Low Dose Naltrexone (LDN): The New Treatment You've Never Heard of...

Low Dose Naltrexone (LDN):  The treatment you've never heard of...

Why haven't you heard about this amazing new breakthrough for conditions ranging from autoimmunity to cancer?  Perhaps because as of yet no company has stepped forward with the billions of dollars needed to do a large-scale study on low-dose naltrexone (LDN).  Unfortunately getting FDA-approval for use is not a straightforward process.  With the patent expired, no drug company has been willing to pay such a large sum when they cannot sell the drug exclusively.

However, if you check PubMed, there are currently over 90 studies published on the various uses of LDN, from pain relief, fibromyalgia, Crohn's disease, multiple sclerosis, systemic sclerosis and even cancer.  I have been using this drug in clinical practice with great results for the past several years and I want to tell you about it...

So how does LDN work?

Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered the mechanism by which a low dose of the opioid antagonist naltrexone, an agent used clinically (off-label) to treat cancer and autoimmune diseases, exerts a profound inhibitory effect on cell proliferation. We believe that opioid receptor blockade by LDN provokes a compensatory elevation in endogenous opioids and opioid receptors that can function even after LDN is no longer available.

These papers revealed that a short-term opioid receptor blockade with naltrexone (LDN), a general opioid receptor antagonist devoid of intrinsic activity, results in an elevation in production of your own opioids and in response to the blockade. Interference of opioid peptide–opioid receptor interactions for a short time each day (from 4-6 hours) with LDN provided a subsequent window of time (18–20 hours) for the increased levels of endogenous opioids and opioid receptors to elicit a robust functional response: the inhibition of cell proliferation.  In addition many patient report an improved sense of well-being and decrease in overall pain, as one might expect with higher levels of opioid production in the body.

Preliminary Research Abounds for cancer and autoimmune disease

Low dose of the opioid antagonist naltrexone (LDN) is being used clinically off-label to treat cancer and autoimmune diseases, by exerting a profound inhibitory effect on cell proliferation.  LDN is an oral medication, generic, inexpensive, and non-toxic, and has been documented to alter the course of both neoplasias and autoimmune diseases such as Crohn's and multiple sclerosis, making this drug especially attractive as a therapeutic agent.

According to this study in Clinical Rheumatology, Low Dose Naltrexone(LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. They suggest that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated.

A study published online in the Cochraine Library in February 2014 discusses using low-dose naltrexone to induce remission in Crohn's Disease.  Although the author conclude there is insufficient evidence to recommend and further research is needed, data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn’s disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo.

In the Journal of Clinical Gastroenterology April 2013, Naltrexone therapy appears safe with limited toxicity when given to children with Crohn’s disease and may even reduce disease activity.

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome involves glial activation and central sensitization in the central nervous system. This can be a difficult disease to treat and patients suffer greatly with severe chronic pain.   An article in the Journal of Neuroimmune Pharmacology showed positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone, in combination with other CRPS therapies.  Perhaps this is because Low Dose Naltrexone (LDN) is known to antagonize the Toll-like Receptor 4 (TLR4) pathway and attenuate activated microglia.

Link to Fibromyalgia and Autism?

Another article posted online in Discovery Medicine came to the following conclusions:

1. Patients on chronic opioids relate autistically.
2. Autism is a hyperopioidergic disorder.
3. Fibromylagia is a hypoopioidergic disorder.
4. Low opioid tone caused by opioid maintenance or fibromyalgia can usually be reversed with low-dose naltrexone.
5. The increase in the incidence of autism may have been caused by the increase in use of opioids for analgesia during childbirth.

The bottom line is that for disorders that involve low endogenous opioid production, like fibromyalgia and chronic fatigue syndrome, Low Dose Naltrexone may prove to be profoundly beneficial.

A January 2013 article written in Arthritis and Rheumatology concluded that evidence continues to show that low dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated.

Motility Agent for Small Intestinal Bacterial Overgrowth (SIBO)

Another novel use of Low Dose Naltrexone has been for aiding motility in SIBO (small intestinal bacterial overgrowth).  Ploesser et al described the use of LDN for aiding the migrating motor complex (MMC) in cleansing the small bowel.  His small study use 2.5mg twice daily in patients with IBS and evidence of SIBO and 4.5mg daily in patients with inflammatory bowel disease.  Approximately 68% of the study patients had improvement in symptoms taking LDN.  According to other research, LDN may have effects on the gut to decrease inflammation, decrease intestinal permeability and stabilize toll like receptors, in addition to aiding motility.

Experimental and Off-label but well tolerated and promising

The use of LDN for chronic disorders is still experimental and considered off-label.  This doesn't stop progressive doctors from prescribing it due to it's safety profile.  The typical dose of LDN is a compounded immediate release tablet from 1.5 to 4.5mg taken at bedtime.   The few reported side effects may be related to opioid blockade at night.  Occasionally patients report anxiety, insomnia, vivid dreaming or nightmares.  There are a portion of patients who already have elevated opioids that may not tolerate the drug. To avoid side effects, I generally start patients on half of intended dose and increase after 7-10 days.  If they still report symptoms, we move the dosing earlier in the day and may still get a beneficial effect.

Low Dose Naltrexone is an oral medication, generic, inexpensive, and non-toxic, and has been documented to alter the course of both neoplasias and autoimmune diseases such as Crohn's and multiple sclerosis, making it an attractive and effective therapeutic agent.

For more on LDN watch my recent interview with Dr. Alex Vasquez ...

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More References:

1. Low Dose Naltrexone Research Trust
2. LDN Clinical Trials 

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Zonulin & Leaky Gut: A discovery that changed the way we view inflammation, autoimmune disease and cancer!

An amazing discovery a few years ago revolutionized our ability to understand the gut and permeability and how this impacts a wide range of health conditions from cancer to autoimmune disease to inflammation and food sensitivities. 

This little molecule, zonulin, has quite a story...

Zonulin is the "doorway" to leaky gut

Zonulin opens up the spaces between the cells of the intestinal lining. That normally occurs, in order for nutrient and other molecules to get in and out of the intestine. However, when leaky gut is present, the spaces between the cells open up too much allowing larger protein molecules to get into the bloodstream where an immunologic reaction can take place. Once that happens, the body is primed to react to those proteins each and every time they appear.  It can also cause leakage of intestinal contents, like bacteria into the immune system creating inflammation and overloading the liver's ability to filter out this garbage.

Triggers that open the zonulin doorway

Based on Dr. Fasano's research, we know that the two most powerful triggers to open the zonulin door are gluten and gut bacteria in the small intestine.  Gliadin causes zonulin levels to increase both in those people who have celiac disease and those who do not.  As the zonulin level rises, the seal  between the intestinal cells diminishes, opening up spaces between cells that allow all sorts of things to pass right through.  This is called "leaky gut".  Its as if the security guard that keeps the bad guys out is taking a nap! Sometimes large food molecules will pass through to the immune system.  The immune system thinks they are foreign invaders and will mount an immune response leading to food sensitivities.  In addition this immune activation leads to more damage to the intestinal cells (called enterocytes) and the gut becomes more inflamed and more permeable or "leaky".  As the damage continues, the microvilli that line the intestines and absorb nutrients become damaged, leading to other nutrient deficiencies.  

Top causes of increased zonulin and development of leaky gut:

1. Overgrowth of harmful organisms, like bacteria or yeast in the intestine 
1. SIBO = small intestinal bacterial overgrowth
2. Fungal dysbiosis or candida overgrowth
3. Parasite infections
2. Gliadin in the diet (gluten containing foods)

Gliadin is a protein in wheat, that like gluten, is a trigger for people with celiac disease. However, a study published in the Scandiavian Journal of Gastroenterology in 2006 clearly showed that gliadin can affect zonulin even in people without the gene for celiac. The researchers concluded that

Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

The significance of this is that gluten affects intestinal permeability in all persons to different extents.  It also means that 100% of patients with autoimmune disease or leaky gut could potentially benefit from a gluten-free diet.

Elevated zonulin levels and leaky gut are also associated with the following:

1. Crohn's disease
2. Type 1 Diabetes
3. Multiple Sclerosis
4. Asthma
5. Glioma
6. Inflammatory Bowel Disease

In conclusion the article states: 

Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer. This new theory implies that [once this path is activated] it can be... reversed by preventing the continuous interplay between genes and the environment.

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Alessio Fasano

Abstract:
The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.