Do You Have Depression? Are you the one who runs into snow wearing shorts?


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Since you were a baby, thermoregulation may be the source of the problem

that triggers your depression or the depression of someone you know.

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You may be a candidate for a research study if you have other key characteristics.

Treatment may help.

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Contact the Juvenile Bipolar Research Foundation.

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Demitri Papolos, MD, is the psychiatrist who, in collaboration with many others, has discovered that body temperature appears to be at the origin of this condition:

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Juvenile Bipolar Disorder, Fear of Harm phenotype.

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Dr. Papolos has written many publications and has published a book, with Janice Papolos, describing this serious disorder. “The Papoloses were the first to sound a national alarm about the dangers of using antidepressant and stimulant drugs with this population of children.”

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Either the link to Dr. Papolos or the Research Foundation, above, can give you further information on treatment.

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Papolos et al have published Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype

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Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.

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Dr. Papolos’ video on treatment points out ketamine nasal spray is off-label

for Bipolar Disorder and he posts this

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PUBLIC WARNING

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Public Warning: Ketamine is a controlled substance.

Administered improperly, or without the guidance of a qualified doctor,

Ketamine may cause injury or death.

No attempt should be made to use Ketamine

in the absence of counsel from a qualified doctor.

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“Off label” means it is FDA approved for another purpose, but he prescribes it for Juvenile Bipolar Disorder. I would add that in qualified hands, ketamine is one of the safest medications we have in our formulary.

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I am not affiliated with Dr. Papolos, but wish to call attention to the dedicated academic work they have been doing for this devastating mood disorder. .

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Of interest, thermoregulation appears to be modulated by low dose naltrexone (LDN).

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It has been anecdotally reported to relieve heat intolerance in persons with Multiple Sclerosis.

I have seen a response with Juvenile Bipolar Disorder/Fear of Harm, and

severe postmenopausal hot flashes were completely reversed by LDN.

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Naltrexone blocks the TLR4 receptor. There is a strong literature on TLR4 and temperature regulation. This raises the interesting question whether anyone has done objective studies to show that low dose naltrexone may be modulating temperature in patients. If you have experience with this, please add your comments below.

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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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Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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

 

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LDN World Database – Low Dose Naltrexone


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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!

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


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


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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!

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.

~~~~~

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

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Vitamin D – A Steroid Hormone, Anti-inflammatory


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The Sunshine Vitamin Controversy

What should normal values  be for calcium homeostasis?

My attention was drawn to Vitamin D several years ago when a review appeared in the journal Neurology, published by the Academy of Neurology, that linked low levels of Vitamin D to Multiple Sclerosis.  The article was unusual for its length and the breadth of research cited over several decades.  More recently, a Johns Hopkins article published “the most conclusive evidence to date” that Low Vitamin D Levels Pose Large Threat to Health.

New publications on Vitamin D seem to appear every week with the focus on levels of 25-hydroxyvitamin D, also written as 25(OH)D. Its half life in serum is ~ 10 days to 3 weeks.

The biologically active form 1,25-dihydroxyvitamin D, written as 1,25(OH)D²,  is made in the kidneys and has a much shorter serum half-life of ~ 4-6 hours, thus making it less useful as a serum marker for measuring.

Sources & Metabolism: Vitamin D is a fat soluble vitamin that’s absorbed in the small intestine from  foods such as egg yolks, fatty fish, fish liver oils, fortified milk, margarine, and cereals.  Bile salts are required for absorption.  Sunlight stimulates the skin to synthesize vitamin D, but exposure of hands and face as little as 15 minutes may not be sufficient and it is not as effective for everyone.  It won’t work in winter months, it won’t work for the aged, for those who have pigmented skin, and it won’t work for those who cover their skin.

Vitamin D Metabolism - click to enlarge

Vitamin D Metabolism

The Controversy –  How Do We Determine Normal Values?

Surprisingly, in a well designed multicenter study of healthy young Hawaiians in their 20’s who were exposed to at least 29 hours of sun per week, 51% were found to have vitamin D deficiency using the usual cut off of 30 ng/ml for normal.  This study from 2007 found the mean concentration of 31.6 ng/ml, and the highest of 62 ng/ml.  It raises the question whether

“it seems prudent to use this value [60 ng/ml] as an upper limit when prescribing vitamin D supplementation,”

rather than the generally published normal range of 30 to 80 ng/ml or even 100 ng/ml quoted in some labs.  This study is important in discussing the controversial question of what normal values should be for calcium homeostasis and reviews several possible explanations for inadequate production of D3 including genetic differences.

They note the highest reported values in “Nebraska outdoor workers… were between 81 and 84 ng/ml” but the assay system differed compared to theirs and results in a higher value.   Reviewing this study that was published in the Journal of Clinical Endocrinology & Metabolism has allowed me just now to readjust my own patient practice.

Laboratory Testing:  results can differ from one laboratory to another.  My hospital sends specimens to ARUP for testing, whereas Quest has acknowledged errors in laboratory testing and problems with standardization as reported by the New York Times here.

Function:  It is important for absorption of calcium and phosphorous from the small intestine, for bone health, osteoporosis, risk of falls, certain cancers(colon, breast, prostate), and possibly 6 to 7 years of longevity.  Deficiency of vitamin D is associated with suboptimal health and possibly increased pain; it is linked to infections, gum disease, hypertension, diabetes, coronary disease, neurological diseases such as Multiple Sclerosis, Parkinson’s Disease, dementia and Alzheimer’s Disease though it may not be causal. Its receptor is found all over the body including the brain.

I recommend this review by one of the best web resources at Memorial Sloan Kettering Cancer Center Herbs & Botanicals.

They quote a reference showing it reduces postmenopausal weight gain and “In adults with impaired fasting blood glucose, giving calcium and vitamin D reduced increases in plasma glucose and insulin resistance….”

It is the only vitamin that is a steroid hormone, and my interest increased on learning that it functions as an anti-inflammatory.  But as I tested blood levels for 25(OH) vitamin D and parathyroid hormone (PTH), I discovered more than 90% of my patients had vitamin D deficiency and a few had hyperparathyroidism.  There are four parathyroid glands next to the thyroid, and for some reason doctors have rarely tested their hormone levels.

***Persons with hyperparathyroidism should NOT take calcium or vitamin D.

It may lead to kidney stones and bone pain:  stones, bones and groans.***

Evidence for Optimizing Vitamin D Concentrations

On the other hand, if vitamin D is low, there is some evidence that replacement with vitamin D3 so that blood levels are in the high normal range, may help pain.  That is, it may raise the pain threshold and possibly have other benefits for health and longevity. It is desirable to avoid toxic levels of D as it causes hypercalcemia with depression, drowsiness, weakness, headache, polydipsia,  bone loss, and metastatic calcifications of many organs, soft tissues and blood vessels.  The generally quoted range of normal for 25(OH) vitamin D is 30 to 80, that varies with the lab.

great-western-divide-wp1

Doesn’t that photo of the Great Western Divide make you want to get outside into the sun?

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes was reviewed by Heike Bischoff-Ferrari et al, in 2006,  though it has been superseded by much additional work since then.

To quote from their article:

This review summarizes the evidence for optimal serum  25(OH)D concentrations. The endpoint selection for this review was based the strongest evidence to date—ie, that from RCTs [randomized controlled trials], consistent evidence from prospective and cross-sectional epidemiologic studies, and strong mechanistic evidence or dose response relations.  BMD [bone mineral density], fracture prevention, lower-extremity function, falls, oral health, and colorectal cancer met these criteria. Weaker evidence exists of a beneficial effect of vitamin D on other diseases, including multiple sclerosis (15), tuberculosis (16), insulin resistance (17, 18), cancers other than colorectal (19 –22), osteoarthritis (23, 24), and hypertension (25–27), but these diseases are not considered here.

They did not review pain studies.  I would add that “weaker” evidence merely means that it must be confirmed by more studies, not that it excludes those conditions.  There is an epidemic of vitamin D deficiency in the country, and the incidence is very high in pain clinics as reported in several studies.

A new multi-center epidemiology study  “Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004”  by Ginde, et al, in 2006,  “demonstrate a marked decrease in serum 25(OH)D levels from the 1988-1994 to the 2001-2004 NHANES data collections.”  And like others before them, they point out:

“Current recommendations for vitamin D supplementation are inadequate to address the growing epidemic of vitamin D insufficiency.”

Summary:

Make sure your doctor checks both your 25(OH)Vitamin D and parathyroid hormone level (PTH) – not thyroid – to determine if you have hyperparathyroidism or if you have normal or low vitamin D.  That will determine if you need replacement or if you should stop using calcium and D as it will cause kidney stones and calcium deposits on your bones leading to pain.

If vitamin D levels are low it may result in increased physical pain and may cause or aggravate many medical conditions.

If PTH levels are high indicating hyperparathyroidism it will cause new painful conditions.

Intake does vary with the patient, the season, the age, but the recommended daily allowance may perhaps be double what it is now.  It is unclear when the federal government will adjust that dosage.   As always, your physician’s recommendation will be based upon blood levels of 25(OH)D and PTH.

Do not make changes in your dosage without careful evaluation.

Could this possibly be one of the most important areas of research this century?

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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