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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Dr. Jill's Story

When you meet Dr. Jill, you will immediately sense her compassion and genuine desire to help people find answers and give them hope that they can feel healthy again.  What you may not know is that her own journey through life-threatening illness was a powerful force in shaping her passion for teaching people how to heal through functional medicine.  Read her story here… 

My Story

Since my childhood, I have always been passionate about seeking answers to complex problems. I believed that the human body could regain health given the right tools.  However, it wasn’t until June of 2001 that I had very personal encounter with my own mortality.  It was then I had put this belief into action...

Sudden Turn of Events … from Doctor to Patient

During my 3^rd year of training in medicine at Loyola University in Chicago, I found an unusual lump in my left breast and with my husband’s insistence; I proceeded to schedule an ultrasound and biopsy.  Although I scheduled the tests, I was not too concerned that this lump might signify something more serious.  A few days later however, my worst nightmare was confirmed with a call from the surgeon.  She said yes, despite all of the statistics against it at the age of twenty-five years old, I had invasive ductal carcinoma (i.e. breast cancer).  I was devastated!  This sudden news sent my very orderly world spinning as I began to process what the next 12 months would hold… several more surgeries, six rounds of aggressive chemotherapy followed by many weeks of radiation, ugh!  I literally went from doctor to patient overnight.  The rest of that year was a blur as I took a leave of absence from medical school to complete this harsh treatment regimen.  During this time, an important part of my plan included nutritional supplementation, daily exercise and prayers for healing.   By the summer of 2002, I had officially “beaten” the cancer but nearly destroyed my body in the process.  Completely bald, malnourished, and down to my lowest weight since fourteen, I was physically depleted but mentally and emotionally still in the game.

From Surviving to Thriving…

At this point, although I had just beaten cancer, I was determined to go further.  My desire was to go from surviving to a place of thriving… full of energy and life!  My unwavering faith in God and my passion for nutrition became instrumental in turning my health around.  The battle against an aggressive deadly breast cancer was only the beginning of my journey.  Six months after completing therapy and returning to medical school, I was once again diagnosed with a very serious medical condition.

Round Two: a Second Diagnosis…

The following year I was diagnosed with Crohn’s disease, a very painful autoimmune disease, in which the body’s own immune system attacks the gastrointestinal lining, causing nutrient depletion, cyclical fevers, fatigue, weakness and ongoing abdominal pain.  Undoubtedly connected to the toxic effect of   chemotherapy on my gut lining, I was determined to beat this new threat as well. In the beginning, my gastroenterologist told me point blank, “Diet has nothing to do with this.”  He also gave me the prognosis that I would need multiple surgeries over my lifetime and would never be completely cured. I was given powerful medications to calm the inflammation, but they did nothing for my symptoms.  I was told that I would require steroids and immune-suppressing medications to control the disease.   Refusing to believe that surgery and medications were the only options, I studied extensively on the healing power of nutritious food and dietary changes.   I began by making major changes in my own diet, eliminating gluten, dairy, and all processed foods and eating nutrient dense options instead.  I also consulted with a wise naturopath who taught me the power of appropriate nutritional supplementation in restoring health and energy and healing the inflammation in my gut.

Back to Optimal Health!

“This sickness will not lead to death... It is for the glory of God” John 11:4

Now over twelve years later, after relentless pursuit of personal healing I am currently in the best health of my life, completely free of breast cancer and healed from Crohn’s disease!   I continue to eat an organic, whole food, gluten-free Paleo-style diet, exercise regularly, and practice my faith through prayer and meditation. It is evident that God healed my body expressly for the purpose of helping others and thus, I am committed to helping people find answers and live vibrantly through functional medicine. More than ever before, I believe that the human body can regain health if given the right tools… and I am living proof!

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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.

The Gut Immune System Connection - An Animated Video

The gut mucosa connects with the largest population of immune cells in the body!  Is it any wonder that in functional medicine we assess your gut function as one of the initial steps in cases of allergies, asthma, autoimmune disease, eczema, crohn's disease, ulcerative colitis, IBS, celiac disease, arthritis and more?  

It’s often the first point of exposure to pathogens.   Many microbes use it as a entry point into the rest of the body. The gut immune system therefore needs to be ready to respond to pathogens but at the same time it is constantly exposed to harmless environmental antigens, food particles and commensal microflora which need to be tolerated. Misdirected immune responses to harmless antigens are the underlying cause of food allergies and debilitating conditions such as inflammatory bowel disease. This animation introduces the key cells and molecular players involved in gut immune connection and disease.



By checking your gut's microbial environment and taking a functional medicine approach to health and wellness, we can actually modulate some of the underlying immune dysregulation and eliminate your symptoms!

Nature Immunology homepage: http://www.nature.com/ni/index.html

Leaky Gut - The Syndrome Linked to Many Autoimmune Diseases...

"Leaky Gut" Syndrome

Hyperpermeability or "leaky gut" syndrome is the name given to a very common disorder in which the cells lining the intestines become "leaky" due to inflammation. The abnormally large spaces present between the cells of the gut wall allow the entry of toxic material into the bloodstream that would normally be eliminated.

The gut becomes leaky in the sense that bacteria, fungi, parasites, undigested protein, fat and toxic waste normally not absorbed into the bloodstream in the healthy state, pass through a damaged, hyperpermeable gut membrane. This can be verified by special gut permeability urine tests or microscopic examination of the lining of the intestinal wall.

Common Causes of Leaky Gut

• Infections - fungal overgrowth, parasitic infections
• Drugs like
• NSAIDS, chemotherapeutic agents
• Crohn's disease or Ulcerative Colitis
• Celiac disease
• Chronic alcoholism
• Strenuous exercise
• Food allergies

Leaky Gut and the Connection to Autoimmune Disease

Leaky gut syndrome is almost always associated with autoimmune disease. In fact, reversing symptoms of autoimmune disease depends on healing the lining of the gastrointestinal tract. Any other treatment is just symptom suppression. An autoimmune disease is defined as one in which the immune system makes antibodies against its own tissues. Diseases in this category include lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren’s syndrome (dry eyes & dry mouth), vitiligo, thyroiditis, vasculitis, Crohn’s disease, ulcerative colitis, urticaria (hives), type 1 diabetes and Raynaud’s syndrome. Fortunately doctors are beginning to realize the essential role that the gut plays in these disease. Understanding the leaky gut phenomenon helps us see why allergies and autoimmune diseases develop and how to design therapies to restore intestinal integrity and reverse leaky gut.

Inflammation is a key trigger for leaky gut

Inflammation causes the spaces between the cells of the gut wall to become larger than usua. Then protein molecules are absorbed before they have a chance to be completely broken down. The immune system starts making antibodies against these larger molecules because it recognizes them as foreign, invading substances. Antibodies are made against these proteins derived from previously harmless foods. The immune system becomes hyperstimulated and over-reactive to substances that are not necessarily supposed to be dangerous.

Human tissues have proteins & antigens very similar to those on foods, bacteria, parasites, candida or fungi. The antibodies created by the leaky gut phenomenon against these antigens can get into various tissues and trigger an inflammatory reaction in that tissue when the corresponding food is consumed or the microbe is encountered. Autoantibodies are thus created and inflammation becomes chronic. If this inflammation occurs in a joint, autoimmune arthritis (rheumatoid arthritis) develops. If it occurs in the brain, myalgic encephalomyelitis (chronic fatigue syndrome) may be the result. If it occurs in the blood vessels, vasculitis (inflammation of the blood vessels) is the resulting autoimmune problem... and so on.

If the antibodies end up attacking the lining of the gut itself, the result may be colitis or Crohn’s disease. If it occurs in the lungs, asthma is triggered on a delayed basis every time the individual consumes the food which triggered the production of the antibodies in the first place. It is easy to see that practically any organ or body tissue can become affected by food allergies created by the leaky gut. Because the foods can trigger delayed reactions, it can often be very hard to pinpoint the triggering entity.

 
Leaky gut may cause increase risk of infection and sensitivity to environmental chemicals

This ongoing inflammation also damages the protective coating of antibodies normally present in a healthy gut called IgA. Since IgA helps us ward off infections we become less resistant to viruses, bacteria, parasites and candida. These microbes are then able to invade the bloodstream and colonize almost any body tissue or organ. In the clinic we often find patients with leaky gut or autoimmune disease also have microbial infections ongoing in the gut.

Not only can leaky gut create food allergies as the proteins we consume are activating antibodies, but the microbes in the gut can cross over into the blood stream creating a toxic burden that overwhelms the liver's ability to detoxify. Often in severe cases of leaky gut, patients will develop sensitivities to perfume, cigarette smoke or other environmental chemicals. Common complaints are also "brain fog", confusion, poor focus/concentration, or memory loss.

Leaky gut also causes malabsorption and nutritional deficiencies

Finally, leaky gut may contribute to a long list of mineral deficiencies because of the ongoing inflammation and damage to carrier proteins. The most common are iron deficiency, vitamin B12 deficiency, magnesium deficiency which can lead to fatigue, neuropathies or muscle pain. Zinc deficiency due to malabsorption can result in hair loss or baldness as occurs in alopecia areata. Copper deficiency can occur in an identical way leading to high blood cholesterol levels and osteoarthritis. Further, bone problems develop as a result of the malabsorption of calcium, boron, silicon and manganese.

Part II - Diagnosis and Treatment of Leaky Gut...

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