Dietary-Induced Analgesia: Theory and Reality

Dietary-Induced Analgesia: Theory And Reality Yoram Shir, MD

Disclosure Information

Nothing to Disclose

Learning Objectives Review current basic and clinical knowledge pertaining to dietary-induced analgesia Describe mechanisms of dietary analgesia Cite the barriers limiting solid research in this field Describe future research possibilities in trying to develop novel dietary-based therapeutics

Epigenetics Of Chronic Pain Chronic pain could be Associated with: –Previous exposures to painful stimuli1 –Multiple socio-economic conditions2 –Childhood stress3 –Weather4 –Diet

Why Testing Diets in Pain Models?

The Partial Sciatic Nerve Litagation Model (PSL)

The PSL Model Chronic “CRPS Type II” like syndrome: –Tactile Allodynia –Mechanical & heat hyperalgesia –Spread to the contra-lateral limb –Sympathetically dependent

CRPS Type II Of The Leg

The PSL Model

The PSL Model – Tactile Allodynia

The PSL Model Could Not Be Replicated In A Different Lab

Environmental Suppression Of PSL Hypernociception Modification of 12 variables has not revealed the source of anti-nociception However, feeding rats with “Israeli” diet reversed the unexplained hyponociception5

Response Duration To Heat (sec)

Dietary Origin vs. Heat Hyperalgesia 20

Noxious Heat Stimuli

16 12 8

*P<0.0001

*

4 0

American Diet

Isreali Diet

Diet & Public Health  Beneficial in major disease: – Cancer6 – Cardiovascular disease7 – Depression8 – Diabetes9 – Kidney stones10 – Retinal disease11 – Rheumatic diseases12

Commercial Rat Show Composition Ingredient (%) Protein Fat Carbohydrates Fiber Ash Soy protein/Total protein

‘American’ diet (RMH1000)

‘Israeli’ diet (AMBAR)

16 6 67.5 4.5 8

21 3.5 67 3 5.5

>85%

<6%

Can We Trust Commercial Rodents’ Diets? Rat chows are standardized for the content but not the source of nutritional ingredients The traditional environmental control in rodents’ behavioral studies does not include diet Until diet is exactly specified, results from different labs should be compared cautiously

Response duration to heat (sec)

Diet vs. PSL-Induced Heat Nonciception 16

P=0.001

12 8 4 0

SOYP

520

510

RMH AMB

CAS

BC

Diet For Pain

?

Diet for a Pain-Free Life: A Revolutionary Plan to Lose Weight, Stop Pain, Sleep Better and Feel Great in 21 Days

How To Get Rid of Sciatica?13 Garlic milk –is prepared by adding the pulp of the crushed garlic in uncooked buffalo milk –the proportion is four cloves to 110 ml of milk

Nutmeg –should be coarsely powdered and fired in gingelly oil –this oil can be applied beneficially on the affected parts as a pain reliever

What Can We Learn From Our Patients?  AN: a 61 years old woman of Indian origin with PHN whose pain aggravates when eating curry SD: a 54 years old woman with painful bilateral breast cysts having problems with coffee NM: a 40 years old woman with post-traumatic neuropathic pain relieved by diet enriched with soy protein

The Analgesic Role Of Macronutrients Dietary fat: –A single high fat, low carbohydrate diet decreased acute pain14 –The analgesic role of n-3 PUFA is supported by sound principles in biochemistry, physiology and evidence-based medicine15

n-3 PUFA Decreases musculo-skeletal & inflammatory pain: –LBP16 –Rheumatoid arthritis17 –Fibrimyalgia/chronic fatigue syndrome15

Difference Score (sec)

Fat Source vs. Heat Nociception 30 20 10 0 corn

soy

sunflower canola

hemp

Mechanisms Of Fatty Analgesia Modification of CA neurotransmission18 Decrease inflammatory markers19 Modulation of TRPV1 receptors20 As reactive oxygen species scavengers21 Improved skeletal muscle glucose uptake and decreased insulin resistance22

Macronutrients Analgesia Carbohydrates: –Sweet analgesia in pups & adult rats23 –Reduce acute pain in human newborns undergoing painful stimuli24 –Could reduce inflammatory pain25

Mechanisms of Carbohydrates Analgesia Modulation of the endogenous opioid system26 Anti-inflammatory27,28 Dopaminergic activation of hedonic pleasure centres in the nucleus accumbens29

Macronutrients Analgesia Proteins and amino-acids: –Taurine-rich diets decreased nociception in a rat model of phantom pain30 –Soy protein decreased nociception in the PSL31 and bone cancer32 pain models and in humans with osteoarthritis33 –Lactoferrin decreased inflammatory pain in rodents & humans34

Other Examples Of ‘Ingestive’ Analgesia Vegetations Curcumin Alpha lipoic acid Vitamin C

A

D

B

E

H

C

F

I

G

J

Common Food & Analgesia Tart cherries: inflammatory pain35 Soy protein: arthritic pain33 Devil's Claw: muskuloskeletal pain36 Ginger: osteoarthritis & rheumatoid arthritis37 Turmeric: inflammatory bowel disease38

Common Food & Analgesia Boswellia: rheumatism and menstrual pain39 Sow Thistle: traditional remedy for generalized pain40 Feverfew: chronic migraines41 Pineapple (bromelain): knee osteoartheritis42 Evening primrose oil: rheumatoid arthritis43

Curcumin Proven anti-inflammatory properties44 –RA –OA –IBD

Curcumin (2g/day) equal to ibuprofen (800mg/day) for OA pain45

Alpha Lipoic Acid  Organosulfur compound essential for 4 mitochondrial enzyme complexes  Found in most foods, especially in internal organs, spinach & broccoli  Proven analgesic properties: – painful diabetic polyneuropathy46 – burning mouth syndrome47 – migraine48

Alpha-Lipoic Acid Vs. Gabapentin In Painful Diabetic Neuropathy49 443 DM patients receiving lipoic acid for 5 years Stopped therapy or switched to gabapentin Untreated group: 73% developed pain within 2 weeks Gabapentin group: –Side effects: 45% –Suboptimal analgesia: 55%

Vitamin C

Important in collagen synthesis & wound repair Powerful antioxidant Blunts stress response Modulates Inflammation Dose-dependent prevention of CRPS after wrist fructures50

Soy Protein & Fat Analgesia

Why Soy? Added in variable quantities to most commercial diets of rodents Contains ingredients with multiple biological beneficial effects

? =

Response duration to heat (sec)

Soy Protein-induced Heat Hypo-Nociceptive * p<0.0001

90 80 70

*

60 50

East West

40

North

30 20 10 0 1st Qtr

Commercial Soy-Deficient Diet

2nd Qtr

Commercial Soy-Rich Diet

3rd Qtr

4th Qtr

Artificial Soy-Based Diet

Response Duration To Heat (Sec)

Soy Protein-induced Heat Hypo-nociceptive * p<0.0001

Commercial Soy-Deficient Diet

Commercial Soy-Rich Diet

Artificial Soy-Based Diet

Response Duration To Heat (Sec)

Heat Hyper-nociception vs. Soy Protein-deficient Diets

* p<0.0001

Artificial Commercial Soy-Based Soy-Deficient Diet Diet

Artificial Soy-Free Diet

White Bread & Cucumbers

Soy Protein Hypo-nociception: Plausible Candidates Amino acids Phytoestrogens Fat Phytates Saponins Phenolic acids (e.g., salycilic, chlorogenic, caffeic & ferulic)

Soy Protein Hypo-Nociception Independent of site, testing methods, strain, food vendor, caloric intake & weight gain31 Mainly when supplemented preemptively but not after nerve injury51 Partially phytoestrogens-dependent52 Could be mediated through cytokine inhibition53 Analgesic synergism between soy protein & fat54

Soy Protein Preemptive Hypo-nociception51

The Combined Effect Of Dietary Fat & Protein54 Difference Score (sec)

30

P < 0.0001

15

0

SOY

soy

CASEIN

soy

CASEIN

corn

ALBUMIN

corn

SOY

corn

CASEIN

ALBUMIN

canola canola

SOY

ALBUMIN

canola soy

Diet vs. TNF -Îą expression in injured nerves *

Soy-rich diet in other neuropathic-like hypernociception models: the SPARC-NULL mouse

Accelerated Disc Degeneration With Age WT 6 months

SPARC -null 6 months SPARC -null 18 months

Degenerating Disc Herniated Disc

Soy Diet vs. Radicular-Like Pain

From The Lab To The Clinic: Soy For Chronic Pain In Humans?

Soy Effect?

Time Magazine, 2006

The Greens They Eat Are Probably Peas And Not Soy!

55 Will Soy Make My Son Gay

Questions asked about soy:  Does it boost brain power or dementia?  Does it shrink penises?  Should boys drink it or will it turn them gays?  Can soy affect menstruation?  Is it true tofu gives you Alzheimer’s?  I really want to use soy but how do you handle  The hair loss thing?

Finally: Soy is feminizing, and commonly leads to a decrease in the size of the penis, sexual confusion and homosexuality. Thatâ&#x20AC;&#x2122;s why most of the medical (not socio-spiritual) blame for todayâ&#x20AC;&#x2122;s rise in homosexuality must fall upon the rise in soy formula and other soy products*56

*James Rutz, chairman of Megashift Ministries and founder-chairman of Open Church Ministries

Pilot Study: Soy In Patients With Neuropathic Pain

20 neuropathic pain patients (median = 56 months)57 6 weeks of soy-rich diet 50% daily protein and fat converted to soy sources

Results: Well accepted by 18/20 patients Area of dynamic allodynia decreased from 213.4 ± 116 to 105 ± 57 cm2 (p<0.09) No significant change in pain

Clinical Study Can preoperative consumption of soy protein prevent chronic post-mastectomy pain?

 Up to 50% of women undergoing breast cancer surgery will develop post mastectomy pain  220 women scheduled for breast cancer surgery & axillary lymph node dissection  A double blind, prospective study comparing soy or milk protein supplemented for 2 weeks prior to surgery  Supported by the National Center for Complementary and Alternative Medicine (NIH)

Outcome  94 women screened  Only 5 recruited  We prematurely terminated the study in 12.2011

ď&#x201A;§Jennifer A. Haythornthwaite: The effects of soy protein on post-thoracotomy pain (Johns Hopkins University) ď&#x201A;§Study terminated before recruitment started

58 Dietary Soy in Fibromyalgia

ď&#x201A;§A randomized, double-blind, placebo-controlled trial ď&#x201A;§20g of soy protein supplementation for 6 weeks were not effective in decreasing pain and other fibromyalgia symptoms

Soy In Trigeminal Neuralgia: The Australian Angle ď&#x201A;§Initiated by the Trigeminal Neuralgia Association of Australia ď&#x201A;§The society recommended members to start consuming soy-rich products

Gender: Male Age: 81 Pain History: since 2000 Diagnosed: by Neurologist as trigeminal neuralgia.

Trigger: touch This was how I was feeling before soy: Location of Pain

Pain Sensation

Pain Level

RH Near Nose

Burning, and Electrical shock strikes

10

Number of Strikes per day

0 = no pain 10 = worst pain

Varies.

Medication/s

Dose

Response

Tegretol (CBZ)

400mg X twice a day

â&#x20AC;&#x153; I do have days when there is no pain at all.â&#x20AC;?

Start of Soy in Diet: June 23rd, 2008 Date

Soy Products

Mg/ml

Times per day X week

Pain Level

Meds

23 Jun

Sanitarium Soy Milk

150 ml

1 X day X wk

10*

30Jun

Sanitarium Soy Milk

150ml

1 X day X wk

0

800mg CBZ

7 Jul

Sanitarium Soy Milk

150 ml

1 X day X wk

0*

800mg CBZ

15 Jul

Vita Soy Milk

150 ml

1 X day X wk

0*

800mg CBZ

21 Jul

Sanitarium Soy Milk

150 ml

1X day X wk

0*

800mg CBZ

28 Jul

Sanitarium Soy Milk

150 ml

1 X day X wk

8*

800mg CBZ

3 Aug

Sanitarium Soy Milk

150 ml

1 X day X wk

0*

800mg CBZ

8 Aug

Sanitarium Soy Milk

150 ml

1 X day X wk

0*

800mg CBZ

25 Aug

Vita Soy Milk *

150 ml

1 X day X wk

0*

800mg CBZ

1 Sep

Vita Soy Milk

150 ml

1 X day X wk

0*

400mg CBZ

8 Sep

Vita Soy Milk

150 ml

1 X day X wk

0*

400 mg CBZ

15 Sep

Vita Soy Milk

150 ml

1X day X wk

0*

800mg CBZ

21 Sep

Vita Soy Milk

150 ml

1 X day X wk

0*

800mg CBZ

28 Sep

I am expecting his report sometime this week.

Date

Comments

30Jun

There are times when I cannot touch my nose without getting an electrical shock. If I blow my nose during these times, I get an instant strike and a burning pain that last for approx.

15 – 20 mins

7 Jul

My present condition is typical of my complaint. In the past I have had 7 – 10 days PAIN FREE and then the pain returns and could last up to 7 days

15 Jul

No burning pain only electrical strikes. “so far apart from one or two sharp strikes – no consistent pain at all”

21 Jul

Painless except for occasional strike. Feel really good

28 Jul

Since last report I have had at least 3 strikes per day followed by burning sensation lasting up to a minute. (note: previously lasted to 20 mins)

3 Aug

Strikes per day - varies from 2 – 3 and some days much more. Burning pain can reach up to 10

8 Aug

This week apart from a few very weak strikes, I have been pain free

25 Aug

I am now into my THIRD painless week. I feel great at the moment. The only time I get a faint strike is when I clean my teeth. I have M.Hudson to stick to the same soy milk as of now ie Vita Soy milk

1 Sep

Still no pain. I am feeling great. AS of today I am reducing my Tegretol from 800mg to 400mg per day

8 Sep

Occasional twinges but NO continuous pain. Still feeling good

15 Sep

I am still pain free except for the odd twinge which doesn’t produce any prolonged pain. I have been alternating my Tegretol between 800 and 400mg – depending on the number of strikes.

I still feel great

21 Sep

Occasional strike but no lingering pain I have written to M.Hudson asking that he holds his medication at the same level as when he started soy rich diet ie 800mg

Research Plan: Soy In Chronic Neuropathic Facial Pain 30 patients with facial neuropathic pain N of 1, double blind cross over study 3 therapeutic phases, each comprising of two 3 weeks periods Soy vs. milk protein, 30-60g/day

Dietary Analgesia Research - Barriers The dominance of Western medicine Disrespect to CAM More difficult to practice: modest variety of common analgesics vs. numerous dietary ingredients Not appealing enough for research investments More complicated and difficult

Summary There is an unhealthy dichotomy between public’s beliefs in CAM and the traditional medical and scientific communities  There is enough clinical & scientific evidence to support a more rigorous exploration of the field  Research in the field does not have to start in the lab – trust your clinical judgment and listen to your patients

Thank You Please eat healthy

References                    

1. Fitzgerald M. Nat Rev Neurosci. July 2005;6:507-20 2. Bergman-S, et al. J Rheumatol. June 2001;28:1369-77 3. Von Korff M, et al. Pain. May 2009;143:76-83 4. McAlindon T, et al. Am J Med. May 2007;120:429-34 5. Shir Y, et al. Neurosci Lett. January 1998;240:73-6 6. Yeb CC, et al. World J Gastroenterol. March 2005;11:1473-80 7. Parikh P, et al. J Am Coll Cardiol. May 2005;45:1379-87 8. Logan AC. Altern Med Rev. November 2003;8:410-25 9. Eriksson KF & Lindgärde F. Diabetologia. September 1998;41:1010-6 10. Siener R, et al. J Urol. May 2005;173:1601-5 11. Schmidt-Erfurth U. Dev Ophthalmol. 2005;38:120-47 12. Geusens P, et al. Arthritis Rheum. June 1994;37:824-9 13. http://www.online-vitamins-guide.com/dietary-cure/sciatica.htm 14. Zmarzty SA, et al. Physiol Behav. July 1997;62:185-91 15. Puri BK. Prostaglandins Leukot Essent Fatty Acids. April 2004;70:399-401 16. Maroon JC & Bost JW. Surg Neurol. April 2006;65:326-31 17. Cleland LG, et al. J Rheumatol. October 1988 18. Chalon S. Prostaglandins Leukot Essent Fatty Acids. October 2006;75:259-69 19. Martin YB, et al. Mol Pain. February 2009;5:8 20. Matta JA, et al. J Physiol. January 2007;578:397-411

References (cont’d)                     

21. Shay KP, et al. Biochim Biophys Acta. October 2009;1790:1149-60 22. Jacob S, et al. Diabetes. August 1996;45:1024-9 23. Ren K, et al. Proc Natl Acad Sci USA. February 1997;94:1471-5 24. Gradin M &Schollin J. Pediatrics. April 2005;115:1004-7 25. Ajani UA, et al. J Nutr. May 2004;134:1181-5 26. Kanarek R, et al. Brain Res. November 2001;920:97-105 27. Nilsson AC, et al. J Nutr. April 2008;138:732-9 28. King DE, et al Am J Cardiol. December 2003;92:1335-9 29. Hajnal A, et al. Am J Physiol Regul Integr Comp Physiol. January 2004;2861:R31-7 30. Belfer I, et al. Neuroreport. September 1998;19:3103-7 31. Shir Y, et al. Anesth Analg. April 2001;92:102-34 32. Zhao C, et al. J Pain. March 2004;5:104-10 33. Arjmandi BH, et al. Phytomedicine. November 2004;11:567-75 34. Togawa J, et al. J Gastroenterol Hepatol. December 2002;17:1291-8 35. Wang H, et al. J Nat Prod. February 1999;62:294-6 36. Grant L, et al. Phytother Res. March 2007;21:199-209 37. Srivastava KC, et al. Med Hypotheses. December 1992;39:342-8 38. Hanai H, et al. Clin Gastroenterol Hepatol. December 2006;4:1502-6 39. Vishal AA, et al. Int J Med Sci. 2011;8:615-22 40. Vilela FC, et al. J Ethnopharmacol. February 2010;127:737-41 41. Cady RK et al. Headache. July-August 2011;51:1078-86

References (cont’d)                 

42. Brien S, et al. QJM. December 2006;99:841-50 43. Belch JJ, et al. Am J Clin Nutr. January 2000;71(suppl 1):352S-6S 44. Belcaro G, et al. Altern Med Rev. December 2010;15:337-44 45. Kuptniratsaikul V, et al. J Altern Complement Med. August 2009;15:891-7 46. McIlduff CE & Rutkove SB. Ther Clin Risk Manag. September 2011;7:377-85 47. Femiano F, et al. Int J Oral Maxillofac Surg. December 2002;31:625-8 48. Magis D, et al. Headache. January 2007;47:52-7 49. Ruessmann HJ, et al. J Diabetes Complications. May-June 2009;23:174-7 50. Zollinger PE, et al. J Bone Joint Surg Am. July 2007;89:1424-31 51. Shir Y, et al. Anesthesiology. November 2001;95:1238-44 52. Shir Y, et al. Anesth analg. February 2002;94:421-6 53. Soleimannejd E, et al. Pain Res Manag. 2008;147:13 54. Perez J, et al. Pain. October 2004;111:297-305 55. Julia McKinnell, Thursday, December 4, 2008, Macleans.ca 56. http://www.wnd.com/2006/12/39253/ 57. Shir Y & Perez J. Pain Res Manag. May 2005;10:31 58. Wahner-Roedler Dl, et al. Evid Based Complement Alternat Med. June 2011;23:350697