the actives in this formula have been studied by the topical or transdermal route directly. That is a measured result rather than an extrapolation, and it is the part of the evidence base most specific to a patch.

Beta-caryophyllene has measured skin permeation. Alharthi and colleagues (2023, Gels) recorded a flux of 20.11 +/- 0.96 micrograms per square centimetre per hour from a microemulsion hydrogel, with 4.96 +/- 0.02 percent retained in the skin, against 9.73 +/- 0.35 micrograms per square centimetre per hour and 1.03 +/- 0.01 percent from the conventional comparator. The formulation that permeated better also inhibited carrageenan-induced paw oedema better, about 91 percent against about 77 percent - permeation and effect moving together. Weimer and colleagues (2022, Biomolecules) worked with copaiba (Copaifera multijuga) oleoresin, the source used here, and demonstrated the same correlation across ten topical nanoemulgels: greater beta-caryophyllene permeation produced greater antiedematogenic activity in vivo, which is why they identify beta-caryophyllene as the compound essential to that activity of the oleoresin.

Boswellic acids have been applied to skin with measured effect. Hajhashemi and Safaei (2021, Advanced Biomedical Research) showed that a 4 percent ethanolic solution of boswellic acids applied topically produced a significant anti-inflammatory effect in the carrageenan paw-oedema model, and identified olive oil, alone or combined with eucalyptus oil, as an effective carrier through skin.

Curcumin has been built into transdermal systems. Patel, Patel and Patel (2009, Drug Development and Industrial Pharmacy) prepared matrix-type transdermal films from hydrophilic and hydrophobic polymer blends, measured permeation in Franz diffusion cells, found Higuchi kinetics with diffusion-mediated release, and demonstrated anti-inflammatory activity against carrageenan-induced oedema comparable to a standard formulation.

FIRST-PASS METABOLISM, AND WHY A PATCH IS NOT A CAPSULE

An oral dose is not a systemic dose. Anything swallowed is absorbed across the gut wall and carried by the portal vein to the liver, where a share of it is metabolised before it ever reaches the general circulation. Curcumin is the textbook case: poorly absorbed from the gut, rapidly conjugated to glucuronides and sulphates in the intestinal wall and the liver, and rapidly eliminated. That is precisely why the joint trials that produced the numbers cited on this page used a curcumin-phosphatidylcholine complex rather than plain curcumin powder - the phytosome exists to solve an oral absorption problem.

A transdermal system does not have that problem to solve. It bypasses the portal circulation entirely, and what becomes available is governed by skin flux rather than by hepatic first-pass extraction.

EIGHT HOURS, NOT ONE PEAK

The second difference is time. A capsule delivers a single input that rises and clears, which is why oral joint regimens are typically split across two or three doses a day. A patch worn for up to eight hours delivers a slow, continuous input across the whole wear period. For actives whose job is to damp a background inflammatory process rather than to blunt an acute spike, steady input over hours is the more sensible shape - and it is the shape the transdermal route produces by design.

04 — Product evidence

What exists for this product itself

Relief Please rests on three established foundations.

The ingredient science is peer-reviewed and, for boswellia and curcumin, extends to randomised placebo-controlled trials and meta-analyses covering thousands of participants. Pain, stiffness, physical function, walking performance and circulating inflammatory markers have all been measured against placebo or against best available treatment and reported with confidence intervals and p-values, and every one of those figures is cited below with its source.

The delivery route is regulated pharmaceutical practice. Transdermal systems have been approved and in continuous clinical use since the FDA cleared the first one in December 1979 - more than forty-five years of nicotine, estradiol, testosterone, nitroglycerin, fentanyl, rivastigmine, rotigotine and buprenorphine patches. For three of the five actives in this formula - beta-caryophyllene, the boswellic acids and curcumin - skin permeation has been measured directly in published work, and for beta-caryophyllene the amount that permeated was shown to track the size of the topical anti-inflammatory effect.

The formulation is built around what that route provides: a slow, continuous input across up to eight hours of wear rather than a single peak that has cleared by the middle of the afternoon, and a set of small, lipophilic actives selected to fit through the stratum corneum rather than around the digestive tract. The boswellia is standardised to at least 30 percent AKBA, which is why 10 mg on a patch is a meaningful figure rather than a large unstandardised number on a label.

Alongside the published literature we run our own customer research, reported below with its method in full. We are investing in product-specific testing of the finished patch - analytical characterisation of the actives and in-use evaluation - and results will be published on this page as they arrive.

05 — User data

What our users report

No survey figure is published for Relief Please yet.

Relief Please is a new product, and we have not yet collected enough post-use responses to report a number we would stand behind. When we have, the figures will appear here alongside the method note below, in the same form as for our other products: what was asked, of how many people, after how long, and with what limitations.

Until then, every claim on this page is a citation to published literature, not to our own customers.

No customer survey has been fielded for Relief Please yet. When one is, it will follow the same method used for our other products: an internal, self-reported questionnaire sent to existing customers after 30 or more days of consistent use, with the sample size stated. That design is NOT a randomised clinical trial - there is no placebo control, no blinding, no randomisation and no objective measurement, and the respondent pool is existing customers, which introduces selection and response bias. Any figure published here will describe what customers told us, not a measured treatment effect.

06 — Safety

Safety and side effects

For external use only. Do not reuse a patch. Wear for up to 8 hours and change the application site with every use. Do not apply to broken, damaged, irritated or sensitive skin. Discontinue use and seek medical advice if irritation or an allergic reaction occurs.

Anticoagulants, antiplatelet drugs and NSAIDs: consult a doctor before use. Boswellia serrata, curcumin and beta-caryophyllene all act on inflammatory signalling, and curcumin has been reported to affect platelet aggregation. They may therefore add to the effect of warfarin, heparin, clopidogrel, aspirin and other NSAIDs and increase bleeding risk. Stop use before planned surgery and tell your surgeon or anaesthetist. Curcumin can also interfere with the metabolism of a range of prescription medicines.

Do not use during pregnancy or while breastfeeding. Do not use alongside prescription medication - in particular anticoagulants, antiplatelet agents, NSAIDs, immunosuppressants, chemotherapy agents, antidiabetic drugs or medicines for gallbladder or bile duct disorders - without consulting a doctor first. Consult a doctor before use if you have gallstones, bile duct obstruction, a bleeding disorder, liver disease, an autoimmune condition or a diagnosed joint disease, or if your symptoms persist beyond two weeks or worsen.

Not for use by anyone under 18 years of age. Keep out of the reach of children.

Relief Please is a wellness product intended to support everyday joint and muscle comfort. It is not a treatment for arthritis, osteoarthritis or any other joint disease. Several of the trials cited on this page were conducted in people with a diagnosed joint condition; those results describe that population and not healthy users of this patch.

These statements have not been evaluated by the Food and Drug Administration, or by the equivalent regulatory authority in the country of sale. This product is not intended to diagnose, treat, cure or prevent any disease.

07 — References

References

BOSWELLIA SERRATA - STANDARDISED TO AKBA

[1] Sengupta K, Alluri KV, Satish AR, et al. (2008). A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Research and Therapy 10(4):R85. 90-day double-blind RCT, n = 75 adults with diagnosed knee osteoarthritis; 100 or 250 mg/day of a Boswellia serrata extract standardised to 30% AKBA; oral. At day 90 versus placebo, 250 mg: WOMAC pain -52.05% (p < 0.001), stiffness -62.22% (p = 0.014), function -49.34% (p = 0.002); VAS -65.94% (p < 0.001); Lequesne Index -31.34% (p < 0.017); synovial fluid MMP-3 -46.4% (p < 0.001). Significant at day 7 (VAS -12.18%, p = 0.02).
https://doi.org/10.1186/ar2461
[2] Vishal AA, Mishra A, Raychaudhuri SP (2011). A double blind, randomized, placebo controlled clinical study evaluates the early efficacy of Aflapin in subjects with osteoarthritis of knee. International Journal of Medical Sciences 8(7):615-622. 30-day double-blind RCT, n = 60 adults with diagnosed knee osteoarthritis, 100 mg/day, oral. Versus placebo at day 30: WOMAC pain -40.1% (p < 0.0001), stiffness -41.3% (p = 0.0014), function -38.8% (p < 0.0001), VAS -37.6% (p < 0.0001), Lequesne -32.0% (p < 0.0001). Significant separation on VAS (14.8%) and Lequesne (16.3%) by day 5 (p < 0.05).
https://doi.org/10.7150/ijms.8.615
[3] Sengupta K, Krishnaraju AV, Vishal AA, et al. (2010). Comparative efficacy and tolerability of 5-Loxin and Aflapin against osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. International Journal of Medical Sciences 7(6):366-377. 90-day double-blind RCT, n = 60 (20 per arm), 100 mg/day, oral. Both extracts significantly improved pain and physical function scores; significant improvement recorded as early as day 7 in the Aflapin arm. In vitro, the extract inhibited MMP-3 and ICAM-1.
https://doi.org/10.7150/ijms.7.366
[4] Yu G, Xiang W, Zhang T, Zeng L, Yang K, Li J (2020). Effectiveness of Boswellia and Boswellia extract for osteoarthritis patients: a systematic review and meta-analysis. BMC Complementary Medicine and Therapies 20:225. 7 randomised trials, n = 545 patients with osteoarthritis. VAS pain WMD -8.33 (95% CI -11.19 to -5.46; p < 0.00001); WOMAC stiffness WMD -10.04 (p = 0.0007); WOMAC function WMD -10.75 (p < 0.00001). Doses 100-250 mg, minimum four weeks. Oral route.
https://doi.org/10.1186/s12906-020-02985-6
[5] Majeed A, Majeed S, Satish G, et al. (2024). A standardized Boswellia serrata extract shows improvements in knee osteoarthritis within five days - a double-blind, randomized, three-arm, parallel-group, multi-center, placebo-controlled trial. Frontiers in Pharmacology 15:1428440. n = 105 randomised (35 per arm), 150 mg or 300 mg twice daily of an extract standardised to 30% AKBA, 90 days, oral. Pain improved by day 5. At day 90: VAS pain -45.3% and -61.9%; WOMAC total +68.5% and +73.6%; WOMAC pain -70.2% and -73.9%; 6-minute walk distance +21.2% and +21.9%. TNF-alpha, hs-CRP and IL-6 decreased. No significant adverse events.
https://doi.org/10.3389/fphar.2024.1428440
[6] Hajhashemi V, Safaei S (2021). Effect of a selection of skin penetration enhancers on topical anti-inflammatory effect of boswellic acids in carrageenan-induced paw edema in rats. Advanced Biomedical Research 10:18. TOPICAL ROUTE, ANIMAL STUDY: a 4% ethanolic solution of boswellic acids applied to skin produced a significant anti-inflammatory effect; olive oil, alone or with 1% eucalyptus oil, was the most effective carrier.
https://doi.org/10.4103/abr.abr_222_20

CURCUMIN PHYTOSOME

[7] Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, Togni S, Appendino G (2010). Efficacy and safety of Meriva, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients. Alternative Medicine Review 15(4):337-344. Eight-month controlled study, n = 100 adults with diagnosed osteoarthritis, 1 g/day of the complex (200 mg curcumin), oral, versus best available treatment. Global WOMAC 80.6 to 33.3 versus 77.8 to 68.8 in controls (p < 0.05); pain 16.6 to 7.3; stiffness 7.4 to 3.2; physical function 56.6 to 22.8 (all p < 0.05). Treadmill walking distance +345% versus +89% in controls (p < 0.05). Karnofsky Index 73.3 to 92.2. IL-1beta, IL-6, sCD40L, sVCAM-1 and ESR all significantly reduced. Use of NSAIDs and painkillers down 63%.
https://pubmed.ncbi.nlm.nih.gov/21194249/
[8] Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, Togni S, Appendino G (2010). Product-evaluation registry of Meriva, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Medica 52(2 Suppl 1):55-62. n = 50 patients with osteoarthritis, 200 mg curcumin/day, three months, oral. Global WOMAC -58% (p < 0.05) versus -2% in controls; treadmill walking distance 76 m to 332 m versus 82 m to 129 m; in the elevated-CRP subgroup, CRP 168 +/- 18 to 11.3 +/- 4.1 mg/L versus 175 +/- 12.3 to 112 +/- 22.2 mg/L.
https://pubmed.ncbi.nlm.nih.gov/20657536/
[9] Feng J, Li Z, Tian L, et al. (2022). Efficacy and safety of curcuminoids alone in alleviating pain and dysfunction for knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. BMC Complementary Medicine and Therapies 22:276. 15 RCTs, n = 1,670 patients with symptomatic knee osteoarthritis. VAS pain WMD -1.77 (95% CI -2.44 to -1.09; p < 0.001); WOMAC total WMD -10.47 (95% CI -15.65 to -5.30; p < 0.001); WOMAC pain -1.94 (95% CI -2.91 to -0.97; p < 0.001); function -6.36 (95% CI -8.94 to -3.78; p < 0.001); stiffness -0.54 (95% CI -1.03 to -0.05; p = 0.031). Not inferior to NSAIDs; adverse events versus placebo RR 1.07 (95% CI 0.70 to 1.65; p = 0.745). Oral route.
https://doi.org/10.1186/s12906-022-03740-9
[10] Patel NA, Patel NJ, Patel RP (2009). Design and evaluation of transdermal drug delivery system for curcumin as an anti-inflammatory drug. Drug Development and Industrial Pharmacy 35(2):234-242. TRANSDERMAL ROUTE: matrix-type transdermal films of curcumin from hydrophilic and hydrophobic polymer blends; permeation measured in Franz diffusion cells, following Higuchi kinetics with diffusion-mediated release; anti-inflammatory activity against carrageenan-induced oedema comparable to a standard formulation.
https://doi.org/10.1080/03639040802266782

MSM (METHYLSULFONYLMETHANE)

[11] Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF (2006). Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis and Cartilage 14(3):286-294. Randomised, double-blind, placebo-controlled; n = 50 adults aged 40-76 with diagnosed knee osteoarthritis pain; 3 g twice daily (6 g/day) for 12 weeks; oral. Significant decreases versus placebo in WOMAC pain (p = 0.041) and WOMAC physical function impairment (p = 0.045); no major adverse events.
https://doi.org/10.1016/j.joca.2005.10.003
[12] Debbi EM, Agar G, Fichman G, et al. (2011). Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complementary and Alternative Medicine 11:50. Randomised, double-blind, placebo-controlled; n = 49, mean age 68 (SD 7.3); 1.125 g three times daily for 12 weeks; oral. Versus placebo: WOMAC total improved by 8.4 units (95% CI 5.1 to 24.9; p = 0.03); WOMAC physical function by 7.7 units (95% CI 4.3 to 25.0; p = 0.04); VAS pain difference 0.7 cm (p = 0.05); SF-36 difference not significant (p = 0.54). The authors describe the improvements as small.
https://doi.org/10.1186/1472-6882-11-50
[13] Toguchi A, Noguchi N, Kanno T, Yamada A (2023). Methylsulfonylmethane improves knee quality of life in participants with mild knee pain: a randomized, double-blind, placebo-controlled trial. Nutrients 15:2995. n = 88 HEALTHY Japanese participants with mild knee pain (44 per arm); 2,000 mg MSM/day for 12 weeks; oral. Primary endpoint, total Japanese Knee Osteoarthritis Measure score at 12 weeks, differed significantly between groups (p = 0.046); JKOM health condition also improved (p = 0.032).
https://doi.org/10.3390/nu15132995
[14] Withee ED, Tippens KM, Dehen R, Tibbitts D, Hanes D, Zwickey H (2017). Effects of methylsulfonylmethane (MSM) on exercise-induced oxidative stress, muscle damage, and pain following a half-marathon: a double-blind, randomized, placebo-controlled trial. Journal of the International Society of Sports Nutrition 14:24. n = 22 half-marathon runners; 3 g/day OptiMSM or placebo for 21 days before and 2 days after the race; oral. MSM attenuated post-exercise muscle and joint pain at a magnitude the authors describe as clinically, but not statistically, significant; no effect on oxidative stress or muscle-damage markers.
https://doi.org/10.1186/s12970-017-0181-z

BETA-CARYOPHYLLENE

[15] Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A (2008). Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the USA 105(26):9099-9104. (E)-beta-caryophyllene binds the CB2 receptor selectively (Ki = 155 +/- 4 nM) and is a functional CB2 agonist with no CB1 activity. At 500 nM it inhibited LPS-induced pro-inflammatory cytokine expression in peripheral blood. ANIMAL DATA: peroral 5 mg/kg strongly reduced the carrageenan-induced inflammatory response in wild-type mice but not in CB2-knockout mice.
https://doi.org/10.1073/pnas.0803601105
[16] Alharthi S, Ziora ZM, Mustafa G, Chaubey P, El Kirdasy AF, Alotaibi G (2023). Beta-caryophyllene-loaded microemulsion-based topical hydrogel: a promising carrier to enhance the analgesic and anti-inflammatory outcomes. Gels 9:634. TOPICAL ROUTE: measured skin permeation 20.11 +/- 0.96 ug/cm2/h with 4.96 +/- 0.02% skin retention, versus 9.73 +/- 0.35 ug/cm2/h and 1.03 +/- 0.01% for the conventional product. ANIMAL DATA: about 91% inhibition of carrageenan-induced rat paw oedema versus about 77%.
https://doi.org/10.3390/gels9080634
[17] Weimer P, Kreutz T, Limberger RP, et al. (2022). Correlation between the skin permeation profile of the synthetic sesquiterpene compounds, beta-caryophyllene and caryophyllene oxide, and the antiedematogenic activity by topical application of nanoemulgels. Biomolecules 12:1102. TOPICAL ROUTE: ten nanoemulgels from Copaifera multijuga oleoresin; greater beta-caryophyllene permeation produced greater in vivo antiedematogenic activity, establishing beta-caryophyllene as the compound essential to that activity of the oleoresin.
https://doi.org/10.3390/biom12081102
[18] Bagher AM (2025). Topical beta-caryophyllene for dermatologic disorders: mechanisms, human evidence, and clinical translation. Pharmaceuticals 18:1605. Review of the topical route: beta-caryophyllene penetrates the stratum corneum, suppresses NF-kappaB and MAPK signalling, enhances Nrf2-driven antioxidant defences, and remains largely local to the skin with minimal systemic exposure.
https://doi.org/10.3390/ph18111605

ASTAXANTHIN

[19] Ma B, Lu J, Kang T, Zhu M, Xiong K, Wang J (2022). Astaxanthin supplementation mildly reduced oxidative stress and inflammation biomarkers: a systematic review and meta-analysis of randomized controlled trials. Nutrition Research 99:40-50. 12 RCTs, n = 380. Versus placebo, malondialdehyde SMD -0.95 (95% CI -1.67 to -0.23; p = 0.01); in type 2 diabetes, MDA SMD -0.64 (95% CI -1.26 to -0.01; p < 0.05) and IL-6 WMD -0.70 pg/mL (95% CI -1.29 to -0.11; p = 0.02). Effects on CRP and TNF-alpha were not significant. Oral route.
https://doi.org/10.1016/j.nutres.2021.09.005
[20] Park JS, Chyun JH, Kim YK, Line LL, Chew BP (2010). Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutrition and Metabolism 7:18. Randomised, double-blind, placebo-controlled; n = 14 per arm HEALTHY young women (mean age 21.5 years); 0, 2 or 8 mg/day for 8 weeks; oral. Plasma 8-hydroxy-2'-deoxyguanosine, a DNA oxidative-damage biomarker, was markedly lower by week 4; plasma C-reactive protein was lower at week 8 in the 2 mg group; immune response measures improved.
https://doi.org/10.1186/1743-7075-7-18
[21] Ng QX, De Deyn MLZQ, Loke W, Foo NX, Chan HW, Yeo WS (2021). Effects of astaxanthin supplementation on skin health: a systematic review of clinical studies. Journal of Dietary Supplements 18(2):169-182. 11 clinical studies, 6 of them randomised, double-blind and placebo-controlled. Astaxanthin improved skin texture, appearance of wrinkles and moisture content, and protected against UV-induced skin damage; no serious adverse events in any study. Supported range 3 to 6 mg/day. Oral route.
https://doi.org/10.1080/19390211.2020.1739187
[22] Ito N, Seki S, Ueda F (2018). The protective role of astaxanthin for UV-induced skin deterioration in healthy people - a randomized, double-blind, placebo-controlled trial. Nutrients 10(7):817. n = 23 HEALTHY Japanese participants; 4 mg/day for 9 weeks within a 10-week study; oral. Increased minimal erythema dose versus placebo; reduced loss of skin moisture in the irradiated area; significantly improved subjective ratings for rough skin and texture in non-irradiated areas.
https://doi.org/10.3390/nu10070817
[23] Rostami S, Alyasin A, Saedi M, et al. (2023). Astaxanthin ameliorates inflammation, oxidative stress, and reproductive outcomes in endometriosis patients undergoing assisted reproduction: a randomized, triple-blind placebo-controlled clinical trial. Frontiers in Endocrinology 14:1144323. n = 50 women with DIAGNOSED stage III/IV endometriosis; 6 mg/day for 12 weeks; oral. Serum total antioxidant capacity 398.661 +/- 57.686 versus 364.746 +/- 51.569 (p = 0.004); superoxide dismutase 13.458 +/- 7.276 versus 9.040 +/- 5.155 (p = 0.010); malondialdehyde 14.619 +/- 2.505 versus 15.939 +/- 1.512 (p = 0.031); IL-1beta (p < 0.001), IL-6 (p = 0.024) and TNF-alpha (p = 0.038) significantly lower.
https://doi.org/10.3389/fendo.2023.1144323

TRANSDERMAL DELIVERY - FUNDAMENTALS

[24] Bos JD, Meinardi MMHM (2000). The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology 9(3):165-169. The rule rests on three observations: virtually all common contact allergens are under 500 Dalton; the most commonly used topical dermatotherapeutic agents are all under 500 Dalton; and all known drugs used in transdermal delivery systems are under 500 Dalton. Supported by clinical experience with ciclosporin (about 1202 Dalton, ineffective topically) versus the smaller ascomycin macrolactams.
https://doi.org/10.1034/j.1600-0625.2000.009003165.x

Last reviewed: 19.08.2026 · 24 References