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A review of the clinical use of low dose naltrexone appeared today by Younger, et al. from Stanford (see e-Pub below).
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Naltrexone is one of the most important medications I have prescribed, alone or in combination with other medications for intractable chronic pain and/or treatment resistant Major Depressive Disorder or Bipolar Disorder. It has been most extensively used anecdotally and off label since 1985 for treatment of Multiple Sclerosis.
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Naltrexone acts on two receptors in the central nervous system: (1) the opioid receptor and (2) the TLR4 receptor on glia.
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(1) The opioid receptor is blocked by naltrexone. Naltrexone cannot be given to someone who uses opioid analgesics because it would cause a severe or unpleasant opioid withdrawal reaction. But in low dose, it can do better than opioids for relief of intractable pain. I would like to see it tried for pain, alone or in combination, before any opioid is started. And if on opioids, taper slowly off opioid in order to see how superior low dose naltrexone is. See case reports elsewhere on this site.
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Low dose naltrexone is quite different than its use in high dose where it is FDA approved for addiction to alcohol and opiates. Naltrexone reduces craving. However, in high dose, it blocks the endorphins, the opiates that your brain produces, thus causing pain and depression.
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(2) The TLR4 receptor was discovered by Bruce Beutler, MD, working at Scripps Research Institute. He won the Nobel Prize in 2011 for that profound work. The TLR4 receptor is found on the microglial cell in the central nervous system. The microglia far outnumber nerve cells in the brain and spinal cord. I discussed a small portion of the vast science of the importance of glia, your innate immune system and inflammatory cytokines, here. This research on glia, the innate immune system, is new, largely in the last 10 to 15 years.
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One of the mechanisms by which opioids create pain is that opioids trigger glia to release pro-inflammatory cytokines, i.e. opioids create a neuroinflammatory response in a manner similar to endotoxin from bacteria. Opioids upset the balance of pro- and anti-inflammatory cytokines to create more pain. Naltrexone does the opposite by its action on the glial TLR4 receptor reducing pro-inflammatory cytokines and relieving pain.
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Inflammation kills! Glia and/or the inflammation produced by glia are involved in many pathological processes: Alzheimer’s, Parkinsons, ALS, MS, chronic pain, depression, autoimmune disease, cancer, atherosclerosis. The TLR4 receptor is necessary for death or destruction of oligodendrocytes and myelin, as occurs in multiple sclerosis. Does that mean low dose naltrexone may play a role in modulating these conditions?
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See reviews by distinguished Professor Linda Watkins, PhD, and Mark Hutchinson, PhD, on glia, neuroinflammation and the neuroimmunopharmacology of opioids. Besides glia, Watkins and Hutchinson have recently discovered Toll-like expression of neuronal receptors in pain states.
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For access to articles on glia, cytokines and the TLR4 receptor, see the RSD Syndrome Association library of key publications. And donate to them. They have supported key research in pain when NIH gave less than half of 1% to pain research in 2006, now far less since the deadly the recession of 2008 and the ever threatened fight over funding the national debt.
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Being interested in glia, and treating so many patients with Major Depressive Disorder who had failed other treatments, I did a review of depression and glia and found the same increase in pro-inflammatory cytokines in depression that are found in chronic pain. Since low dose naltrexone is anti-inflammatory, i.e. it modulates or resets the balance of pro-inflammatory and anti-inflammatory cytokines that are produced by glia, I felt it important to try in Major Depressive Disorder. Besides, I had seen its profound effect on so many different forms of intractable pain for many years. Use of LDN has never been associated with toxicity and rarely any side effects.
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My patient had severe suicidal ideation with Major Depressive Disorder for more than three months, unchanged after treatment at a psychiatric center where she had stayed almost four weeks. She began with 4.5 mg in the office and 25 minutes later, on the drive home, her appetite returned! She walked in the house and her dad was astonished – she no longer walked like she was 105 years old! She had the energy to do her laundry and cook for the family for the first time in more than three months.
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Another person for whom I prescribe naltrexone for Major Depression, wrote to me saying Massachusetts General, a Harvard Hospital, was starting clinical trials of low dose naltrexone for Major Depressive Disorder. Other new clinical trials of low dose naltrexone can be found here.
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Jared Younger, PhD, from Stanford first published on the use of naltrexone in fibromyalgia – see my discussion here.
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Today in PubMed, ahead of print, Dr. Younger et al. publish a review of low dose naltrexone, a glial modulator.
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The use of low-dose naltrexone (LDN) as a novel
anti-inflammatory treatment for chronic pain
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Authors Younger J, Parkitny L, McLain D.
Journal
Clin Rheumatol. 2014 Feb 15. [Epub ahead of print]
Affiliation
Abstract
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. We review the evidence 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. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
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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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02/16/2014 at 4:31 pm
I use LDN and it helps. Taken right before bedtime (I have to use Zolpidem to punch me into sleep and then when I awaken a few hours later Tizanidine and Gabapentin to push me back into sleep) the LDN helps me sleep more deeply at least for a few hours. I do sleep better and in turn have a little less pain and a bit of a decrease in flu like symptoms. I believe I have been taking this for 8 months and because I have battled Fibro and ME/CFS for about 40 years I KNOW the difference when something works and when it doesn’t. I noticed it helped by the second night of taking it.
02/27/2014 at 6:40 pm
A new patient of Dr. Sajben I started taking LDN (4.5mg 3 x a day) just a few days ago for chronic neuropathic pain throughout my body, especially along the spine. I felt some improvement in the form of reduced pain, enhanced mood, more energy and all around greater well-being after just one dose. The next day (yesterday) the difference was even more obvious. This morning I woke up for the first time in months without major soreness and malaise. Clearly, major changes are happening in my body. My hope is that these improvements will continue to build over time.
The only side effect I am experiencing is some insomnia due to what I would describe as excess energy. I just don’t feel tired at my usual bed time (though I take a morning dose of LDN, not night time). Once I am asleep, I do not wake up nor do I have unusual dreams or other adverse experiences. Last night was already better than the first, so hopefully the insomnia will resolve over the next days or weeks.
In any event, I am very glad I tried LDN. It may well be a game changer for me.
Robert
02/27/2014 at 9:03 pm
For those in the LDN community who feel you must never take more than 4.5 mg, this is an example of why it is important not to be dogmatic about dosage. Sadly, some of my patients on LDN forums have felt forced to sign off because of dogma that does not relate to their experience. He had no response at 1 mg for 5 days or 2 mg for 5 days, 4.5 mg or 9 mg. It was only taking 4.5 mg x 3 that he first felt response, and this correlates with other patients I have seen. It is dose dependent.
One Caution: with Multiple Sclerosis a low dose may be critical, only in that condition.
02/28/2014 at 9:37 am
Update 2/28: Last night I had no problems falling asleep nor did I have any insomnia at night. Maybe, it was because I took my morning dose at 7:00am instead of 9:00 am, i.e., two hours earlier. My sense is actually that that’s not the case. The first two days on LDN in general were almost euphoric during the day, which translated into insomnia at night. Yesterday and today, I felt and feel more normal, though still improved in the ways I described.
09/16/2015 at 9:55 pm
I am 46 years old, 160 lbs, 6’2″, male.
I recently started LDN for nerve related foot pain (burning underneath after walking + frequently feels cold on top).
I started at 1.5 mg for 3 days, then 2.25 mg for 2 days and then 4.5 mg (10 days now).
For the first few days, I slept better and also felt really good when waking up. My mood was better during the day as well. But no change in pain. When I increased to 4.5 mg, I expected / hoped for more positive changes, but after 10 days I have not noticed improvement in pain. I still sleep better, but the initial mood improvement (on lower dose) is gone.
I am thinking that I probably went too fast and should go down to 3 mg and increase slowly from there, but I am not sure if that is the best approach.
In your experience, what would the best approach from here to find the proper dosage?
How long time on each dose before moving on to the next dose to try?
How big increments?
Thanks!
Jimbo
10/06/2015 at 11:07 pm
I would be happy to help. Please call my office to schedule a visit. Your doses and schedule are not what I recommend.
10/27/2015 at 11:17 pm
I do schedule time with physicians who call from all over the world asking me to teach them what I do.
It is not legal for an M.D. to give medical advice to patients they have not seen. If you wish an appointment, please call the office.
08/21/2016 at 11:27 am
It is illegal to give medical advice without a consultation. This site is educational only. Please call for appointment.
10/11/2017 at 9:28 pm
FDA has approved 50 mg and higher for addiction to opioids and alcohol.
Those are not low doses, and not used for pain and inflammation.