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


Low Dose Naltrexone


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.


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.”


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.


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


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.


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.


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


20 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.

  3. sandrasi Says:


    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.


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

    • Nancy Sajben MD Says:

      Dextromethorphan alone is very helpful for pain relief. I do not know of any literature on it reducing tolerance/dependence on opioids.

      • Loretta Tirone Says:

        Hi Dr. Sajben, Please could you add me to your email list under my newer address: LorettaCT3@yahoo.com ? As an RSD sufferer, I highly value your opinion an your emails are of great interest to me. I use LDN cream and ketamine troches (the ketamine spray burnt the inside of my nostrils a lot even after the compounding pharmacist changed the pH, so I had to go back to the troches for breakthrough pain), and have used it in combination with dextromethorphan. I am thankful that I found that information, and again, would love to be included in your emails at LorettaCT3@yahoo.com. I’m currently exploring energy medicine–Quantum Touch–as well. Thank you for all you do!!!! Loretta Tirone

        • Nancy Sajben MD Says:

          There is a link at column top right: “Subscribe to Posts” and “RSS posts.”
          Use that function and you will be automatically enrolled with notice of the new posts.

  6. Nancy Sajben MD Says:

    Dr. Sajben is adding this recent comment here. It was placed on the Welcome page where it remains, but may be more useful here as the topic is naltrexone. It has remarkable analgesic properties on its own, but part of the analgesic relief may be due to discontinuing opioids. Opioids cause pain.

    I’m a 67 year old male who has had Crohns since I was 20 yrs old. Currently I have only 3ft of small bowel left and have had an ilestomy since 1975. I have chronic dehydration and have a port in my chest to get a liter of IV fluid/day, chronic fatigue, am in stage 3 kidney failure for 30yrs. Plus kidney cysts, kidney stones in left kidney(200+ passed since 1975) and peripheral neuropathy in my feet, legs and hands. I have been on Remicade for about 7 years, 3yrs at 5mg/mic and then 4yrs at 10mg/mic and now back to 5mg/mic after starting Naltroxane. I have also been on Fagyl as needed over the years. The Remicade or Flagyl or both caused the neuropathy. The Neuropathy has been treated with Lyrica, Neuraton and several other types. I was a zonbie for several years. Then came Vicoden and then Methadone 30mg/day. I had to wean myself off the Methadone for three months and cold turkey for two weeks. During this time I didn’t sleep for three months.

    The Veterans Hospital in Ann Arbor, Mi started me on 4mg of Naltroxane 31/2 months ago and I’m a new person.
    [Edits: I have made this sentence a paragraph unto itself. Spell: naltrexone. He started 3-1/2 months ago]

    I had been hospitalized for a port infection and a methadone overdose due to the infection in May of this year. My sons notice that they could touch my feet after I was put on Narcan for the overdose. After getting out of the hospital I got online to get info on Narcan/Naltroxane. The chronic fatigue is 95% gone, my foot and leg pain went from a 10/10 to about 4/10 now. The VA just increased my dose to 5mg per day at my request to see if there is more relief obtainable. So far it looks like the top limit if I need it may be 8mg/day.The 3/mg buffer I have now is for future use if needed. Sorry for the long dissertation but all this info is important and I hope I have helped you and others that have issues like me. I will answer and questions posted.

    God Bless,

  7. Jenny Young Says:

    Dr. Sajben, I have been diagnosed with CRPS for 2 1/2 years now. We have tried nerve blocks and I was almost in remission with them but I overdid it on Easter of last year and have been on a downward spiral since spreading from my left lower leg only to my now to my entire body. Too many therapist have made me decline. It is unfortunate that have only found one place out of many who knew what they were doing (they were the ones who almost had me in remission after 2 weeks of seeing them when I had not been able to walk in 1 1/2 years at the time). Unfortunately, now that it has spread like wild fire in me, they are not able to help me as much either. I am currently receiving a series of ketamine infusions at 1040 mg each day. Right now I am at the boosters and already having terrible pain which I believe to be from withdrawals from either the ketamine or the reportedly high dose of ativan I was receiving and rapidly discontinued after 10 days of use 3 times a day with the infusions. The withdrawals were severe insomnia, severe depression, severe anxiety and I stressed so much that my pain has returned in a week that was gone from the infusions. This dr did prescribe dextromethorphan 100 mg. I see that you prescribe much less. This was a doctor I will not be seeing often as he is in a different state from me. Is that too high of a doseage? And should it be used with ketamine low dose capsules or ketamine infusions? And do you prescribe this medication for CRPS even when people have never used opioids? Because I don’t take opiods. Hate them. Too many side effects to use them.

  8. Jenny Young Says:

    One more thing, I just clicked on the RSS to add me and it isn’t working. Is there a different way to add me to your email list for updates?

  9. Heather Says:

    In 2015, I was suicidal. I had just undergone 15 rounds of ECT and was suffering severe memory loss and cognitive impairment. My depression did not go away.

    Dr. Sajben prescribed ketamine and within a few days, I was getting back to normal. I started to get out of bed and get dressed for the first time in years. I drove myself to my 3 week follow-up appointment. This may sound like nothing , but leaving my home alone and driving myself was unheard of at that time.

    My life has been completely transformed. Sometimes I feel a little depressed, but even my worse depressions, which last 3 days with daily ketskime , are NOTHING compared to my life on ineffective antidepressants.

  10. Tonia Says:

    I was recently given LDN from my neurologist for ms
    When I begin the 4.5 dose within a couple days I am in awful pain! So I wake up to take a 5/250 Vicodin and go to bed with the LDN…. is this dangerous? Or am I negating the benefits? I’m hoping the muscle rigidity will pass and I won’t need the am Vicodin… anyone else haves this issue?
    Thank you

  11. Brian Schwartz,PhD Says:

    Hi Doctor Sajben. I am profoundly sorry that you are not well. Although you gave up on me a few years back, I continue to follow your thoughts and research evidence on your site. I take fairly large amounts of ketamine at this point unfortunately combined with alprazolam to keep my sanity although I will probably be demented. Nothing else has worked for me and the ketamine is unfortunately affecting my liver and ex..treme congestion in my nasal passages, eyes, and esophagus I also have gerd. I am at a loss and life is not fun. C’est la vie after 17 years of intractable pain. Anyway I hope that you are doing better and wish you well. If you should hear of anything that might help me further, as we tried an awful lot with marginal success, please let me know.


    • Nancy Sajben MD Says:

      Dear Brian,

      I am so sorry to hear of your suffering. I’ve written on this blog about the deadly risk of tolerance — to opioids, to ketamine. Neuroinflammation is the result and that increases pain.

      Detox is the only way to begin to reset.
      No one knows how long it will take. Will it last years? or be better after a few weeks?

      What is new – more than ever get people in high positions at NIH to be single handedly empowered to revolutionize research in pain treatment.

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