Pain Management

PAIN MANAGEMENT

Synopsis:
Background
Nutritional Approaches to Managing Pain
Suggested Supplementation
References

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 can be acute or 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.

Chronic pain is often resistant to conventional medical treatments (MedicineNet 2012; Lumley 2011; Coluzzi 2011). Moreover, pain management of chronic pain using medication may come with grave long-term side effects.  For example, common pain medicines like paracetamol 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 there are several natural compounds that can be used to target some mechanisms of pain to provide relief without debilitating side effects.

 

 

Acute pain is generally short-lived and 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 (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):

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).

Nociceptive Pain and Inflammation

Inflammation and nociceptive pain go hand-in-hand.

Inflammation is initiated upon tissue injury and sets off reactions that prime the nervous system for pain sensing. 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.

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 reduce inflammation is an effective means of interfering with the process of pain sensitization. Paracetamol, which is commonly used as a painkiller, does not reduce inflammation.  Another common painkiller, ibuprofen, is a nonsteroidal anti-inflammatory drug (NSAID) – it relieves pain and reduces inflammation. Unfortunately, such drugs and others like them are very effective for reducing inflammation and pain, they often cause alarming side effects.

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.

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 non-medicative interventions that may be useful for chronic pain include meditation, biofeedback, acupuncture, electrical stimulation, and surgery (NIH MedlinePlus 2012). However, in cases that do not respond to these interventions, patients may have no other choice but to resort to medication.

While initial treatment recommendations will vary based upon diagnosis (e.g., nociceptive vs. neuropathic), the most commonly used medications 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 Pain Medications

In an effort to relieve suffering, many chronic pain patients turn to analgesics such as paracetamol 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, paracetamol has become one of the most widely used analgesics. Although paracetamol can be safe when used appropriately, it can also be extremely dangerous. For example, unintentional paracetamol overdose is responsible for approximately 15,000 hospitalizations each year, and is the leading cause of acute liver failure in the US (Woodcock 2009). Patients taking paracetamol should follow these recommendations (Saccomano 2008):

• Do not exceed a maximum dose of 4 grams/day (equivalent to 8 x 500 mg tablets)
• Remember that many prescription pain medications also contain paracetamol
• Recognize that paracetamol is also called APAP, acetaminophen, 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).

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).

Despite the wide variety of medications for 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 can encourage dependence and have side effects, which include (Friedrich 2012):

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

 

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.

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.

Diet

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).

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).

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.

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).

Vitamins

• 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). 
  
  If vitamin D levels are low, vitamin D supplementation may result in significant improvements in pain (Selfridge 2010). 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).
   
• 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

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

• Curcumin (as highly absorbed BCM-95®): 400 – 800 mg daily
• B-Complex Vitamins (many of these should be included in high potency multi-vitamin supplements): 
  • Thiamine (B1): 75 – 125 mg daily
  • Riboflavin (B2): 50 mg daily
  • Niacin (B3): 50 – 190 mg daily
  • Folate (preferably as L-methylfolate): 400 – 1000 mcg daily
  • Vitamin B6 (preferably as pyridoxal-5-phosphate): 75 – 105 mg daily
  • Vitamin B12: 300 – 600 mcg daily
  • Biotin: 300 – 3000 mcg daily
  • Pantothenic acid: 100 – 600 mg daily
• Fish oil (with olive polyphenols): providing 1400 mg EPA and 1000 mg DHA daily
• Capsaicin gel (topical): Per label instructions
• Vitamin D: 5000 – 8000 IU daily; depending upon blood levels of 25-OH-vitamin D
• Ginger; standardized extract: 150 – 300 mg daily
• Milk thistle (standardized extract): 750 mg daily
• Melatonin: 0.3 – 5 mg before bed (sometimes up to 10 mg)
• Methylsulfonylmethane (MSM): 3000 – 6000 mg daily
• Boswellia serrata (as highly absorbable AprèsFlex™): 100 mg daily
• Gamma Linolenic Acid (GLA): 300 – 600 mg daily
• Vitamin C: 1000 – 2000 mg daily
• Proanthocyanidins (as Pycnogenol®): 50 – 100 mg daily
• Natural Vitamin E: 100 – 400 IU alpha-tocopherol and 200 mg gamma-tocopherol daily
• DL-Phenylalanine: 500 mg daily
• Saffron (standardized extract): 180 mg daily, in two divided doses with food
• L-tryptophan: 500 – 1500 mg daily

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