Low Dose Naltrexone “LDN” and Dextromethorphan off label for Pain, RSD, Chronic Fatigue, Fibromyalgia, MS, Crohn’s Disease

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Low Dose Naltrexone

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Low dose naltrexone, or LDN, has been prescribed “off label” for persons with many conditions including intractable pain, chronic fatigue syndrome, complex regional pain syndrome, RSD, Multiple Sclerosis, Parkinsons Disease, IBS, inflammatory bowel disease, autoimmune diseases and Crohn’s Disease to mention only a few. Low dose naltrexone is not a cure but may be potentially helpful for selected persons with these conditions. It appears to have little or no toxicity at this low dose – a few persons report transient insomnia, nausea or vivid dreams.

Naltrexone and and naloxone are both classified as morphinans, meaning morphine-like. The action of the morphinans and dextromethorphan is on the glia. This discussion relates to those medications. Refer to the paper titled Morphinan Neuroprotection by Zhang, below.

How does it work?

Naltrexone and dextromethorphan are anti-inflammatory. They act centrally and are very different from, and without the toxicity of commonly used anti-inflammatory medications such as ibuprofen or steroids.

They inhibit Superoxide, a free radical, and reduce the toxicity of peroxynitrate metabolism and the excitotoxic effects of glutamate. The mechanism of action occurs at the microglia in spinal cord and brain where they are neuroprotective. Microglia are the immune cells of the central nervous system. Microglia are not only the hallmark of pathology in Multiple Sclerosis but they also play a major role in pain and other degenerative neurological conditions. Reducing the damaging effect of these potent neurotoxins improves function of the immune system and various organ tissues including the spinal cord and brain.

There is evidence that they also increase the release of neurotrophic factors BDNF and GDNF (Jau-Shyong Hong, PhD, at the NIEH/NIH,personal communication).

Chronic pain alters central processing by changing the neurochemistry and the anatomy. This can lead to premature aging of the brain with loss of gray matter and brain atrophy as reported on MRI’s of persons with chronic low back pain. This may also occur in other stress-related disorders, such as chronic depression or post-traumatic stress disorder.

There has been a blossoming of basic neuroscience research on microglia that began in the 1980′s. At the American Pain Society meetings in San Diego in May 2009, there were hours of lectures for several days on the basic science of microglia and pain mechanisms.  This confirms the experience that I have seen clinically.

I am grateful to have the guidance of patients, physicians, and scientists in learning about the use and mechanisms of low dose naltrexone, with special thanks to Dr. Jau-Shyong Hong, PhD, Chief of Neuropharmacology at NIEH/NIH. He is one of the country’s leading experts on microglia, opioid antagonists and morphinans and has published some of the references below.

New science shows naltrexone to be a potent anti-inflammatory — much stronger and with a much different mechanism than the weaker cox inhibitors such as ibuprofen, Vioxx, Celebrex, Naproxen with none of those adverse side effects. Dr. Hong reports that in animal studies, dextromethorphan is even stronger than naltrexone.

Naltrexone is one of a few compounds called morphinans, meaning it has a structure similar to morphine, but naltrexone blocks morphine-like medication:  it is an antagonist.  For detailed discussion of morphinans refer to the article by Zhang et al, listed below.

There are links to further understand the basic science in medical publications and references below. We all owe thanks to patients whose clinical recovery with the use of low dose naltrexone has kept this work alive since its effect on the immune system in Multiple Sclerosis and HIV/AIDS was discovered by Bernard Bihari, MD, in 1984. He was a Harvard trained academic neurologist based in NYC. Their testimony can be found in the book mentioned below or in many web sources. The excitement of their recovery and their fundraising prompted UCSF and Stanford to begin double blind studies now 25 years later.

Recent clinical research

In 2009, Drs. Younger and Mackey of Stanford Pain Center reported a double blind study of low dose naltrexone in persons who had fibromyalgia more than 10 years and showed 30% improvement in pain and fatigue. They now plan a larger study. Bruce Cree, MD, of the UCSF Multiple Sclerosis Clinic in 2008 reported improvement usinglow dose naltrexone in a masked placebo controlled study to evaluate quality of life in MS [reference below] testing only pain, cognitive function and mental health. They propose doing a larger study to measure other functions in MS. In the 2007 study by Jill Smith, MD, at Hershey Medical Center [reference below], 67% of persons with Crohn’s Disease achieved remission in a few weeks, and total 89% had a response to therapy. As described in their publication: Endogenous opioids and opioid antagonists have been shown to play a role in healing and repair of tissues.”Dr. Smith has received a $500,000 grant from NIH to continue research on low dose naltrexone for Crohn’s Disease.

Multicenter studies on LDN for persons with Multiple Sclerosis have been done in Italy and Scotland.  New research is starting in Scotland that will include study of the toxicity of peroxynitrate metabolism in MS first proposed by a Nobel winning scientist in 1991, see the reference on peroxynitrate metabolism and Dr. Gilhooly’s references, below.  Scotland has the highest incidence of MS in the world, even higher than Great Britain and Ireland.  Dr. Gilhooly’s patients reported remarkable improvement in function on LDN that led to him starting this work.

My experience prescribing LDN

I have been prescribing naltrexone for 6 years in ultra-low microgram doses, and more recently prescribing low dose naltrexone at doses of 1 to 4.5 mg.  It is one of the most exciting developments in pain medicine and neurodegenerative diseases that I have ever seen.  It was previously unimaginable to me to see some persons with intractable pain now pain free and off opioids because of low dose naltrexone or a similar medication that will soon be posted on this weblog.

I have not yet been able to predict who will respond to low dose naltrexone with decrease in symptoms, but many patients have had profound relief. Often it may reduce intractable pain to zero despite failing to respond for many years to all known therapies. Inability to predict a response to pain is true of many classes of medication that we trial “off label” for pain relief and even those that are FDA approved for pain. Paradoxically, the same is true for morphine and similar strong opioids.  In fact, opioids relieve pain and opioids create pain at the same time, and it is not uncommon for pain specialists to see individuals with severe pain despite using high dose opioids.

“Off label” use means it is not FDA approved for these purposes.  Instead, low dose naltrexone is used in small doses of 1 to 4.5 mg at bedtime that must be made by a compounding pharmacist, rather than the 50 mg tablets or higher doses that are FDA approved for prevention of addiction and alcoholism.

Many thanks to the sponsors and speakers of the Fourth Annual Conference on Low Dose Naltrexone which was held for the first time on the West Coast at USC on October 8, 2008 – they have provided other references attached below.

Naltrexone became available as a generic drug many years after 1984, and thus there is no profit in this use for pharmaceutical companies.  Only recently, has the science progressed enough to understand its new uses.  Therefore what you may read in various sources on the web may be the “old science,” whereas the articles below are the “new science.”

I will be updating this page in the near future but wanted to make these recent publications and documents available now.

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Update June 22, 2010: Check back for patient case reports I will be publishing soon now that I have more specific information on how morphinans work on path pathways and on the central nervous system.

I recommend this book:

The Promise of Low Dose Naltrexone Therapy

by Elaine A. Moore & Samantha Wilkinson, McFarland & Company Inc., 2009

The Promise of Low Dose Naltrexone Therapy

“Grounded in clinical and scientific research, this book describes the history of naltrexone, its potential therapeutic uses, its effects on the immune system, its pharmacological properties, and how the drug is administered. It also lists … patient resources, and includes interviews with LDN patients and researchers.”

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If you are unable to view and print PDF files below,

download the free PDF reader.

If you do not have Microsoft Powerpoint software to view slides,

download the free Microsoft Powerpoint Viewer.

Download sizes are in parentheses to the right of each download link.

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Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone, involvement of toll-like receptor 4 (TLR4)

Morphinan Neuroprotection by Zhang, Hong, Kim, et al, Crit.Rev.Neurobiol. 16(4):271-302, 2004 (PDF)  450k

Microglia Mediated Neurotoxicity Molecular Mechanisms. Block Zecca Hong, Nature Reviews Neurosci 8:57, 2007 (PDF) 529k

Peroxynitrites in MS,  Dr Tom Gilhooly, Scotland, USC 4th Annual LDN Conference 2008 (PDF)  77k

LDN research on MS in Scotland Dr Tom Gilhooly, USC 4th Annual LDN Conference, 2008 (Powerpoint)  12M

LDN In MS, Bruce Cree MD, UCSF Poster, 2008 (PDF)  154k

A Pilot Trial of LDN in Primary Progressive MS, Gironi et al, Multiple Sclerosis 14:1076–1083, 2008 (PDF)  222k

LDN for Treatment of MS – Clinical Trials Are Needed, Patel, Ann Pharmacotherapy 41 (9):1549, 2007 (PDF)  114k

LDN Improves Active Crohns Disease, Jill Smith MD et al, Am J Gastroenterology 2007 (PDF) 121k

LDN Immune System Autism & HIV, Vojdani, USC 4th Annual LDN Conference, 2008(Powerpoint)  5.7M

LDN Immune System Autism & HIV, Vojdani Part 2, USC 4th Annual Conference, 2008 (Powerpoint)  3.6M

Naltrexone ULD Decreases Side Effects and Potentiates the Effect of Methadone 2003 JP&SM Cruciani Arbuck  (PDF) 80KB

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Update December 10, 2010:  For further research publications on glia, please refer here.

Refer here for a case report of severe RSD responding primarily to naltrexone.


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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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7 Responses to “Low Dose Naltrexone “LDN” and Dextromethorphan off label for Pain, RSD, Chronic Fatigue, Fibromyalgia, MS, Crohn’s Disease”

  1. Nancy Sajben MD Says:

    Yes, I have used ultra low dose naltrexone since ~2003 in patients who use opioids for pain. In many, it markedly improves pain, improves function to a level not achieved with opioids, and allows them to significantly reduce their opioid dose.

  2. liz Says:

    Dr. Sajben

    Do you know of or have any cases of LDN being used for intractable thalamic pain usually called post-stroke pain ( TIA in my case)?

    Did it help in these type of cases?
    Opiates are generally useless in these cases as you know.
    Thanks.

  3. sandrasi Says:

    Hi,

    My daughter is 17 years old and has RSD, has had Sympathetic Nerve blocks, has gone through the Pain Rehab Program at Cleveland Clinics Childrens Hospital, and has had two rounds of Ketamine Infusions. She is still in stage one. Her PM started her on Dextromethorphan HRB 25mgs/5ml every eight hours for pain. She seems to be responding to the medication. She told me last night that the burning pain is subsiding. She also takes Cymbalta off label 90mgs per day, which has helped with the pain as well. She was prescribed Percoset for severe pain, which she only takes maybe once or twice per week.

    I wanted to ask you if you believe that RSD spreads from limbs? She started with an ankle sprain when she was 11 years old. Now she has been diagnosed with full body by a well know RSD doctor, but her PM claims that RSD does not spread. My daughter also has severe stomach issues, and it is difficult to keep food down. That is my major concern with her right now. I know that she is not your patient but I would like to know what your take is on RSD.

    My daughter also suffers from POTS, asthma and migraine headaches.

    I look forward to hearing from you.

  4. Heidi Shultz-Hartfield Says:

    Fellow readers, I was diagnosed with RSD 10 months ago. Full of desperation and a sense of losing my entire life, I made an appointment with Dr. Sajben (only after seeing multiple other doctors that only prescribed pain meds and nerve blocks). It has been 7 days since my appointment with Dr.Sajben and I have gone hours throughout my day with almost zero pain. I can say I almost feel normal and for those of you who have RSD, almost is GREAT!! The only side effect I am experiencing is drowsiness which is a welcome one after the amount of pain I have been experiencing . If your are wondering if you should make the decision to see Dr. Sajben if your in pain, the answer is yes. I’d be happy to answer any questions regarding my personal experience- heidihartfield@gmail.com

  5. Douglas Lewis, D.Sc. Says:

    Dr Sajben,

    In the past several years the research literature has suggested a very active role for Toll Like Receptor 4 (TLR4) in mediating much of the neuroinflammation, brain injury, behavioral alteration, and addictive-like behavior seen in pain patients. The empirical use opf low dose naltrexone now can be seen in the light of it being an effective TLR4 antagonist. Unfortunately. Rx naltrexone is (-) naltrexone which is also mu-opioid receptor antagonist which makes use of opioids while using the low dose (-) naltrexone much less effective than if we had (+) naltrexone, a much more specific TLR4 antagonist with little mu opioid antagonist activity (1/2800 as much as the (-) isomer).

    I know that Dr Kenner Rice at NIDA is the synthetic source for research quantities of (+) naltrexone, but have yet to find a commercial source for bulk (+) naltrexone.
    In the mean time, pre-dosing opioid doses with dextromethorphan is pehaps a rational alternative. A 125-150 mg dose prior of an opioid dose has been effective in enhancing the effect and reducing the rate of tolerance dependence suggesting a TLR4 antagonism as well as the NDMA activity.

    I come at the is problem from the perspective of a forensic toxicologist who is also a pain patient. As I am intolerant of NSAIDs (severe renal damage from them) I hav ebeen forced to explore the safest and most effective treatments that allow me to continue my work and remain cognitively functional as well as physically able to perform.

    I do see light as the end of the tunnel for many pain patients as the teasing of TLR4 activity is made fro mu opioid activty and pain relief is not always followed by drug dependence.

    Regards,

    Douglas Lewis, D.Sc.
    President
    United States Drug Testing Laboratories


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