PAIN AND INFLAMMATION
Pain could be defined as an unpleasant sensation and/or emotional experience associated with tissue injury. We usually speak of two types of pain: acute pain and chronic pain. Acute pain is pain that occurs suddenly after a specific trauma or injury and disappears after treatment. Chronic pain, on the other hand, is pain that persists after the injury has been corrected.
Many pathologies of inflammatory origin are accompanied by pain. Inflammation is the immune system’s response to any damage to the body’s tissues, whether caused by pathogenic agents such as viruses and bacteria or by an injury caused by trauma, fracture or cut. When an injury occurs, the damaged cells release algogenic (pain-producing) substances that induce the activation and stimulation of pain receptors (nocioreceptors). This response to pain and the need to repair tissue damage increases the levels of certain proinflammatory substances such as prostaglandins E2 (PGE2) and leukotrienes, molecules derived from arachidonic acid produced by the oxidative action of the enzymes cycloxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), respectively.
It is very important to be able to resolve the inflammation before it becomes chronic and for this purpose there are different treatments. The most common is the administration of drugs which, although effective, in most cases have numerous adverse effects. A safer and sometimes very effective alternative would be natural medicine, acupuncture, physical rehabilitation and physiotherapy. Often, pain control is not possible from a single perspective, so that a combined therapy could provide positive results, since it would allow us to reduce or avoid high doses of drugs that could be toxic in the long term.
Among the most common inflammatory conditions we can highlight osteoarthritis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn’s disease, among others, and inflammation caused by trauma, fractures, post-surgery, etc. Many of these situations require a quick intervention to relieve the pain caused by these processes. If what we are looking for is a natural and respectful alternative with our body, below, we detail a series of natural ingredients with excellent analgesic and anti-inflammatory properties, which in addition to acting effectively does not cause the harmful side effects of some chemical drugs with anti-inflammatory activity.
Curcuma longa is a plant that has been used in traditional Indian medicine for thousands of years for the treatment of diseases of inflammatory origin. Its active ingredient, curcumin, encompasses a broad spectrum of pharmacological activities as it has anti-inflammatory, hypoglycemic, antioxidant, healing and antimicrobial properties.1 Many authors have demonstrated its potential application for the treatment of various inflammatory conditions such as arthritis, ulcerative colitis, cancer, inflammatory bowel disease (IBD), pancreatitis, dermatitis and diabetes, among others. It has also demonstrated a detoxifying and protective effect against liver disease.2
As a treatment for osteoarthritis (OA), it has been shown to have a positive effect in reducing pain and stiffness, acting on the core of the joints to stop inflammation.3 Regarding its mechanism of action, it is known to act by reducing the expression of pro-inflammatory cytokines through the NF-κB pathway and inhibiting the expression of COX-2, 5-LO and the synthesis of PGE2, which results in a notable decrease in pain and an improvement in joint function.4 On the other hand, there is a study showing that turmeric is as effective as an NSAID against osteoarthritis, and also has fewer side effects.5
One of the pharmacokinetic problems with curcumin is its low bioavailability, mainly due to its poor absorption. Fortunately, there are much more bioavailable forms of curcumin on the market, such as Curcuma Meriva®, which, because it is phytosomized with soy lecithin phosphotilcholine (1:2), allows greater absorption (up to 30 times more compared to Curcuma longa ES).6
The Boswellia serrata extract (EBS), like Curcuma longaextract, has been and is commonly used in traditional Ayurvedic medicine for the treatment of pain caused by chronic inflammatory diseases such as rheumatoid arthritis (RA), IBD, OA, and asthma, among others.7 Its anti-inflammatory effects are given by the boswellic acids present in its resin among which β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid are noteworthy. Many authors have tried to elucidate the mechanism of action of these acids and their application for the treatment of OA. It is known that EBS suppresses leukotriene formation by inhibiting the enzyme (5-LO). In addition, recent studies demonstrate its role in inhibiting the proteolytic activity of cathepsin G (CATG) and the synthesis of microsomal prostaglandin E synthase (mPGES)-1, thereby blocking PGE2 synthesis.8 Other studies indicate that EBS counteracts decreases in glycosaminoglycan (GAGs) levels and prevents the secretion and activity of metalloproteases (MMPs), which could prevent articular cartilage degradation. In studies with arthritic rats, EBS demonstrated its potential effect in reducing the number of leukocytes in the synovial fluid and improving lameness and local pain.9 For all these reasons, the scientific community has begun to show interest in EBS, with many clinical studies showing its positive effects in reducing joint pain and inflammation and improving joint function, without the adverse effects associated with NSAIDs and corticosteroids. 10,11
HUMULUS LUPULUS (Hops)
Hops contain a large number of phytochemicals with a broad spectrum of biological activities. Due to its sedative effect, it has been used for many years as a natural remedy for treating insomnia and anxiety. Another characteristic of the plant is its powerful antioxidant effect, capable of combating oxidative stress generated by various free radicals. Among all its ingredients, it is worth highlighting the so-called alpha-acids, used in beer brewing for their bitter taste, which have shown great potential to help the body’s natural response to fight inflammation and pain. In terms of their mechanism of action, alpha-acids act by inhibiting the enzyme inducible nitric oxide synthase (iNOS), PGE2 and other key pathways in the process of pain caused by inflammation.12 Studies have shown that they may be a natural alternative to NSAIDs but with fewer adverse effects. 13
HARPAGOFITUM PROCUMBENS (Harpagophytum)
Harpagophytum procumbens (HP), commonly called harpagophytum or “devil’s claw” due to the shape of its fruits, is an herbaceous plant of African origin whose roots are used in traditional medicine as anti-inflammatory agents for the symptomatic treatment of arthritis and rheumatism. Its pharmacological activity is conferred by the iridoid terpene derivatives present in the root, harpagoside being the most important of them all. In vitro studies demonstrate its anti-inflammatory activity by decreasing the synthesis and release of pro-inflammatory factors such as the activating transcription factor AP-1 in murine macrophages, the expression of certain cytokines such as TNF-α and interleukin-6 (IL-6) and the decrease in COX-2 mRNA levels.14 On the other hand, HP extract also exhibits the ability to prevent oxidative stress. 15
A natural component present in the body with excellent anti-inflammatory and analgesic properties that is commonly used in the treatment of OA. Several studies have shown that its chondroprotective effect is enhanced when combined with other nutraceuticals such as chondroitin and glucosamine.16 Thanks to its sulphur content, MSM contributes to the maintenance of healthy connective tissues by neutralising free radicals that hinder the restoration of the cellular matrix of cartilage. Its anti-inflammatory power is due to its role as an inhibitor of the transcriptional activity of nuclear factor kappa B (NF-κB), which is responsible for the expression of genes encoding pro-inflammatory cytokines. The inhibitory effect of MSM on NF-κB results in the down-regulation of mRNA for interleukin IL-1, IL-6 and tumour necrosis factor α (TNF-α) in vitro. Moreover, MSM can also reduce iNOS and COX-2 expression thereby decreasing the production of vasodilatory agents such as nitric oxide (NO). With the reduction of cytokines and vasodilatory agents, the influx and recruitment of immune cells to sites of local inflammation is inhibited.17
Phenylalanine is an essential amino acid that humans need to incorporate through diet. It is involved in the synthesis of tyrosine, a precursor of catecholamines such as noradrenaline and adrenaline or neurotransmitters such as dopamine. DL-phenylalanine acts as a blocker of enzymes in the central nervous system responsible for degrading certain natural morphine-like hormones (endorphins, enkephalins) and thus enhances the endogenous analgesic effect. As a result of its functions in the body, DL-phenylalanine helps to relieve pain, improves mood, reduces the symptoms of some neurological diseases, promotes alertness and vitality and contributes to memory and learning.
THIAMINE (Vitamin B1)
Vitamin B1 may play an important biophysiological role in the conduction and excitability of nerve endings. Animal model studies have shown that vitamin B1 significantly reduces neuronal hyperexcitability, inhibits thermal hyperalgesia and partially reverses injury-induced alterations in sodium currents.18 Therefore, it is believed that treatment with high doses of thiamine may be an effective tool for the relief of painful processes caused by injury, inflammation or degeneration in the nervous system. In addition, at high concentrations, thiamine may have an analgesic effect by increasing the synthesis of serotonin and GABA in various areas of the brain.19
Neuropathic pain is caused by a primary lesion or dysfunction of the nervous system, which misinterprets stimuli. It is usually chronic pain and gabapentin derivatives are commonly used as treatment. However, this drug is known to have several side effects (drowsiness, tremors, anxiety, etc.). A much safer natural alternative would be uridine. This is an essential nucleotide in the synthesis of phospholipids in cell membranes and is necessary for the formation of the membrane of dendrites and the filament cells that make up the nerves. It is therefore thought that supplementation with disodium uridine-5′-monophosphate could help the regeneration of damaged nerves. It acts by inhibiting leukocyte recruitment at sites of local inflammation and therefore helps to reduce the intensity of pain in the face of any type of inflammation.
Zinc is an essential micronutrient involved in many vital enzymatic reactions in the body. It contributes to the normal metabolism of proteins, fats and carbohydrates, to the maintenance of normal bones, to the normal functioning of the immune system and protects cells against oxidative damage. One of the main causes of OA is oxidative stress. Reactive oxygen species (ROS) act by damaging the main components of cartilage and joints, so combating the action of free radicals can be a very useful tool in the fight against the disease. Zinc acts as a cofactor for several antioxidant enzymes such as superoxide dismutase, catalase, glutathione reductase, peroxidase and others. Acceptable levels of zinc contribute to the maintenance of normal joint function and protect cells from oxidative damage.20 Furthermore, some studies show that zinc may help to alleviate RA symptoms by inhibiting the inflammatory response.21
In conclusion and on reflection, it seems easy to think that if we combine all the nutrients described in this article in a single product, in the correct doses and proportions, we could have in our hands a natural, effective and safe tool to combat pain caused by inflammatory processes, improving the quality of life of people who unfortunately suffer from these pathologies.
- Gupta S. C. et al. Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials. The AAPS Journal; 2013 Vol. 15, No. 1, January.
- Aggarwal B. B. et al. Potential Therapeutic Effects of Curcumin, the Antiinflammatory Agent, Against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases. Int J Biochem Cell Biol; 2009, 41(1): 40–59.
- Jurenka J.S et al. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 2009; 14(2):141-53.
- Henrotin Y. et al. Curcumin: a new paradigm and therapeutic opportunity for the treatment of osteoar¬thritis: curcumin for osteoarthritis management. SpringerPlus; 2013, 2: 56.
- Kuptniratsaikul V. et al. Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study. Clinical Interventions in Aging; 2014, 9: 451-458.
- John Cuomo et al., Comparative Absorption of a Standardized Curcuminoid Mixture and Its Lecithin Formulation, Journal of Natural Products, 2010.
- Ammon, H. Boswellic acids and their role in chronic inflammatory diseases. In Anti‐inflammatory nutraceuticals and chronic diseases. Springer International Publishing AG, Switzerland. 2016. (pp. 291–327).
- Siemoneit, U. et al. Inhibition of microsomal prostaglandin E2 synthase‐1 as a molecular basis for the anti‐inflammatory actions of boswellic acids from frankincense. British Journal of Pharmacology, 162(1), 2011, 147–162.
- Abdel-Tawab M. Boswellia serrata An Overall Assessment of In Vitro, Preclinical, Pharmacokinetic and Clinical Data. Clin Pharmacokinet, 2011, 50 (6): 349-369.
- Muhammed Majeed et al., A pilot, randomized, double‐blind, placebo‐controlled trial to assess the safety and efficacy of a novel Boswellia serrata extract in the management of osteoarthritis of the knee Phytotherapy Research. 2019; 33:1457–1468.
- Raveendhara R. Bannuru et al, Efficacy of Curcumin and Boswellia for Knee Osteoarthritis: Systematic Review and Meta-Analysis. Semin Arthritis Rheum. 2018; 48(3): 416–429.
- Z. Zhao et al. Inhibitors of nitric oxide production from hops (Humulus lupulus L.). Biol Pharm Bull, 2003, 26 (1): 61-5.
- M. Lamay et al. In vitro and in vitro cocloxygenase inhibition by a hops extract. Asia Pac J Clin Nutr. 2004, 13 (suppl):4-10.
- Fiebich, B. et al. Molecular Targets of the Anti-inflammatory Harpagophytum procumbens (Devil’s claw): Inhibition of TNF and COX-2 Gene Expression by Preventing Activation of AP-1. Phytother. Res. 2011, 26, 806–811.
- Schaffer, L. et al. Harpagophytum procumbens Prevents Oxidative Stress and Loss of Cell Viability In Vitro. Neurochem. Res. 2013, 38, 2256–2267.
- Andri M.T. Lubis, Comparison of Glucosamine-Chondroitin Sulfate with and without Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial, Acta Med Indones-Indones J Intern Med, 2017, Vol 49:2, p.105-111.
- Butawan M. et al Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement. Nutrients, 2017, 9, 290.
- Song X.S et al. Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology 2009; 110 (2):387-400.
- Jurna I. Analgesic and analgesia-potentiating action of B vitamins. Schmerz 1998; 12(2):136-141.
- Ostalowska A. et al. Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with pri¬mary and secondary osteoarthritis of the knee joint. Osteoarthritis and Cartilage. 2006;14(2):139-45.
- Simkin, P., Oral zinc sulphate in Rheumatoid Arthritis. The Lancet; 1976, 2(7985):539-42.