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Low Dose Naltrexone

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About Naltrexone

Naltrexone is a drug originally approved in 1984 as a treatment for drug and alcohol substance abuse. Naltrexone is an Opioid Antagonist and acts by binding to Opioid Receptors and preventing endorphin release during substance abuse. [1][2]

Naltrexone has been used at low doses (often around 4.5 - 5 mg), called Low Dose Naltrexone (LDN), in multiple diseases including:[12][13][14]
AIDS
Arthritis
Cancer
Fibromyalgia
Lupus
Multiple Sclerosis (MS)

More recently, LDN has shown promise as a treatment for Inflammatory Bowel Diseases (IBD)[6].

LDN Forum

We have a forum dedicated to Low Dose Naltrexone with additional information and discussion.

Low Dose Naltrexone Studies

The two studied conducted with LDN showed very promising results:

Study One
Study Two

Why Naltrexone?

Chronic administration of certain Opioids, such as Morphine, is known to inhibit the normal Immune Response to Infection and Delay Wound Healing. Morphine Over-Induces the Pro-Inflammatory Cytokines upregulated after tissue injury, and Inhibits production of proteins important for Wound repair.[8][9][10][11]

One of the first type of cells to respond to an infection are Macrophages. When Macrophages detect the presence of bacteria by the bacterial cell wall component, Lipopolysaccharide (LPS), they respond (in part) by secreting certain Pro-Inflammatory factors, which have a myriad of effects, including stimulating other cells to respond to the site of infection and secrete pro-inflammatory factors as well.
Naltrexone blocks Opiate - Induced Immune Cell Depletion
Opiates have been shown to reduce the numbers of Immune Cells including Lymphocytes, or decrease responsiveness of Immune Cells (such as in Natural Killer (NK) Cells and Phagocytosis by Macrophages), and reduce ADCC (Antibody Dependent Cellular Cytotoxicity). [12][13][14]

Many of these Opiate - Induced Immunosuppressive effects can be reversed with Naltrexone administration. [12][13][14]
Naltrexone Blocks the Morphine-Induced Over-Production of Inflammatory Factors
Certain Opioids, such as Morphine, have been shown to increase production and secretion of the Pro-Inflammatory factors by Immune Cells in response to LPS treatment (i.e. IL-6, IL-12, TNF-a) while reducing the production and secretion of Anti-Inflammatory factors (i.e. IL-10).[8]

The Opioid Antagonist, Naltrexone, when co-administered with Morphine to LPS-treated Macrophages will abate the Morphine-based over-induction of Pro-Inflammatory factors while also normalizing the Morphine-based under-induction of Anti-Inflammatory factors. Naltrexone treatment, in the absence of Morphine does not have an effect on the Macrophage's normal induction of Pro- and Anti-Inflammatory factors upon LPS stimulation, it appears to only normalize the Morphine-based effects. [8]

Low Dose Naltrexone (LDN) use in Crohn's Disease Patients

A trial of Low Dose Naltrexone (LDN) in patients with Moderate to Severe Crohn's Disease (as determined by CDAI >220) were treated with 4.5mg/day Naltrexone for 3 months.[7]
LDN Treatment:
Decreases CDAI
A Greater Percentage of Patients given LDN had CDAI decrease by 70 or more after 3 months of treatment compared to Placebo.
- 88% of LDN-treated patients had reduced CDAI by 70 or more
- 40% of Placebo-treated patients had CDAI lowered by 70 or more.
Promotes Healing of GI Mucosa
More Patients treated with LDN reduced Crohn's Disease Endoscopy Index Severity Score (CDEIS) by 5 points or more than Placebo treated Controls.
- 78% LDN Treated Patients
- 28% Placebo Control Patients
Increases Remission Rates
More Patients treated with LDN achieved Remission than Placebo treated Controls.
- 33% LDN Treated Patients
- 8% Placebo Control Patients

Naltrexone Dosage / Route of Administration

Naltrexone dosage for substance abuse treatment can range between 12.5 - 150 mg/day. [2]

Naltrexone is usually administered by oral dosing is sold under the brand names Depade and ReVia although can be administered via patch [3] or by sustained release injection, once per month, under the brand name Vivitrol [4][5].

Side Effects

Side Effects for Naltrexone is usually mild and many patients report no adverse symptoms. Most side effects disappear shortly after Naltrexone dose is stabilized.[2]
Common Side Effects Include:
Nausea
Vomiting
Headache
Dizziness
Fatigue
Insomnia

References

1. Narcotic Antagonists: Naltrexone Pharmacochemistry and Sustained-Release Preparations. NIDA Research Monograph, Number 28. 1981. Accessed Aug 2012. http://archives.drugabuse.gov/pdf/monographs/28.pdf

2. Leavitt SB. Evidence for the efficacy of naltrexone in the treatment of alcohol dependence (alcoholism). Addiction Treatment Forum. Naltrexone Clinical Update. Accessed Aug 2012. http://dpt.samhsa.gov/pdf/NTXWPFinalPDF.pdf

3. Wermeling, D.P. et al. Microneedles permit transdermal delivery of a skin-impermeant medication to humans. Proceedings of the National Academy of Sciences. 2008; 105(6):2058-2063. http://www.pnas.org/content/105/6/2058.full

4. Comer, Sandra D., et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence. Archives of General Psychiatry. 2006; 63(2):210-218. http://archpsyc.jamanetwork.com/data...1/YOA50089.pdf

5. http://www.drugabuse.gov/publication...ioid-addiction

6. Lesica C. Gastro-Hep News. Gastroenterol Hepatol (N Y). 2007; 3(3): 160–162. http://www.ncbi.nlm.nih.gov/pmc/arti.../GH-03-160.pdf

7. Smith JP, Bingaman SI, Ruggiero F, et al. Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn’s Disease: A Randomized Placebo-Controlled Trial. Dig Dis Sci. 2011; 56(7): 2088-2097. http://www.ncbi.nlm.nih.gov/pmc/arti...ihms373349.pdf

8. Peng X, Mosser DM, Adler MW, et al. Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages. Journal of Leukocyte Biology. 2000; 68(5): 723-728. http://www.jleukbio.org/content/68/5/723.full.pdf+html

9. Martin JL, Charboneau R, Barke RA, Roy S. Chronic Morphine Treatment Inhibits LPS Induced Angiogenesis: Implications in Wound healing. Cell Immunol. 2010; 265(2): 139-145. http://www.ncbi.nlm.nih.gov/pmc/arti...hms-230284.pdf

10. Martin JL, Koodie L, Krishnan AG, et al. Chronic Morphine Administration Delays Wound Healing by Inhibiting Immune Cell Recruitment to the Wound Site. Am J Pathol. 2010; 176(2): 786-799. http://www.ncbi.nlm.nih.gov/pmc/arti...H176000786.pdf

11. Dave RS and Khalili K. Morphine-treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: Impact on inflammation and oxidative stress in the Central Nervous System. J Cell Biochem. 2010; 110(4): 834-845. http://www.ncbi.nlm.nih.gov/pmc/arti...ihms188492.pdf

12. Szczytkowski JL. Conditioned Effects of Heroin on
Proinflammatory Mediators. 2009. https://cdr.lib.unc.edu/indexablecon...=uuid:e743550b

13. Hayes AW, Thomas JA, Gardner DE. Immunotoxicology and Immunopharmacology, Third Edition (Target Organ Toxicology Series). 2007. CRC Press.

14. Brown N. and Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Medical Hypotheses 2008. http://www.hypermed.com.au/HyperMED%...ty_of_life.pdf

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