Low Dose Naltrexone and Complex Regional Pain Syndrome Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University in St. Louis President, Specialists in Gastroenterology

Disclosures Speakers Bureau: Speakers Bureau: Salix, Entera Health, Forest Salix, Entera Health, Forest Off label use of medication Off label use of medication

Naltrexone Anti-opioid Anti-opioid Approved by the FDA in 1985 to treat opiate dependence (Revia ®, Depade ® and extended-release Vivitrol ® Approved by the FDA in 1985 to treat opiate dependence (Revia ®, Depade ® and extended-release Vivitrol ® Dose of 50mg–100mg daily for opiate dependence Dose of 50mg–100mg daily for opiate dependence

Off Label Use of Meds  Common for GI  Proton pump inhibitors  Anti-depressants  Prednisone, Immune-suppressants  Antibiotics  New for GI  Low dose naltrexone Legal and ethical in the confines of one’s own practice

LDN 2005  LDN part of Rx  Prokinetic alternative  Improve immunity

LDN: History  : Penn State endorphin research  1985: Rx for AIDS (NYC)  Mid 90’s: Rx for MS (NYC) Zagon et al. Science 1983;221: Bihari. AIDS Patient Care. 1995;9:3.

LDN: Rx Reports Published  Cancer  AIDS  Fibromyalgia  MS  Complex regional pain syndrome  IBS  Crohn’s Disease  Ulcerative colitis Anecdotal  CFS  RA, AS, SLE  Parkinson's disease  Hailey-Hailey & Psoriasis  Rosacea & Eczema  RLS  IC & CP  Sarcoidosis  Dercum’s disease 1100 SIG patients

Ulcerative Colitis: LDN Rx Weinstock. J Clin Gastroenterol 2014;48:742.  Pt failing Remicade – high risk of colectomy  Now in remission 6 years – LDN added to biologic Rx

Crohn’s Disease: LDN Rx  40 y.o. WF s/p total colectomy; intestinal recurrence 4 yrs later; failing Remicade: diarrhea and fatigue  LDN 4.5 mg added; Endo & Clin remission in 2 mo  Remission 5 years

CD and MS: LDN Rx  CRC screening of severe MS pt – ileitis without sx  2 weeks: MS clinical benefit  1 year: MS clinical benefit; ileal ulcers healed

Endogenous Opioids  B-endorphins, enkephalins, endomorphin, dynorphin  Opioid cells locations:  Entire nervous system  Adrenal glands  GI tract  Myenteric plexus  Mucosal plexus  Intestinal endocrine cells

Endorphins: Functions  Regulate cell growth  Decrease inflammation  Decrease permeability  Stabilize Toll-like receptors  Decrease microglia activation  Decrease cytokine release  Shift from TH2 to TH1  Improve GI motility

ActivatedCell  Regulates T- & B-cell production production  Maintains blood vessel barriers barriers Opioid Cell/Receptor Functions Endorphins

ContinuousOver-activatedReceptors Inflammation and Endothelial cell barrier disruption Narcotics, LPS, Thrombin “Breaking Bad”

How Does LDN Work?  LDN displaces endorphins from receptors for 4 hours  Cells sense opioid deficiency and rebound via a positive feedback mechanism  Receptors increased  Met-enkephalin production x fold

Activated Receptors Endorphins & receptors lead to decreased T- and B-cell activity & less permeability LDN effect

Ehlers-Danlos Syndrome Bone and joint conditions Hypermobility Bone fracture Joint dislocation Soft tissue joint disease (Often seen by Pain Management Physicians) Additional syndromes Dermal changes Dental involvement GYN/OB disorders Vasomotor: postural orthostatic tachycardia/autonomic dysfx Vascular abnormalities Anxiety disorder Hernias Acid reflux Irritable bowel syndrome

Complex Regional Pain Syndrome  CRPS (AKA Reflex Sympathetic Dystrophy)  Spontaneous and/or evoked neuropathic regional pain with:  Vasomotor dysfunction  Motor/trophic dysfunction  Sudomotor/edema and sweating

Complex Regional Pain Syndrome  Incidence:  5.46 per 100,000 person years (Mayo)  26.2 per 100,000 person years (Netherlands)  Netherlands = 6-fold larger study (600,000 patients)  Female predominance: 4 to 1 (in each study)  Familial reports in Europe  Natural Hx:  Mayo - 75% spontaneous complete remission  Drexel University – 0/656 pts (dur y)

CRPS Triggers: Bone fractures (46%in Mayo study) Sprains Trauma (injections, nerve injury, surgery, burns, and frostbite) Nerve injury Infection Stroke Myocardial infarction Pregnancy All associated with inflammation

CRPS: GI disorders Dysbiosis – narrow microbiome spectrum Dysbiosis – narrow microbiome spectrum Increased intestinal permeability Increased intestinal permeability Painful syndromes including irritable bowel syndrome are common in CRPS Painful syndromes including irritable bowel syndrome are common in CRPS SIBO may be a factor in up to 50% of IBS pts and it can cause systemic inflammation and extra-intestinal disorders (fibromyalgia, restless legs syndrome, rosacea, and chronic pelvic pain syndromes) SIBO may be a factor in up to 50% of IBS pts and it can cause systemic inflammation and extra-intestinal disorders (fibromyalgia, restless legs syndrome, rosacea, and chronic pelvic pain syndromes)

CRPS: Potential roles for LDN  Pathophysiology  Neurogenic inflammation – Reduce activity  Glial pain sensitization - Reduce activity  Vasomotor dysfunction - ?Endothelial permeability  Inflammatory triggers – Reduce cytokines and regulate T and B cell activity  Increased intestinal permeability – Repair gut immunity, permeability and motility reducing SIBO

CRPS: LDN Rx 2 cases with improvement Chopra. Neuroimmune Pharmacol 2013;8:470-6

CRPS: SIBO and LDN Rx 53 y.o. WF 12 yr pain, 40 yr IBS, yrs poor sleep, & Sx for 45 yrs of Ehlers-Danlos  Abnl LBT and sleep study:  Xifaxan & LDN  CPAP  Relapse at 1 yr:  Xifaxan  CPAP Rx maximized  Promotility Rx  LDN continued  Remission 1 mo later

Remission & successful retreatment Weinstock et al. Pain Physician. Submitted 2015

Ehlers-Danlos and CRPS Ehlers-Danlos syndrome Genetic disorder – prevalence 0.2 – 2% Bone fracture common Central pain sensitization GI symptoms common – autonomic dysfx and/or bacterial overgrowth 5 reported cases of CRPS in EDS prior to 2013 Complex regional pain syndrome Familial - coincidence vs. common genetic risk Bone fracture common Central pain sensitization GI symptoms common – autonomic dysfx: risk for bacterial overgrowth EDS in 25% of CRPS pts in one pain management practice from

Are Ehlers-Danlos & CRPS Linked? Ehlers-Danlos syndrome Connective tissue laxity leads to obstructive sleep apnea OSA leads to hypoxia driven inflammation Gastrointestinal symptoms common – autonomic dysfx and/or bacterial overgrowth Bacterial overgrowth leads to inflammation Complex regional pain syndrome Sleep disturbances are very common Possible ongoing trigger to CRPS Gastrointestinal symptoms common – autonomic dysfx: risk for bacterial overgrowth Possible ongoing trigger to CRPS

Are Ehlers-Danlos & CRPS Linked? Are Ehlers-Danlos & CRPS Linked? Internet poll of RDS support group adult members Irritable bowel syndrome Present in 99/177 (56%) Vs. 3%-20% in USA Sleep apnea Present in 59/177 (33%) Vs. 3%-28% in USA

Future CRPS Study Irritable bowel syndrome Prevalence Prevalence of positive LBT Effect of treating SIBO Ehlers-Danlos syndrome Prevalence Correlation with IBS and OSA Effect of treating with low dose naltrexone Sleep apnea Prevalence sleep disturbance Prevalence of positive sleep study Effect of treating OSA

SIBO RLS Pi-IBS IBS Inflamm Immune Idiopathic syndromes SIBO Individual Syndromes Linked to SIBO Overlapping P-physiology FMS Rosacea CPPS Others Dysbiosis SIBO Genetic Risk