Nutrition and Neuropathic Pain
By Hal S. Blatman, MD

Thanks to:
Janssen Pharmaceutica Products, L. P.
For financial support of this presentation

Outline of Presentation:

Consequence of stimulation of pain-sensitive structures
Early sign of disease or tissue damage

Nociceptive Pain

• Result of physiological activity in the normal pain receptors
• No primary dysfunction of the nervous system
• May indicate a disorder in any other system or organ

   Is not always the result of ongoing tissue damage.

• Results from dysfunction of the central or peripheral nervous system
• Involves different kinds of pain
• Reflects different pathophysiological mechanisms
• Carpal Tunnel Syndrome
• Diabetic neuropathy
• Post-herpetic neuralgia
• HIV myelopathy
• Paraneoplastic
• Chemotherapy induced
• Trigeminal neuralgia
• Entrapment syndromes
• Radiculopathies
• Complex Regional Pain Syndromes (Types I & II); RSD, Causalgia
• Phantom limb pain
• Post radiation plexopathy
• Paresthesias – may result from abnormally increased function of the sensory nervous system
• May be spontaneous or stimulus-induced
• Spontaneous pain—discharge of peripheral C-nociceptors
• Excitation of small myelinated A-delta nociceptive cutaneous afferent fibers
• Ectopic impulses in the nociceptive pathways
• Unmyelinated C-fiber muscle afferents responsive to noxious mechanical and chemical stimuli
• Allodynia—pain induced by stimulus that is not normally painful
• Hyperalgesia—increased pain produced by a stimulus that normally causes pain
• Both occur in the same patient

Plastic Changes Of The Nervous System

All components of the nervous system react to alterations in their environment

• peripheral nerves
• spinal cord
• brain

Sensitization and expansion of receptive areas of neurons after nociceptive input to the spinal cord.

How Does Nutrition Impact Neuropathic Pain

• Nutrition has some impact on causation
  • Foods may contribute to nervous system damage
• Nutrition has some impact on healing
  • Foods may facilitate the healing process
• Nutrition has some impact on treatment
  • Foods and supplements may directly treat the nervous system injury

Foods and Medications That Contribute to Nervous System Damage Should Not Be Eaten

• Nutrasweet/Aspartame
• Olestra
• Margarine
• Aspartame
  • Aspartame causes elevation in serum methanol
    • Knopp et al., J Toxicol Environ Health, 1976;2:417-428
  • Aspartame causes increase in serum methanol in rats and humans
    • Stegink et al J Nutr. 1983:113:1600-1606
  • Aspartame completely metabolized in gut and absorbed as aspartate, phenylalanine, and methanol, but doesn’t cause heath problem
    • Leon et al. Arch Intern Med. 1989;149:2318-2324
  • Oral aspartame caused rise in serum methanol in men and rats
    • Cappellini Metabolism 1991;Jun;40(6):612-18
  • Dietary labeled aspartame results in labeled formaldehyde bound to tissue in rats
    • Trocho et al. Departament de Bioquimica, Universitat de Barcelona, Spain.
  • Repeated
    • by Hertelendy et al. Gastroenterol. 1993;88:737-743

ICMP Journal Spring 1997 (International Congress for Medical Professionals)

• Aspartame
  • 40% aspartic acid
  • 50% phenylalanine
  • 10% methanol -- converts to
    • Formaldehyde and formic acid (ant sting poison)
• Free methanol is created when heated above 86°F
  • Cumulative poison – slow rate of excretion
  • 7.8 mg/day (EPA)
  • Average diet drink 15-36mg/can
• Woodrow et al. Journal Appl Nutr 35(1):42-53

Methanol Is Neurotoxic

• CNS dysfunction
• Brain tumors
• Chronic widespread body pain in some patients

Olestra

• Big kooshball of cholesterol molecules
• Supposedly too large to be absorbed
• Unable to be broken down in the body
• Passes through the intestinal tube
• Looks like fat
• Tastes like fat
• Cooks like fat
• Absorbs fat soluble vitamins
  • A, E, D, K
• Vitamin E may be important in neuropathic pain
• Rejected by a Canadian Food Regulatory Agency
• P&G withdrew its application for approval in the UK
• CSPI says that P&G did not adequately support its claim that adding vitamins to olestra containing foods counteracts olestra’s tendency to inhibit absorption of some nutrients
• Vitamin A, E, D, K
• Danger is not a few potato chips
• Danger is
  • Breakfast with eggs cooked in olestra
  • Lunch with french fries cooked in olestra
  • Dinner with dessert made with olestra
• Body did not get much needed fat soluble vitamins this day

Margarine

• In the late 1800’s Napoleon ran out of butter, held a contest to find a replacement
• Scientist bubbled hydrogen gas through vegetable oil, creating margarine, won contest
• During WW II there was a shortage of butter in this country coffee, cigarettes, toast, butter, bullets
• Margarine became an industry, and we won the war
• Then it was discovered that
  • Insects won’t eat it
  • Mold won’t grow on it
  • It will not support life
  • It will not sustain life
• So it was put into food and fed to people!
• Bubble Hydrogen gas through vegetable oil
  • turn it into poison

Prepared Food – Shelf Life

• The reason it was put into food in 1940’s was to increase shelf life
• Essential fatty acids decrease shelf life
• Go rancid when exposed to heat, light, oxygen
• Hydrogenation improves shel f life
• Example: peanut butter can be kept unrefridgerated in the pantry, never growing mold
• And if food won’t grow mold, it won’t grow people

3 Primary Effects of Hydrogenated Oil

• Cholesterol levels rise
  • Prostaglandin balance changes
• Effects on gastric acid secretion, inflammation, blood vessel constriction
• Cell membrane composition

Partially Hydrogenated Vegetable Oil

Most serious danger is related to cell membrane composition

Cell Membrane Composition

• Two layers of fat – bi-lipid layer
• Specific ratio
  • Omega-6 essential fatty acids
  • Omega-3 essential fatty acids
• Triglycerides
• Phospholipids
• Protein

Job of Cell Membrane

• Nutrients in, waste out
• Active and passive transport
• Remain flexible and alive
• Neurons transmit information

Cell Membrane

In order to perform these functions optimally:

• Membrane composition is very important
• The fats we eat are the raw materials that make up cell membranes
• Every cell made or repaired that day

When We Eat Hydrogenated Oil Every Cell in The Body That Gets Made Or Repaired That Day Incorporates Plastic Into The Cell Membrane

Plastic Membranes

• Do not transmit nutrients
• Do not transmit waste
• Lose their flexibility
• Neuron transmission is not normal

With years of eating hydrogenated oil — Our body becomes like a Genuine GM Truck Fixed with Plastic Parts After Eliminating Hydrogenated Oil From the Diet. It takes 4 months to get it out of the Red Blood Cells. Let’s Look at:

Essential Fatty Acids
Naming Fatty Acids—Omega What?

• String of carbon atoms, carboxylic acid group on one end
• Linoleic acid
• 18:2w6
• Absolutely required for human health
• Cannot be synthesized by humans
• There are Two
  • Linoleic Acid (LA)
• 18:2w6
  • Alpha-linolenic acid (LNA)
• 18:3w3
• Can be considered vitamins
• Humans cannot form double bonds at omega 3 or omega 6 positions

Saturated fatty acid

• All carbons along the chain have two hydrogen atoms, the last carbon has three
• No double bonds
• Very rigid and hard
• Butter, coconut oil, beef fat

Mono-Unsaturated fatty acid

• MUFA
  • Single unsaturated bond
  • Most important is oleic acid
• High amounts in:
  • Olive oil, canola oil, peanut oil, sunflower oil, safflower oil, chicken fat
  • 18:1w9

Polyunsaturated fatty acid

• PUFA
  • Two or more double bonds
• Vegetable oils
• Nut oils (walnut, almonds)
• Fish oils
• Both essential fatty acids are PUFA

Four oils account for 96% of vegetable oils used in USA

• Soybean
• Cottonseed
• Corn
• Canola

Unfortunately, many of the polyunsaturated fatty acids in American diet have been partially or fully hydrogenated (saturated) to make margarine or vegetable shortening and increase shelf life.

When fats are used in deep frying, they are oxidized and altered beyond the ability of our enzymes to recognize them.

Membrane Fatty Acids Are Important

• Cell nutrition
• Inflammation
• Pain

How Are They Important in Inflammation

• Local redness
• Heat
• Pain
• Swelling

Regulated by Chemical Mediators

• Eicosanoids
• Kinins
• Complement proteins
• Histamine
• Monokines

Eicosanoids

• Short lived hormone-like substances
• Present in tissues throughout the body
• Function as mediators
  • Inflammation
  • Blood clotting
  • Vascular dilation
  • Immunity
• Produced from omega-6 and omega-3 polyunsaturated fatty acids present in cell membrane phospholipids
• Released from cell membranes by phospholipases

Eicosanoids — Regulate Inflammation

• Four classes
  • *Prostaglandins
  • *Leukotrienes
  • Thromboxanes
  • Prostacyclins
• *Pro-inflammatory
• *Anti-inflammatory

Eicosanoids From Omega-3

• Prostaglandins 3-series
• Leukotrienes of 5-series
• Weak inflammatory mediators
• Weaker than those produced from arachidonic acid

Arachidonic acid – from diet

• Meat
• Eggs
• Peanut oil

Linoleic Acid (Omega-6 EFA)

• Converted to arachidonic acid
  • Major FA released in response to tissue injury
• Direct precursor of pro-inflammatory mediators (PGE-2)
• And LTB4 (leukotrienes)

METABOLIC PATHWAYS OF ESSENTIAL FATTY ACIDS

Metabolic Pathways

• Can increase levels of DGLA (Dihomo-Gamma-Linolenic Acid) by ingesting oils rich in GLA (gamma linolenic acid)
  • Evening primrose oil
  • Borage oil
  • Black currant seed oil

Alpha-linolenic Acid (LNA – w3) – From Diet

• Green leafy vegetables
• Soybeans
• Spirulina
• Canola oil
• Flaxseed oil

Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA)

• Derivatives from LNA (alpha linolenic)
• Occur naturally in fish, esp. cold water

Final Conversion

Fatty Acids to Eicosanoids

• Cyclooxygenase
• Lipoxygenase
• Enzymatic pathways

METABOLIC PATHWAYS OF ESSENTIAL FATTY ACIDS

Anti-inflammatory Drugs

• Aspirin
• Ibuprofen
• Inhibit cyclooxygenase and PGE2

Balance Eicosanoids

• Type of prostaglandins or leukotrienes produced during inflammatory response is determined by composition of cell membrane lipids
• Directly influenced by type of fats in diet

Balance

• Problems arise when one type EFA predominates over the other
• Imbalance in eicosanoid production
• USA omega-6/omega-3 = 20-25:1
• Ideal 4:1

Omega 6:Omega 3

• Ratio 100 years ago is estimated to be between 3:1 and 5:1
• Agricultural practices have effect:
  • Free-range chicken egg -- w6:w3 = 1.3:1
  • Corn fed USDA chick egg -- = 19.4:1

Nutritional Balancing

• Displace arachidonic acid from membrane
• Compete with arachidonic acid and change balance of eicosanoid synthesis
  • Toward anti-inflammatory mediators
  • Away from pro-inflammatory mediators

Fish Oil Supplementation

• Significant improvement in joint tenderness and joint swelling in RA patients after 24 weeks
  • Kremer et al. Arth and Rheum 1990;33(6):810-20.
• Other studies support use of fish oil
  • Heart disease, hypertension, cancer, atopic dermatitis, diabetes (causes neuropathy)

Evening Primrose Oil Supplementation

• Rheumatoid arthritis
• Atopic eczema
• Kunkle et al. Prog Lipid Res 1982.

Omega-3 Fatty Acids

• Dose 4 gm daily EPA+DHA in divided doses
• Suggest 6 week trial
  • McCarren et al, abstr. Am J Clin Nutr 41;874a, 1985
  • Glueck et al, abstr. Am J Clin Nutr 43;710, 1986

Recommendations:
Dose of oils

• Omega 6 EFA – 6-9 g/day
• Omega 3 EFA – 4-6 g/day
• Therapeutic levels may be higher
• Almost no known toxicity

Lecithin

• Mostly composed of B-vitamin choline
  • Also linoleic acid, inositol
  • Phosphatidyl choline
• Comprise cell membrane
• Part of myelin sheath for
  • Neurons
• Important also for
  • Muscle cells
  • Disperse fats for processing and removal (reduce arteriosclerosis)
• Dosage – 3,600 + mg/day
• Deficiency – fatty deposition in organs, impaired brain/nerve/ muscle function
• Toxicity - none

Manipulation of Essential Fatty Acids
Changes can be noticed within a couple of weeks. Changes mature over several months.

Nutrition and Healing Neuropathic Pain
Provide nutrients necessary for healing

Alpha Lipoic Acid

• Synthesized by animals and humans
• Readily absorbed orally
• Converted easily to reduced form dihydrolipoic acid (DHLA)
• Potent antioxidant in fat- and water- soluble mediums
• ALA and DHLA (dihydrolipoic acid) are both antioxidants
• Both regenerate vitamins C and E
• Increase intracellular glutathione and coenzyme Q10
• Appears capable of chelating metals—mercury and cadmium
• Mercury shown to cause neuronal cell injury and death
• Several animal studies demonstrated effectiveness in prevention of reperfusion injury
  • Cardiac and brain
• May be helpful to reduce nerve cell injury
• Improves nerve conduction velocity in diabetic animals
• Used extensively in Germany to treat diabetic neuropathy
• Reduces lipid peroxidation
  • Believed to play role in development of diabetic neuropathy
• Prevents hyperglycemia-associated complications
• Dosage
  • 300-600 mg/day orally
• 100, 600, 1200 mg/day IV for 19 days showed significant decrease in pain, burning sensation, paresthesia, numbness in feet with 600 and 1200 mg/day
• Dosage
  • 800 mg/day orally for 4 months
• Effect on cardiovascular autonomic neuropathy
  • Modest improvements in heart rate variability
• Coleman et al Environ Toxicol Pharmacol 2001

Alpha Lipoic Acid
Safety, Toxicity, Side effects

• Oral LD50 in dogs 400-500 mg/kg
• Allergic skin reactions in humans at high doses

Diabetic Neuropathy

The results of the Diabetes Control and Complications trial have unequivocally shown that, for type I diabetics, tight glucose control dramatically delays the onset and slows the progression of diabetic polyneuropathy and that the overall benefits of intensive insulin therapy generally outweigh the risks. Similar results are emerging for type II diabetes, and it is generally now agreed that any improvement in glycemic control is beneficial.

Alpha Lipoic Acid

• Enhances insulin function
• Improves insulin sensitivity
• Able to protect nerves from free radical damage
• Coleman et al., Environ Toxicol Pharmacol 2001

Burning Mouth Syndrome

• Double blind controlled study
• Alpha lipoic acid for 2 months
• Significant symptomatic improvement
• Improvement maintained at 1 year in over 70%
• Famiano J Oral Pathol Med May, 2002

Diabetic Neuropathy
Lipid peroxidation of nerve membranes suggested as mechanism for ischemia/hypoxia causing neuropathy.

Diabetic Neuropathy

• Investigated nailfold video-capillaroscopy
• Showed ALA improves microcirculation
• Haak Jan 2000

Diabetic Neuropathy and Nitric Oxide (NO)

• Plasma nitrites/nitrates – two-fold below normal.
• Plasma content normalized with ALA treatment.
• Activation of NO protective system involved in therapeutic effect of ALA
• Strokov Oct, 2000

Nitric Oxide

• Alpha lipoic acid and vitamin C
  • Improve Nitric Oxide mediated vasodilation in diabetic patients
• Heitzer et al, Free Radic Biol Med 2001

Fatty Acid Metabolism

• Oxidative stress and fatty acid metabolism in diabetes
  • May lead to impaired nerve perfusion
  • Contribute to development of peripheral neuropathy
• Alpha lipoic acid and evening primrose oil
  • Improved NCV
  • Improved endoneurial blood flow in rats with streptozotocin-induced diabetes
• Ford et al, Metabolism 2001

Retrobulbar Optic Neuropathy

• Oral folic acid returned visual function to normal
• Hsu, Jan 2002

Carpal Tunnel Syndrome

• Direct correlation with deficiency in P-5-P
• 100-200 mg/day pyridoxine for 12 weeks reduces symptoms
• Patients who do not respond to B6 may have enzyme deficiency, unable to convert to P-5-P

Pyridoxal-5-Phosphate

• Cofactor in synthesis of neurotransmitters
  • Control depression, pain perception, anxiety

Pyridoxine

• Animal studies suggest B6 deficiencies impair conversion of alpha-linolenic acid to EPA and DHA
  • Pronounced reduction in production of DHA
  • May explain lack of effect of flax seed oil compared to fish oil in some studies

METABOLIC PATHWAYS OF ESSENTIAL FATTY ACIDS

Pyridoxal-5-Phosphate

• Safety, toxicity, side effects
  • None known
• Reports of peripheral neuropathy with very high dose B6
• B6 will reduce efficacy of levodopa in controlling parkinsonian symptoms
• Dose
  • RDA 2-4 mg/day
  • Therapeutic dose 50-200 mg/day
    • P-5-P or B6

B12, Folate, B6

• Double blind, placebo controlled trial
• Reduced homocysteine levels
• Decreased rate of restenosis after coronary angioplasty
• Arterial blood supply to neurons thought to be involved in etiology

Alzheimer’s Disease
Vitamin B12

• Cofactor in several metabolic pathways
• Deficiency
  • Reduced converion homocysteine to methionine
  • Elevated homocysteine levels
    • Associated with poor word recall in elderly
    • Increased risk of silent brain infarction
  • Central demyelination

Quality of Life Study:
Migraine Headache

• Disease is a deterioration of normal function:
  • Body is not getting what it needs
    • Faulty assimilation
  • Body is unable to remove wastes and toxins
    • Poor elimination

CAM Study (complimentary and alternative)

• Remove obstacles to cure by focusing on improving assimilation and elimination
• Allow body’s inherent abilities of repair and recovery

Treatment

• Improve nutrient assimilation
  • Enzymatically rendered fish protein with bioactive peptides and amino acids
  • Blend of probiotics
• 21 different ingredients to improve nutritional status of liver and kidneys
  • Minerals, vitamins, herbs, glandulars

Results with Migraine Headache

• 8/40 no improvement
• 24/40 almost total relief
• 8/40 various degrees of improvement
• Sensenig et al Alternative Medicine Review

Cisplatin Chemotherapy

• Protective effect of Vit E for peripheral sensory neuropathy
• Bove et al, J Exp Clin Cancer Res 2001

Vitamin Deficiencies May Contribute

• Vitamin E
  • Neurological abnormalities
• Pantothenic acid
  • Burning feet syndrome
• Magnesium
  • Mental derangement
  • Muscle weakness
  • Irritability
• Potassium
  • Muscle cramps
  • Weakness

Foods to Increase Nutrients

• Vitamin E
  • Vegetable oils, wheat germ, nuts, green leafy vegetables
• Pantothenic acid
  • Animal tissues, whole grain cereals, legumes
• Magnesium
  • Seeds, nuts, legumes, unmilled grains, chlorophyll of green vegetables
• Potassium
  • Nuts, whole grains, meats, fruits
• Vitamin B-6
  • Chicken, fish, liver, eggs, unmilled rice, oats, soy beans, walnuts
• Vitamin B-12
  • Animal products (produced by bacteria)

Olive Oil

• Antioxidant, able to scavenge free radicals
• Protection against peroxidation
  • Decreased LDL, increased HDL
• Improves control of hypertriglyceridemia associated with diabetes
• Modifies production of inflammatory cytokines
• Enhances gall bladder emptying
• Assists in gastric ulcer healing, promotes resistance to NSAID induced ulcerogenesis

Hyperglycaemia

• Retinopathy caused by:
  • Increase in free radicals
  • Increase in lipid peroxidation
  • Increase in glycosylation endproducts
  • Decreased antioxidants
• Kumar et al 2001

Diabetic Retinopathy

• Administer antioxidants to diabetic rats
  • Inhibit development of diabetic retinopathy
• Kowluru et al

Treatment Experience

• Nutrition has a profound effect on the treatment of RSD
• Nutrition has a profound effect on treatment of migraine headache
• Nutrition has a profound effect on treatment of myofascial pain

General Rules

• No aspartame in diet
• Try to avoid use of statin medications
• Seriously limit
  • Sugar (especially soda)
  • Hydrogenated oil
• Add nutrients
  • Essential fatty acids, especially omega 3
  • Magnesium
  • B vitamins
  • Alpha lipoic acid
• Go SLOW
• The sicker the patient, the slower to go
• These dietary changes induce detoxification
  • Rapid change may cause
    • Fever, increased pain, nausea, vomiting (ugly sick)
• Patients may go back to previous diet and will feel better
• Return to the practitioner and say they feel better eating ‘bad food’

Statin drugs and Neuropathy

• Long term exposure to statins may substantially increase the risk of polyneuropathy.
• Gaist et al. Neurology, May 2002