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Pathophysiology of Pain
The International Association for the Study of Pain (IASP) defines pain as, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. The nature of pain includes emotional and physical suffering.
Acute pain is usually nociceptive. Nociceptive pain arises from somatosensory pain receptor as a response to potential or actual non-neural tissue damage (pain originating from somatic: joint, muscle, ligament, or visceral organs: appendix, kidney). Nociceptors respond to heat, cold, vibration, stretch stimuli, and chemical substances released from tissues in response to tissue disruption or inflammation.
Chronic pain is a pathological process, when acute pain becomes chronic and persists more than 3 months, continuous or recurrent. Chronic pain may persist in the absence of tissue damage. Permanent structural alterations in specific brain areas are implemented in the development of chronic pain. There is growing evidence for hippocampal involvement in pain pathophysiology, particularly, hippocampal abnormalities after nerve injury-induced pain in mice, as well as reduced hippocampal volume in patients with chronic pain. It is important to decrease the intensity of acute pain and assure sufficient nutrition for the purpose of diminishing or preventing permanent changes in the nervous system that may transform to chronic pain.
More than 1.5 billion people worldwide suffer from chronic pain – the disabling condition affecting quality of life and putting financial burden on the patients and their families.
Pathophysiology of Pain
- Chronic primary pain is an idiopathic pain, that cannot be better explained by another chronic pain condition: fibromyalgia syndrome, irritable bowel syndrome, chronic pelvic pain, chronic regional pain syndrome.
- Chronic cancer pain is caused by the cancer itself and by the cancer treatment (surgical, chemotherapy, radiotherapy, and others).
- Chronic postsurgical and posttraumatic pain develops after a surgical procedure or a tissue injury (trauma or burns), lasting 3 months or more after surgery or tissue trauma. Other causes must be excluded (a pain from pre-existing condition, infection, recurrent malignancy).
- Neuropathic pain is a demonstrable lesion or the disease of the somatosensory nervous system, caused by nerve compression or the abnormal processing of pain signals by the brain and spinal cord. Neuropathic pain can be an increased response to a painful stimulus (hyperalgesia) or a painful response to normally a non-painful stimulus (allodynia).
- Chronic headache and orofacial pain is a headache or orofacial pain that occurs on at least 50% of the days during at least 3 months (temporomandibular disorders, post-traumatic trigeminal neuropathic pain, migraine).
- Chronic visceral pain originates from the internal organs of the head and neck region and the thoracic, abdominal, and pelvic cavities.
- Chronic musculoskeletal pain is a nociceptive pain characterized by persistent inflammation of infectious, autoimmune or metabolic etiology, such as rheumatoid arthritis, and by structural changes affecting bones, joints, tendons, or muscles
Neurochemistry of Pain Pathway
Neurotransmission of Pain
There are three classes of transmitter compounds: excitatory neurotransmitters, inhibitory neurotransmitters, and neuropeptides.
- Neuropeptides: Substance P and neurokinin A serve as excitatory neuropeptides in the somatosensory system. The key inhibitory neuropeptides are the enkephalins and somatostatin.
- Excitatory Neurotransmitters: glutamate and aspartate amino acids. They activate N-methyl-D-aspartate (NMDA) pain receptors. Recent animal study showed NMDA receptors in primary afferent terminals undergo a dramatic increase in their functionality by brain-derived neurotrophic factor (BNDF) during neuropathic pain. This is likely due to potentiation of the synapses between primary afferents and dorsal horn neurons during chronic pain.
- Inhibitory Neurotransmitters: amino acids glycine, gamma-amino-butyric acid (GABA), acetylcholine (Ach), and Serotonin.
Product Description of the Primary Ingredients
ProleevaMax consists of a patent-pending proprietary formulation of Choline L-Bitartrate, Curcumin 95%, 5-Hydroxytryptophan (from Griffonia Simplicifolia Seed Extract), L-Arginine HCI, L-Glutamine, L-Serine, gamma-Aminobutyric Acid (GABA), Piperine Black Pepper Extract 95%, Boswellia Extract (Boswellia serrata) 65% Boswellic Acid, 98% Trans-Resveratrol (Polygonum cuspidatum Extract (root)), Matcha Green Tea Leaf Powder, Panax Ginseng Root Powder, and Vitamin B6 (Pyridoxine HCI) .
All the ingredients above fall into the classification of Generally Recognized as Safe (GRAS) as defined by the Food and Drug Administration (FDA) (Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act).
Patients with pain disorders may have increased nutritional demand and require certain amino acids in the amount that cannot be obtained from normal diet alone. Complex of amino acids included in ProleevaMax plays crucial role in modulation of pain. In addition, ProleevaMax contains ingredients of herbal supplements with antinociceptive, anti-inflammatory, and antioxidant properties. For centuries, people used herbal medicine for variety of diseases. Nowadays, with support by clinical trials, herbalism is proving to be effective as adjunctive in a treatment of pain, fatigue, and inflammation.
Choline amino acid occurs naturally in the body for various biological functions, including the synthesis of acetylcholine, an important neurotransmitter. In the case of chronic pain and inflammation, research studies showed that choline selectively acts as an agonist of alpha7- type nicotinic acetylcholine receptors (α7nAChRs) expressed in both non-neuronal and neuronal cells responsible for pain regulation and suppression . Moreover, the activation of these receptors by choline may provide anti-inflammatory potential against underlying inflammatory cascades. Interestingly, the action on these receptors does not pose any risk of addiction or dependency. A study in postoperative patients revealed that choline supplementation activated the α7nAChR and other types, including the α8 and α9-containing nicotinic receptors. However, choline failed to activate the α4β2 subtypes responsible for addiction and gastrointestinal symptoms, evidence that choline supplementation is safe. The activation of α-nicotinic receptors in both the central and peripheral nervous system suppresses the inflammatory cytokines, including the tumor necrosis factor (TNF) and trans-nucleation of nuclear factor kappa b. In case of pain, choline attenuates the prostaglandin-E2 (PGE2)-induced pain through the α7nAChR activation and relieves inflammatory hyperalgesia. Thus, oral choline administration modulates the nitric oxide/cGMP/ATP-sensitive potassium channels pathway that import relief against persistent pain and inflammation . Other anti-inflammatory mechanisms of choline involve the modulation of the vagal anti-inflammatory system and reducing tissue-damaging components such as lactate dehydrogenase, urea, creatine kinase, and uric acid .
5-hydroxytryptophan (5-HTP) is a naturally occurring amino acid responsible for various beneficial effects. The body converts 5-HTP to tryptophan, an essential amino acid for synthesizing proteins, enzymes, neurotransmitters, and muscle. In the case of chronic pain and inflammation, research studies showed that 5-HTP suppresses the expression of nitric oxide and interleukins (IL-6), inhibiting the progression of the inflammatory cascade. Through this mechanism, 5-HTP modulates the activation and functions of certain enzymes, including cyclooxygenase-2 (COX-2), protein kinase (ERK), and inducible nitric oxide synthase (iNOs) that play important roles in the development and progression of inflammation . Moreover, the analgesic potential of 5-HTP is attributed to antioxidant activity that neutralizes and removes reactive free radicals, preventing tissue and cellular damage against oxidative stress. In a research study, the 5-HTP significantly protected the human fibroblast cells against the damage of reactive free radicals and preserved their integrity . Furthermore, studies found a significant role of 5-HTP in reducing fibromyalgia symptoms and migraine frequency. It improves early fibromyalgia symptoms, including anxiety, muscle pain, and sleep problems [10, 11]. Various studies reported that 5-HTP supplementation reduced the number of migraine attacks and headaches by 71% and 70%, respectively . In the case of stress, research studies reported that 5-HTP mediates anxiety, improves serotonin levels, and reduces the symptoms of panic disorders and depression [13, 14]. Thus, the presence of 5-HTP in PROLEEVAMAX™ provides relief against chronic inflammation, anxiety, stress, and pain.
L-arginine is an important amino acid responsible for synthesizing proteins and amino acids and also imports other biological functions, including improvement of blood circulation and aids muscle recovery. It helps the production of nitric oxide in the body, which helps regulate blood flow, cellular communication, and mitochondrial function. In the case of chronic pain, L-arginine is reported in research studies with significant analgesic properties. In patients with sickle cell disease, the administration of L-arginine improved the pain episodes and reduced the urge for potent opioid analgesics . Moreover, it lowered the pain score at the patient’s discharge without any side effects at a dose of 300mg/kg daily for five days. Another study in diabetic animals revealed that L-arginine supplementation significantly improved the abnormal sensitivity to chronic pain and pain caused by temperature changes. Besides the analgesic potential of L-arginine in patients with congestive heart failure, it significantly improved clinical outcomes such as immune function and creatine clearance . In the case of inflammation, L-arginine showed inhibitory potential against pro-inflammatory cytokines, such it decreases the levels of nuclear factor (NF)-κB levels, interleukin-6, interleukin-1β, and tumor necrosis factor-α. Also, it modulates the activities of enzymes responsible for inflammatory cascade, including metalloproteinase (MMP)-2, iNOS, and MMP-9 enzymes [18, 19]. Thus, L-arginine supplementation helps manage chronic pain, muscle damage, and underlying inflammations.
Gamma-Aminobutyric Acid (GABA) 99%
GABA is an important neurotransmitter in the body with an inhibitory potential against the neuronal activity. As a supplement, GABA is considered safe and effective for various health benefits. In the case of inflammation, GABA modulates the pro-inflammatory mediator’s production and inhibits an inflammatory cascade. Research studies showed that GABA interferes with the expression of enzymes (iNOs), NF-kB, and pro-inflammatory cytokines (interleukins and TNF-α), importing an anti-inflammatory potential and healing property. It also suppresses the expression of inducible nitric oxide synthase and nitric oxide production, providing anti-inflammatory activity. These potential anti-inflammatory actions of GABA suppress underlying inflammatory cascade and help manage chronic medical conditions in the body .
Interestingly, GABA helps with depression, supports optimal sleep, and imports calming effects that improve quality of life and mental health. The antidepressant potential of GABA is attributed to the modulation of dopamine, norepinephrine, and 5-HTP levels in the hippocampus region. Also, in case of stress, GABA is found to decrease beta waves, increase alpha waves and improve levels of antibodies in the body, inducing relaxation and anxiolytic properties. Research studies reported that a low GABA in the body is associated with high sensitivity to pain, depression, and anxiety . Thus, in PROLEEVAMAX™, along with the anti-inflammatory potential of GABA against chronic inflammatory conditions, the active component of GABA provides calming and relaxing effects on chronic pain, enhancing the quality of life and wellness.
Glutamine is a naturally occurring amino acid with therapeutic potential against certain diseases and muscle wasting. In the case of chronic pain and inflammation, L-glutamine suppresses and reduces the hyperalgesia and inflammatory cascade through various mechanisms. In chronic pain, a research study on L-glutamine supplementation showed a significant reduction in pain and decreased the urge for opioid analgesics in participants . The participants reported a 21% to 100% reduction in the use of opioids for pain after L-glutamine supplementation. Additionally, the L-glutamine supplementation decreased the need for emergency or hospitalization among the participants. The anti-inflammatory potential of glutamine involves:
- Inhibiting the NF-κB signaling pathway.
- Stimulating cytoprotective factors, like heat-shock proteins (HSP).
- Regulating inflammatory cytokines production.
Research studies reported that L-glutamine suppresses the activation of the NF-κB pathway and NF-κB-dependent gene expression, providing inhibitory potential against underlying inflammations . Interestingly, the composition of L-glutamine in ProleevaMax helps muscle function, relieves fatigue, and improves the quality of life. Research studies on glutamine revealed that it supports energy-producing processes such as gluconeogenesis and the Krebs cycle that improves energy production, help glycogen storage, and import anti-fatigue property . Moreover, l-glutamine supplementation prevents the accumulation of ammonia through a different mechanism. Notably, ammonia accumulation disrupts energy metabolism and glycogen storage, causing fatigue. Thus, the prevention of ammonia accumulation in the muscles or body by glutamine helps the management of chronic fatigue. Studies also showed that glutamine supplementation prevents muscle damage by modulation of creatine kinase, myoglobin, lactate dehydrogenase, and aspartate transaminase levels in the blood . Hence, L-glutamine significantly supports the management of chronic pain, inflammation, and fatigue in patients.
L-serine is an important amino acid for proteins and neurotransmitter synthesis in the body. The FDA categorizes it as a “Generally Recognized as Safe” ingredient under CFR172.320. Research studies reported significant pharmacological actions of l-serine, including anti-inflammatory, analgesic, and antioxidant potentials. In inflammation, l-serine effectively suppresses the signaling pathways and levels of pro-inflammatory cytokines, including interleukins (IL-1ß). Moreover, it increases the endogenous concentrations of glutathione and superoxide dismutase responsible for protecting DNA and preventing cellular damage against reactive oxygen species . Also, l-serine activates the glycine receptors, suppressing pro-inflammatory cytokine release that prevents an underlying inflammatory cascade . In a study of patients with pain, the combined administration of l-serine and eicosapentaenoic acid imported analgesic activity that relieved pain and improved comfort through their neuroprotective activity .
Curcumin is very well known as an effective and potent anti-inflammatory, antioxidant, and analgesic constituent of Curcuma longa (turmeric). Research studies on curcumin revealed significant therapeutic potential in managing inflammation, healing, and other medical conditions, including knee pain, heart diseases, irritable bowel syndrome, diabetes, and osteoarthritis. The anti-inflammatory and analgesic mechanisms of curcumin are attributed to the suppression of pro-inflammatory cytokines and, ultimately, the inflammatory cascade. A study on the post-operative management of patients showed significant pain and fatigue reduction with a 500mg dose of curcumin . Research studies reported that curcumin supplementation could reduce arthritic pain and associated post-operative discomfort. In case of inflammation, curcumin suppresses the expression of tumor necrosis factor (TNF), nuclear factor kappa b (NF-kB), prostaglandins-E2, and certain enzymes responsible for an inflammatory cascade . Notably, curcumin supplementation modulates the activities of iNOs, Lipoxygenase, Phospholipase A2, and Cycloxyenase-2 enzymes, helping manage chronic inflammatory conditions. Another anti-inflammatory and analgesic action of curcumin involves the inhibition of macrophage migration. Research studies in animals showed that curcumin significantly suppressed the elevation of monocyte chemoattractant protein 1 (MCP-1) and monocytes (precursor of macrophages), indicating a protective effect against chronic inflammation. The inhibition of NF-kB by curcumin indirectly decreases the other inflammatory mediators, including ICAM-1, E-selectin, P-selectin, VCAM-1, and ELAM-1 [42, 43]. Thus, these mechanisms either prevent inflammation development or exacerbate existing chronic inflammatory conditions. Interestingly, 400mg curcumin for managing acute algesic episodes provided similar efficacy to 100mg nimesulide and 1000mg acetaminophen [44-46].
Boswellia Extract (Boswellia serrata)
Natural health practices have used boswellia for centuries to treat various chronic inflammatory disorders. The scientific research on boswellia is beginning to unveil potential uses for the resin and its extracts.
Boswellia and its active ingredients, such as boswellic acid, have a good anti-inflammatory effect on the body. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation. Modern medicine and pharmacology strongly point out to its use as an antiarthritic, antiinflammatory, antihyperlipidemic (controls blood lipids), antiatherosclerotic (anticoronary plaque), analgesic (pain-reliever) and hepatoprotective (protects the liver) .
Piperine is considered safe as a dietary supplement and additive in specific formulations for human consumption. In PROLEEVAMAX™, piperine is added to enhance the bioavailability of curcumin and other ingredients for optimal therapeutic properties against chronic pain and inflammation. However, studies also showed the anti-inflammatory effect of piperine isolated from black pepper through inhibiting enzymes (COX-2) and inflammatory cytokines (TNF-α and Interleukins-6) involved in the inflammatory cascade . Notably, curcumin showed poor absorption in the absence of piperine. Thus, a dose of up to 5-7mg/kg in a formulation with curcumin is found safe and effective for the enhancement of absorption of active ingredients. Studies reported that 20mg of piperine increased curcumin bioavailability by 2000%. Animal studies revealed that a dose of up to 5mg, 15mg, or 50mg/kg once daily showed no side effects or toxicity . Thus, a dose of 15mg-20mg of piperine is safe for human use, showing no unwanted effects.
Matcha Green Tea Extract
Matcha green tea is a popular variety of common green tea with a higher amount of active constituent and enormous health benefits. It is a rich reservoir of antioxidant constituents and also delivers anti-fatigue and anti-inflammatory properties. Research studies showed that matcha green tea import relaxation and stress-reducing potentials, helping the management of fatigue and depression [49-52]. The major constituents of matcha green tea include L-theanine, caffeine, and epigallocatechin gallate (EGCG). The compositions of these phytochemicals in matcha green tea neutralize and remove reactive free radicals that preserve cellular integrity and help the suppression of inflammatory cascade, resulting in the prevention of various medical conditions . In the case of chronic fatigue syndrome, research studies on green tea supported physical performance in the fatigued condition. It also promoted calmness and relaxation along with the regulation of glutathione and inflammatory mediators [50, 51]. Interestingly, studies reported that the combination of arginine and l-theanine in matcha green tea import significant stress-reducing properties that benefit psychological stress conditions . Thus, matcha green tea in PROLEEVAMAX™ imports anti-fatigue, anxiolytic and antioxidant properties that help with stress and chronic fatigue and also reduce the risk of underlying inflammations.
Panax Ginseng Root Powder
Panax ginseng contains active phytochemicals such as ginsenosides investigated for various health benefits, including anticancer, anti-inflammatory, analgesic, and antioxidant potential. In the case of inflammation, the active constituents in Panax ginseng significantly suppress the NF-κB signaling pathway and also inhibit the production of interleukins, tumor necrosis factor-α, and enzymes like COX-2 and iNOs responsible for inflammatory cascade [57, 58]. As a result, Panax ginseng does not allow inflammatory processes and helps the management of various underlying chronic inflammatory conditions. Research studies on Panax ginseng showed that it also acts on other components, such as expression and activation of inflammatory cytokines, significantly ameliorating the symptoms and progression [57, 58]. In the case of chronic pain, research studies reported that Panax ginseng helps the suppression of pain associated with inflammation, neuropathy, and other chronic types. Studies in patients with fibromyalgia showed that Panax ginseng supplementation significantly improved stress, pain, and quality of life .
Moreover, other analgesic potentials of Panax ginseng are attributed to the suppression of inflammatory enzymes, cytokines, and signaling pathways, inhibition of calcium channels, modulation of neurotransmitters in the nervous system, and regulation of estrogen receptors . These mechanisms help the management of chronic pain associated with inflammation, neuropathy, and other pain types. Besides, Panax ginseng significantly imports anti-fatigue potential and also helps the reduction of depressive symptoms.
Japanese Knotweed (Polygonum Cuspidatum Extract (root) 98% resveratrol) is a rich source of antioxidant agents that also provide anti-inflammatory potential. It helps prevent oxidative stress and improves cellular integrity. In the case of inflammation, studies reported that grape seed extract suppresses the release and expression of pro-inflammatory cytokines (IL-6, IL-8, IL-1β and tumor necrosis factor-alpha, etc.) responsible for inflammation progression or development . Moreover, it modulates gut microbiota, improves gut immune response, and supports optimal gut microbiota. These gut health benefits may help the management of inflammatory conditions in the gastrointestinal tract. Additionally, grape seed extract supplementation increases the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-beta-1, helping suppress inflammations . Other anti-inflammatory mechanisms of grape seed extract involve the modulation of inflammatory enzymes such as inducible nitric oxide synthase and also reduction in the expression of other signaling components involved in inflammation progression [65, 67].
Vitamin B6, also known as pyridoxine, belongs to the vitamin B family and is important for metabolism, immune response, neurotransmission, and other physiological functions. Studies on vitamin B6 revealed significant anti-inflammatory and analgesic potential in the management of various chronic medical conditions. It effectively inhibits the pro-inflammatory cytokines (TNF-α, interleukins) and also suppresses the enzymatic activity of inflammatory enzymes such as COX-2 and iNOs responsible for inflammatory cascade [70, 71]. Additionally, past studies on Vit B6 found a positive association of Vit B6 deficiency with various inflammation signs. The potential role of Vit B6 in metabolic reactions, including the regulation of neurotransmitters like serotonin, GABA, and melatonin, helps improve pain, memory, and sleep . Research studies found significant positive results with the consumption of Vit B6 in the management of back pain, carpal tunnel syndrome, migraine headaches, and diabetic neuropathy . It acts on the thalamic-evoked nociceptive burst discharge and helps suppression of pain sensation. While some studies linked the analgesic potential of Vit B6 with its antioxidant and anti-inflammatory activities.
List of Abbreviations
- Ach – Acetylcholine
- BNDF – Brain-derived neurotrophic factor
- COX – Cyclooxygenase
- EAA – Excitatory amino acid e
- NOS – endothelial nitric oxide synthase
- FDA – Food and Drug Administration
- GABA – Gamma-amino-butyric acid
- GRAS – Generally Recognized as Safe
- IASP – International Association for the Study of Pain
- IL-1β – Interleukin-1 beta
- IL-6 – Interleukin-6
- iNOS – inducible nitric oxide synthase
- IDO1 – Tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 5-LOX – 5-lipoxygenase 5-LOX
- NF-κB – Nuclear factor kappa-light-chain-enhancer of activated B cells
- NMDA – N-methyl-D-aspartate
- NO – Nitric oxide
- NOS – Nitric oxide synthase
- nNOS – Neuronal nitric oxide synthase
- PGE2 – Prostaglandin E2
- ROS – Reactive oxygen species
- TNFα – Tumor necrosis factor alpha
FAQs for Physicians
Yes! As a matter of fact, we encourage for ProleevaMax to be an adjunct to a patient’s existing therapy. Over time, we recommend assessing and evaluating the continuing need of medications.
ProleevaMax can and may reduce the patient’s need for prescription medication. Numerous case studies have proven a patient can take the ingredients in ProleevaMax™ without negative effects to prescription medications.
However, we recommend all patients should always consult with a healthcare professional before taking ProleevaMax.
ProleevaMax was specifically formulated for patients suffering from chronic pain due to inflammatory conditions. We have specifically included amino acids and supplements to address the “root cause” of chronic inflammation.
The amino acids signal the body to:
- Inhibit pro-inflammatory proteins.
- Increase antioxidants, which destroy free radicals, hence inflammation.
- Decrease pain signals by the nervous system.
- Reduce oxidative stress and inflammation.
For the average person to find the correct concentrations and/or combinations of supplements to target chronic inflammation and pain is hard to do, extremely time-consuming, and costly.
Because of the high quality of our production process, the ingredients in our product will enter your system much faster than other supplements. Some patients have seen results in as little as a week.
Each person is different, and it may take longer for ProleevaMax to reach its full potential in your system. Although we have seen a great success rate, it does not work for everyone. For the best chance of success, we recommend staying on ProleevaMax for at least 2 to 3 months.
All ingredients in ProleevaMax are listed in the FDA Generally Recognized as Safe (GRAS) Food Substances document. Also, there have been numerous clinical trials using these supplements and there have been no reports of any negative side effects. In fact, in several clinical studies, far higher doses of these ingredients were used with no reported interactions or negative side effects.
Nutraceuticals are categorized by the FDA as “dietary supplements”. These are extracts, concentrates, or combinations of vitamins, minerals, botanicals, herbs, or dietary substances “for use by man to supplement the diet by increasing the total dietary intake.”
Producers of nutraceuticals are required to register their facility with the FDA, and are expected to comply with Current Good Manufacturing Practices – these outline FDA standards that manufacturers must abide by in order to be allowed to manufacture nutraceuticals and/or dietary supplements, such as facility standards, employee practices, and sanitation requirements. This is to ensure that the product is produced in a safe manner.
The FDA has also provided labeling standards for dietary supplements, and there are unique expectations for how dietary supplements are marketed and what claims they can make.
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