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LDN Rx at SIG: 2005-2016, N>1400

LDN for Autoimmune and Inflammatory Diseases Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University School of Medicine President, Specialists in Gastroenterology. LDN Rx at SIG: 2005-2016, N>1400. Alopecia areata Chronic fatigue synd. Chronic pelvic pain

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LDN Rx at SIG: 2005-2016, N>1400

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  1. LDN for Autoimmune and Inflammatory DiseasesLeonard Weinstock, MDAssociate Professor of Clinical MedicineWashington University School of MedicinePresident, Specialists in Gastroenterology

  2. LDN Rx at SIG: 2005-2016, N>1400 • Alopecia areata • Chronic fatigue synd. • Chronic pelvic pain • Complex regional pain ^ • Constipation * • Dercum’s disease • Eczema • Fibromyalgia * • Ganglionopathy ^ • HIV * • Inflammatory bowel dis. *^ • Irritable bowel syndrome * • Multiple sclerosis *^ • Restless legs syndrome * • Rheumatoid arthritis • Sarcoidosis ^ • SIBO * * Published; ^ To be discussed

  3. Outline • History of LDN • Mechanisms of action of LDN • Autoimmune and inflammatory diseases • Crohn’s disease • Ulcerative colitis • Sarcoidosis • Autonomic ganglionopathy • Complex regional pain syndrome • Multiple sclerosis

  4. LDN Hx: Modulator of Opioid & Receptor Activity (MORA) • Zagon et al. Science 1983;221:671-3. 1979-81: MOA studied (Zagon – Penn State) 1985: Rx for AIDS (Bihari) Mid 90’s: Rx for MS (Bihari) LDN = low dose naltrexone (1.0- 4.5 mg/d) vs. 50mg–100mg daily for opiate and alcohol dependence (FDA IND 1985) vs. ultra low dose 0.001 mg in Oxytrex

  5. Endogenous opioids& receptors • Peptides: B-endorphin, enkephalins, endomorphin, dynorphin • Receptors • CNS and PNS • GI tract • Myenteric plexus • Mucosal plexus • Endocrine cells of intestinal mucosa • Lymphocytes

  6. Endorphins • Endorphins produced in most cells • Regulate cell growth including immune cells • Disorders of the immune system can occur with unusually low levels of these endorphins • Met-Enkephalin is the most influential endorphin

  7. Opioid Growth Factor (OGF) Met-Enkephalin = Opioid Growth Factor OGF binds to the Opioid Growth Factor Receptor (OGFr) Two elements are required for health: opioid production and cell interaction

  8. Methionine enkephalin: role in immunoregulation MENK binds to opioid receptors on immune and cancer cells. Binding site: CD4+Foxp3+ regulatory T cells (Tregs) which suppressing immune system to keep balanced immunity Tregs reveal a relationship between the endocrine and immune systems Zhao. IntImmunopharmacol 2016;37:59-64. Li. Cancer BiolTher2015;16:450-9.

  9. MENK & immunology & cancer MENK delayed development of tumor in S180 tumor bearing mice and down-regulated level of Tregs Cancer study – 50 pts – isolated lymphocyte subpopulation evaluations in peripheral blood before and after culture with MENK MENK inhibited CD4+T cells, CD8+T cells, CD4+CD25+ Tregs and natural killer cells Wang. Hum VaccinImmunother2014;10:1836-40.

  10. LDN MOA LDN blocks the OGF receptors only for a few hours – leads to a rebound effect; in which both the production and utilization of OGF is greatly increased. Endorphins now interact with the more-sensitive and more-plentiful receptors and assist in regulating cell growth and immunity

  11. LDN MOA Reduces/regulated T-cells, Natural Killer cells, IL-2 and TH-1 improve native immune system Shift from TH1 to TH2 decreases general inflammation

  12. Additional MOA – Toll receptors Li. Med Hypotheses 2012;79:754-6. Hutchinson et al. Brain Behav Immun 2010;24:83-95. • Endothelial receptors – possible MOA for IBD • GI receptor allows for increase in bacterial translocation – exacerbated by exogenous opioids • LDN may stabilize receptor and decrease bacterial translocation • Glial receptor • Activated microglia cause neuroexitability and enhanced pain via toll-like receptor 4 pathway • LDN antagonizes pathway

  13. LDN & inflammatory bowel diseases First reported in Crohn’s disease Subsequently reported in ulcerative colitis Both related to autoimmune, inflammatory, and microbiome disturbances with active cytokines

  14. Case 1 • 40 y.o. WF with Crohn’s disease – s/p total colectomy, recurrence in ileum 4 yrs later • Failing infliximab: diarrhea and fatigue

  15. Case 1 • Addition of LDN 4.5 mg • Endoscopic and sx’ic remission within 2 mo

  16. Crohn’s disease – 3 open label studies • Smith. LDN therapy improves active Crohn's disease. Am J Gastroenterol 2007;102:820-828. • Shannon. LDN for treatment of duodenal Crohn’s disease in a pediatric patient. Inflamm Bowel Dis 2010;16:1457.

  17. Crohn’s disease - LW • Open label study: 4.5 mg LDN in moderate • to severe CD (N=33 adults) • Failing 5-ASA followed by 6-MP and/or IFX • LDN Rx: 40 ±43 wks (max 200 wks) • 5 withdrew - AE (mild-mod) • Positive clinical response in 15/33 pts • 11 of 15 responders: C-scope before and after Rx: 8 complete healing, 1 partial healing and 2 unchanged • Weinstock. J Clin Gastro 2014

  18. Crohn’s disease – RCT #1 • LDN as adjunctive therapy in adults • Biologic therapy was an exclusion • 88% of LDN (N=18) had 70-point decrease in CDAI scores vs. 40% of control (N=16) • After 12 wks, 78% of LDN had response in CD endoscopy index severity score vs. 28% controls • 33% of LDN had endoscopic remission vs. 8% controls Smith et al. Dig Dis Sci 2011;56:2088-97.

  19. Crohn’s disease – RCT #2 • LDN as sole therapy in 14 children • LDN (0.1 mg/kg) vs. placebo for 8 wks • CDAI: 34±3 decreased to 22±4 (P=0.005) • 25% went into remission • No serious AE Smith et al. J ClinGastroenterol 2013;47:339-345.

  20. Fibromyalgia: RTC study • LDN 4.5 mg/day vs. placebo • N=31 women • Randomized, double-blind, placebo-controlled, counterbalanced, x-over study. • Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue Younger et al. Arthritis Rheum 2013 Feb;65:529-38.

  21. Fibromyalgia: RTC study • LDN 4.5 mg/day vs. placebo • N=31 women • Randomized, double-blind, placebo-controlled, counterbalanced, x-over study. • Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue Younger et al. Arthritis Rheum 2013 Feb;65:529-38.

  22. Fibromyalgia: RTC study (cont.) • 28.8% pain reduction with LDN vs. 18.0% reduction with placebo (P = 0.016) • LDN improved general satisfaction with life (P = 0.045) and improved mood (P = 0.039) • 32% had a significant reduction in pain plus a significant reduction in either fatigue or sleep problems vs. 11% response rate with placebo (P = 0.05) • LDN equally tolerable as placebo. No serious side effects were reported Younger et al. Arthritis Rheum 2013 Feb;65:529-38.

  23. Sarcoidosis • Granulomatous disorder with T-cells • & macrophages in multiple organs • CD3+ cells, CD4+ cells w/ HLA-DR antigen, & high CD4/CD8 ratio in bronchus • CD4+ CD29+ memory T-cells increased Iida K et al. Thorax 1997;52:431-7.

  24. Sarcoidosis • Special T-cell interactions in pulmonary and liver sarcoidosis • Activated memory T-cells with CD11a Iida K et al. Thorax 1997;52:431-7.

  25. Sarcoidosis: Pathogenesis • Genetic susceptibility with functional polymorphisms • Exposure to antigens leading to activation of macrophages • Attainment of T-cell immunity against antigens mediated by antigen processing and presentation by macrophage Zissel

  26. Sarcoidosis vs. Crohn’s disease • Similar pathology • Unregulated T-cell activity • Non-caseating granulomas

  27. Sarcoidosis Rx: Role for LDN • Regulate T-cell growth – (Treg) • Regulate B-cell growth • Decrease inflammation • Decrease permeability • Stabilize Toll-like receptors • Decrease microglia activation • Decrease cytokine release • Shift from TH2 to TH1 • Improve GI motility

  28. Sarcoid Case 1 Rash Fatigue Adenopathy Liver/Spleen

  29. Case 1 • AH 73 y.o. AAF – supraglotic resection in 2001 d/t sarcoidosis. Sx weak voice, painful rash, fatigue, and parotitis • Rash prevention • by minocycline • Hx MTX neuropathy • Referred abnl CT • LDN – prescribed

  30. Progress 2015 February - LDN 1 mg/day March - less dyspnea, fatigue, able to stop minocycline w/o rash March – LDN increased 12 days to 4.5 mg May – Dec - less DOE, more energy July & Dec – CT’s showed reduction in the size of the splenic lesions and liver lesions

  31. 12/2014 11/2011 Before LDN

  32. 12/12 - 10 mo LDN 7/15 - 5 mo LDN

  33. 12/15 – 10 mo LDN 12/14

  34. Sarcoid Case 2 Pulmonary Fatigue

  35. Case 2: PFB 64 y.o. AAF • 26 yr pulmonary sarcoidosis • 2 yr home O2 (24 hr/d; 2 L) • Dyspnea (rest/activity) and dry cough • 7/15 - Prednisone 20 mg • Last used 16 yr ago • 8/15 - LDN

  36. Case 2: PFB 64 y.o. AAF • 9/15 – 1 mo LDN • No change • 10/15 - 2 mo LDN • Less fatigue • Less dyspnea • O2prn for vigorous activity • Prednisone taper started

  37. Sarcoid Case 3 Pulmonary

  38. Case 3: PLB 63 y.o. WM • Abnl CXR 17 yr ago – Bx: granulomas • Hx osteopenia • 2 yrs dyspnea with activity • 8/20/15 - LDN • 4.5 mg (titrated up from 1.5 over 2 wks)

  39. Case 3: PLB 63 y.o. WM • 1 mo after LDN – unchanged • 2 mo after LDN – less short of breath • 3 mo after LDN – asthma from allergens

  40. Sarcoidosis Rx: Role for LDN Experience needed – enroll AA pts • Pulmonary response w treadmill testing • Anti-inflammatory markers

  41. LDN side effects: neurologic Ploesser J, Weinstock LB, Thomas E. Internat J Pharm Compound 2010:171-173. • Anxiety 15.7% • Drowsiness 11.6% • Headache 11.6% • Insomnia 8.3% • Muscle pain 8.3% • Vivid dreams 5.0% • Mood change 3.3% • Trouble concentration 1.7%

  42. LDN: additional side effects Ploesser J, Weinstock LB, Thomas E. Low Dose Naltrexone: Side Effects and Efficacy in Gastrointestinal Disorders. Internat J Pharm Compound 2010:171-173. • Nausea 12.4% • Abd. pain 11.6% • Diarrhea 8.3% • Anorexia 8.3% • Rash, hot flashes, weight gain 0.1% each

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