Pain is an unpleasant sensory experience, either acute or chronic, affecting millions of people worldwide¹. It is highly prevalent, with 1 in 5 individuals suffering from persistent pain², often associated with sleep disturbances³. Some common manifestations include joint pain, back or neck pain, nerve pain and headaches4,16. These data highlight the growing need for effective and reliable strategies to manage pain and discomfort.
Palmitoylethanolamide (PEA) is among the most clinically studied nutraceuticals for supporting the body’s response to inflammation and discomfort⁵. It contributes to the regulation of the endocannabinoid system, supports physiological homeostasis and helps manage occasional aches and discomfort⁵. However, standard PEA presents some limitations: it primarily acts on pain pathways rather than directly targeting receptors, which may result in a slower onset of action; its effectiveness can vary depending on individual conditions such as oxidative stress or chronic inflammation; and its high lipophilicity combined with poor aqueous solubility may limit absorption and bioavailability⁶.
To overcome these limitations, combining PEA with complementary bioactive compounds represents a more advanced approach. Acmella oleracea, traditionally used in South America for pain relief, contains spilanthol, a bioactive substance capable of directly modulating pain receptors and stimulating the peripheral nervous system⁷. Due to its structural similarity to endocannabinoids, spilanthol can interact with cannabinoid receptors, inhibiting nociceptive transmission and enabling a faster response⁸,⁹. In addition, it modulates key inflammatory mediators and pathways, including nitric oxide, prostaglandins, NF-kB and MAPK¹⁰⁻¹³, and contribute to oxidative balance by enhancing endogenous antioxidant defenses⁸.
The combination of PEA and Acmella oleracea therefore enables a dual-action strategy targeting both central and peripheral pain pathways¹⁴. PEA supports central regulation by mitigating neuroinflammation, while spilanthol acts on peripheral receptors to provide more rapid relief⁵,¹¹. Together, they offer complementary mechanisms of action, a faster onset and more sustained effects, while also supporting inflammatory and oxidative balance⁵,¹¹.
Wellpea® is a patented formulation based on PEA and Acmella oleracea, specifically developed to optimise this synergistic interaction. Leveraging food-grade excipients and proprietary engineering technology, it enhances its ability to disperse in aqueous environments, potentially improving bioaccessibility. The formulation is characterised by a dual-acting mechanism, an optimised self-dispersing profile and versatile delivery formats.
Its efficacy is supported by clinical evidence. In a 4-week open-label study involving 60 adults with chronic low back pain and sciatica, Wellpea® led to significant improvements. At least 50% of participants achieved pain reduction to mild levels (NRS < 4), with effects becoming evident after 12 days and significant improvements observed as early as day 3. Neuropathic pain scores (DN4) decreased from 5.72 to 1.62 and 100% of subjects reported satisfaction with the treatment15.
These findings highlight the potential of a dual-action strategy for daily discomfort management, combining rapid onset with sustained benefits.
Further randomised, controlled studies are planned to confirm these preliminary results and strengthen the scientific evidence supporting Wellpea®.
References
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- Lurie, Jacob Michael MD, MPH; Javaid, Amal MD. Visualizing Global Chronic Pain. Anesthesia & Analgesia 138(4):p 918-919, April 2024. | DOI: 10.1213/ANE.0000000000006564
- Duo L, Yu X, Hu R, Duan X, Zhou J and Wang K (2023) Sleep disorders in chronic pain and its neurochemical mechanisms: a narrative review. Front. Psychiatry 14:1157790. DOI: 10.3389/fpsyt.2023.1157790
- GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis. Lancet. 2020;396:1204–1222.
- Valenza, M.; Facchinetti, R.; Steardo, L.; Scuderi, C. Palmitoylethanolamide and White Matter Lesions: Evidence for Therapeutic Implications. Biomolecules 2022, 12, 1191. https://doi.org/10.3390/biom12091191
- Skaper SD, Facci L, Fusco M, Della Valle MF, Zusso M, Costa B, Giusti P. Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain. Inflammopharmacology. 2014; 22(2): 79-94. DOI: 10.1007/s10787-013-0191-7
- Spinozzi, E.; Ferrati, M.; Baldassarri, C.; Cappellacci, L.; Marmugi, M.; Caselli, A.; Benelli, G.; Maggi, F.; Petrelli, R. A Review of the Chemistry and Biological Activities of Acmella oleracea (“jambù”, Asteraceae), with a View to the Development of Bioinsecticides and Acaricides. Plants 2022, 11, 2721.https://doi.org/10.3390/plants11202721
- Yien RMK ,Gomes ACC, Goetze Fiorot R, Miranda ALP, Neves GA, Andrade BDS, Costa FN, Tributino JLM, Simas NK. Alkylamides from Acmella oleracea: antinociceptive effect and molecular docking with cannabinoid and TRPV1 receptors. Nat Prod Res. 2023 Aug-Sep;37(18):3136-3144. doi: 10.1080/14786419.2022.2142221. Epub 2022 Nov 4. PMID: 36331425.
- Alperth F, Feistritzer T, Huber M, Kunert O, Bucar F. Natural Deep Eutectic Solvents for the Extraction of Spilanthol from Acmella oleracea (L.) R.K.Jansen. Molecules. 2024; 29(3):612. https://doi.org/10.3390/molecules29030612
- Wu LC, Fan NC, Lin MH, Chu IR, Huang SJ, Hu CY, Han SY. Anti-inflammatory effect of spilanthol from Spilanthes acmella on murine macrophage by down-regulating LPS-induced inflammatory mediators. J Agric Food Chem. 2008 Apr 9;56(7):2341-9. doi: 10.1021/jf073057e. Epub 2008 Mar 6. PMID: 18321049.
- Abdul Rahim R, Jayusman PA, Muhammad N, Mohamed N, Lim V, Ahmad NH, Mohamad S, Abdul Hamid ZA, Ahmad F, Mokhtar N, Shuid AN, Mohamed IN. Potential Antioxidant and Anti-Inflammatory Effects of Spilanthes acmella and Its Health Beneficial Effects: A Review. Int J Environ Res Public Health. 2021 Mar 29;18(7):3532. doi: 10.3390/ijerph18073532. PMID: 33805420; PMCID: PMC8036807. https://doi.org/10.3390/ijerph18073532
- Lee, B. W. Botany, Ethnopharmacology, Phytochemistry, Biological Activities of Acmella oleracea: A Comprehensive Review. Preprints 2026, 2026011259. https://doi.org/10.20944/preprints202601.1259.v1
- Huang WC, Wu LY, Hu S, Wu SJ. Spilanthol Inhibits COX-2 and ICAM-1 Expression via Suppression of NF-κB and MAPK Signaling in Interleukin-1β-Stimulated Human Lung Epithelial Cells. Inflammation. 2018 Oct;41(5):1934-1944. doi: 10.1007/s10753-018-0837-0. PMID: 29959625.
- Data on file, 2024
- Manuscript submitted
- https://www.iasp-pain.org/resources/terminology/