When it comes to joint health the conversation often centers around structural support – reinforcing, lubricating, and soothing the joint space. Healthy joints are protected and cushioned by layers of connective tissue called cartilage that allows them to move freely without any grinding or contact between the bone surfaces themselves. A special fluid in the joint capsule, called synovial fluid, is also extremely important for joint function. It acts as a natural lubricant and cushions joint movement. In conditions such as osteoarthritis, injury, and even in aging, there is a reduction in synovial fluid and a loss of cartilage that
The endocannabinoidome (eCBome) is a broader and more appropriate term than the old endocannabinoid system (ECS), and incorporates the more recent research into this fascinating area.
What is the eCBome
Briefly, eCBome is a protective, and communication network that exists all over the body, and interacts with hormonal, nervous, immune, endocrine, microbiome, and other systems of the body. The eCBome plays a major role in the health and disease of many organs of the body including; the reproductive system in both males and females, hormonal system, kidneys, liver, gut microbiome, heart and circulatory system, nervous system, skin among other tissues.
The ecBome consists of a number of molecules called endocannabinoids (eCBs) that bind to various receptors, including cannabinoid receptors 1 and 2, plus a few others, and enzymes that manufacture and break down the eCBs. In that regard the eCBome offers a new target for natural health products for maintenance of good health and optimal function of the body.
Since there are multiple targets- the enzymes, receptors and the eCBs, it is possible to manipulate one or more of these targets. For example, by stimulating or inhibiting various receptors. Alternatively, one can increase the synthesis of eCBs by providing the building blocks for the production of eCBs through the intake of certain fatty acids like omega 3. Similarly, one can reduce the breakdown of the eCBs by inhibiting the enzymes that breakdown the eCBs.
In this regard, PEAk Pain Relief is specifically formulated with the view of manipulating various eCBome components to help deliver help achieve inflammation and pain relief effectively, and quickly.
What is PEAk Pain Relief?
PEAk Pain Relief contains a number of natural health ingredients that support, and optimize the functioning of the eCBome through the use of well-defined and clinically tested ingredients that provide multiple mechanisms of action. PEAk Pain Relief contains the following ingredients:
- Magnesium glycinate
Let us discuss rationale of each of these ingredients:
The herb boswellia serrata is a well-known ayurvedic herb, and is a powerful anti-inflammatory comparable to, and perhaps even more potent than curcumin. The ingredient is standardized to the major actives called boswellic acids which represents a large group, with the key actives of keto-boswellic acids (KBA), and alpha keto boswellic acids (AKBA) which are responsible for the anti-inflammatory and analgesic activity. PEAk Pain Relief contains both these actives in high concentrations for maximum relief of inflammation. Boswellia has been extensively studied in various inflammatory conditions including rheumatoid, osteo-arthritis as well as asthma.
Quercetin is a well-known flavonoid with excellent antioxidant function which readily mops up oxygen, and nitrogen free radical species that are released which further initiate cell damage, and start the whole inflammatory process. Quercetin reduces inflammation by a different mechanism than boswellia. Quercetin has been found to act in a synergistic manner with a number of herbs like curcumin, green tea and resveratrol. In addition, quercetin is effective in reducing the damage done by mast cells which are specific type of immune cells that are overly active during allergies, pain and inflammation, and which release their powerful chemicals at the site of damage.
Magnesium in the form of glycinate is a powerful muscle relaxant as well as being the key component in the action of many enzymes in the body. Magnesium’s inclusion provides the much-needed relaxation of muscles as well as assisting, and optimizing the synaptic plasticity, which is the ease with which nerve signals move to and fro from the brain to the distant tissues. Synaptic plasticity is compromised in many disease conditions besides pain and muscle damage, for example the damage caused by AGE`s (advanced glycation end products) produced when excess sugars (as in pre-diabetes and diabetes) bind with various proteins in the body (lining of the blood vessels, enzymes, skin etc.) causing loss of function of the proteins. Finally, magnesium in the glycinate form is a highly bioavailable, which means it is well absorbed by the body without causing the typical gastro-intestinal side-effects attributed to some other forms of magnesium.
Palmitoylethanolamide (PEA) a molecule that is naturally found in various food sources like alfalfa, butter, peanuts, egg yolk, and soy. In addition, the body naturally produces PEA upon demand whenever there is damage and danger to the cells of the tissues
How does PEA act?
PEA is made locally, and acts locally by the cells when tissues come under threat. PEA acts on the eCBome (see previous blogs) through multiple mechanisms including:
- GPR55 receptor: was originally thought of as the third cannabinoid receptor. Activation of this receptor, like CB2 has a number of health protective effects like preventing cholesterol plaque formation, reducing toxic LDL levels as well as protective effects on the kidneys, brain, gastro-intestinal tract and the heart.
- PPAR-alpha receptor: activation of this receptor helps prevent and reduce inflammation. This is a key receptor in pain relief and inflammation.
- Prevents uptake of AEA, one of the key eCBs there by prolonging its action.
- Prevents degradation of eCBs like AEA and 2-AG, the enzyme FAAH breaks down AEA, PEA acts as an alternate dance partner for the enzyme FAAH, freeing AEA for a prolonged action.
- TRPV1 receptor: another receptor, which is associated with inflammation. Inhibiting this receptor reduces inflammation.
- Mast cell stabilizer: mast cells contribute greatly to inflammation through the release of powerful chemicals within their payload like histamine and various cytokines, powerful cellular signaling molecules, which take part in the inflammatory process. Mast cells are one of the first responders at the scene when there is damage. PEA basically makes mast cells “chill out” and reduce their aggressive behaviour by preventing the release of their contents.
Mechanisms 3, 4 and 5 above are often referred to as the “entourage effect”.
PEA has been a hidden gem until now, with over 60 years of research on this fascinating molecule (see the blog “PEA the hidden gem”) for various conditions, but especially for pain and inflammation. In many human studies, PEA at 1200 mg daily dose worked as effectively, but with far greater safety as some of the well known over the counter drugs like ibuprofen. In other studies, PEA was successfully combined with other prescription opioid and narcotic drugs, necessitating lower dose of the opioid or narcotic. One of the unique features of PEA is that it has been studied and found effective in painful conditions that are resistant to treatment like diabetic neuropathy as well as sciatica and lumber compression injuries and neuropathic pain, which is very difficult to treat.
This is a proprietary ingredient of two well-studied Chinese herbs- Scutellaria Baicalensis and Senegalia catechu, which have a proven synergistic effect in reducing inflammation and pain. The mechanism of action is different and acts by inhibiting both the COX-2 and LOX enzymes, which play a critical role in generating powerful inflammatory molecules like prostaglandins and leukotrienes (see fig 2 below).
The herbal dynamic duos have been extensively studied in both animal and human studies for safety and effectiveness. In addition, two separate human studies looked at a head-to-head comparison with prescription drugs– naproxen and celebrex, two powerful NSAID`s (non-steroidal anti-inflammatory drugs) often used in patients with osteo-arthritis. In both cases the effects on pain and inflammation were similar to the prescription drugs, however, the herbal combination was more effective than celebrex in terms of relief of stiffness, and joint function, and had a quicker onset of action (within 3-5 days for relief!) whilst the NSAID`s took longer time to kick in (see fig 1 below). Moreover, unlike the NSAID`s which produced side-effects on the stomach, and the kidneys, the herbal combination had minimal or no side effects. Univestin™ also greatly improves joint mobility, flexibility and range of motion (see fig 1 below).
Figure 1. Summary of WOMAC scores for physical function across three time points.
Figure 2: Enzymatic pathways in the initiation and progression of the inflammatory response
Classical NSAIDs inhibit the COX-1 and COX-2 branches of the COX pathway at varying ratios, whereas selective COX-2 inhibitors primarily inhibit the COX-2 branch. Univestin™ inhibits both COX1/COX-2 and 5-LO enzymatic activity with a balanced approach thereby decreasing the metabolism of AA to prostaglandins, and leukotrienes. Univestin™ also decreases levels of the pro-inflammatory cytokines TNFα, IL-1β, and IL-6, and the key gene expression regulators, NFκB and PPARγ, which results in reduced Cox-2, 5-lo, TNFα,IL-1β, IL-6 but not COX-1 gene expression. Univestin™ is a potent anti-oxidant and acts as a metabolic “sink” for reactive oxygen species (ROS), thereby reducing the detrimental oxidative stress produced in the wear and tear process on joints.
PEAk Pain Relief is a new and powerful combination of some well-known, and a few novel ingredients, with multiple and different mechanisms of action so as to give a broader relief from pain and inflammation quickly, effectively and safely.
Sampalis J and Brownell A, “Univestin Human Clinical Efficacy:
A Randomized, Double Blind, Placebo and Active Comparator Controlled Pilot Study of UP446, a Novel Dual Pathway Inhibitor Anti-Inflammatory Agent of Botanical Origin” Nutrition Journal 2012, 11:21: 11-21
Levy RM, “Efficacy and Safety of Flavocoxid, a Novel Therapeutic, Compared with Naproxen: A Randomized Multicenter Controlled Trial in Subjects with Osteoarthritis of the Knee”
Adv Ther (2010) 27(10):731-742.
Pillai L et-al, “GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin” Opinion Vol. 2010; 26: 1055–1063
Arjmandi B et-al, “A combination of Scutellaria bacicalensis and Acacia catechu extract for short term symptomatic relief of joint discomfort associated with osteoarthritis of the knee” J Med Food, 2014; 17: 707-713
Keppel Hesselink JM. Autacoids: “A New Fundament for Pain Medicine of the 21th Century. Anaesthesia. Critical Care and Pain Management”. 2016; 1: 3-6.
Keppel Hesselink JM. “Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical”. J Pain Res. 2013; 6: 625-634.
A Biasiotta, et-al. “Efficacy of palmitoylethanolamide in patients with painful neuropathy. A clinical and neurophysiological open study”. Preliminary effects. European Journal of Pain Supplements. 2010; 4: 77.
Truini A et-al. “Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy”. CNS Neurol Disord Drug Targets. 2011; 10: 916-920.
Marini I et-al. ”Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain”. J Orofac Pain. 2012; 26: 99-104.
Keppel Hesselink JM. “New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide”. The Open Pain Journal. 2012; 5: 12-23.
Keppel Hessellink JM. “Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome”. J Pain Res. 2015; 8: 729-734.
Esposito E and Cuzzocrea S. “Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma”. Mini Rev Med Chem. 2013; 13: 237-255.
Keppel Hesselink JM and Hekker TA. “Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series.” J Pain Res. 2012; 5: 437-442.