Low Dose Naltrexone Presented By: Craig Batagowski, PharmD, IACP (Presenter) Created By: Kiley Shelley, PharmD Candidate (Creator) Edited By: Paraj Patel, PharmD Candidate (Editor)

What is Naltrexone? Opiate antagonist on mu receptors FDA approved for treatment of alcohol and opiate addiction Oral dose generally 50 mg daily Blocks opioid receptor 24 hours per day Behavioral Modification FDA approved - by blocking opiate receptor you prevent addicted patients from being able to obtain euphoria achieved by taking drugs or alcohol

Low Dose Naltrexone (LDN) Use in Irritable Bowel Disease Use in Chronic Fatigue Syndrome and Fibromyalgia Use in Thyroid Disorders Use in Digestive Relief Quicker onset and relief for digestive issues

What is Low Dose Naltrexone? (LDN) Same active drug as Naltrexone(Vivitrol) available on the market Doses ranging from 0.5 to 4.5 mg daily (10-40x lower doses than traditional dosing) Seems to be effective in autoimmune diseases Currently there is a lack of sufficient clinical studies Doses 10-40x lower than traditional dosing of naltrexone in addiction Endorphins and opioid receptors are involved in almost every biological system that regulates the immune response Lack of studies could be why the drug is used less

Very Low dose Naltrexone (VLDN) Adjunct therapy to opioid treatment Reduces titration of opioids Reduces tolerance of opioids

Naltrexone Doses Alcohol & opioid addiction 50 mg (standard dosing) Low Dose Naltrexone 0.5 – 10 mg Very Low Dose Naltrexone 1- 5 mcg

How does LDN work in the body? Many disease states are caused by malfunctioning of immune system Immune system is regulated by endorphins Endorphins act primarily on opiate receptors Blocking opiate receptor with LDN for about 6 hours = increased endorphin production Increased endorphins can correct the immune system malfunction Blocked for 6 hours, vs. 24 hours with traditional dosing

What side effects occur with LDN? Agitation Headache Insomnia Constipation Diarrhea Nightmares Stomach cramping Flu-like symptoms Vivid Dreams Reduced renal function Elevated liver enzymes May gradually increase the dose to target dose to avoid side effects Insomina, nightmares, vivid dreams most common

LDN in irritable bowel disease (IBD) Crohn’s Disease (CD) and Ulcerative Colitis (UC)

How can LDN be beneficial in IBD? Standard approach to IBD treatment: 1. Decrease inflammation in intestinal lining 2. Suppress immune system 3. Administer antibodies against pathogenic antigens Steroids, antibiotics, biologics, pain relievers About 50% of patients do not achieve remission on biologics Patients may also develop resistance over time due to antibodies Biologics are expensive and more potential side effects Resistance due to antibodies to biologic protein in meds

LDN in Crohn’s Disease Dr. Jill Smith and colleagues More than 50%of patients had already failed or had side effects to biological agents Patients on LDN had more symptomatic, endoscopic, and histologic improvement compared to group that was not taking LDN Several patients demonstrated clinical response & closure of fistulas

LDN in Crohn’s Disease Study Presented at the 2015 American Gastroenterology Association meeting 37 of 56 patients experienced complete or partial remission on LDN therapy Results support potential use of LDN for active Crohn’s Disease in those not responding or achieving remission with standard regimens

LDN in Ulcerative Colitis Unlike Crohn’s Disease, large controlled trials have not been completed Typically LDN is offered in those failing standard therapy, including biologics In combination with biologics, may lead to remission

Benefits and limitations of LDN for IBD 1. Mucosal healing 2. Decreased inflammation 3. Does not suppress immune system 4. Does not increase risk of infection 5. Low toxicity Further studies are needed to make any firm conclusions regarding the likelihood of responding to LDN therapy

LDN in chronic fatigue syndrome (CFS) and Fibromyalgia (FM)

How can LDN be beneficial in cFS and FM? No clear etiology or treatment Associated with physiological abnormalities – immune dysfunction Definitions of these diseases do not address underlying cause for disease Unlikely that there is a single causative agent or process occurring, so simple RX is not likely to be totally effective Not addressing underlying cause = physician has no incentive to determine the underlying abnormalities that are occurring

Standard treatment for cfs and fm Muscle relaxants, antidepressants, NSAIDs, stretching, exercise FDA approved for FM: pregabalin (Lyrica), duloxetine (Cymbalta), milnacipran (Savella) 2% of patients experience complete recovery 64% of patients experience some improvement 50% of physicians not confident in knowledge of CFS or FM 40% of patients remain unable to work - Tx approved for FM is simple, symptomatic tx

Ldn in cfs and/or fm Over 4,000 patients in study 85% on LDN improved by 4th visit 56% of patients reported significant improvement

Benefits & limitations of LDN for CFS & FM 1. Proven effective 2. Physicians can prescribe it and help patients without investing extensive time and multiple visits 3. Low toxicity Further studies are needed to make any firm conclusions regarding the likelihood of responding to LDN therapy

LDN in thyroid disorders Graves’ Disease and Hashimoto’s Disease

How can LDN be beneficial in thyroid disorders? Unbalanced immune system attacks the thyroid LDN can modulate immune system to reduce abnormal production of antibodies LDN can also benefit in depression, insulin resistance, diabetes, obesity, anxiety, and other related chronic illnesses Graves’: antibody stimulates thyroid receptor = hyperthyroid Hashimoto: antibody and inflammation destroy thyroid gland tissue = hypothyroid LDN improved transport of TSH into cells, increases T4 to T3, and reduces T4 to reverse T3

Benefits & limitations of LDN for thyroid disorders 1. Can reduce abnormal inflammation and normalize immune abnormalities 2. Improves transport of thyroid hormone into cells 3. Low toxicity Further studies are needed to make any firm conclusions regarding the likelihood of responding to LDN therapy

In summary… LDN Effective and low toxicity Clinically beneficial for Crohn’s Disease and Ulcerative Colitis May be effective at improving symptoms of Chronic Fatigue Syndrome and Fibromyalgia Should be considered in patients with symptoms suggestive of thyroid disorders such as Hasimotos Disease LDN - IBD: promotes mucosal healing, decreases inflammation, and improved QOL

resource Elsegood L ed. The LDN Book. White River Junction, VT: Chelsea Green Publishing; 2016.

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