Pain and the Immune System – It’s Not Just About Neurons – Naltrexone

01/25/2011 — Nancy Sajben MD

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The Immune System and Pain

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There is a whole new way of thinking of about pain that has nothing to do with pain being

transmitted by nerve cells in well defined nerve pathways.

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In the last few years, we have learned it has to do with activation of glia and the immune system.

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Pain is a central neuroimmune activation.

There is close interaction of nerve pathways and the central immune system.

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Neuroimmune responses parallel but do not always mirror peripheral immune responses.

The differences are critical.

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The science of understanding immune cell-glia and glia-neuronal interactions is in its infancy.

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What are glia?

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Glia are cells in the central nervous system (CNS), the brain and spinal cord. Ninety percent of the cells in the CNS are glia – microglia, astrocytes, oligodendroglia, perivascular glia. Glia outnumber neurons by a factor of 10 to 1.

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Microglia and astrocytes are immune cells that can release inflammatory responses with harmful effects on nerve cells such as inflammation, toxicity, and excitability. However, scientists are beginning to show that activation may also lead to good outcomes that are helpful for nearby glia and neurons, protecting against inflammation, toxicity and restoring normal pain signaling. In other words, they can restore balance.

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Beneficial and pathological microglia

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Neuroinflammation is a normal and necessary process in the acute phase, but not when it takes on a life of its own and creates persistent pain or disease directed against normal tissue (autoimmune response). They may fail to release protective agents (e.g. BDNF, Brain-Derived Neurotrophic Factor).

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Neuron-glia Tetrapartite Synapse

Glial activation from pro-inflammatory to anti-inflammatory state

(click image to enlarge)

Image from Milligan, E, Watkins, L. Pathological and Protective Roles of Glia in Chronic Pain,

Nature Reviews 10:23-36 (2009)

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Neuroinflammatory Disorders

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There is an growing body of evidence that shows many diverse diseases are characterized by neuroinflammation, such as Alzheimers, Parkinson’s Disease, ALS, Multiple Sclerosis, neuromuscular and myofascial syndromes and neuropathic pain, fibromyalgia, and chronic fatigue syndrome. Our research plans to show activation of glia in other conditions: Tourette’s Syndrome, dystonia, blepharospasm, and torticollis. A neuronal model no longer works to explain these conditions.

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What the heck is microglial activation and priming?

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How do glia become activated? They are always active, not activated but active, surveying their environment. Something must occur for them to become activated. Similar to a bee sting that primes your immune system, the first bee sting will not kill the person who is allergic, but BOOM! the second sting can kill. Glia can become primed by a first pain, but when pain next occurs, glia become activated and they respond faster, harder, longer.

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When activated, they change shape like amoeba and migrate to the site of injury or infection or stroke or dead cells where they proliferate, release cytokines, and phagocytose (consume) targets such as virus, dead tissue, important in wound healing. Microglia and astrocytes can release neuroexcitatory and pro-inflammatory products and growth factors for pain and hyperalgesia. See links to several recent publications on glia here, and mechanisms here and here. Microglia can repair the CNS. Or, an injury may heal and be long gone, but chronic pain may persist for years. How do we turn it off? The signal is no longer telling us about a new danger.

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The goal of research is to find ways to interact with the cascades of pro-inflammatory molecules and receptors to restore balance in the system. This is a major paradigm shift in treatment of chronic pain that has already led to many insights. Refer articles here.

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Toll Like Receptors

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Like all immune competent cells, glia have a myriad of receptors on their cell surface membranes. One of the more important are the Toll Like Receptors (TLRs) that are innate immune receptors in the CNS, discussed here. See image, below. TLRs “are key regulators of both innate and adaptive immune responses. The function of TLRs in various human diseases has been investigated….These studies have shown that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma…. [They] may contribute to susceptibility to severe neonatal inflammatory diseases, allergies, and autoimmune diseases.” Other studies have shown “Toll-like receptors (TLRs) are essential in the host defense against infections. They also have functional roles in tumor progression and their ligands affect tumor cell proliferation, anti-apoptosis and immune escape. The expression or up-regulation of TLRs has been detected in various tumor cells.” “Dysregulation of these signaling pathways has severe consequences, and causes many autoimmune diseases and chronic pathological inflammation.”

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The Toll Like Receptors are not like other receptors. Not these snug little pockets where naltrexone binds. Instead the Toll Like Receptors are like an entire football field, with enormous nooks and crannies. Unlike other receptors, they have enormous interactions with many molecules and medications, e.g. naltrexone is a TLR4 inhibitor, an immune modulator, amitriptyline is a TLR4 inhibitor. And “Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression.” That source is referenced here. Opioids create pain, not just the dread opioid induced hyperalgesia. Glia also contain cannabinoid receptors. Glia produce endogenous cannabinoids and they inactivate them.

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Toll-Like Receptors.

(Image courtesy of SABiosciences, click to enlarge)

Their action on IL-10 is key and more on that will be posted here later.

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Antibodies for pain?

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Some pain syndromes have been found to produce distinct antibodies.

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There is small but growing evidence that the immune system plays a role in Complex Regional Pain Syndrome, CRPS. These individuals have inflammatory markers in spinal fluid and tissue fluids. Recent studies have found antibodies against nervous system structures, specifically, “autoantibodies against an inducible autonomic nervous system autoantigen” in 30 to 40% of persons with CRPS.

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In 2010, a small study found that intravenous immunoglobulin (IVIG) can provide relief in a tiny percentage of patients. IVIG potentially interferes with those autoantibodies and reduces, i.e. downregulates, the inflammatory cytokines that are important in mechanisms of pain and hyperalgesia in the brain and the body. This study has many limitations but it is a first for IVIG.

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JJ Van Hilten et al have found HLA antigens associated with Complex Regional Pain Syndrome with fixed dystonia. “Our results encourage future studies to evaluate the role of HLA-B62 and HLA-DQ8 in different subtypes of CRPS.” This gene family has important immunologic functions.

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And, epidemiology studies show that persons with CRPS are more likely to have asthma.

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The study of glia is in its infancy but it is growing rapidly in many directions. There are drugs that can distinguish activated glia for targeted treatment, new methods of visualizing glia, new sites for pharmacologic intervention, and nanotechnology to deliver medication directly to the inflammation. ` More will come provided there is philanthropic support for this work. It is heartbreaking that NIH contributes less than 1% of its research dollar to pain.

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My thanks to the Reflex Sympathetic Dystrophy Syndrome Association, RSDSA.org, for sponsoring a workshop on Glia and Neuroinflammation that brought together the world’s foremost scientists and provided a unique forum for them to interact and learn from each other.

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It is hoped that their next workshop this year will be on imaging glia. We need to extend the work that has barely begun.`

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Posted in Alzheimers Disease, Chronic Fatigue, Complex Regional Pain Syndrome, CRPS, Fibromyalgia, Glia, Immune Cells, Immune System, Multiple Sclerosis, Naltrexone, Parkinson's Disease, Research, RSD. Tags: , , , , , , , , , , , . 4 Comments »

LDN World Database – Low Dose Naltrexone

01/19/2011 — Nancy Sajben MD

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This is a database of persons who have tried low dose naltrexone, their diagnosis, dosage and response to it, if any. The database lists many different medical conditions.

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For example, persons with Multiple Sclerosis, will choose the link above, that has hundreds of persons with MS who have tried naltrexone. Don’t forget to see more pages once you reach the bottom. For a graph of the overall responses, then go back to the main link on Multiple Sclerosis where you see these choices:

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To view the database please click HERE

To view the Graph on how people feel about LDN please click HERE

To add your experience with LDN please click HERE – of course first select the condition you have, so your entry falls into the proper category.

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If your condition is different, just select the condition from the list on left.

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For example for fibromyalgia:

To view the database please click HERE

To view the Graph on how people feel about LDN please click HERE

To add your experience with LDN please click HERE

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Here for Irritable Bowel Syndrome, Crohn’s or Ulcerative Colitis.

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If your condition is not listed, check Other on the left side of the list.

This forum is from LDN Research Trust, a registered non-profit Charity based in the UK, with participants from many countries internationally.

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I will soon be posting several case reports of my patient responders, persons with intractable pain from various conditions. Some have been pain free one or two years on naltrexone. Some who had years of previously intractable pain have responded to low dose naltrexone and remained pain free more than one year after discontinuing LDN.

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MECHANISM

for those who like to know the science

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We have known for decades that naltrexone binds to the mu opioid receptor. It blocks the effect of opioids like morphine at the mu receptor. We now know it also acts at another receptor.

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You may wish to watch this video that explains Toll Like Receptors, TLRs for short. This is a lecture by Dr. Rachel Allen, whose PhD in immunology is from Oxford University. After that, she worked at Cambridge University on innate immune receptors such as the TLR’s.

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In 2008, it was shown that naltrexone binds at one of the Toll Like Receptors, the TLR4 receptor. There are 13 Toll Like Receptors, and so far they have studied naltrexone only at one of them, the TLR4. That is important because the TLR receptors are part of the innate immune system.

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The Toll Like Receptors are not like other receptors. Not these snug little pockets where naltrexone binds. Instead the Toll Like Receptors are like an entire football field, with enormous nooks and crannies where it has many interactions with many molecules. Now, in 2010, scientists are asking if naloxone or naltrexone is acting at TLR4 or even higher up in the cascade.

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The study of immune cell glial interactions is in its infancy. Glial cells are the immune cells in your central nervous system (brain, spinal cord). They are very involved in dysregulation of pain systems, neuroinflammation, and some neurological diseases such as Multiple Sclerosis, Alzheimer’s, Parkinson’s Disease, ALS, infections of the brain, etc.

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One of our distinguished glial scientists, Linda Watkins, PhD, in October 2010, said we are not even sure naltrexone binds to the Toll Like Receptor. Rather, it involves AKT1, close to the TLR4 receptor, very very high up in the cascade at the dimerization step, the recruitment of CD14. This is being worked out now.

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Dr. Watkins with Kennar Rice, PhD, from NIH/NIDA, et al, has a paper in press in Cell:

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Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non-stereoselective activation of toll-like receptor 4 (TLR4), a recently recognized key glial receptor participating in neuropathic pain as well. This discovery identifies a means for separating the beneficial actions of opioids (opioid receptor mediated) from the unwanted side-effects (TLR4/glial mediated) by pharmacologically targeting TLR4. Such a drug should be a stand-alone therapeutic for treating neuropathic pain as well. Excitingly, with newly-established clinical trials of two glial modulators for treating neuropathic pain and improving the utility of opioids, translation from rats-to-humans now begins with the promise of improved clinical pain control.

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For chronic pain, targets of interest are: glial attenuation, p38 MAPK inhibition.

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Of interest, a commonly prescribed pain medication, amitriptyline, is a TLR4 inhibitor (Hutchinson, 2010).

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You can read many new publications on glia that I posted on my site here, or find it from the banner at top:

Donate to Eliminate Neuropathic Pain

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I am a member of a Neuroinflammation Research Consortium that will be studying these many conditions, some that are painful, others that are not. They involve glia and neuroinflammation.

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For more discussion of mechanisms of action of naltrexone and other publications I have posted, see here, particularly the paper by Zhang, Hong, Kim et al.

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Finally, for those who may feel they are losing heart because medicine has been too slow to adopt the use of low dose naltrexone, let me point this out:

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Dr. Linda Watkins is a University of Colorado Distinguished Professor of Psychology & Neuroscience at the University of Colorado Boulder. She is a world-renown leader in glia research and the neurological applications of glial attenuation, with a focus on alleviation of chronic pain. She is the recipient of the highest award for distinguished basic science research from the American Pain Society and the 2010 John Liebeskind Pain Management Research Award from the American Academy of Pain Management. She has over 300 peer-reviewed publications including articles in Nature, Science, Nature Neuroscience, and Journal of Neuroscience. She received over $2 million in NIH grants supporting 6 generations of IL-10 gene therapy research culminating in XT-101.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

Posted in Arthritis, Chronic Fatigue, Chronic Pain, Complex Regional Pain Syndrome, Crohn's Disease, CRPS, Fibromyalgia, Glia, Hyperalgesia, intractable pain, Irritable Bowel Syndrome, Low Dose Naltrexone LDN, Multiple Sclerosis, Naltrexone, RSD, Ulcerative Colitis. Tags: , , , , , , , , , , , , , , , , . 2 Comments »

Should LDN be used with other disease modifying drugs for Multiple Sclerosis?

03/16/2010 — Nancy Sajben MD

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I asked an expert, Dr. Ian Zagon

He was very kind to respond

~Dr. I

Dr. Ian S. Zagon is Distinguished Professor of Neural and Behavioral Sciences at The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania.

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His response:

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There are so many misconceptions about LDN that we could spend an hour correcting all of this ancedotal information. The problem is that patients do not read the literature, and offer their “opinions” as if this is true.  LDN is a great example of the good and bad about the internet.

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LDN is an immunosuppressant – it works through the opioid growth factor – opioid growth factor receptor axis

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OGF (LDN) acts as an inhibitor of the cell cycle, increasing p16 and p21 in the cyclin-dependent kinase inhibitory pathway. We are in the midst of writing all of this up for publication. On a practical basis, you would not recommend an immunostimulant to someone with MS or Crohn’s Disease (we just finished a Phase II trial on LDN and Crohn’s right now – worked nicely).

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LDN should be fine for MS – with or without other therapy

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I suspect you will find that you will be tapering your patient off of other therapies very shortly, and having your patient on LDN only.

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Remember – use around 3 mg/day

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Start your patient with LDN daily – try it in the evening.

If there is disturbed sleep, switch to the morning (it will make no difference in efficacy)

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Skip’s Pharmacy in Boca Raton, FL – they are on the web – has excellent LDN (some compounding pharmacies do not use the right bulking agents and the LDN is weak or inactive).

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[PJ's Prescription Shoppe in San Diego makes high quality capsules. And I do at times prescribe a suspension that is easier to adjust doses. The important thing is to use Avicel filler ( microcrystalline cellulose) and do not make SR sustained release capsules....ns]


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I wanted to add that OGF is the real, natural biological peptide and its mechanism is on native physiological processes. LDN is merely a tool to access and take advantage of the OGF-OGFr axis.  There are other ways of taking advantage of this system as well.

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Secondly, OGF and LDN work nicely in combination with chemotherapy as well

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We have a great clinical study going showing that OGF and gemcitabine are a terrific combo for treatment of advanced pancreatic cancer. Patients on OGF alone have lived for 2 years, and right now we have a patient on OGF and gemcitabine who is out around 15 months – and is doing splendidly. We have a paper out on OGF and pancreatic cancer – Phase I. Another study, phase II, is in press in Open Access Journal of Clinical Trials – look for it.

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Another woman, lives close by me, who was an aerobics instructor and has MS, has been taking LDN. She has made a remarkable recovery and is back teaching aerobics. Her family donated $50,000 to our research in honor/appreciation for our discovery, and 8 months later (the other day in fact) she gave us another $50,000. We have a group of researchers now doing the science.

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Dr. Zagon

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Posted in Low Dose Naltrexone LDN, Multiple Sclerosis, Naltrexone. Tags: , . 7 Comments »

Multiple Sclerosis & Low Dose Naltrexone – One Woman’s Story

03/09/2010 — Nancy Sajben MD

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Vicki Finlayson and Low Dose Naltrexone

Before naltrexone relieved pain and symptoms of Multiple Sclerosis,

she had used Oxycontin and morphine for a year and a half

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While prescribing low dose naltrexone (LDN) for patients with pain in recent years, I have become deeply impressed with it. Of course, it is inescapable to get very far on the internet without seeing a flood of videos and comments on the use of low dose naltrexone for Multiple Sclerosis. I once spent an entire afternoon reading the literature and watching the videos of patients, doctors, and researchers. How I wish I had the links so I could post them here now! The stories of Dr. Pat Crowley sitting at his desk as his patients in County Kilkenny, Ireland, described the successes they had had with multiple sclerosis touched my heart deeply. Naltrexone is not a cure but its beneficial effects on the immune system have been described here and were first noted by Dr. Bihari in 1985. Dr. Crowley sees results in at least 70% of patients, particularly with neurogenic bladder.

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Vicki Finlayson has had a remarkable recovery from severe Multiple Sclerosis. I hope you will watch her interview here. It was recorded October 2008 at the Fourth Annual LDN Conference held for the first time on the West Coast at the University of Southern California, and is recounted below. Since then she has made it her mission to advocate for clinical trials of this medication but it has been difficult for patients to find doctors who will prescribe it.

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Has medicine come to the point where we no longer listen to patients, only to drug representatives that are only allowed by Congress and the FDA to discuss what has been fully approved with all its risks and benefits? Well….frankly, we are not always told all risks nor are they always discovered until years later. Naltrexone is an opiate antagonist. It will block morphine and similar pain medication. In much higher doses it has been approved for safety by the FDA in 1984 as treatment for opiate addiction, and in 1995, FDA approved for treatment of alcohol dependence. Doctors have been reserved about prescribing it off label for patients who request low doses of naltrexone for medical conditions such as Multiple Sclerosis. But the tradition of using medication “off label” for uses not approved by FDA is still alive. Weighed against the dangers of the illness relative to a small dose of a medication that appears to be benign, it appears to be a worthy endeavor to test.

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How tragic is it to hear a person with Multiple Sclerosis have to define their day in the world by how far apart the bathrooms are when needed for neurogenic bladder? That is the story that urged one Scottish research doctor to pay attention when his patient said low dose naltrexone cured his neurogenic bladder. That changed that doctor’s research career. When years of fatigue and heat intolerance may soon be gone because of this small dose, how can a doctor turn down trying it for a patient? I did a few years ago, to my everlasting regret. I know better now. In my defense back then, I had not heard any information from that patient or anyone about its favorable off label use. It was a call from another doctor. I would like to think that if the patient had made an appointment with me or written to tell me a little about it, I would have said I’d read on the subject.

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Vicki’s Story

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Vicki Finlayson had Multiple Sclerosis for 12 years and was very disabled for several of those years with Secondary Progressive Multiple Sclerosis.

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She tells how she was on Avonex for 6 years that caused flu-like symptoms so severe she was in bed for two days after each injection. She was so disabled her husband had to help her dry her hair. The medications used for Multiple Sclerosis caution about suicide risk and her husband hid knives at night for fear of what she would do to herself. She was unable to work, on medicare and social security disability. She missed the ability to work and says, “I lost so much dignity, I lost my sense of everything my parents ever taught me.”

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She detoxed herself off of opioid medication that had been prescribed for pain. Her doctors failed to help her do that. Apparently, she says, they had no experience with how to take her off those medications. And she began to take low dose naltrexone 4.5 mg. It took away all of her symptoms, including heat intolerance.

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She is delighted to be off of disability and back to work selling durable medical equipment to doctors. And she has been inspired since then to help others by raising money for research on use of low dose naltrexone for Multiple Sclerosis.

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Here is how she did it

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She walked 56 miles from her home in Auburn California to Sacramento in scorching hot 100 degree weather – without any heat intolerance that she had had for years before – to try to get the ear of the governor. She held fund raisers. And she got the attention of Dr. Bruce Cree of the UCSF Multiple Sclerosis Clinic to do the first academic trial on use of low dose naltrexone in Multiple Sclerosis, research which apparently was funded by her efforts. She is indefatigeable in her effort to help others.

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Dr. Cree’s poster presentation on the positive research outcome is here along with other scholarly publications on naltrexone. The publication can be read here: “A rapid on-line publication of the first randomised controlled trial of low dose naltrexone in MS in the Annals of Neurology has been reported prior to hard copy publication. The study randomised 80 people with MS to receive LDN or placebo in a cross-over study where people took the LDN or placebo for eight weeks, then swapped to the other study drug. This appears to be the first drug trial in MS that was not funded by the pharmaceutical industry, but by the participants themselves.”

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He closes with: “In conclusion, in this exploratory, single center study, 8 weeks of treatment LDN was associated with symptomatic benefit with respect to mental health, pain and perceived cognitive deficits in MS. Confirmation of these findings in a multicenter trial will be necessary to make definite conclusions about the possible symptomatic benefit of LDN in MS. A longer duration of treatment is necessary to determine whether LDN has any benefit with respect to physical outcome measures.”

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Here is a link to more clinical trials on low dose naltrexone, and here is a

summary of the first European LDN conference in April 2009 at Glasgow University.

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Vicki is very realistic about the chance of this work being extended by any university, NIH or the National Multiple Sclerosis Society. They rely on tens of millions of dollars to do the costly multi-center long term drug studies that must be done for this condition. That will not happen with a drug that is inexpensive, generic, and holds no promise from which any pharmaceutical company may ever hope to profit. Without such double blind studies, many, if not most doctors would be unlikely to prescribe this simple, inexpensive, low dose medication.

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Please see comments, below, that point to an excellent resource called LDNAware.org. “This website is your worldwide gateway to Low Dose Naltrexone information, resources and events.  LDN Aware is a volunteer group devoted entirely to spreading knowledge and raising public awareness about LDN as a treatment for autoimmune disease, cancer and HIV/AIDS.”

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Should LDN be used with other disease modifying drugs for Multiple Sclerosis?

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In my next post of May 16, 2010, an expert answers that question.


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“Never doubt that a small group of thoughtful committed citizens can

change the world; indeed, it’s the only thing that ever has.”


- Margaret Mead

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The material on this site is for informational purposes only, and

is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

Posted in Low Dose Naltrexone LDN, Multiple Sclerosis, Naltrexone. Tags: , , . 9 Comments »
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