Low dose naltrexone

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Low dose naltrexone (LDN), where naltrexone is used in doses approximately one-tenth those used for drug/alcohol rehabilitation purposes, is being used as an "off-label" treatment for certain immunologically-related disorders. The use of LDN for such diseases as cancer was discovered and developed by Ian Zagon, PhD in animal and in vitro research, and LDN's broader clinical effects in humans were discovered by Bernard Bihari, MD.

In Milan, Italy, a sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Their data clearly indicated that LDN is safe and well tolerated in patients with PPMS. That only one patient showed any progression of PPMS during the six-month period of this trial is extraordinary, as is the occurrence of a statistically significant reduction in spasticity. Multiple Sclerosis. 2008 Sep;14(8):1076-83. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. http://msj.sagepub.com/cgi/content/abstract/14/8/1076

Low-dose naltrexone (LDN) may be useful in treating fibromyalgia, according to research published online April 22 in Pain Medicine. Jarred Younger, Ph.D., and Sean Mackey, M.D., of the Stanford University School of Medicine in Palo Alto, Calif., analyzed data from 10 women with fibromyalgia who went through a single-blind crossover trial with two weeks of reporting symptom severity with no treatment; two weeks of placebo; eight weeks of daily low-dose naltrexone (4.5 milligrams); and a two-week washout period with no treatment. Overall, the treatment reduced fibromyalgia symptoms by 30.2 percent above placebo in the group, the investigators found. During placebo and treatment phases, symptoms were reduced by 2.3 and 32.5 percent, respectively. Six subjects were classified as drug responders. Baseline erythrocyte sedimentation rate predicted more than 80 percent of variance in response to the drug, the researchers report. "Fibromyalgia is a costly condition, both in terms of lost productivity, and the cost of available treatments. LDN is an inexpensive drug, with total costs usually running under $40 per month. There are several additional advantages to LDN. The drug is easily dosed, with a once-a-day schedule. Side-effects are infrequent and mild," the authors write. "We conclude that LDN is a drug that should be researched more thoroughly for the treatment of fibromyalgia, and perhaps more generally for conditions associated with elevated erythrocyte sedimentation rate." The American Fibromyalgia Syndrome Association provided financial support for the study. http://snapl.stanford.edu/research/ldn.html

The results of a successful open-label pilot study at Pennsylvania State University College of Medicine were reported to an international gastroenterology conference in Los Angeles in May 2006. The trial demonstrated the safety and efficacy of LDN in a group of patients with Crohn's disease, thought of as an autoimmune disorder by many Drs. Dr. Jill Smith, Professor of Gastroenterology at Pennsylvania State University's College of Medicine, found that two-thirds of the patients in her pilot study went into remission and fully 89% of the group responded to treatment to some degree. She concluded that "LDN therapy appears effective and safe in subjects with active Crohn’s disease."[1] Smith and her colleagues have since received a substantial NIH grant and are proceeding with a definitive Phase II placebo-controlled clinical trial.

In addition, there is some in vitro data that indirectly suggest the potential benefits of LDN therapy. Many anecdotal accounts and case reports have also been cited in favor of LDN therapy. Some of the many conditions for which LDN has been reported as beneficial include multiple sclerosis (in particular, the primary progressive variant[2]), Crohn's disease, HIV/AIDS, chronic fatigue syndrome, irritable bowel syndrome, psoriasis, fibromyalgia, ALS, autism in children, depersonalization disorder, and cancer. Several clinical trials have been planned and a few are currently taking place.

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[edit] Pharmacology

LDN has been theorized to work in multiple modalities. Without formal studies, there is no formal conclusion as of yet, but the generally accepted theory posited originally by Dr. Bihari is as follows:

Beta-endorphins are important regulators of the immune system. Naltrexone, which is a pure antagonist to narcotics, causes an artificial blockade of the endorphin/opioid receptors in the brain. However, unlike the normal (50mg) dose of naltrexone used to treat drug addiction, which maintains this blockade continuously for 24 hours (preventing any derived pleasure from taking the drugs), low dose naltrexone (3mg to 4.5mg) blocks the endorphin receptors for only a few hours. During that time, endorphins fail to attach to the receptors and the body apparently compensates by creating more. (Note that Dr. Bihari prescribes LDN to be taken at bedtime to take advantage of the body's pre-dawn(2am-4am) boost in endorphin production.) Once the low dose naltrexone dose has been metabolized, the body is left with a "normal" amount of endorphins as compared to healthy controls, which consequently normalizes the immune function.

This theory of LDN's mechanism contradicts the widely-held belief that autoimmune diseases are caused by an overactive immune system. However, since 2005, at least 3 separate scientific reports have described an underlying immunodeficiency as being characteristic of four different autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, Crohn's disease and chronic fatigue syndrome.[3][4][5] In addition, recent scientific research has demonstrated abnormally low beta-endorphins in all forms of multiple sclerosis.[6]

In April 2006 an LDN conference was held at the National Cancer Institute. Several lecturers were present discussing the use of LDN in Crohn's disease, multiple sclerosis, general autoimmune disease, and cancer. One participant, Burton M. Berkson MD PhD of Las Cruces, New Mexico discussed his successful experience treating metastatic pancreatic cancer and B cell lymphoma with LDN at bedtime.

Dr. Berkson described one patient who was diagnosed with "terminal" and metastatic pancreatic cancer at a well-respected oncology center. After treatment with a healthy life style program and LDN at bedtime he is alive, well, and back at work almost 5 years after diagnosis. Today, he is described as free of symptoms[6].

Another patient with greatly enlarged lymph nodes in his neck, axillae, and groin and diagnosed with a B cell lymphoma was found to be free of signs and symptoms after 6 months of LDN therapy.[7]In his presentation, Dr. Berkson used before and after CT and Pet scans to show improvement, or reversal, of the disease process in four patients.

[edit] Controversy

Critics point out that the drug companies and doctors refuse to test LDN on multiple sclerosis patients, as LDN boosts the immune system. As a prevailing theory is that MS patients have over-active immune systems, many do not feel that LDN is a safe drug for those with MS. Critics also point to the fact that some doctors who prescribe LDN to MS patients do it via a telephone conversation, without even seeing the patients or their medical records, for which they receive a payment from the person for the phone consultation. Some who use LDN can experience vivid dreams for the first couple weeks and those with multiple sclerosis can also suffer increased stiffness in the beginning of use.

[edit] Conferences

The most recent (now annual) LDN Conference was held on 11 October 2008 at USC Health Sciences Campus, Los Angeles, California, USA.

The first European LDN Conference was held on 25th April 2009 at The Western Infirmary, Glasgow, Scotland, UK. The next is on 23rd-24th April 2010.

[edit] References

  1. ^ *Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS (April 2007). "Low-dose naltrexone therapy improves active Crohn's disease.". Am J Gastroenterol 102 (4): 820–8. doi:10.1111/j.1572-0241.2007.01045.x. PMID 17222320. 
  2. ^ Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G (2008). "A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.". Multiple Sclerosis 14 (8): 1076–83. doi:10.1177/1352458508095828. PMID 18728058. 
  3. ^ *Thewissen M, Linsen L, Somers V, Geusens P, Raus J, Stinissen P (June 2005). "Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients.". Ann N Y Acad Sci 1051: 255–62. doi:10.1196/annals.1361.066. PMID 16126966. 
  4. ^ *Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B, Lees W, Novelli M, Bloom S, Segal AW (25 February 2006). "Defective acute inflammation in Crohn's disease: a clinical investigation.". Lancet 367 (9511): 668–78. doi:10.1016/S0140-6736(06)68265-2. PMID 16503465. 
  5. ^ *Vernon SD, Reeves WC (April 2006). "The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome.". Pharmacogenomics 7 (3): 345–54. doi:10.2217/14622416.7.3.345. PMID 16610945. 
  6. ^ *Gironi M, Furlan R, Rovaris M, Comi G, Filippi M, Panerai AE, Sacerdote P (2003). "Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis.". J Neurol Neurosurg Psychiatry 74 (4): 495–7. doi:10.1136/jnnp.74.4.495. PMID 12640071. 

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