Low Dose Naltrexone Update 2016: Broad Spectrum Treatment Insights

1. Low Dose NaltrexoneUpdate 2016 Leonard Weinstock, MD, FACGPresident, Specialists in Gastroenterology Associate Professor of Clinical MedicineWashington University in St. Louis St. Louis, Missouri

2. LDN: Grass-Roots Movement

3. The Grass is Growing • February 2016 – 3rd LDN Conf.; 9/17 – 4th Conf. • Websites • LDNscience.org • LDNResearchTrust.org • LDNnow.org • LDNinfo.org • Dudleyslowdosenaltrexonesite • Finnish LDN site • lowdosenaltrexone@yahoogroups.com • Industry – Immune Therapeutics • The LDN Book (2016) and others

4. 173 “Responsive” ConditionsAs reported by papers, online support groups, and pharmacists • Read between the lines • Idiopathic • Inflammation • Autoimmune • Pain

5. LDN Treatment for Diseases Published Clinical Studies • Crohn’s diseases • Irritable bowel • Multiple sclerosis • Fibromyalgia • Complex regional pain syndrome • Cancer • Ulcerative colitis • Restless legs syndrome

6. LDN “Responsive” Conditions:Organized by Organ System • Malignancies - 18 • Neurologic - 37 • Ocular - 18 • Pulmonary – 9 • Rheumatologic - 39 • Renal/Urologic - 36 • Vasculitis - 9 • Cardiac - 6 • Dermatologic - 40 • ENT - 5 • Endocrine - 9 • Gastrointestinal - 17 • Hematologic - 13 • Infections - 7 See the last 26 slides

7. Conditions: “A – V” • Acquired immune deficiency syndrome Acute disseminated encephalomyelitis • Acute hemorrhagicleukoencephalitis • Addison's disease • Agammaglobulinemia • Alopecia areata • Amyotrophic lateral sclerosis • Ankylosingspondylitis • Anti-GBM/TBM nephritis • Anti-mag IgM peripheral neuropathy • Anti-phospholipid syndrome • Anti-synthetase syndrome • Asthma • Atopic allergy • Atopic dermatitis • Autoimmune aplastic anemia • Autoimmune cardiomyopathy • Autoimmune enteropathy • Autoimmune hemolyticanemia • Autoimmune hepatitis • Autoimmune inner ear disease • Autoimmune lymphoproliferativesynd. • Autoimmune pancreatitis • Autoimmune peripheral neuropathy • Autoimmune polyendocrine syndrome • Autoimmune progesterone dermatitis • Autoimmune thrombocytopenic purpura • Autoimmune urticaria • Autoimmune uveitis • Balo disease/Balo concentric sclerosis • Bechets syndrome • Berger's disease • Bickerstaff's encephalitis • Blau syndrome • Bullous pemphigoid • Cancer (various cancers may respond) • Castleman's disease • Celiac disease • Charcot-Marie-Tooth syndrome • Chronic fatigue syndrome (CFS) • Chronic inflammatory demyelinating polyneuropathy • Chronic recurrent multifocal osteomyelitis • Churg-Strauss syndrome • Cicatricialpemphigoid

8. Cogan syndrome • Cold agglutinin disease • Complement component 2 deficiency • Complex regional pain syndrome • Cranial arteritis • CREST syndrome • Crohn’sdisease • Cushing's syndrome • Cutaneous leukocytoclasticangiitis • Dego's disease • Dercum's disease • Dermatitis herpetiformis • Dermatomyositis • Diabetes mellitus type 1 • Diffuse cutaneous systemic sclerosis • Discoid lupus erythematosus • Dressler's syndrome • Eczema • Ehlers-Danlos • Enthesitis-related arthritis • Eosinophilicfasciitis • Eosinophilic gastroenteritis • Epidermolysisbullosaacquisita • Erythema nodosum • Essential mixed cryoglobulinemia • Evan's syndrome • Fibrodysplasiaossificansprogressiva • Fibromyalgia (FMS) • Fibrosingaveolitis • Folliculitis (non-bacterial) • Gastritis (immune-based) • Gastrointestinal pemphigoid • Giant cell arteritis • Glomerulonephritis • Goodpasture's syndrome • Graves' disease • Guillain-Barrésyndrome (GBS) • Haemolytic anaemia • Hailey-Hailey disease • Hashimoto's encephalitis • Hashimoto's thyroiditis • Henoch-Schonleinpurpura • Herpes gestationis • HIV (with various immune disorders) • Hypogammaglobulinemia • Idiopathic constipation • Inflammatory demyelinating diseases

9. Idiopathic pulmonary fibrosis • Idiopathic thrombocytopenic purpura • Idiopathic urticaria • IgA nephropathy • Inclusion body myositis • Inflammatory demyelinating polyneuopathy • Interstitial cystitis • Irritable bowel syndrome • Juvenile idiopathic arthritis • Juvenile rheumatoid arthritis • Kawasaki's disease • Lambert-Eaton myasthenicsyndrome • Leukocytoclasticvasculitis • Lichen planus • Lichen sclerosus • Linear IgA disease (LAD) • Lupoid hepatitis • Lupus erythematosus • Lyme Disease • Lymphoma • Majeed syndrome • Ménière's disease • Microscopic polyangiitis • Miller-Fisher syndrome • Mixed connective tissue disease (MCTD) • Morphea • Mucha-Habermann disease • Multiple sclerosis (MS) • Myalgicencephalomyelitis (ME) • Myasthenia gravis • Myositis • Neuromyelitisoptica • Neuromyotonia • Occularcicatricialpemphigoid • Opsoclonusmyoclonus syndrome • Ord thyroiditis • Parkinson’s disease • Palindromic rheumatism • PANDAS (pediatric autoimmune • Neuropsychiatric dis. after streptococcus) • Paraneoplasticcerebellar degeneration • Paroxysmal nocturnal hemoglobinuriaParry-Romberg syndrome • Pars planitis • Parsonnage-Turner syndrome • Pemphigus

10. Pemphigus vulgaris • Perivenous encephalomyelitis • Pernicious anaemia • POEMS syndrome (plasma-cell proliferative disorder) • Polyarteritisnodosa • Polymyalgia rheumatic (PMR) • Polymyositis • Primary biliary cirrhosis (PBS) • Primary sclerosing cholangitis (PSC) • Progressive inflammatory neuropathy • Prostatitis (non-bacterial) • Psoriasis • Psoriatic arthritis • Pure red cell aplasia • Pyodermagangrenosum • Rasmussen's encephalitis • Raynaud phenomenon • Reiter's syndrome • Relapsing polychondritis • Restless leg syndrome • Retroperitoneal fibrosis • Rheumatoid arthritis • Rheumatoid fever • Sarcoidosis • Schmidt syndrome • Schnitzler syndrome • Scleritis • Scleroderma • Sjögren's syndrome • Small intestinal bacterial overgrowth • Spondyloarthropathy • Stiff person syndrome • Still's disease • Subacutebacterial endocarditis (SBE) • Susac's syndrome • Sweet's syndrome • Sydenham chorea • Sympathetic ophthalmia • Takayasu's arteritis • Temporal arteritis • Tolosa-Hunt syndrome • Transverse myelitis • Ulcerative colitis • Undiff.connectivetissue disease • Undifferentiated spondyloarthropathy • Vasculitis • Vitiligo

11. LDN MOA • Naltrexone displaces endorphins bound to OGF receptors • Affected cells become deficient in OGF and results in: • Receptor production and sensitivity is increased to capture more OGF • Production of OGF is increased to compensate for the perceived shortage of OGF

12. 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

13. LDN MOA Control of T- and B-cell production Alter Natural Killer cells and cytokine production Shift from TH1 to TH2

14. Additional MOA Li. Med Hypotheses 2012;79:754-6. Hutchinson et al. Brain Behav Immun 2010;24:83-95. • Toll receptors allows for increase in bacterial translocation (worse w/ narcotics) • LDN stabilizes receptor and decreases bacterial translocation • Microglial receptor • Activated microglia cause neuroexitability and enhanced pain via toll-like receptor 4 pathway • LDN antagonizes pathway • Decrease in auto-antibody production – seen in thyroid….?IBS, ?IBD

15. LDN – Seeing is believing Sarcoidosis

16. Sarcoidosis • Granulomatous disorder with T-cells • & macrophages in multiple organs • Activated memory T-cells with CD11a • GI involvement – stomach, intra-peritoneal nodes, liver, and spleen Iida K et al. Thorax 1997;52:431-7.

17. 73 yo AAF – severe supraglotic adenopathy 2001 (6 yrs tracheostomy) • Active sx: 2 yr painful rash and 40 yr fatigue • Rash prevention • by minocycline • Referred abnl CT • LDN – prescribed

18. Progression before LDN 12/2014 11/2011

19. Progress 2015 February - LDN 1 mg/day March - less dyspnea, less fatigue, able to stop minocycline w/o rash March – LDN 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

20. With Treatment 5 mo LDN 10 mo LDN

21. With Treatment Before LDN 10 mo LDN

22. LDN – Seeing is believing Restless legs syndrome • LBT: methane excretor • Rifaximin • 3 treatments over 7 yrs • 2 with neomycin • Naltrexone 2.5 qHS • Remission 7 yrs

23. RLS Study: Role of LDNSequential Rx • Chart review (1/06 - 12/14): • Rif-LDN Rx: N= 52; 40 pt ≥1 OV after Rx • Rifaximin 1650 mg/day/2 weeks immediately followed by LDN • 38/40 had chronic GI symptoms • LBT positive in 37 by pre-2009 standards, 7 reread as normal and 3 ND • 4 men; 36 women

24. Rifaximin-LDN Sequential Rx Responders = 65%

25. LDN Dose Evaluation Responders = 78% vs. 47% No difference in AE

26. RLS: LDN Rx • 23 responders without AE: LDN for x =107 wks (now up to 7 yrs) • AE led to cessation of LDN in 6/40 (15%) • 3/6 AE were in responder group (LDN for 6, 8 and 28 wks)

27. LDN Rx where original LBT normal by 2009 standards Responders = 57%

28. LDN – Seeing is believing Restless legs syndrome • RLS ten years • Urge to move at night • Terrible time on flights • Sleeps with body pillow • LBT: negative • Naltrexone 2.5 mg qHS • Immediate relief with LDN

29. MS – Seeing is believing • Severe MS pt had ileitis without sx • 2 weeks: MS clinical benefit • 1 year: MS clinical benefit; ileal ulcers healed

30. MS - publications • 40 pts: Reduction of spasticity resulted; disability progressed in 1 • 80 pts: Improved mental health and QOL • 96 pts double blind: No difference vs. placebo in pain or fatigue • SIBO symposium 2014 – several practitioners with experience in many patients Gironi. Mult Scler. 2008. Cree. Ann Neuro. 2010. Sharafaddinzadeh et al. Mult Scler. 2010.

31. Multiple Sclerosis – new data • Penn State retrospective chart review • 215 Rx w LDN 2/3rd had relapsing-remitting • LDNfor meanof2 ¼ yr. Many on other Rx. Turel. J Clin Psychopharm. 2015.

32. Multiple Sclerosis – new data Turel. J Clin Psychopharm. 2015.

33. Multiple Sclerosis – new data Turel. J Clin Psychopharm. 2015.

34. MS – Ireland Experience 130 Relapsing remitting MS 14 Primary progressive MS RRMS – “approximately 70% have received some benefit; most say no progression” PPMS – “all have done well” Patrick Crowely, MD. Ireland. LDN 2016 Conference

35. MS – Seeing is believing • 32 y.o. with MS – double vision • MRI – positive • LDN started at 3 mg • Increased to 4.5 mg • At 5 months – • No visual disturbance • MRI at 6 month • – decrease in size and no longer enhancing Jill Cottel, MD. LDN 2016 Conference

36. UC – Seeing is believing • 45 y.o. man failing IFX • LDN added to biologic Rx - remission 7 yrs Weinstock. J Clin Gastroenterol 2014;48:742.

37. Adjunctive LDN Rx: Outcome • Duration - LDN for 69 ±88 wks (up to 270) • 6MP: 3/6 responded (2 failed, 1 stopped d/t AE) • 2 of 6 responders re-scoped - complete response • Other failures: two IFX, one 3-drug combo pt, one 4-drug combo pt, and one 5-ASA pt who failed 6MP in past Weinstock. J Clin Gastroenterol 2014;48:742.

38. UC LDN Rx: Recent Cases

39. LDN use to stop 6MP Relapse: 12% in 12 mo 26% in 24 mo (76% on 5-ASA)

40. LDN Rx for UC • Low toxicity, low cost • Additive owing to different MOA • Safe/effective with biologics for long time • Can work with 6MP • Role as monotherapy to be determined • RCT important • High-placebo Sx response • Need endoscopic outcomes

41. Skin Disorder in Celiac Pt 53 yo celiac disease Dx 14 yr ago - rare accidental exposures which cause severe diarrhea. Hx Hashimoto's Rash 5 years ago - face, top of feet, antecubital fossa, and underarms Burns like sunburn and itches Occurs 16-18 times/month and lasts all day

42. Celiac Skin Disorder (untreated)

43. Celiac Skin Disorder - treated Started LDN First month - 6 attacks Second month - 2 attacks Decreased duration

44. Conclusion • Seeing is believing but high quality studies are needed for acceptance of LDN • See next set of slides to see what conditions might be treatable • Primum non nocere • Consent form • Prevent withdrawal • Limit promises

45. LDN “Responsive” Conditions by Organ Systems Cardiac Autoimmune cardiomyopathy Dressler's syndrome Kawasaki's disease Polyarteritisnodosa Pyodermagangrenosum Subacute bacterial endocarditis

46. Dermatologic Alopecia areata Anti-synthetase syndrome Atopic allergy Atopic dermatitis Autoimmune progesterone dermatitis Autoimmune thrombocytopenic purpura Autoimmune urticaria Bechet’s syndrome Blau syndrome Bullous pemphigoid Cicatricialpemphigoid

47. Dermatologic Cutaneous leukocytoclasticangiitis Dego's disease (thrombotic vasculopathy) Dercum's disease Dermatitis herpetiformis Dermatomyositis Diffuse cutaneous systemic sclerosis Discoid lupus erythematosus Eczema Epidermolysisbullosaacquisita

48. Dermatologic Erythema nodosum Essential mixed cryoglobulinemia Hailey – Hailey Disease Henoch-Schonleinpurpura Herpes gestationis Kawasaki's disease Lichen planus Lichen sclerosus Linear IgA disease Majeed syndrome Microscopic polyangiitis Morphea

49. Dermatologic Mucha-Habermann disease Parry Romberg syndrome Pemphigus Pemphigus vulgaris POEMS syndrome Psoriasis Pyodermagangrenosum Schnitzler syndrome

50. Ears, Nose, Sinus, Throat Autoimmune inner ear disease Churg-Strauss syndrome Cogan syndrome Ménière's disease Susac's syndrome