Understanding and Managing Neuropathic and Inflammatory Pain

1. Understanding and Managing Neuropathic and Inflammatory Pain Leonard Weinstock, MD, FACGSpecialists in Gastroenterology St. Louis, Missouri

2. Disclosures • Speakers bureau: Salix, Allergan • Naltrexone use is off-label • I am not a pain management doctor

3. Outline • Broad discussion of pain • Mechanisms of inflammatory and sensory induced pain • Mechanisms of neuropathic pain • Naltrexone for pain management in my practice • Review list of LDN responsive conditions

4. Types of Pain: Somatic General • Sensory – via sensory nerves from extremity to spinal cord • Neuropathic pain • Central – increased microglial activity • Peripheral

5. Types of Pain: Gastrointestinal • Visceral hypersensitivity – gut-gut brain and brain-gut – sensory stretch receptors • Note large amounts of opioid cells in the gut • Peritoneal pain

6. Sensory pain

7. Sensory pain Stimulation of sensory nerves by trauma, heat, etc. Feed back to spinal cord and brain Tattoo Booth #3 in Portland Airport

8. Inflammatory-induced sensory pain Cytokines activate sensory nerve endings

9. Neuropathic pain

10. Increased central input GABA Sprouting sympathetic and AƁ axons Nociceptive neuron Dorsal Root ganglion Substance P Glutamanate Sodium channel accumulation 2nd order neuron

11. Inflammation Ischemia Toxicity Trauma Pressure

12. Neuropathic pain Inflammation Autoimmune Ischemia Trauma Pressure

13. Cytokines – involved in inflammatory and neuropathic • Small secreted proteins • Specific effect on the interactions and communications between cells • Lymphokine (made by lymphocytes), Monokine (cytokines made by monocytes) Chemokine (cytokines with chemotactic activities) • Interleukin (cytokines made by one leukocyte and acting on other leukocytes) • Pro-inflam and anti-inflam cytokines

14. Cytokines – in inflammatory and neuropathic pain • Involved initiation and persistence of pathologic pain - directly activating nociceptive sensory neurons • Inflammatory cytokines • Involved in nerve-injury/inflammation-induced central sensitization • Related to contralateral hyperalgesia (e.g., CRPS) • Key players: IL-1β, IL-6, and TNF-α Zhang, Int Anesth Clin 2007

15. Endorphins, T-cells, and LDN • Endorphins activate Mu-receptor – endogenous opioid effect for analgesia • Regulate T-cells • Reduce cytokines and subsequent sensory pain • Reduce cytokines and subsequent mast cell activity

16. LDN Direct Effect for Pain Control Li. Med Hypotheses 2012;79:754-6. Hutchinson et al. Brain Behav Immun 2010;24:83-95. • Microglia – nerve cells • Multiple disorders have activated microglia causing neuroexitability and enhanced pain via Toll-like receptor 4 pathway • LDN blocks this receptor

17. Personal Experience with Pain Disorders and LDN Rx Irritable bowel syndrome Restless legs syndrome Fibromyalgia Complex regional pain syndrome Ehlers-Danlos syndrome Postural orthostatic tachycardia and mast cell activation syndromes Sarcoidosis

18. Pain Disorders and LDN Rx • IBS • Decrease cytokines and subsequent increased IP • Decrease lymphocytes near gut nerves • Efficacy – ˆ 50% (usually in combo w antibiotic) • RLS, FMS, CRPS, EDS, POTS and MCAS, Sarcoidosis

19. Inflammatory changes in SIBO • Interleukins – IL 1ß, 6, 8, 12 • TNF-alpha • LPS translocation – alter brain chemistry • T- lymphocytes – produce cytokines • Mast cells – release of pain mediators • Substance P – direct action on sensory ending • Integrin B-7 (vasc. perm.) – passage of inflammatory cells into tissue Riordin. Scand J Gastroenterol 1996;31:977-84. Lin. JAMA 2004;292:852-8. Hughes et al. Am J Gastroenterol 2013;108:1066-74. Martinez et al. Gut 2013;62:1160-8.

20. Role of Mast Cells in IBS Normal IBS Abdominal pain and severity correlated with the number of mast cells <5µm Proximity to nerves Elevated tryptase and histamine Barbara. Gastroenterology. 2004;126:3.

21. Mast cells • Irritable bowel syndrome (Barbara. Gastro 2004) • Mast cell activation syndrome – IC common in IBS • Interstitial cystitis (Sant. Urology 2007) • Chronic prostatitis (Done. J Urol 2012)

22. Intestine-derived MC-activation Triggers CNS-originated MC-activation Triggers Adenylate cyclase, Activating peptide, Calcitonin gene related peptide, Corticotrophin releasing hormone, Myelin basic protein, Nerve growth factor, Neurotensin, Sub. P IL-1,IL-33, LPS, VIP, Butyrophillin, neurotensin, caselin, glialdin, gluten, reactive O2, C. diff toxins, rotavirus MC Vasoactive Mediators Histamine Bradykinin Endothelin IL-6,8 Nitric oxide Serotonin Tryptase Urocortin Vasoactive GF VIP Inflamm. & Neurotoxic Mediators IL-1,6,8,13,17,32 Monocyte chemotactic protein-1 Prostaglandin D2 Serotonin Tryptase TNF-alpha

23. Pain Disorders and LDN Rx • IBS • RLS • Neuropathic pain & increased CNS excitability – dopaminergic dysfunction and thalamic opioid deficiency. PET – severe RLS – increased endorphin release. Autopsy – less overall ME/E • LDN improve endorphin deficiency in thalamus • Decrease inflammation - reduce hepcidin levels allowing more iron to get into brain – better dopamine function • 57% marked-moderate improvement – with and without antibiotic • FMS, CRPS, EDS, POTS and MCAS, Sarcoidosis The LDN Book 2016

24. Pain Disorders and LDN Rx Yang. Medicine. 2017. Pimentel. Ann Rheum Dis 2004 • IBS, RLS • Fibromyalgia – common in IBS-d and risk of IBS increased (7.4 vs. 4.4 per 1000 pt/yr) • To be discussed by Dr. Younger • Note: FMS highly associated with SIBO and thus needs more than LDN • Abnl LBT: • 3/15 (20%) controls • 93/111 (84%) IBS subjects (p<0.01) • 42/42 (100%) with fibromyalgia (p<0.0001 vs controls, p<0.05 vs IBS • CRPS, EDS, POTS and MCAS, Sarcoidosis

25. Pain Disorders and LDN Rx • IBS, RLS, FMS • Complex regional pain syndrome • One OSA/IBS-SIBO/EDS - 8 yr disease • LDN, OSA and SIBO Rx (Weinstock. A A reports. 2016.) • Two opioid partial responders • One opioid failure • EDS, POTS and MCAS, Sarcoidosis

26. Pain Disorders and LDN Rx • IBS, RLS, FMS, CRPS • Ehlers-Danlos syndrome: joint pain d/t: • Entrapment of nerves owing to subluxations of joints or thoracic outlet obstruction • Increased glial activity in brain which irritates brain or spinal column sensory nerves • CRPS • Mast cells in tissues or next to nerves Scheper. Arthritis Care Res. 2017. Weinstock. A A reports. 2016. Seneviratne. Am J Med Genet C Semin Med Genet. 2017 • POTS and MCAS, Sarcoidosis

27. Ehlers-Danlos Syndrome • Central hypersensitivity • Mast cells in tissues • Release 200 mediators • Potential to block Toll-like receptor 4 with LDN

28. Pain Disorders and LDN Rx: EDS • Celiac pt w diet refractory dermatitis herpetiformis and EDS joint pain • 2 yrs of rash – remission in 3 mo; 2 years maintained improvement in joint pain

29. Pain Disorders and LDN Rx • IBS, RLS, FMS, CRPS, EDS • POTS and MCAS • Case 1 – decrease in body pain, increased energy, decrease in GI symptoms • 33 additional POTS patients in clinic, 27 had LBT (26 female, 1 male, mean age 35): MCAS in 27% and EDS in 42% • GI symptoms in all: mid/lower abdominal pain (96%), bloating (92%), nausea (85%), constipation (73%), diarrhea (58%), and heartburn (58%) • Sarcoidosis

30. POTS & SIBO & LDN Weinstock,. Submitted to BJM Case Rep. 2017. Antibiotic Rx helped GI Sx in 10/15 helped POTS Sx in 4/15 Low dose naltrexone helped GI Sx in 7/11 helped other POTS/MCAS Sx in 5/11 (1 POTS, 2 both, 2 MCAS)

31. Pain Disorders and LDN Rx • IBS, RLS, FMS, CRPS, EDS, POTS and MCAS • Sarcoidosis • Skin – “pain like a hot poker” requiring chronic tetracycline (and H-S megaly) (LDN - 4.5 mg - report in press: Sarcoidosis, Vasculitis and Diffuse Pulmonary Disease ) • Joint, parotid gland (in my nurse – LDN - 3 mg) • Reduce T-cell activity (decrease cytokines) and inflammatory pain

32. LDN Responsive Disorders Which ones are associated with PAIN???

33. LDN “Responsive” Conditions by Organ Systems Cardiovascular/vasculitis Autoimmune cardiomyopathy Dressler's syndrome Kawasaki's disease Polyarteritis nodosa Subacute bacterial endocarditis

34. 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 Cicatricial pemphigoid

35. Dermatologic Cutaneous leukocytoclastic angiitis Dego's disease (thrombotic vasculopathy) Dercum's disease Dermatitis herpetiformis Dermatomyositis Diffuse cutaneous systemic sclerosis Discoid lupus erythematosus Eczema Epidermolysis bullosa acquisita

36. Dermatologic Erythema nodosum Essential mixed cryoglobulinemia Hailey – Hailey Disease Henoch-Schonlein purpura Herpes genatalis Kawasaki's disease Lichen planus Lichen sclerosus Linear IgA disease Majeed syndrome Microscopic polyangiitis Morphea

37. Dermatologic Mucha-Habermann disease Parry Romberg syndrome Pemphigus Pemphigus vulgaris POEMS syndrome Psoriasis Pyoderma gangrenosum Schnitzler syndrome Sweet’s syndrome

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

39. Endocrine Addison's disease Autoimmune polyendocrine syndrome (APS) Cushing's syndrome Diabetes mellitus type 1 Graves' disease Hashimoto's thyroiditis Ord’s thyroiditis POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) Schmidt syndrome (APS)

40. Gastrointestinal Autoimmune hepatitis Autoimmune enteropathy Autoimmune pancreatitis Celiac disease Churg-Strauss syndrome Crohn’s disease Eosinophilic gastroenteritis Gastritis

41. Gastrointestinal Gastrointestinal pemphigoid Lupoid hepatitis POEMS syndrome Polyarteritis nodosa Primary biliary cirrhosis Primary sclerosing cholangitis Pyoderma gangrenosum Ulcerative colitis

42. Hematologic Agammaglobulinemia Antiphospholipid syndrome Autoimmune aplastic anemia Autoimmune hemolytic anemia Autoimmune lymphoproliferative syndrome Castleman's disease – lymph node hyperplasia Cold agglutinin disease Evan's syndrome Majeed syndrome Paroxysmal nocturnal hemoglobinuria (PNH) Pernicious anemia Pure red cell aplasia

43. Infections Complement component 2 deficiency – increase risk of infections Human immunodeficiency virus (HIV) Hypogammaglobulinemia (leads to infections) Lyme Disease PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections) Sydenham chorea

44. Malignancies Bladder Cancer Breast Cancer Carcinoid Colon & Rectal Cancer Glioblastoma Liver Cancer Lung Cancer (Non-Small Cell) Lymphocytic Leukemia (chronic) Lymphoma (Hodgkin's and Non-Hodgkin's)

45. Malignancies Malignant Melanoma Multiple Myeloma Neuroblastoma Ovarian Cancer Pancreatic Cancer Prostate Cancer (untreated) Renal Cell Carcinoma Throat Cancer Uterine Cancer

46. Neurologic Acute disseminated encephalomyelitis Acute hemorrhagic leukoencephalitis Amyotrophic lateral sclerosis Anti-mag IgM peripheral neuropathy Autoimmune peripheral neuropathy Bickerstaff's encephalitis Charcot Marie Tooth syndrome Chronic inflammatory demyelinating polyneuropathy Cranial arteritis Guillain-Barré

47. Neurologic Hashimoto's encephalitis Idiopathic inflammatory demyelinating diseases Inflammatory demyelinating polyneuopathy Lambert-Eaton myasthenic syndrome Miller-Fisher syndrome Multiple Sclerosis Myalgic Encephalomyelitis Myasthenia gravis Neuromyelitis optica Neuromyotonia Opsoclonus myoclonus syndrome

48. Neurologic PANDAS Parkinson’s disease Parry Romberg syndrome Parsonage-Turner syndrome – brachial neuritis Perivenous encephalomyelitis POEMS syndrome (polyneuropathy) Polyarteritis nodosa Progressive inflammatory neuropathy

49. Neurologic Rasmussen's encephalitis Restless leg syndrome Stiff person syndrome Susac's syndrome (headache, muscle pain, …) Sydenham chorea Tolosa-Hunt syndrome (headache, orbital pain,…) Transverse myelitis

50. Ocular Autoimmune uveitis Balo disease – headache, muscle spasms Blau syndrome – rash, arthritis, uveitis Cogan syndrome – ocular inflm, arthrits Kawasaki's disease - vasculitis Miller-Fisher syndrome Neuromyelitis optica Ocular cicatricial pemphigoid Opsoclonus myoclonus syndrome