The Pain Cascade

It starts with the arachidonic acid cascade of inflammation. Arachidonic acid (ARA) is an omega-6 fatty acid that is produced from linoleic acid, an essential fatty acid. When there is too much of it, the body produces a variety of enzymes – COX-1, COX-2, and 5-LOX – to break it down. Unfortunately, these enzymes can cause some serious side effects. Over expression of COX-1 may cause blood clots, leading to heart attacks and strokes. COX-2 and 5-LOX produce compounds involved in chronic inflammation, destroying joints, tissues, causing pain, and setting the stage for degenerative disease.¹

But there are a number of natural compounds that inhibit these pathways of inflammation and help reduce inflammation from oxidative stress through their antioxidant action. Some of nature’s most effective pain relievers and anti-inflammatory compounds are found in hops alpha acids, turmeric’s curcumins, white willow, ginger, and rosemary.

Hops alpha acids

The bitter element in beer, hops alpha acid extracts have been shown to inhibit inducible nitric oxide synthase (iNOS), prostaglandin E2, and other key enzymatic COX-2 pathway substances in the management of pain caused by inflammation.² In a pilot study comparing it to 400 mg of ibuprofen over nine hours, results suggest that alpha acids from hops may represent a natural alternative for minor pain and inflammation, possibly providing important long-term safety advantages over OTC pain relievers.³

Turmeric

Curcumin in the Indian herb turmeric, is a powerful COX-2 inhibitor; it also blocks 5-LOX and other inflammatory factors.⁴ Furthermore, its antioxidant activity neutralizes both reactive oxygen species (ROS) and nitrogen oxygen species (NOS) preventing these free radicals from creating inflammation.⁵  A 2023 meta-analysis that included 20 randomized controlled trials found turmeric extract and curcumin were effective for musculoskeletal disorders and worked by reducing post-exercise pain, inflammation, oxidative stress, and muscle soreness. It also found curcumin to be exceedingly safe at doses ranging from 120 mg to 1,500 mg.⁶

White Willow

The bark of this ancient botanical, used in Traditional Chinese Medicine since 500 A.D., contains salicin, which was later purified to salicylic acid and then synthesized into acetylsalicylic acid. Acetylsalicylic acid is what constitutes aspirin. Aspirin is often used to treat pain and fever, but the drug is notorious for causing pain and damage to the stomach mucosal lining and is not recommended in conjunction with blood-thinning medications. The salicin in white willow alone is not enough to reduce pain or inflammation; however, in conjunction with antioxidant polyphenol and flavonoid compounds, the bark’s compounds were found to be effective for back pain without stomach distress.^{7 8}

Ginger

This herb contains many compounds, most notably gingerols, that exhibit potent antioxidant activity. Ginger has a long history of use in Ayurvedic and Chinese medicines for inflammatory disease caused by oxidative stress.⁹

Rosemary

Rosemary contains powerful antioxidant compounds, which inhibit the iNOS enzyme as well as scavenging the oxidative activity of other free radicals.¹⁰

PEA (palmitoylethanolamide)

A fatty acid-like substance that naturally occurs in trace amounts in foods and is produced in all bodily tissues, including the central nervous system. It is believed to be produced in response to injury or inflammation as a protective mechanism, although production is not believed to be able to keep up with chronic inflammation or pain that may exhaust PEA levels.¹¹ PEA has been studied for over 50 years and research has found that it works through several mechanisms to reduce inflammation and pain.^{12 13} In human clinical trials, PEA has been shown to reduce pain associated with mild to moderate knee osteoarthritis, temporomandibular joint (TMJ) arthritis, pelvic pain, carpal tunnel syndrome, sciatic pain, and more.^{14 15 16 17 18} Standard doses range from 600 to 1,200 mg per day.¹⁹

Next time you experience minor aches and pains from inflammation, tap Mother Nature’s medicine cabinet for natural relief.

References

1. Wang, B., Wu, L., Chen, J., Dong, L., Chen, C., Wen, Z., Hu, J., Fleming, I., Wang, D.W. (2021). Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Sig Transduct Target Ther, 6(94). https://doi.org/10.1038/s41392-020-00443-w
2. Vazquez-Cervantes, G. I., Ortega, D. R., Blanco Ayala, T., Pérez de la Cruz, V., Esquivel, D., Salazar, A., & Pineda, B. (2021). Redox and Anti-Inflammatory Properties from Hop Components in Beer-Related to Neuroprotection. Nutrients, 13(6), 2000. https://doi.org/10.3390/nu13062000
3. M. Lemay, M.A. Murray, A. Davies, H. Roh-Schmidt, R.K. Randolph: in vitro and ex vivo cyclooxygenase inhibition by a hops extract. Asia Pac J Clin Nutr. 2004, 13(Suppl):S110.
4. Rao C. V. (2007). Regulation of COX and LOX by curcumin. Advances in experimental medicine and biology, 595, 213–226. https://doi.org/10.1007/978-0-387-46401-5_9
5. Rahman, I. (2009). Dietary polyphenols mediated regulation of oxidative stress and chromatin remodeling in inflammation. Nutr Rev, 66(Suppl 1), S42-S45. Doi: https://dx.doi.org/10.1111%2Fj.1753-4887.2008.00067.x
6. Doyle, L., Desomayanandam, P., Bhuvanendran, A., Thanawala, S., Shah, R., Somepalli, V., & Bachu, S. (2023). Safety and Efficacy of Turmeric (Curcuma longa) Extract and Curcumin Supplements in Musculoskeletal Health: A Systematic Review and Meta-Analysis. Alternative therapies in health and medicine, 29(6), 12–24. http://alternative-therapies.com/oa/index.html?fid=2961224
7. Nahrstedt, A., Schmidt, M., Jäggi, R., Metz, J., & Khayyal, M. T. (2007). Willow bark extract: the contribution of polyphenols to the overall effect. Wiener medizinische Wochenschrift (1946), 157(13-14), 348–351. https://doi.org/10.1007/s10354-007-0437-3
8. Vlachojannis, J. E., Cameron, M., & Chrubasik, S. (2009). A systematic review on the effectiveness of willow bark for musculoskeletal pain. Phytotherapy research : PTR, 23(7), 897–900. https://doi.org/10.1002/ptr.2747
9. Blumenthal, M. (2003). The ABC clinical guide to herbs. American Botanical Council.
10. Lo, A. H., Liang, Y. C., Lin-Shiau, S. Y., Ho, C. T., & Lin, J. K. (2002). Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis, 23(6), 983–991. https://doi.org/10.1093/carcin/23.6.983
11. Clayton, P., Hill, M., Bogoda, N., Subah, S., Venkatesh, R. (2021 May). Palmitoylethanolamide: a natural compound for health management. Int J Mol Sci, 22(10), 5305. doi: 10.3390/ijms22105305
12. Artukoglu, B. B., Beyer, C., Zuloff-Shani, A., Brener, E., & Bloch, M. H. (2017). Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain physician, 20(5), 353–362.
13. Hesselink, J. M., & Hekker, T. A. (2012). Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series. Journal of pain research, 5, 437–442. https://doi.org/10.2147/JPR.S32143
14. Steels, E., Venkatesh, R., Steels, E., Vitetta, G., & Vitetta, L. (2019). A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology, 27(3), 475–485. https://doi.org/10.1007/s10787-019-00582-9
15. Marini, I., Bartolucci, M. L., Bortolotti, F., Gatto, M. R., & Bonetti, G. A. (2012). Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. Journal of orofacial pain, 26(2), 99–104.
16. Calignano, A., La Rana, G., Giuffrida, A., Piomelli, D. (1998). Control of pain initiation by endogenous cannabinoids. Nature, 394(6690), 277-281. https://doi.org/10.1038/28393
17. Artukoglu, B. B., Beyer, C., Zuloff-Shani, A., Brener, E., & Bloch, M. H. (2017). Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain physician, 20(5), 353–362.
18. Paladini, A., Fusco, M., Cenacchi, T., Schievano, C., Piroli, A., & Varrassi, G. (2016). Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain physician, 19(2), 11–24.
19. Artukoglu, B. B., Beyer, C., Zuloff-Shani, A., Brener, E., & Bloch, M. H. (2017). Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain physician, 20(5), 353–362.