Low Dose Naltrexone for Immunological-Related Disorders

October 2008, was truly an historic month! We witnessed the final days of the most historic presidential campaign in US history and the enactment of the Emergency Economic Stabilization Act of 2008 that would eventually pump $700 billion into an economy that has turned into a recession and perhaps headed toward depression. Imbedded in that historic Act was to me the most notable piece of the legislation –   the Mental Health Parity and Addiction Equity Act of 2008 ending rampant discrimination against Americans suffering from substance use disorders. Another October event was the Fourth Annual LDN Conference at the University of Southern California Health Sciences Campus in Los Angeles, California.1

LDN is the acronym for Low Dose Naltrexone. This was the fourth time the conference focused on this therapy signaling a rising level of confidence in the low dosage use of this opioid antagonist to treat a growing number of immunological-related disorders. Although the use of natrexone in the treatment of such conditions is not directed related to addiction or its treatment, I find its development to be so fascinating that I feel compelled to comment on it.

Naltrexone (Revia®, Depade®, Trexan®,Vivitrol®) is a powerful opioid receptor antagonist that is very useful in the treatment of opiate and alcohol dependence. It was the first US Food and Drug Administration (FDA) medication approved to treat a drug craving, specifically alcohol craving. This gave scientific validation to the idea that drug craving is an actual biologic manifestation and not merely manipulation by addicts to excuse a relapse.  Naltrexone was first approved to treat opioid addiction in 1984 as a medication that would block the effects of opioids if a recovering addict were to experience a “slip” after detoxification. The medication blocks opioid receptors in the brain preventing the addict from experiencing any effects and thereby preventing relapse. In reality, naltrexone is actually an endorphin/enkephalin receptor antagonist because our natural brain and body receptors are there for naturally-generated, endogenous, opiate-like brain chemicals: our endorphin/enkephalin neurotransmitters, rather than for external opioid drugs. Heroin, Vicodin®, Demerol®, Oxycontin® and other external opioid chemicals that by coincidence happen to mimic the chemical “signature” for our body’s own endorphin/enkephalin receptors. The FDA granted naltrexone approval for the treatment of alcohol dependence in 1995 after the medication was shown to reduce alcohol cravings in recovering alcoholics. Many clinicians and treatment programs continue to employ natrexone to treat a variety of “off-label” conditions (medical uses for non-FDA approved treatment indications) such as methamphetamine, nicotine, and other drug cravings. It has even been used to curb a “cutter’s urge to mutilate their skin. For these uses, naltrexone is usually prescribed at the same dose of 50 mg. to 150 mg. originally approved for blocking effects of opioid drugs or alcohol cravings and lasting 24 to 72 hours.  The rationale for using naltrexone to treat compulsive behaviors and drug dependencies other than opioids or alcohol is the hypothesis that cravings for these activities emanate from the same brain areas and involve the same neurotransmitters regardless of the specific drug being abused or the compulsive behavior practiced. The theory is if naltrexone can control alcohol and heroin craving, it could also control cravings for other drugs of abuse and compulsive behaviors like cutting and gambling.

In 1983, Dr. Ian Zagon discovered that naltrexone prolonged the survival of mice suffering from neuroblastoma cancer.2 During the mid 1980s, Dr. Bernard Bihari of Beth Israel Medical Center in New York began human research on the use of naltrexone at low doses of 1.5, 3 or 4.5 mg./day to treat AIDS and ARC. His work was presented at several International Conferences on AIDS in the late 1980s.3,4 He also began using LDN to treat a variety of immune system related illnesses and opened the door for additional research. Today, investigators are looking at LDN to effectively treat a vast number of difficult and often treatment resistant oncological and immunological disorders. By the October 2008, Dr. Bernard Bihari and a number of medical practitioners reported beneficial effects from Low Dose Naltrexone in the treatment of:
Alzheimer’s Disease
Amyotrophic lateral sclerosis (ALS)
Ankylosing Spondylitis
Autism Spectrum Disorders
Autoimmune Polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED)
Behcet’s Disease (a type of vasculitis)
Bipolar Disorder (Mood Disorder)
Cancers –
Bladder Cancer
Breast Cancer
Carcinoid
Colon & Rectal Cancer
Gliobastoma
Liver Cancer
Lung Cancer (non-small cell)
Lymphocytic Leukemia (chronic)
Lymphoma (Hodgkin’s & Non-Hodgkin’s)
Malignant Melanoma
Neuroblastoma
Ovarian Cancer
Pancreatic Cancer
Prostrate Cancer (untreated)
Renal Cell Carcinoma
Throat Cancer
Uterine Cancer
Celiac Disease (gluten intolerance)
Chronic Fatigue Syndrome
CREST Syndrome (limited scleroderma)
Crohn’s Disease (granulomatous colitis & regional enteritis)
Chronic Obstructive Pulmonary Disease     (COPD or emphysema)
Depression
Endometriosis
Endometriosis
Fibromyalgia
HIV/AIDS
Infertility
Irritable Bowel Syndrome (IBS)
Multiple Sclerosis (MS)
Murine Inflammatory Bowel Disease
Myalgic Encephalomyelitis (ME)
Obsessive Compulsive Disorder (OCD)
Parkinson’s Disease
Pemphigoid (blistering skin disease)
Premenstrual Syndrome (PMS)
Polycystic Ovarian Disease (PCOD) or Syndrome (PCOS)
Polymyalgia Rheumatica (PMR)
Primary Lateral Sclerosis (PLS)
Psoriasis
Rheumatioid Arthritis (RA)
Sacoidosis
Scleroderma
Stiff Person Syndrome (SPS)
Systemic Lupus Erythematosis (SLE)
Transverse Myelitis
Ulcerative Colitis
Wegener’s Granulomatosis (a type of vasculitis)

Reports on the efficacy of LDN to decrease severity of symptoms, stop the progression of or even reverse the development of the conditions listed above have been anecdotal  rather than “empirical” (rigorous scientific) to determine their validity.

Although there is a lack of empirical studies to confirm LDN’s beneficial effects, the large number of anecdotal reports and the fact that the low dosages used exposes patients to only minimal, if any of naltrexone’s side effects, is enough for some scientists to recommend its use as a general health tonic as well as for specific medical conditions. Norman Brown and Jaak Panksepp, neuroscientist at Embry-Riddle Aeronautical University in Daytona Beach Florida speculate that LDN can be used as a buffer for a large variety of physical and mental ailments due to its ability to beneficially modulate both the immune system and regulate positive neurotransmitter affects. Brown and Panksepp agree that LDN supports immune-modulation that can reduce cancerous and inflammatory autoimmune processes. They also cite the ability of LDN to up-regulate endorphin/enkephalin activity to promote stress-resilience, exercise, social-bonding, and emotional well-being when reducing problems of autism and depression.16

The proposed mechanism of action for LDN’s positive effects on treating such a wide spectrum of disorders is due to its ability to up-regulate endorphin levels in the body. Dr. Bernard Bihari discovered that the human body produces almost all of its daily quantity of beta-endorphins between 2 am and 4 am. Partially blocking endorphin receptors for that 2 hour duration by administering a very low dose (1.4 to 4.5 mg) of naltrexone at bedtime supposedly stimulates the brain’s production of more endorphins than usual in an attempt to overcome the partial blockage of its endorphin/enkephalin receptor sites. Dr. Bihari found that doses below 1.5 mg. had no effects on blood levels of beta-endorphins during the following daytime hours and doses larger than 5 mg. caused too great of an endorphin blockage. His research revealed that LDN at bedtime resulted in a doubling to tripling of beta-endorphins circulation in the blood the next day.6 Animal research by Dr. Ian Zagon showed that LDN resulted in a marked increase in circulating met-enkephalin levels as well.5 Endorphins have been found to play a central role in the beneficial orchestration of our immune system. Endorphins/enkephalins alter the development, differentiation, and function of immune cells which have opioid-related receptors on their cell membranes. Bone marrow progenitor cells, macrophages, natural killer cells, immature thymocytes, T-Cells and B-Cell are all affected by endorphin management.5 Increasing levels of the body’s natural opioid neurotransmitters (endorphins/enkephalins) via LDN therapy, is projected to result in more positive management of the human immune system. Those who suffer from immunological-related disorders have low levels of endorphins.5,6

Despite the enthusiasm generated by the last four national LDN conferences and of those who are finding it effective in the treatment of many difficult to treat immunologic disorders, the prospect that LDN will soon be fully approved by the FDA is not certain. The FDA will require rigorous testing of LDN for each specific medical condition it is being used to treat. The testing process for each condition is costly despite the 1983 US Orphan Drug Act. Since naltrexone’s original drug patent has expired, it is more profitable for pharmaceutical firms to develop new medications than to invest in developing new uses for a patent expired medication. Further, most of the immunologic-related disorders that it could potentially benefit are rare. Drugs developed to treat very rare conditions (affecting less than 200,000 individuals) often become “orphan drugs” because there is little financial incentive for pharmaceutical companies to invest millions of dollars on the research needed to gain full FDA approval. This economic reality is the reason very promising medications are often abandoned or orphaned by drug companies.   Orphaned Drugs can still be used to treat “off-label” medical conditions and groundswell movements like the National LDN Conferences help to establish and promote such therapies.

A final comment, I was doing some research on the history of cocaine in the 1960s and remember coming across Uber Coca, a treatise authored by Dr. Sigmund Freud in 1884. Dr. Freud’s enthusiasm for positive medical uses of cocaine prompted him to recommend it for the treatment of over 360 medical conditions. It is now clear that Freud’s early enthusiasm stemmed more from the euphoric effects that cocaine generated for the prescribing physicians than from actual health improvements shown by their cocaine treated patients. Similarly, current investigators should curb their enthusiasm as they see LDN therapy deliver positive outcomes with so many difficult to treat diseases. Empirical research is needed to confirm their positive anecdotal observations. If the US Pharmaceutical Industry is not willing to invest in this promising medical treatment, perhaps it is time for public or government entities to step in and take it to the next step.

Darryl S. Inaba, PharmD., CADC III
February 2009

References

1. A Revolution in Research: The Fourth Annual LDN Conference (2008), Post-Conference Report & Multimedia, http://www.ldninfo.org/conf2008.htm accessed 12/6/08.

2. Zagon IS, McLaughlin PJ, (1981), Naltrexone prolongs the survival time of mice treated with neuroblastoma, Life Sci, 28:1095-1102.

3. Bihari, B, Curriculum Vitae (2008), http://www.ldninfo.org/bbihari_cv.htm accessed 12/12/08.

4. Bihari B, Drury F, Ragone VP, Ottomanelli GA, McCoy J, Buimovici-Klein E. Low-dose naltrexone in the treatment of AIDS. Presented at the IV International Conference on AIDS, Stockholm, Sweden, June 1988

5. Low Dose Naltrexone Homepage (2008), http://www.ldninfo.org/index.htm accessed 12/6/08.

6. LDN and Autoimmune Disease (2008), http://www.lowdosenaltrexone.org/ldn_and_ai.htm accessed 4/25/08.

7. LDN and Cancer (2008), http://www.lowdosenaltrexone.org/ldn_and_cancer.htm accessed 12/6/08.

8. Agrawal, YP (2005), Low dose naltrexone therapy in multiple sclerosis, Med Hypothesis, 64(4):721-4.

9. Patel, PN (2007), Low dose naltrexone for treatment of multiple sclerosis: clinical trials are needed. Ann Pharmacother, 41(9):1549-50.

10. Good, P (2006) Low-dose naltrexone for multiple sclerosis and autism: does its benefit reveal a common cause? Med Hypotheses, 67(3):671-2.

11. Gironi, M et. al. (2008), A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis, Mult Scler, 14(8):1076-83.

12. Smith, JP et. al. (2007), Low-dose naltrexone therapy improves active Crohn’s disease, Am J Gasteroenterol, 102(4):820-8.

13. Kariv, R et. al. (2006), Low-dose naltrexone for the treatment of irritable bowel syndrome: a pilot study, Dig Dis Sci, 51(12):2128-33.

14. Matters, GL et. al. (2008), The opioid antagonist naltrexone improves murine inflammatory Bowel disease, J Immunotoxicol, 5(2):179-87.

15. Boyle, P (2006), Low Dose Naltrexone, presentation at Second Annual LDN Conference April 7, 2006, National Library of Medicine, Bethesda, Maryland http://www.lowdosenaltrexone.org/_conf2006/p_boyle.pdf accessed 12/5/08.

16. Brown, N and Panksepp, J (2008), Low-dose naltrexone for disease prevention and quality of life, Med Hypotheses Nov. 26, 2008, Epub ahead of print, http:www.ncbi.nlm.nih.gov/pubmed/19041189?ordinalpos=1&itool=entrezsystem2.Pent accessed 12/5/08.