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Health Protocols

Pain (Chronic)

Targeted Nutritional Interventions


Honokiol is a polyphenolic compound from the bark of the magnolia tree (Magnolia grandifolia). Magnolia bark extracts have been used traditionally as sedatives to improve sleep and relieve anxiety, and honokiol is being investigated for its potential usefulness in treating inflammatory pain (Alexeev 2012; Woodbury 2013).

Like other polyphenols, honokiol has oxidative stress-reducing and anti-inflammatory activities. In addition, it appears to cross the blood-brain barrier and interact with certain neurotransmitter receptors in the brain (Woodbury 2013; Alexeev 2012). Laboratory research shows honokiol and some of its derivatives activate certain GABA receptors (Bernaskova 2015), and may also interact with receptors for glutamate, dopamine, and serotonin, and influence acetylcholine signaling (Alexeev 2012). One form of honokiol has even been shown to stimulate cannabinoid receptors that may be involved in decreasing pain perception (Gertsch 2012).

In one study, treatment with honokiol reduced pain-related behaviors in mice in experimental models of inflammation (Lin 2009). Findings from other animal studies indicate honokiol may decrease acute inflammatory pain without causing motor or cognitive side effects, and may prevent and decrease some of the chronic pain-related changes in the brain (Woodbury 2015; Lin 2007).


Palmitoylethanolamide (PEA) is a lipid compound that occurs naturally in tissues throughout the body, including the central nervous system. It can also be found in foods such as soy lecithin, egg yolk, and peanuts (Mattace Raso 2014; LoVerme 2005). A growing body of research suggests PEA supplementation may be effective for relieving pain from a variety of causes without triggering adverse side effects (Artukoglu 2017; Paladini 2016; Gabrielsson 2016). Most of the existing preclinical research indicates that PEA works by changing the expression of certain genes and reducing inflammatory signaling, but other possible mechanisms for its analgesic effect have also been proposed, including its ability to stimulate signaling through cannabinoid receptors in the nervous system (Gabrielsson 2016; Di Cesare Mannelli 2013; Skaper 2012; Khasabova 2012).

Several clinical trials have shown that PEA can reduce pain from a broad array of causes, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy, sciatic nerve compression, carpal tunnel syndrome, osteoarthritis, low back pain, failed back surgery, stroke-related nerve pain, multiple sclerosis, dental pain, chronic pelvic pain, post-herpetic neuralgia, and vaginal pain (Hesselink 2012). In an observational study of individuals with chronic pain due to a variety of conditions who were unable to control their pain with usual therapies, adding 600 mg PEA twice daily for three weeks followed by once daily for another four weeks decreased average pain intensity scores in all participants who completed the study (Gatti 2012).

In a randomized controlled trial, 636 participants with pain due to compression of the sciatic nerve received either 300 mg PEA daily, 600 mg PEA daily, or placebo in conjunction with their usual pain medications for three weeks. Both doses of PEA resulted in greater pain reduction than placebo, and the higher dose was more effective than the lower dose. In fact, those in the 600 mg group experienced more than a 50% reduction in pain scores (Keppel Hesselink 2015). In 118 patients with nerve pain, 30 days of standard treatment plus 600 mg PEA daily was more effective than standard treatment alone (Dominguez 2012). A randomized clinical trial found that 900 mg PEA daily for one week followed by 600 mg daily for one week was more effective than ibuprofen, at a dose of 600 mg three times daily for two weeks, for relieving temporomandibular joint (TMJ) pain (Marini 2012).

Micronized preparations of PEA have also been studied. Micronization results in smaller particles that may be absorbed more readily. Micronized PEA, at doses of 600–1,200 mg/day, reduced pain in subjects with diabetes- or trauma-related nerve pain, chronic pain after failed back surgery, and acute pain from tooth extraction (Cocito 2014; Paladini 2017; Bacci 2011). In a report of 100 cases of nerve pain related to spinal disorders, the inclusion of an ultra-micronized PEA supplement in pain management therapy showed promising results (Chirchiglia 2017). A meta-analysis found that women with chronic pelvic pain due to endometriosis appear to benefit from the combination of 800 mg micronized PEA daily plus 80 mg per day of polydatin, a natural free radical-reducing agent found in grapes and red wine (NIH 2017; Indraccolo 2017). In a randomized controlled trial, the combination of PEA and polydatin was more effective than placebo for reducing abdominal pain in irritable bowel syndrome patients (Cremon 2017).

Omega-3 Fatty Acids

Fatty acids are essential nutrients derived from dietary intake of fats. They are an important source of energy for the body, and serve a variety of other biologic functions.

Greater dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) has been linked to a reduction in both inflammatory and neuropathic pain, and has been shown to be beneficial for decreasing pain associated with rheumatoid arthritis, dysmenorrhea (pain during menstruation), inflammatory bowl disease, and neuropathy (Tokuyama 2011). Conversely, excessive levels of omega-6 PUFAs, such as arachidonic acid, are associated with inflammatory activities, an effect that can be offset by the simultaneous consumption of omega-3 PUFAs (Surette 2008).

Arachidonic Acid’s Destructive Cascade
Figure 1: Arachidonic Acid’s Destructive Cascade

In response to arachidonic acid overload, the body increases its production of enzymes like 5-lipoxygenase (5-LOX) to degrade arachidonic acid. Not only do 5-LOX products directly stimulate cancer cell propagation, but the breakdown products that 5-LOX produces from arachidonic acid (such as leukotriene B4, 5-HETE, and hydroxylated fatty acids) cause tissue destruction, chronic inflammation, and increased resistance of tumor cells to apoptosis (programmed cell destruction) (Poff 2004; Bachi 2009; Larré 2008; Sundaram 2006; Zhi 2003; Penglis 2000; Rubinsztajn 2003; Subbarao 2004; Laufer 2003; Julémont 2004).

It is important to understand that 5-LOX is not the only dangerous enzyme the body produces to break down arachidonic acid. As can be seen in Figure 1, both cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) also participate in the degradation of arachidonic acid.

COX-1 causes the production of thromboxane A2, which can promote abnormal arterial blood clotting (thrombosis), resulting in heart attack and stroke (Nakahata 2008). COX-2 is directly involved in cancer cell propagation, while its breakdown product (prostaglandin E2) promotes chronic inflammation (Suzuki 2011). Most health-conscious people already inhibit the COX-1 and COX-2 enzymes by taking low-dose aspirin, curcumin, green tea, and various flavonoids such as resveratrol.

A more integrative approach to this problem, however, would be to also reduce levels of arachidonic acid, which is the precursor of 5-HETE and leukotriene.

Experts believe that another mechanism responsible for the anti-inflammatory effect of omega-3 PUFAs has something to do with their metabolites (i.e., resolvins), which possess potent anti-inflammatory properties (Serhan 2005). Resolvins bind and activate receptors on immune cells and neuronal cells leading to alterations in pain transduction in the spinal cord and a dampened inflammatory response (Serhan 2002; Ji 2011). The positive effect of omega-3’s on neuropathic pain has been partially explained by their ability to block voltage-gated sodium channels (VGSCs), ultimately interfering with pain signaling (Ko 2010).

Because omega-3 PUFAs are associated with positive effects on cognition, mood, and behavior (Kidd 2007), they may also be beneficial to central pain processing (Manson 2010). Omega-3 supplementation can also help reduce anti-inflammatory analgesic consumption (Goldberg 2007), which might in turn reduce the associated risk of developing gastrointestinal side effects. Since omega-3’s do not interact with most analgesic drugs, some experts recommend their concomitant use (along with conventional analgesic therapies) for the management of both inflammatory and neuropathic pain (Shapiro 2003).

Gamma Linolenic Acid – the beneficial omega-6 fatty acid

Gamma linolenic acid (GLA) is a plant-derived omega-6 most abundant in seeds of an Eastern flower known as borage. Although a member of the omega-6 family, it is metabolized differently than other omega-6s.

GLA plays an important role in modulating inflammation throughout the body, especially when incorporated into the membranes of immune system cells (Johnson 1997; Ziboh 2004). Early in 2010, a team of Taiwanese researchers discovered that GLA regulates the inflammatory "master molecule" nuclear factor-kappaB or Nf-kB, preventing it from switching on genes for inflammatory cytokines in cell nuclei (Chang 2010).

A separate mechanism by which GLA and other beneficial fatty acids reduce inflammation is by activating the powerful peroxisome proliferator-activated receptor (PPAR) system (Hontecillas 2009). PPARs are intracellular receptors that modulate cell metabolism and responses to inflammation. The class of antidiabetic drugs called thiazolidinediones (such as Actos® or pioglitazone) acts by targeting PPARs—but unlike GLA, they can be deadly.

In studies, GLA has been shown to relieve pain that results from a variety of conditions, including neuropathy, breast pain, and rheumatoid arthritis (Horrobin 1993; Ranieri 2009; Hansen 1983) (Chaggar 2009).


  • B Vitamins – Vitamins B1 (thiamine), B6 (pyridoxine), and B12 (cyanocobalamin/ methylcobalamin) are not only beneficial for managing pain that may result from a vitamin B deficiency, but are also effective (alone or in combination) with other conventional medications for various painful diseases (e.g., degenerative spine disease, rheumatic diseases, low-back pain, and tonsillectomy pain) (Proctor 2001; Koike 2006; Ponce-Monter 2012).

    The administration of a mixture of vitamins B1, B6, and B12 has also been shown to reduce neuropathic pain in humans and animals (Caram-Salas 2006), and can therefore help treat peripheral neuropathies (Medina-Santillan 2004). Benfotiamine (a better absorbed derivative of vitamin B1) has also been suggested for reducing inflammatory and neuropathic pain in humans (Sanchez-Ramirez 2006).Evidence suggests that neuropathic pain plays a considerable role in many cases of chronic pain, and that B-vitamins primarily provide relief by targeting pathways associated with central neural pain processing (Mibielli 2009).

  • Vitamin C – Vitamin C (ascorbic acid), a versatile antioxidant, may act as another natural shield against pain. Accumulating evidence indicates that free radicals play a role in the exaggeration of pain hypersensitivity (Lu 2011). Vitamin C has been linked to a rapid and consistent anti-nociceptive (pain–relieving) effect in animal studies (Rosa 2005). A 2011 animal study revealed that the administration of the antioxidants Vitamin C and E inhibited pain related to peripheral injury. The authors concluded, "supplementation or treatment with both vitamins might be an option in patients suffering from specific pain states" (Lu 2011). Administration of vitamin C also reduces spontaneous pain associated with postherpetic neuralgia, which is a type of peripheral neuropathic pain (Chen 2009). Prophylactic vitamin C supplementation has also been linked to a 5-fold decrease in the incidence of complex regional pain syndrome among patients who recently underwent foot/ankle surgery (compared to no treatment) (Besse 2009).

  • Vitamin D – Vitamin D is a prohormone version of an important hormone called 1,25-dihydroxycholecalciferol or 1,25-dihydroxy vitamin D, also known as calcitriol (Dusso 2005). Vitamin D, once converted into calcitriol, inhibits inflammation by regulating some of the genes responsible for producing pro-inflammatory mediators (i.e., cytokines) (Manson 2010). In addition to being associated with pain due to bone softening (i.e., osteomalacia), vitamin D deficiency has also been linked to fibromyalgia, chronic widespread pain (CWP), and an unusual pain syndrome characterized by musculoskeletal and bone pain (Gloth 2004; Manson 2010). In addition, administration of vitamin D was found to significantly reduce pain for women with chronically painful periods in a randomized double-blind placebo controlled study (Lasco 2012).

    Life Extension recommends routine vitamin D deficiency testing for all individuals with pain complaints. If vitamin D levels are low, vitamin D supplementation may result in significant improvements in pain (Selfridge 2010). Life Extension suggests that blood levels of 25-hydroxyvitamin D should be kept between 50 and 80 ng/mL for optimal health.

  • Vitamin E – Vitamin E has been associated with a reduction in the severity of cyclic breast pain, a condition affecting as much as 69% of women (Pruthi 2010). It is also effective at relieving the pain associated with menstrual cramps (Ziaei 2005). In experimental models, supplementation with tocotrienols (a certain type of vitamin E) has been shown to improve neuropathic pain intensity associated with both diabetic and alcoholic neuropathy in animal models (Kuhad 2009; Tiwari 2009). The analgesic effects of vitamin E may be partially explained through its antioxidant properties, which involve blocking the production of reactive oxygen species (ROS) that are involved in neuropathic pain. Vitamin E’s analgesic effect may also be related to its ability to make the brain less sensitive to pain (Kim 2006).

Miscellaneous Natural Compounds

  • Curcumin – Curcumin is the major component of turmeric, a spice that gives Indian curry its distinct color and taste. In addition to its use as a food additive, curcumin has been widely used as an herbal medicine, due to its antioxidant and anti-inflammatory properties (Singh 2007). Specifically, curcumin has been shown to reduce levels of the inflammatory mediators TNF-α, IL-1β, and IL-6, which contribute to nociceptor hyper-sensitivity (Cho 2007; Kim 2007). Since curcumin has been shown to have analgesic effects, it may be useful for a variety of pathological pain conditions (Yeon 2010). For example, curcumin is used in India for managing traumatic and postoperative pain (Agarwal 2011) and has been linked to a reduction in neuropathic pain in experimental models (Zheng 2011).

  • Ginger - Ginger (Zingiber officinale) has analgesic and anti-inflammatory properties that soothe progressive muscle pain (Black 2010). Certain wild ginger species have anti-nociceptive characteristics, and have been used traditionally to treat toothaches, muscle sprains, and swollen cuts/sores (Khalid 2011). Researchers have also found that regular consumption of ginger is an effective pain reliever for arthritis patients, as well as muscle injury due to exercise (Black 2010). For the treatment of menstrual pain, ginger has been found to be as effective as conventional analgesics such as ibuprofen (Ozgoli 2009). Long term administration of ginger reduced TNF-α expression and augmented levels of the anti-inflammatory hormone corticosterone in rats, suggesting it relieves pain by suppressing inflammation (Ueda 2010).

  • Proanthocyanidins – Proanthocyanidins (tannins) belong to a group of chemical compounds called "flavonoids", which provide a variety of beneficial functions for humans (e.g., their well-known antioxidant and anti-inflammatory affect). Grape seed is an especially rich source of proanthocyanidins, which have been associated with symptom reduction in a variety of painful diseases (e.g., diabetic neuropathy and chronic pancreatitis) (Banerjee 2001, de la Iglesia 2010). Other sources of proanthocyanidins include berries, seeds, flowers, and leaves (de la Iglesia 2010). The mechanism(s) by which proanthocyanidins alleviate pain are not well understood, but some evidence indicates that central interaction with dopamine receptors may be involved (DalBo 2006).

  • Melatonin – Melatonin is a naturally occurring hormone that is synthesized by the pineal gland and regulated by the environmental light/dark cycle (Kaur 2011). Melatonin can reduce pain through its beneficial effect on sleep, as well as its analgesic properties. It is also a potent antioxidant, and has been shown to reduce the pain associated with a variety of chronically painful conditions (e.g., fibromyalgia, irritable bowel syndrome, and migraine) (Wilhelmsen 2011). A study in infants found that melatonin powerfully relieves pain by suppressing levels of the IL-6 and other inflammatory cytokines (Gitto 2012). Melatonin is such a remarkable compound that its chemical structure may be the basis of new analgesic drugs for the treatment of pain associated with cancer, headache, or even surgical procedures (Srinivasan 2010).

  • Methylsulfonylmethane - Methylsulfonylmethane (MSM) is an organic sulfur-containing compound (Debbi 2011) found in a variety of fruits, vegetables, grains, and meats. Among its many beneficial functions, MSM has been shown to display anti-inflammatory and antioxidant properties (AMR 2003). MSM has been successfully used to treat pain associated with osteoarthritis (OA) of the knee (Debbi 2011) and is not typically associated with any significant adverse side effects (Kim LS 2006). When combined with Boswellia seratta MSM significantly reduced the need for NSAIDs compared to placebo among subjects with knee osteoarthritis, suggesting the combination exerted considerable anti-inflammatory action (Notarnicola 2011).

  • Korean angelica - Decursinol is a medicinal compound found in the roots of the Korean flower called Angelica gigas Nakai (Korean angelica) (Song 2011). It has been widely utilized in traditional oriental medicine as a treatment regimen for pain associated with menstruation, arthritis, migraine, abdominal pain, and other miscellaneous injuries (Kim 2009). Researchers suggest that decursinol may act in the central nervous system to exert its analgesic effect, or interfere with nociception (Choi 2003). Scientists report laboratory evidence showing that an active constituent derived from Korean Angelica inhibits activation of nuclear factor-kappa B (Nf-kB), a DNA transcription factor that is involved in many inflammatory and disease states (Kim 2006). More recent studies indicated that co-administration of decursinol and acetaminophen resulted in synergistic effects, which enabled acetaminophen to be therapeutic at lower-than-normal doses. This acetaminophen-sparing effect implies that decursinol may inhibit the COX (cyclooxygenase) enzymes (Seo 2009).

  • Capsaicin - Capsaicin, the compound that gives chili peppers their spicy taste, also has medicinal value as an over-the-counter topical pain reliever. It is well tolerated, and comes in a variety of formulations such as creams, gels, lotions, patches, and sticks (Robb-Nicholson 2011). It has been shown to be an effective analgesic for low-back pain, as well as chronic pain originating in the muscles, tendons, and ligaments (Chrubasik 2010). Topical capsaicin has also been associated with a significant reduction in neuropathic pain (England 2011). Researchers believe its analgesic effect occurs as a result of its ability to reduce the amount of nerve fibers in the application area (upon long-term administration), as well as its capacity for interfering with nociception (i.e., defunctionalization). Both of these actions ultimately contribute to a local decrease in responsiveness to a wide range of sensory stimuli (Anand 2011; Jones 2011).

  • DL-Phenylalanine – While L-phenylalanine is a naturally occurring amino acid that is a precursor to dopamine and related neurotransmitters (Fernstrom 2007), D-phenylalanine appears to slow metabolic breakdown of endogenous opioids (Kitade 1990). DL-phenylalanine, which is a mixture of both stereoisomers, may therefore provide an analgesic and mood-boosting effect. Some limited studies suggest that supplementation with phenylalanine might provide pain relief (Kitade 1990; Donzelle 1981), but larger, well-designed studies have failed to corroborate these early observations (Mitchell 1987; Walsh 1986). Evidence is currently insufficient to draw firm conclusions as to the pain-relieving efficacy of DL-phenylalanine.

Boosting Serotonin Signaling

Saffron & L-Tryptophan – Antidepressant medications provide analgesia via various mechanisms, including by boosting levels of serotonin, which helps the brain control pain sensations (Dharmshaktu 2012). Therefore, since the amino L-tryptophan and bioactive compounds in saffron may modulate serotonergic activity within the brain, some innovative scientists have proposed them as potential central pain relievers (Amin 2012; Ceccherelli 1991).

Hepato-protective Nutrients

N-acetyl-cysteine & milk thistle extract – For those taking high-doses of acetaminophen for pain relief, supplementation with hepato-protective nutrients such as N-acetyl-cysteine and milk thistle extract may provide a means of reducing drug-induced liver damage (Abenavoli 2010; Bajt 2004).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.