Understanding and Combatting Chronic Pain

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Summary and Quick Facts for Chronic Pain

  • Chronic pain can drastically reduce quality of life and is often resistant to medical therapies. Opioid medications are addictive and have the potential to ruin lives, if not used very judiciously. Excessive use of NSAIDs like ibuprofen increases risk of many health problems.
  • In this protocol, learn about the risks of long-term pharmaceutical pain management strategies. Also discover that several natural compounds have been shown to target some of the fundamental mechanisms of pain, to provide relief without debilitating side effects.
  • A supplement called palmitoylethanolamide (PEA) has been shown in several clinical trials to reduce pain due to a variety of causes. PEA modulates inflammatory signaling and interacts with the body’s endocannabinoid system but does not cause psychotropic effects.

What is Chronic Pain?

Chronic pain, unlike acute pain, can last for months or even years. Chronic pain can drastically reduce quality of life, and unfortunately it is not always easy to determine the factors contributing to the pain.

Conventional medical treatments are wrought with adverse side effects, such as opioid addiction. Even over-the-counter drugs have been linked to adverse effects—acetaminophen overdose is the leading cause of acute liver failure in the United States.

Pain can be broadly classified as nociceptive (resulting from activation of peripheral pain receptors) or neuropathic (resulting from injury or dysfunction in the nervous system). Nociceptive pain is intrinsically linked with inflammation, while neuropathic pain may be more difficult to treat.

Natural interventions such as honokiol and palmitoylethanolamide (PEA) may help relieve pain without the adverse effects common to pharmacologic pain therapy.

What are Conventional Medical Treatments for Chronic Pain?


  • Exercise
  • Behavioral therapy
  • Meditation
  • Biofeedback, and others


  • Non-opioid pain relievers (eg, acetaminophen and/or non-steroidal anti-inflammatory drugs [NSAIDs])
  • Opioids
  • Antidepressants (eg, tricyclics and serotonin-norepinephrine reuptake inhibitors [SNRIs])
  • Antiepileptic drugs (eg, gabapentin, pregabalin, and other anticonvulsants)
  • Muscle relaxants (eg, benzodiazepines)
  • Topical analgesic agents

What Dietary Changes Can Be Beneficial for Chronic Pain?

Several types of dietary interventions have been linked with pain relief:

  • Periods of fasting
  • Low glycemic index diet (ie, high protein, low carbohydrate)
  • Vegetarian/vegan diets
  • Diet rich in antioxidants (fruits and vegetables)

What Natural Interventions May Be Beneficial for Chronic Pain?

  • Honokiol. Honokiol, a polyphenol extracted from the bark of magnolia trees, has long been used to improve sleep and relieve anxiety. It may also help relieve inflammatory pain.
  • Palmitoylethanolamide (PEA). PEA, a lipid present in tissues around the body, may be effective for relieving pain from many causes without adverse effects. Many clinical trials have demonstrated its effectiveness.
  • Omega-3 fatty acids. Greater dietary intake of omega-3 polyunsaturated fatty acids has been linked to a reduction in both inflammatory and neuropathic pain.
  • Gamma linolenic acid (GLA). GLA, a plant-derived omega-6 fatty acid that helps modulate inflammation throughout the body, has been shown to relieve pain from a variety of conditions.
  • B vitamins. Vitamins B1 (thiamine), B6 (pyridoxine), and B12 are beneficial for many painful diseases. A mixture of these vitamins has also been shown to reduce neuropathic pain.
  • Vitamin C. Evidence suggests free radicals play a role in exaggerated pain hypersensitivity. Several animal and clinical studies indicate vitamin C may help relieve nociceptive pain.
  • Vitamin D. Vitamin D metabolites help inhibit inflammation. Deficiency is linked with several painful conditions. Administration of vitamin D was found to reduce pain for women with chronically painful periods and may help relieve pain from other causes as well.
  • Curcumin. Curcumin has been shown to have analgesic effects and may be useful for a variety of pathological pain conditions. It reduces levels of inflammatory mediators involved in nociceptive pain hypersensitivity.
  • Ginger. Ginger has analgesic and anti-inflammatory properties. Certain species can be helpful in reducing pain from muscle sprains, arthritis, menstruation, and others.
  • Melatonin. Aside from its well-known role as “the sleep hormone,” melatonin is also a potent antioxidant and has been shown to reduce the pain associated with a variety of chronically painful conditions (eg, fibromyalgia, irritable bowel syndrome, and migraine).
  • Additional natural compounds that may be helpful for managing chronic pain include vitamin E, proanthocyanidins (such as from grape seed), methylsulfonylmethane (MSM), and others.

2 Introduction


The sensation of pain arises in the nervous system. It has a variety of causes, but the experience of pain is variable and subjective.

Pain is both acute as well as chronic.

Acute pain is a protective mechanism that makes you aware of an injury (NIH MedlinePlus 2012; Cleveland Clinic 2008).

In contrast to acute pain, chronic pain is persistent and can last for months or years. Chronic pain can drastically reduce quality of life. We now know that 79% of chronic pain patients report disruptions in daily activities and 67% indicate that chronic pain negatively impacts their personal relationships (NIH MedlinePlus 2012; MedicineNet 2012; Vo 2008).

Chronic pain is often resistant to conventional medical treatments (MedicineNet 2012; Lumley 2011; Coluzzi 2011). Moreover, pharmacologic pain management of chronic pain is hindered by grave long-term side effects.

Opioids are wrought with adverse effects and have significant addiction potential, but poorly appreciated is that even over-the-counter pain medicines like acetaminophen and ibuprofen are linked with liver damage, kidney damage, and even heart attack (Woodcock 2009; Peterson 2010).

In this protocol, you will learn about the risks of long-term pharmaceutical pain management strategies. You will also discover that several natural compounds have been shown to target some of the fundamental mechanisms of pain to provide relief without debilitating side effects.

3 Understanding Pain

Acute pain follows a predictable, finite pattern and is generally short-lived, self-limiting, as well as easy to diagnose and treat. Pain that persists for longer than three months, and is not progressively better, is referred to as "chronic". It can be difficult to pinpoint the exact factors that cause chronic pain to persist over time (Lumley 2011).

Although there are many ways to organize different types of pain, one of the most popular and accepted schemes utilizes the following eight classifications to differentiate pain complaints (Smith 2005):

Classification of Pain Examples
Severity Mild, Moderate, or Severe
Duration Acute or Chronic
Location Lower back, Abdomen, or Head
Origin Nociceptive or Neuropathic
Body system Muscular, Neurologic, or Skeletal
Mechanism Central or Peripheral
Diagnosis Cancer or Non-cancer
Response to treatment Opioid-responsive or Opioid-resistant

There are 2 major categories of pain; nociceptive and neuropathic (NINDS 2012):

Nociceptive pain guards the body against potential injury. It occurs as a result of the activation of peripheral pain receptors called nociceptors, which are activated by injurious stimuli. The stimuli is converted into an electrical signal, which is conveyed along nerve cells into the spinal cord or brain, where it is perceived as an unpleasant sensation (Cohen 2011).

Neuropathic pain occurs as a consequence of either injury or dysfunction in the nervous system. It produces a variety of unusual pain sensations that have been described as burning, crushing and "pins & needles." Unlike nociceptive pain, neuropathic pain often persists for prolonged periods of time, even after the original trauma and/or dysfunction is addressed (Costigan 2009). Since neuropathic pain is more complex than nociceptive pain, it is consequently more difficult to treat (Vorobeychik 2011).

4 Nociceptive Pain and Inflammation

Inflammation and nociceptive pain go hand-in-hand.

Inflammation is initiated upon tissue injury and sets off a cascade of biochemical reactions that prime the nervous system for pain sensing. Moreover, long-term inflammation reinforces adaptive changes in the nervous system that can cause the sensation of pain to become exaggerated or inappropriate (Ji 2011). For example, inflamed tissue (e.g., an arthritic knee) may be excessively tender and even a light touch might cause pain, a phenomenon known as allodynia.

Nociceptive pain does not occur spontaneously, it must be triggered within the nervous system. This task is accomplished by specialized receptors called nociceptors.

When you experience an injury, several inflammatory mediators including prostaglandins, tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL-1β), and interleukin-6 (IL-6) are released at the site of the injury and interact with nociceptors, facilitating the transmission of pain signals through the nervous system. If you have a chronic inflammatory condition (e.g., osteoarthritis), then increased levels of inflammatory mediators at the affected site (e.g., a joint), as well as systemically, predispose you to increased pain sensations.

Therefore, taking steps to ease inflammation is an effective means of interfering with the process of pain sensitization. This is why drugs like acetaminophen (the active ingredient in Tylenol®) and ibuprofen, which are anti-inflammatory in nature, relieve pain. Unfortunately, though these drugs and others like them are very effective for reducing inflammation and pain, they often cause alarming side effects, which compromises their long-term risk vs. benefit profile (see The Potentially Lethal Side Effects of Over-the-Counter Pain Medications; below).

A variety of natural anti-inflammatory compounds are able to target inflammation by reducing the synthesis of inflammatory mediators, or modulating inflammatory pathways. As will be discussed later, many natural compounds exert powerful anti-inflammatory activity without causing unwanted side effects. See section titled "Targeted Nutritional Interventions".

5 Pain Management

The scientific approach to pain management demands a step-wise approach, which utilizes lower risk interventions first. In many cases, these lower-risk interventions are helpful for relieving chronic pain. For example, a recent review found that exercise and behavioral therapy were effective at decreasing pain and increasing functioning among patients with chronic pain (Hassett 2011). Other nonpharmacologic interventions that may be useful for chronic pain include meditation, biofeedback, acupuncture, electrical stimulation, and surgery (NIH MedlinePlus 2012). However, in those cases that do not respond to initial pain management treatment options with lower risk interventions, patients with chronic pain may have no other choice but to initiate pharmacologic therapy.

Pharmacologic therapy is one of the most popular treatment options for managing chronic pain. While initial treatment recommendations will vary based upon diagnosis (e.g., nociceptive vs. neuropathic), the most commonly used agents include (Bajwa 2012):

  • Non-opioid analgesics (acetaminophen and/or NSAIDs)
  • Opioids
  • Antidepressants (tricyclics and serotonin-norepinephrine reuptake inhibitors [SNRIs])
  • Antiepileptic drugs (gabapentin, pregabalin, and other anticonvulsants)
  • Muscle relaxants
  • Topical analgesic agents

The Potentially Lethal Side Effects of Over-the-Counter Pain Medications

In an effort to relieve suffering, many chronic pain patients turn to over-the-counter analgesics such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) (Hersh 2007). However, since these drugs do not require a prescription from a doctor, patients may incorrectly assume that they do not need to be as careful about dosing as they would with a prescription analgesic. Therefore, it is important for chronic pain patients to become educated about the most serious adverse side effects that can occur with popular non-prescription analgesics (Wilcox 2005).

Since it was first marketed in 1955, acetaminophen has become one of the most widely used analgesics in the United States. In 2008, approximately 25 billion doses of acetaminophen were sold in the US alone (FDA 2009). Although acetaminophen can be safe when used appropriately, it can also be extremely dangerous. For example, unintentional acetaminophen overdose is responsible for approximately 15,000 hospitalizations each year, and is the leading cause of acute liver failure in the US (Woodcock 2009). Patents taking acetaminophen should follow these recommendations (Saccomano 2008):

  • Do not exceed a maximum dose of 4 grams/day
  • Remember that many prescription pain medications also contain acetaminophen
  • Recognize that acetaminophen is also called APAP, paracetamol, and acetyl-para-aminophenol
  • Do not use with other NSAIDs (without medical consultation), which increases the risk of kidney toxicity
  • Do not take with alcohol, which increases the risk of liver toxicity

NSAIDs such as ibuprofen and naproxen can significantly reduce pain associated with a variety of conditions. However, NSAID use is also associated with significant adverse effects such as gastrointestinal bleeding, peptic ulcer disease, high blood pressure, edema (i.e., swelling), kidney disease, and heart attack (Peterson 2010). For example, long-term use of NSAIDs can lead to impaired glomerular filtration, renal tubular necrosis, and ultimately chronic renal failure by disrupting prostaglandin synthesis, which can impair renal perfusion (Weir 2002). Even in NSAID users without overt kidney dysfunction, subclinical irregularities in kidney function are sometimes observed (Ejaz 2004).

Aspirin (a type of NSAID) is commonly used to treat minor aches and pains, as well as being prescribed at low doses (i.e., 81 mg daily) for heart protection and stroke prevention. Aspirin irreversibly inhibits an enzyme called cyclooxygenase-1 (COX-1) in platelets, which is why it poses a greater risk of bleeding (i.e., hemorrhage) than other NSAIDs (Hersh 2007). Therefore, patients taking aspirin should avoid the simultaneous use of anticoagulant drugs and/or alcohol (without talking to their doctor first). In addition to bleeding, aspirin can also cause side effects such as heartburn, nausea, vomiting, stomach ache, ringing in the ears, hearing loss, and rash (NIH 2011). See Figure 1 for more information about the role of cyclooxygenase in inflammatory reactions.

Despite the wide variety of pharmacologic therapies available for patients with chronic pain, a recent report published by an international panel of experts has pointed out that current conventional treatment schemes are lacking in efficacy and often impose unacceptable side effects (Coluzzi 2011). For example, opioids are the most commonly prescribed class of medication in the United States for short-term relief of chronic pain, and yet, their efficacy and negative side effect profile have many experts questioning their use in this way; especially since the increase in opioid availability has been accompanied by an epidemic of opioid abuse and overdose (Von Korff 2011; Friedrich 2012). In addition to the potential for dependence, patients beginning opioid therapy should also be aware of other common side effects, which include (Friedrich 2012):

  • Constipation
  • Nausea
  • Excessive sleepiness
  • Itchiness (i.e., pruritus)
  • Headache
  • Respiratory depression

According to the World Health Organization’s (WHO) "analgesic ladder", opioids are not recommended for chronic pain unless the pain can be described as moderate to severe, and/or has not responded to previous (non-opioid) treatment approaches. Consensus xxpert guidelines only recommend opioid therapy for managing chronic (non-cancer) pain once all other reasonable lower risk and lower cost pain management interventions have failed (WHO 1990; Chou 2009).

In an effort to reduce the risk of serious adverse outcomes associated with narcotic pain relievers, Congress has recently mandated that the FDA create the Risk Evaluation and Mitigation Strategies (REMS), which requires drug companies to develop special educational programs for physicians and for patients who are prescribed these potentially dangerous medications (Okie 2010). While opioid therapy can be used for chronic (non-cancer) pain in a safe way, it must be initiated properly, and only in select patient populations (i.e., physicians should carefully screen for mental disorders and history of substance abuse) (Edlund 2007; Chou 2009).

Opioids & Endocrine Dysfunction

Evidence linking long-term opioid use to a decline in endocrine function and subsequent hormonal imbalance has been accumulating for some time now, but recent data have garnered renewed attention (Katz 2009).

The molecular structure of opioids makes them well equipped to interfere with the normal function of the endocrine system. Evidence suggests this influence occurs in the hypothalamus and pituitary gland (brain regions) and the gonads (reproductive organs). Opioids tend to decrease gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus, in turn decreasing the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland (Katz 2009).

This up-stream disruption has significant implications, especially concerning the ability of the endocrine system to produce additional hormones that rely on steady levels of GnRH, LH, and FSH. As a result of this hypothalamic-pituitary-gonadal axis suppression, the long-term use of opioids is associated with the development of hypogonadism (Katz 2009; Aloisi 2009). Opioids have also been known to reduce testosterone levels, which is associated with increased cholesterol levels and decreased insulin sensitivity (Woodall 2011).

Fortunately, most of these abnormalities can be identified through hormone level testing as well as patient history and physical examination. The following table summarizes some common endocrine-related problems associated with long-term opioid use (Woodall 2011; Vuong 2010; Merza 2010):

Common Endocrine-Related Problems Associated With Long-Term Opioid Use
Decreased body hair Infertility
Adrenal dysfunction Decreased libido
Decreased growth hormone Osteoporosis
Miscellaneous hormonal abnormalities Depression
Erectile dysfunction Missed menstrual periods

The three main therapeutic options available for patients experiencing these side effects are (Woodall 2011):

  1. Switch to a different type of opioid (i.e., opioid rotation);
  2. Switch to a non-opioid analgesic; or
  3. Initiate hormone replacement therapy (HRT). A recent study among male chronic pain patients concluded that long-term testosterone replacement therapy was associated with an increased quality of life and decreased pain ratings (Aloisi 2011).

Centrally-acting Drugs for Pain Relief

Chronic activation of peripheral pain sensors (nociceptors), such as occurs in osteoarthritis, for example, can alter central neural pain processing over time. The ongoing nature of chronic pain, and the adaptive nature of the central nervous system both contribute to biochemical alterations that increase pain sensitivity and cause the brain to become accustomed to processing pain. This phenomenon is known as central sensitization.

When the central nervous system has become "sensitized" to pain, painful sensations can be augmented because they are no longer only a nociceptive response, but are now being reinforced by mechanisms within the brain and spinal cord (Mease 2011).

Thus, chronic pain has a peripheral and a central element.

Evidence shows that patients with osteoarthritis of the knee are more sensitive to pain at other sites on their body than are healthy controls (Bradley 2004). This is because the brains of people afflicted with chronic pain have adapted to processing pain and have become hyper-responsive to painful stimuli.

The central element of chronic pain does not respond to traditional therapies such as anti-inflammatory drugs because they cannot modulate the transmission of pain within the sensitized central nervous system. Therefore, drugs such as antidepressants and antiepileptics can complement traditional anti-inflammatory drugs by modulating central biochemistry.

In the case of antidepressant drugs, it appears that the mechanism by which they provide pain relief is somewhat independent from their mood-altering affects (McCleane 2008), while antiepileptics alter pain signaling by modulating calcium signaling in the brain, which is also a mechanism by which they control seizures (Mease 2011).

For many people with chronic pain, centrally acting drugs are effective adjuvants to traditional pain therapies. Moreover, because central processing is a critical element of neuropathic pain, centrally-acting drugs are a mainstay of treatment in this setting (Yalcin 2009).

6 Nutrition and Pain


Recent evidence suggests that certain types of dietary interventions may have significant effects on chronic pain, especially severe forms of chronic pain (Tennant 2011). Also, chronic pain can result in a decreased protein intake and increased sugar and starch intake. These dietary changes result in wasting (i.e., catabolic state) (Tennant 2011).

Although the exact parameters of an "anti-pain" diet have not yet been recommended by any clinical organization (Tennant 2011), the scientific literature contains plenty of data indicating a strong link between food and pain. For example, periods of dietary fasting has been linked to the temporary relief of pain among many patients (Bell 2007). For longer term pain relief, some experts suggest a high protein, low carbohydrate diet (i.e., low glycemic index), which has been associated with decreases in pain sensitivity and inflammation (Ruskin 2009). Likewise, several studies have shown that a vegetarian/vegan diet is also beneficial to patients with chronically painful conditions (Bonakdar 2009).

Consuming a diet rich in antioxidants may also be helpful for the relief of chronic pain. This is because antioxidants neutralize free radicals and oxidative stress, which play a significant role in persistent pain conditions and have been linked to an increase in pain sensitivity (Tall 2004).

Some researchers believe that many of these dietary interventions activate the endogenous opioid system, which is the body’s natural defense against pain (Bell 2007). Moreover, documenting dietary history to ensure adequate protein intake can help chronic pain patients avoid muscle loss and weakness (Tennant 2011).

7 Nutrients


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 a major component of turmeric, a spice that gives Indian curry its distinct color and taste. In addition to its culinary use, curcumin has long been part of traditional medicine and appreciated for its anti-inflammatory properties (Razavi 2021). Specifically, curcumin has been shown to reduce levels of the inflammatory mediators TNF-α, IL-1β, and IL-6, which contribute to nociceptor hypersensitivity (Singh 2018). Since curcumin has been shown to have analgesic effects in numerous clinical trials, it may be useful for a variety of pain conditions. For example, systematic reviews of clinical trials have shown curcumin use may improve pain in osteoarthritis and rheumatoid arthritis (Bagherniya 2021; Shokri-Mashhadi 2021). Curcumin is also used in India for managing traumatic and postoperative pain and has been shown to reduce chronic neuropathic pain in animal models (Du 2021; Saffarpour 2021; Abdelrahman 2021).

One potential challenge with curcumin use is its limited oral bioavailability (Mahmood 2015). Upon ingestion, curcumin is rapidly metabolized into various related molecules, which may not provide the same benefits as free curcumin (Kurita 2013). Researchers have explored different ways to improve the bioavailability of curcumin, including combining with galactomannans (fiber) from fenugreek to form curcumagalactomannosides. In one double-blinded crossover study with 50 participants, the novel curcumin preparation had 45.5-fold higher bioavailability of free curcuminoids than unformulated curcumin (Kumar 2016).

  • Boswellia serrata ‒ Boswellia serrata is a plant native to India that has been used for centuries in Ayurvedic medicine. The plant’s resin contains numerous terpenes and four major pentacyclic triterpenic acids knowns as bowellic acids (eg, acetyl-11-keto-β-boswellic acid, or AKBA). These boswellic acids have anti-inflammatory activity, including inhibition of 5-LOX, IL-1β, and TNF-α (Siddiqui 2011). Boswellia extracts have been shown in systematic reviews of clinical trials to improve pain in osteoarthritis (Yu 2020; Cameron 2014). A small placebo-controlled crossover study demonstrated that a single dose of Boswellia serrata (250 mg) increased pain tolerance in healthy adults (Prabhavathi 2014). In a report of four patients with chronic cluster headaches, Boswellia extract was associated with reduced frequency and intensity of headaches (Lampl 2012).
  • Black Sesame ‒ Sesame is a flowering plant that is grown in tropical regions worldwide. Its seeds and oils are often used in food and may also possess antinociceptive and anti-inflammatory activity (Monteiro 2014). Sesame oil was shown to reverse the overexpression of IL-1β and TNF-α in an animal model of neuroinflammation (Mohamed 2021). In a trial of 50 patients with osteoarthritis of the knee, sesame supplementation significantly reduced pain intensity compared with placebo (Eftekhar Sabat 2013). And in study with 88 subjects with acute musculoskeletal pain, treatment with a proprietary mixture of curcumin, Boswellia, and black sesame oil extracts resulted in pain relief comparable to acetaminophen. Interestingly, while both groups experienced similar reduction in sensory pain, the herbal preparation was greater than eight times more effective than acetaminophen at relieving the emotional aspects of dealing with acute pain (Rudrappa 2020).
  • 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).