Complex Regional Pain Syndrome – Review of Inflammation & Meta-analysis

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Neurology, the journal of the Academy of Neurology, has published “Inflammation in Complex Regional Pain Syndrome, a systematic review and meta-analysis” on July 1, 2013.

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The study was supported by grants from the Australian National Health and Medical Research Council, the Canadian Institute of Health Research, the Dutch consortium on CRPS and the Dutch Ministry of Economic Affairs.

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They found “a proinflammatory state in blood, blister fluid, and CSF.” Profiles differed in acute and chronic cases.

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Levels of neuropeptides in blood and blister fluids were not higher in CRPS than in controls.

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The inflammatory profile reflected a generic chronic pain state. There was no signature specific to CRPS. Chronic pain is associated with higher levels of proinflammatory activity.

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Acute cases did differ from chronic. But affected limbs did not show higher levels of inflammation than limbs that were not affected.

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Of interest, they found significant variability in concentrations of inflammatory factors which may suggest the data reflects methodological errors. Or it may suggest that CRPS is not a distinct disorder but is a collection of disorders that appear similar clinically, or the inflammatory response is not consistent, or that important clinical subgroups exist, for example hot vs cold CRPS or variations that present with significant autonomic disorders or systemic involvement.

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They noted a recent review of treatments that found little evidence that prednisolone improves symptoms of CRPS. And they note conflicting evidence for free-radical scavengers (dimethyl sulfoxide and N-acetylcysteine). They point out the latter trials were small and of mixed quality, however I have personally seen patients who respond to those treatments.

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They recommended formal, large, high quality studies to assess the efficacy of cytokine inhibitors (TNFα inhibitors) or immunosuppressive medication. They recommended more in vivo work on the immunomodulatory effects of analgesic medications such as morphine that has, in vitro, been shown to decrease the anti-inflammatory cytokine IL-10 and increase the proinflammatory IL-12 thus predisposing to more pain.

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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 – Low Dose Naltrexone – Prescribing Doctor Videos

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Prescribing Doctor Videos

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The low dose naltrexone, LDN, website is managed by volunteers in England, in particular Linda Elsegood, Trustee. All the videos are no doubt helpful, but I would point out particular interviews:

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Rachel Allen, PhD – England – Dr. Allen received her PhD in Immunology from Oxford, then did work in Cambridge on the innate immune system.  She discusses the innate and adaptive immune system, glia, cytokines, and dendritic cells. This video focuses on Toll-Like Receptors which is where naltrexone acts to block pro-inflammatory cytokines that create pain. The pro-inflammatory cytokines are involved in autoimmune and other diseases.

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Jarred Younger, PhD – Stanford researcher  – has published studies using LDN on persons with fibromyalgia.  He discusses plans for testing it on other conditions possibly including depression and using it for children.

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Pradeep Chopra, MD – Anesthesiologist in Rhode Island – uses LDN for CRPS. With Mark Cooper, PhD, they have published two cases. The publication acknowledges my contribution in teaching them my experience. I have prescribed LDN for years in many persons with intractable pain. Prof. Cooper came to San Diego for two days November 2011, to meet and interview eight of my patients who had 100% responses with LDN for their years of intractable pain. Four responders had been able to discontinue LDN with no further recurrence of pain for years, and four remained on LDN with complete response.

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Since I had no time to publish, Dr. Cooper later asked that I teach Dr. Chopra about LDN which I did over several hours. After noting in the paper that Dr. Chopra’s patient did not fully respond, I suggested to Dr. Chopra that he increase the dosage as I find not all respond to 4.5 mg. A large percentage of persons with intractable pain need higher doses. Finally, there are two populations that need lower doses than 4.5 mg but most persons with pain can be started at that dose.

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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.

~~~~~

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.

.

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

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PeaPure – Palmitoylethanolamide for Nerve Pain or Migraine

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PeaPure is a glial modulator. It is available in Italy and the Netherlands as a food supplement and has been studied in multicenter clinical trials in Europe for several years. It is well tolerated with no side effects and is very helpful for neuropathic pain, headache, and osteoarthritis. It is anti-inflammatory and neuroprotective.

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Because it inhibits astrocyte activation and the over-expression of pro-inflammatory molecules and signals, it is being investigated in Alzheimer’s Disease.

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The mechanism of action of PEA was discovered in 1993 by Nobel laureate Rita Levi-Montalcini in her work on nerve growth factors. She found it is involved in metabolism of mast cells and published a series of papers on its self-healing effect of the body in response to inflammation and pain. Two recent publications from Jan M Keppel Hesselink, MD, PhD, and his colleagues at the Institute for Neuropathic Pain, Amsterdam, The Netherlands, describe case reports, one of which is the case of a woman with CRPS.

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The purpose of this post is to clarify dosing of PeaPure and how to take it for a sudden flare of pain. My apologies for failing to recall the source of these instructions which I believe was from the manufacturer and from here and here. The latter includes an excellent review of its mechanism.

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Description of PeaPure® 400 mg capsules
PeaPure® is a food supplement based on a natural and fatty-acid like compound.
The substance palmitoylethanolamide (PEA) is a physiologically active molecule that the body produces naturally.
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What the user should know prior to ingestion:
•    There are no known significant side effects.
•    PeaPure® can be taken simultaneously with other medicine. In case of doubt, it is recommended to first consult your doctor or a pharmacist.
•    Use during pregnancy is NOT recommended.
•    PeaPure® does not contain sugar, yeast, allergens, sorbitol, magnesium stearate, povidone or other ingredients.

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Dosage and administration
Administration: During or after the meal, swallow 1 capsule together with water, or sprinkle the content of the capsule on your food.

Dosage:  may use 30 mg/kg
First 2 months: 3 times 1 capsule daily
Next 2 months: In case of a positive result, 2 times 1 capsule daily
After 4 months, you can consider the following:
•    Continue taking 2 times 1 capsule daily.
•    Reduce the ingestion to 1 times 1 capsule daily.
•    Stop the ingestion.

In case of regression, it is recommended to increase the dosage to 2 or 3 times 1 capsule daily.
It is possible to continue taking PeaPure® in the correct dosage.
Do not exceed the recommended daily dosage.

Daily dosage Recommended Daily Dosage in %
palmitoylethanolamide 1200 mg (= 3 capsules)     —-


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Dosage for children [update  July 30, 2013]: Use up to 30 mg/kg body weight.

Doses up to 50 mg/kg BW have been proven safe in children and doses up to 100 mg/ kg BW in adults

PeaPure can be easily swallowed, or for patients with severe swallowing problems, the capsules can be openend and PEA can be sprinkeled over a meal or mixed with yoghurt or so.

PeaPure can also be taken easily under the tongue, by opening the special designed capsule and poring the powder on a spoon and getting it under the tongue. (Especially of use in patients suffering great pain and for instance in Lou Gehring’s disease). Or the capsule can easily be swallowed.

Dose recommendations of PeaPure

Dose recommendation: start with 1200 mg daily in 2 to 3 doses (e.g. 2 capsules after breakfast and 1 capsule after diner). In case of severe pain, migraine or for special indications such as Lou Gehrings disease it is recommended to open the capsule and put the PEA under the tongue for longer periodes of time. The PEA dissolves in the mouth and is absorbed via the oral mucosa to enter directly into the body, not being partly digested in the gut. This gives a jumpstart which might be desirable, but is not always necessary.

PEA is the body’s own modulator, and not a painkiller such as NSAIDs and morphine. It does mostly need some weeks to slowly bring the body in balance on a number of biological levels. As PEA has a number of modulating effects, both on the short term as well as slowly increasing, there are patients experiencing quick pain relief within some days. There are also patients who need more time (especially in chronic pain situations). Therefore the recommendation is to test the efficacy of PEA during two months in cases of chronic pain before deciding on its efficacy.

If pain decreases more than 30% one can reduce the dose of PeaPure to 2 times 400 mg. If pain increases under PeaPure treatment, as some chronic pain syndromes sometimes waxes and wanes (given the weather, given excercise, food, etc) it is recommended to increase the dose to 800 mg twice daily.

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Warnings

•    It is not allowed to use food supplements as replacement for a varied diet.
•    Keep this food supplement dry and at room temperature. Keep out of reach of small children.

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Content and ingredients
30 vegetarian capsules
Each capsule contains 400 mg palmitoylethanolamide (PEA).
Ingredients: palmitoylethanolamide, hydroxypropyl methylcellulose (capsule)

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Palmitoylethanolamide is sold as PeaPure, a food supplement, available from the Netherlands and imported by a local pharmacy here. I have submitted a paper for publication on the treatment of vulvodynia and proctodynia with PeaPure and a topical cream. That source will be posted once it is accepted.

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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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~

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 or contact your local psychiatrist.

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

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Spinal Cord Stimulators

For some reason my two browsers do not show the comments sent to this post, below, and therefore I am posting them now. I would emphasize the last comment by a very experienced nurse who has seen many complications of spinal cord stimulators. For persons with CRPS/RSD, I have seen many others. The saddest are those who had stimulators inserted and now the pain of CRPS is worst at the site of the “stim.” If the leads are ripped out from under the skin, the track of those leads may forever be the worst pain on the body.

10 Responses to “RSD – CRPS – Complex Regional Pain Syndrome – Long Distance Patients”

  1. Robyn H Says:
    08/04/2010 at 8:16 am  
    I broke my hip and wrist during a fall at a local skating rink in my hometown in Georgia. The hip healed fine after surgery and two weeks later, surgery was performed on my right wrist. Immediately after surgery, the pain was different. I was soon diagnosed with RSD and put on several medications and therapy three times a week. After many weeks of oxycontin, oxycodone, neurotin, topamax, klonopin, robaxin and paxil and four nerve blocks (SGB), it was suggested I receive the spinal cord stimulator. Through research on the internet, I found Jim Broatch with the RSDSA organizaton who advised me there were other alternatives in treating RSD. I discovered Dr. Nancy Sajben in San Diego. She has been treating RSD with oral ketamine and naltrexone. I saw Dr. Sajben in her office July 19th and began treatment. Since beginning treatment, I have been able to go off the opiods and have had a 70% improvement in my range of movement of fingers and arm and decreased pain levels to the extent that I can now tolerate physical therapy. I have had no “flare ups” since beginning treatment. Dr. Sajben has changed my life for the better and given me hope for the future. Thank you, Dr. Sajben!

    • Nancy Sajben MD Says:
      08/04/2010 at 6:00 pm   Remarkably, in one and one-half days, she no longer needed high dose oxycodone which she decreased 95% on her own as pain was 40% better. That was before ketamine reached a dose where it began to have an effect and before naltrexone was prescribed. The later addition of those two helped even more. By the start of week two, she was able to discontinue the last 5% of oxycodone and is 70% better off opioids. She was started on a few other medications than mentioned in her comments: rational polypharmacy. Since January, she was unable to move her fingers, unable to write or pick up anything with the right hand. Less than ten days after we started treatment, the fingers had regained modest motion. She could hold a pen, write, pick things up with the fingers, fold laundry, pack luggage, and best of all her seven year old daughter said: “Mommy, I can hold your hand for real now.” Allodynia and hypersensitivity of the hand is so much better that she is likely to be able now to make progress in physical and occupational therapy. It was too painful prior to her visit. There has not been one flare of CRPS since day one on July 19, 2010, despite using the hand in ways not possible for seven months.

  2. Lori Morris Says:
    01/11/2011 at 6:45 pm   I would first like to thank you for your specialization in CRPS. My husband was diagnosed with CRPS in March 2010. He suffers in his lower left extremity (left foot/ankle) with all the signs of CRPS. He has gone through extensive pain management since that time. He has used oral meds, morphine, oxycontin, and now methadone, and also takes lyrica and nortriptylene along with lortab as needed. He has had no relief with these meds. He has had one nerve block with no relief, so a second block was not attempted. On Friday Jan. 7th the SCS trial was done and today Jan. 10th removed due to it causing pain in his lower back and side. The jolting the SCS caused in these areas could not be over come with reprogramming the SCS. Today, his pain management doctor discussed the Drug Delivery Therapy, which is not crazy about doing and after reading your information regarding SCS and Pumps I too am having second thoughts. However, the doctor did mention that there were 2 clinics that specialized in CRPS. One at John Hopkins and the other at UCLA. His doctor recommends the UCLA clinic and that is how I got to your page. I have been doing my research on CRPS since my husband was first diagnosed and am always looking for anything new in the medical field. I have read all your information regarding the Ketamine and Naltroxene treatments your patients have received and will be discussing these with his local pain management doctor. So, again I just want to thank you in advance for your specialization and your web page. Who knows, we just may meet some day.

    • Nancy Sajben MD Says:
      01/15/2011 at 6:17 pm   CRPS is unlike any other pain syndrome because it can be spontaneous or triggered by something very slight. Pain can involve the entire body. There is a high incidence of suicide. Despite that, there is a hope that it may be entirely reversible or, at least, put into remission. What a joy to see that happen and to share in the recovery!!!

  3. Traci Says:
    03/29/2011 at 6:01 am I posted on your main blog, but haven’t heard back. I know you wanted information regarding issues or problems with Spinal Cord Stimulators, so here is some information that you can add to your file. I can also be contacted for additional information because this issue continue to date.

    In one of your posts you asked for input from patients that currently have a SCS. I currently have a Medtronic SCS it was implanted early 2010 and I ended up having swelling in my Lt (affected) foot/ankle every time I would charge the “re-chargeable battery”. No one at Medtronic could figure out the issue. I turned into their “human lab rat”. After several months of this I was told to switch from a rechargeable battery to a non-rechargeable batter. Thus another operation… which I did. After this surgery (I have a paddle with 16 electrodes) all 8 electrodes on the Lt side that used to supply stimulation to my Lt foot/ankle now hit my pelvic area – thus I can no longer utilize these electrodes. And out of the 8 electrodes on the Rt 2 are providing stimulation to my Lt foot and the other 6 are hitting the wrong areas. In addition to this I have had continual instances where I am getting a very sharp pain/ sharp twinge (like a jolt) around where the electrodes area. When this happens if I turn off the SCS the pain immediately stops. I’ve been on a conference call with a Senior Engineer of Medtronic and a local Rep in person with me to do reprogramming… The Engineer only wanted to know if the electrodes were putting out stimulation. He didn’t want to know what the amperage was at before I could feel it or in what part of the body the stimulation was felt. These should have been critical pieces of information. All he wanted to state was that the electrodes were working. As for the Sharp Pain / Sharp Twinges that continue to occur in the electrode area their Senior Engineer has no idea what is causing this. He asked me to run an experiment the next time it happened – I did exactly what he wanted and reported back the findings. I have yet to hear back from Medtronic. They do not want to back up their product and they are not willing to admit that their is a problem. Although I have 2 doctors including a Neurosurgeon that feel there is some type of fault in their product or that it is faulty. Hopefully this gives you some additional information you were seeking. Please feel free to email me if you would like to discuss further. I am continuing my uphill battle with Medtronic.

    I have spoke with Medtronic as recently as yesterday and they can not explain the continual sharp pain/sharp twinge that I continue to get where the paddle that holds the electrodes is placed. The “Patient Relations Rep” that has been assigned to me, (at one point she tried to tell me she was from their “Legal Department” and she was later introduced by a team member as a “Patient Relations Representative”), doesn’t feel this is a big issue. She told me yesterday that this is “just medicine” and sometime they can get it right and other times it just doesn’t work out… The Senior Engineer at their company can not figure out what the problem is, so he just wants to reset the “INS”. I asked exactly what the “INS” was and the Patient Relations Rep couldn’t answer that question. I have already had my system reset numerous times (too many to count) and reprogrammed numerous times.

    The trial was aproximately $25,000; the hospital expenses alone and cost for the SCS implant were over $150,000 and the secondary surgery to replace the rechargeable battery with a non-rechargeable battery was aproximately $53,000. This is all for a system the now has 2 out of 16 electrodes that hit the correct area, creates an intermitent sharp pain/sharp twinge in the spinal area where the electrodes/paddle is placed, and they aren’t sure how to resolve this issue. But I was told yesterday that their system was working properly by their rep.

    • Nancy Sajben MD Says:
      04/01/2011 at 2:48 am  Traci, thank you for your comments and for placing your second comment in this section where others with CRPS may be more likely to see it.

      One of the simplest ways to respond to the issues you pose is to say that a renowned pain specialist colleague, trained in Anesthesia Pain at Harvard 40 years ago, does not put in spinal cord stimulators, does not recommend them and does not refer patients for them. He trained in how to use them when they came out, just as he trained for morphine pumps. He has never placed either in a patient.

      The common sense question is: Show us the data. Five year long term data with complications. Invasive procedures do have potential risks.

      The body tissue of a person with CRPS is very volatile, very different than any other condition I know. Any surgery, any procedure in that person is a risk not to be taken lightly. Just a needle stick for blood draw or vaccine can trigger CRPS.

      There is no question it is a big money maker. Several can be placed in many patients in a few hours. In no time at all, it has become an industry. And that kind of wealth can control the way pain management is practiced in this country. It doesn’t pay to do anything else. NIH doesn’t try. Show us the research.

      Nothing interests me more than the neuropharmacology approach I use for CRPS and “intractable” pain from the many conditions my patients have. I wish you lived nearby.

  4. Maureen Says:
    01/22/2012 at 5:57 am   
    I just had the scs implanted two weeks ago. I am getting that sharp pain and burning near the battery site. It happens with the scs on or off. I really am wishing I never got it. I feel that the small relief that I am getting is not worth it. Are you telling me that the leads can never come out and no MRI ever? I do believe they can be removed.

    • Nancy Sajben MD Says:
      01/24/2012 at 4:41 pm   
      I believe they can be removed, but they may become tethered to the spinal cord itself. I presume that may occur when they have been in for some time. I do not implant these, but one of the foremost anesthesiology pain specialist in the country, Harvard trained in pain management, will not put these in and will not refer patients for them.

    • Nancy Sajben MD Says:
      01/24/2012 at 4:43 pm   editAgain, specifically, if tethered to the spinal cord, or some other complication, they cannot be removed.

  5. Barb Fosdick Says:
    06/07/2012 at 11:25 pm   editI have been a surgerical nurse for 40 years and have seen many patients receive SCS…and many, many fail, or return to surgery for fractured electrode wires, misplaced wires, or infected battery pockets, besides complicated problems, or “lack of positive results, or battery revisions, or electrode repositionings.” Some patients have even developed spinal fluid leaks when the spinal dura layer has been torn during implanting the electrode wires, and they develop severe headaches, and have to return to surgery for the leak to be repaired. Many pain management doctors are convincing patients that this is a great way to treat their pain, and they find out in 2-6 months that they wish they never had agreed to it. Sure, there are some patients that get some relief, but this procedure has been pushed on the population of chronic pain patients, when they are at their worse condition, and willing to try anything….at any expense, and the companies and implanting doctors are getting the money. More patients need to learn the truth about these devices! Anomymous…. and never allowed them to put one of those things in me…but many tried!

RSD/CRPS, Multiple Sclerosis, LDN & Ketamine

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It is rare for me to see a patient who is not complex.

They have failed so many treatments for so many years before they call.

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This is the report of a lovely woman in her early 70′s with progressive Multiple Sclerosis for 30 years and paraplegia that has forced her to use an electric scooter the last 5 years, and power wheelchair the last 2o years. Because of total paralysis of the right lower limb, she fell and shattered her femur, the thigh bone, in August 2009. Tragically, and all too often, the surgeon failed to diagnose Complex Regional Pain Syndrome [CRPS], even failed to visit her in the hospital. CRPS increased the fatigue she had already had from Multiple Sclerosis.

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Thankfully a physical therapist suggested the diagnosis.

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Why is pain management not a required subject for physicians?

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I have written elsewhere that the American Pain Society discovered that our National Institute of Health, NIH, devotes less than half of 1% of their research dollar to pain research. Of 28 NIH institutes, none for pain, three for addiction. This will not change soon. The only hope is that RSDSA.org will succeed in collaborating with all pain organizations, groups with dystonia, chronic fatigue in order to give a voice and research dollar to advances.

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Before seeing me in September, she had 11 sympathetic blocks with no benefit.

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Does it make you wonder why 11 were done?

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How does insurance authorize 11 when 10 had no benefit? I have just learned that a doctor must indicate at least 50% relief before another will be authorized. That explains it.

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Then she was given opioids including tramadal and Butrans patch which rendered her a “zombie,” sedated, poor memory, unable to function. She tried 4 or 5 treatments of Calmare with no benefit but was advised she needed a clear neural pathway for it to work. That was not possible due to the Multiple Sclerosis.
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Lyrica caused severe edema. Gabapentin 1400 mg/day caused weight gain, increased her appetite  more than usual, but she remained on it. She craves sweets more than usual, at times uncontrollably. Perhaps it can be slowly tapered now. Advil 600 mg gave some benefit but caused ulcers that required Nexium.

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Since her initial visit a few weeks ago, she became 60% better during her two week stay.

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I will highlight only two of the new medications started.

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It may also be said that opioids are not the answer.

Opioids may perpetuate pain.
They may produce paradoxical pain or opioid induced hyperalgesia or windup.

They may block the effect of ketamine and other adjuvants that would otherwise lower pain.

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Of importance is that she was not able to tolerate clothing on her right lower limb for three years, not even a sheet, and now she is able to sleep through the night without pain for the first time in three years and able to wear a skirt. This allows her to go out with family to restaurants and even to enjoy shopping with her daughter. Her dose of ketamine is very small relative to most of my patients and she uses it only once or twice a day since most of the new medications have brought her pain down.

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At her first visit one month ago, she rated pain from 6 to 8 on a scale of 10, average 7/10. Now 60% better, ranging from zero to 7, average 4. Yes zero pain, sleeping through the night without pain and waking without pain. She had not been able to tolerate touch to the right thigh or foot and would pull her skirt above the thigh, removing her shoe.

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Now she indicates pain continues to improve.

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Of interest, despite an abundance of concern that low dose naltrexone [LDN] may flare her Multiple Sclerosis, we were easily able to increase the dose to triple what is usually called “LDN.” This did not flare her condition and may be one of the most effective medications she is taking for pain.

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What is LDN?

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The FDA has sanctioned its use in the USA only in doses of 50 to 400 mg for addiction to opioids and alcohol.

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Low dose naltrexone [LDN] is a fascinating medication. It has been used in low dose in persons with Multiple Sclerosis since 1985 when a Harvard trained neurologist in New York City, Dr. Bihari, first discovered that it relieved all disability in some patients with Multiple Sclerosis and prevented recurrent attacks. Since then, doctors in Scotland, where they have the highest incidence of Multiple Sclerosis, find that one of the earliest signs of recovery in this population is relief of neurogenic bladder. It is said that persons with Multiple Sclerosis must remain on LDN for 1.5 years before they might fully assess its value.

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 Multiple Sclerosis may be flared unless very small doses of LDN are used.

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Many with Mulitple Sclerosis cannot tolerate more than 2 or 3 mg, perhaps due to spasticity. There is a great deal of dogma on the web about its mechanism, dosing and timing for off label use. Use the search function on this site to review the prior discussions I posted on LDN, MS, CRPS.

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Naltrexone is a glial modulator.

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What’s that?!

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By serendipity, four years ago I discovered naltrexone in low dose may relieve chronic intractable pain. I had been using it for perhaps eight years in microgram doses but I found in milligram doses it is even more profound.

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The mechanism of naltrexone and a wee bit of glial research is discussed here. The Nobel Prize was awarded last year for the discovery that these glia are your innate immune system. They are profoundly important in many diseases including chronic pain, Major Depression, Multiple Sclerosis, Alzheimers, Parkinsons Disease, ALS, Autism. They produce inflammatory cytokines that lead to inflammation.

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Now that she has been home for two weeks, on a number of medications that I started, not just the ketamine and LDN, I hope she will comment on her experience and her progress since flying back to the east coast after her brief visit here.

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It is often essential to taper off opioids to allow other medication to work.

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I feel she was able to benefit from these low doses of medication because she tapered off all opioid medication prior to her visit, thus allowing her system to recover and respond to these medications. We will know more in the next few months as she slowly titrates up on some of the medications that were started.

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Next year on her return, we may be able to withdraw some of the medications depending on how well she is doing.

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Finally, ketamine does cause her to have brief side effects. Her husband likens the effect the same as half a glass of wine: “She’s really cute.” Thankfully, most people have no side effects and if they do, they rarely last more than 20 minutes.

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She sends an update below, 80 to 90% better. Hopefully this will continue to improve over the next months as she slowly increases the medication we started. And ketamine has an additive effect in some. It is anti-inflammatory.

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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 or contact your local psychiatrist.

~~~~~

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

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RSD, Complex Regional Pain Syndrome – a case report

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Severe Pain for Three Years,

 80% better in 10 days

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“This has been life altering.”

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This is a very bright young woman who was an all state volleyball player until onset of Complex Regional Pain Syndrome three years ago in the right hand and wrist. It began after blood was drawn from the hand for a chemistry study and, one week later, the fingers turned black, lost blood flow, followed by emergency surgery for removal of a blood clot from the back of her hand. She woke after surgery, tearing the sheet off due to intense pain on light touch — that is called allodynia — and then developed severe edema from the hand to the shoulder.

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It was four excruciating weeks before the diagnosis of complex regional pain syndrome was made.

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CRPS or RSD is a diagnosis that every MD,

every surgeon, every ER doctor,

every psychiatrist and psychologist, every nurse and therapist should know how to diagnose.

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Because she was a minor, they would not do nerve blocks.

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She developed contractures of the fingers and hand,

was unable to move the fingers.

  A major university hospital diagnosed Munchausen Syndrome;

mom was diagnosed with Munchausen’s by proxy.

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This happens so often. This is 2012.

If it’s not the doctors,

it’s the insurance companies

creating roadblocks to diagnosis or treatment or both.

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Why is pain management not taught at medical schools?

Only 3% of schools today give 30 hours instruction in four years, Yale most recently.

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At a major university hospital two hours away, she failed to respond to 14 stellate and brachial plexus blocks. But the wound reopened by itself, the stitch fell out. The psychiatry department evaluated her after she was so drugged with methadone, she does not even recall the interview. They diagnosed Munchausen Syndrome. That changed everything. Relationship went sour. Distrust of MD’s began and was confirmed many times in many places along the northeastern corridor and Texas.

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That fall, she became a student at the university of her dreams. The diagnosis of CRPS was confirmed at their university medical center hospital where they wanted to continue the same blocks that had failed. Elsewhere, the chief of a renowned ivy league university pain service wanted to talk to her only about spinal cord stimulators, declined by the family.

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In May 2010, she qualified for an NIH study of neurotropin double blind 6 weeks on, 6 weeks placebo. Failed.

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She was seen by Dr. Schwartzman in Philadelphia October 2011, and sent from there to NYC to rule out neuroma dorsum right hand, negative.

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On Lyrica, she gained 20 lbs, then back to 130 lbs baseline when off of Lyrica. Intolerance to Morphine – hives, Duragesic – total body itching. Ambien – hallucinations, Lunesta – hyper. Benadryl helped somewhat. Detoxing from Nucynta – lips were bright red.

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Her weight dropped from 130 to 115. Many medications were trialed and failed. Marinol helps pain slightly and gives the best sleep in years, better appetite. It does cause anxiety, but she had not slept in three years, and it gives 4 to 6 hours of good sleep. She developed sharp bitemporal headaches. I advised headache is a side effect of Pristiq —- now thankfully discontinued and better.

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Since August 2011, she has had CRPS pain in the right leg, worse walking, weight bearing.  There is discoloration of the dorsum hand usually, at times along proximal forearm, recently at right foot and leg. She had edema up to the shoulder measuring 30 cm. Nails growth faster at the right hand, possibly less hair growth right hand. Temperature usually cooler on the right hand, at times at night the hand and foot become hotter. No change in sweating noted.

The first year, she had almost total loss of function in the hand with pain and contractures —and forced herself to move the fingers with OT and PT, then home exercise. She still has days when the fingers remain flexed, but 98% of the time there is full movement as she continually tries to use the hand/fingers to write and type. Nose may become ice cold and tingly since CRPS spread to right side of face and right lower limb. At times tingling fingers. She struggles with memory when pain is severe and with lack of sleep.

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Pain ranges 7 to 10, average 8. Edema was significant for one year, now comes and goes. Allodynia is present hands and feet, now a different scale than before when she could not even be in the car.

However, with weight bearing and walking, pain of the right lower limb became most intense.  She will be 21 in July, but on a bad day was unable to leave her bedroom to walk downstairs as pain was too severe. She would communicate with family by loudly calling or texting. It was unthinkable to make plans for the next week due to severe pain. She has osteoporosis with atrophy of the right upper limb, and has had color changes and edema of the hand.

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She lives in an eastern state inland, two hours away from the mid Atlantic seaboard and major medical center. She failed ketamine infusion at a major university medical center on the east coast. The cost and inconvenience was significant and the family did not know that ketamine may fail to have any effect if taking opioid analgesics. Once mom discovered that, she was able to wean off the opioid medication. Ultimately, after many more interventions, much later, in crisis, she did benefit from IV ketamine infusion, and was able to regain some movement of her fingers on the right hand, but there was no lasting relief. It was a struggle to obtain approval through her insurance.

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She has been spending a great deal of time in bed for months. Morning stiffness is widespread for one to two hours. Bending is difficult, feels as if “hit by a bus,” but she does stretching, moving, distraction and Yoga when able.

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Much better in 10 days

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Day one: pain of the entire right side, face, trunk, limbs, rated 7 to 10 on a scale of 10, average 8. She guards the dominant right hand and the signature is difficult. Atrophy of the right upper limb is present, nails longer on the right hand, dusky dark erythema and long jagged scar over the dorsum right hand, mild erythema of the right upper and right lower limbs.

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On the first day, in the office, she tried the first dose of ketamine nasal spray and after a repeat dose, she was puzzled, thinking to herself, then let us know she realized she was able to concentrate. A small dose is not enough to relieve severe pain, but even major depression can vanish at that dose. Two sprays relieved the brain fog of depression; pain was still 8 on a scale of 10. Blood pressure and pulse did not change before and after doses. She felt hopeful.

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In the next few days she was able to do the unthinkable: make plans with friends, walk 45 minutes, become active, and remain active in a way that had not been possible. She was far more active with much less pain.  Over the weekend, six days after she arrived, after we had sequentially added several new medications, she found the dosage of nasal and sublingual ketamine that worked for her. She has actually had times when she was pain free. As noted during prior ketamine infusions, she requires a far higher dose than most patients to achieve effect. The plan now is to use higher doses at home when time permits for best effect, and booster sprays of nasal ketamine as needed when away from home. She can carry it in her pocket. There is no need for ICU infusions and the fight to get insurance coverage for those stays.

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Of great significance, she has even made plans for the entire summer.

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More details of her case will be added, as time permits. For now, this page is here to allow the patient and family and others to send comments. She will continue slow titration of other medications that will take three months before reaching the target dose, before we can assess efficacy. Based on my experience treating chronic intractable neuropathic pain including CRPS, it is possible these medications will be able to stabilize and relieve pain without ketamine.

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See other case reports of treatment of CRPS here, here, and here.

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You can read some of the science of pain, glia and inflammation. Ketamine is significantly anti-inflammatory. Three of her new medications are glial modulators. Treatment of severe chronic pain usually involves rational polypharmacy, not one medication and not medication alone. It requires a holistic approach to heal: P.T., O.T., massage, cognitive behavioral therapy, guided imagery, visualization, positive thinking, remaining active, and other modalities that depend upon the underlying cause: physical, emotional, spiritual, and financial. The treatment for CRPS is not specific for that condition alone, but the gains can be possible with tremendous discipline, effort, single minded determination and the loving support of friends and family.

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Be cautious of spinal cord stimulators. Try everything else first.

They can create pain and scarring or tether the spinal cord.

Be proactive.

Remember that guidelines and strategies for diagnosis and treatment are outdated.

Support RSDSA.org if you can.

They support high quality pain research.

You can go directly to their site or donate to them (not me)

using the link at the top of my site here.

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Patients and doctors do not understand that opioids create pain.

A 2006 publication from Vanderbilt shows how much better pain can be to taper off.

The abstract:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

The article:

Significant pain reduction in chronic pain patients after detoxification from high-dose opioids.

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More on this young woman’s journey coming.

It’s been busy!

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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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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, you will need to telephone my office.

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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CRPS Two Years, Pain Free on Low Dose Naltrexone

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Girl with CRPS cold type two years, pain free on naltrexone 3 mg

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KR, 17 year old seen 11/4/11, with Complex Regional Pain Syndrome [CRPS] involving left lower limb from foot to hip, onset 3/09. She has nonspecific immune system abnormalities and many food sensitivities that caused leaky gut syndrome and 30 lb weight loss with certain foods causing the stomach to be rock hard and vomit. Elimination diet allowed her to regain 30 lbs.

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CRPS diagnosed February 2011, two years after first symptoms. The leg was cold, purple, mottled with allodynia. Pain had been 9 on scale of 10 for weeks prior to my visit when she was started on prednisone 60 mg x 1 week, 40 mg 1 week, and a few days on 20 mg, dropping her average pain to 4/10. Pain at my visit 11/4/11, ranged from 4 to 9, average 5, that was 40% better after prednisone. She takes a wheelchair to school and for distance, is able to walk short distances with cane, and without cane she concentrates walking slowly to avoid limp. She is very bright, highly motivated and described the limb as cold, aching, throbbing, shooting, stabbing, sharp, tender, burning, exhausting, tiring, miserable, unbearable. Pain severely interfered with walking, work, sleep, enjoyment of life, general activity, and relations with others. At rare times, the limb would jump. Numbness was present posteriorly off and on, especially when sitting, not present when standing.

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She had good health until mononucleosis at age 13 in October 2007. A few weeks later irritable bowel syndrome began (IBS-C), then CRPS began after injury March 2009, reinjury July 2009, then no problems until February 2011. The initial injury occurred when roughhousing with a friend, and her foot pulled her toes in a dorsiflexed position. The next day it was swollen and purple with bruising pain after the first injury. She was in a boot for several weeks. CRPS improved, she went to Peru climbing Machu Pichu when she was reinjured again. The foot was swollen, burning with allodynia. She was taken to a hospital in Chile where they wrapped the foot, advised to take Advil. Once home, she went to physical therapy. It resolved in 6 weeks.

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February 2011, fulfilling PE for high school, she tried out for swim team. Day two, she had pain from kicking in the water and was never able to get back into the water. She was in crutches the next 2.5 months and began physical therapy three times weekly since then. Pain began in the sole of the foot, but a slip and fall in the rain caused pain to spread to the hip. A flare in the past month caused pain much more in the left knee after prolonged sitting for tests. She now takes her wheelchair to school which she began to use early October 2011. She was in the chair consistently two weeks, now only as needed, and never uses it at home. She has used a cane since later April when she got off her crutches. In hot weather, the cold left lower limb sweats profusely. No hair changes. On prednisone, toes nails grow faster. She has used warm and cold compresses to relieve pain. She failed gabapentin when it caused her to be nonfunctional on 900 mg/day with no relief. Lyrica caused hives. Nortriptyline caused personality change, becoming very mean, an Atilla the Hun, opposite her usual good nature. Cymbalta 20 mg – severe dry throat, thick mucous, medications lodged in esophagus. Tried Tramadol 25 mg TID and Naproxen 500 bid.

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Incidentally, she saw a neurologist at Children’s Hospital in 2009 due to sudden onset of diplopia that was found due to allergy to contacts, and resolved with new contacts. She saw an allergist in 2010, and tested positive for nonspecific autoimmune disorder: ANA 1:160 speckled, positive for food sensitivities, and after four months of stopping certain foods, ANA was negative: gluten, dairy, garlic, broccoli, lima beans, banana, asparagus, pineapple, oyster, mushroom. While eating those foods she had IBS-C, stomach would harden, causing vomiting, and she lost 30 lbs, was 120 before —- it is part of the leaky gut syndrome that prevented her to absorb certain nutrients. She has regained weight and all symptoms resolved. She does not have dry mouth or dry eyes. She is sensitive to normal doses of medications like her grandmother.

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Exam: Toes are cold on the left. At the moment, no changes in hair, skin color, temperature, sweating. Stretch reflexes symmetrical, brisk in both lower limbs. She uses a cane but is able to walk slowly without limp, carefully, holding both arms stiffly at her side as she concentrates on walking. Sensory examination was not detailed due to patient discomfort and long trip from home that was very tiring.

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Treatment: Prednisone was rapidly tapered off. Begin 1 mg low dose naltrexone [LDN]. Begin N-acetyl cysteine [NAC] 600 mg x 3/day for “cold” CRPS – it is reported to take 3 or 4 months to help.

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Reponse: Mom wrote a few days later, “On the way home from our visit in La Jolla, K started to experience sensation in her leg. You had asked her at the appointment if she had numbness and she could feel some in the back of her leg. She didn’t realize the extent of it. The Naltrexone [1 mg] seems to be awakening areas of her leg. She has felt more muscle pain as well. She feels this may be because she is able to use more muscles in her leg with the increased feeling. She also had her foot stepped on the next day (Saturday). In the past, she would have been incapacitated with the pain for a couple weeks. With the Naltrexone, she felt very little pain at all. We were both very excited to see these changes. :) She is at about a level 3 to 4 in pain.”

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Encouraged mom to continue increasing LDN as tolerated.

11/16/11, ” K is pain free at 3 mg of Naltrexone. We are not sure of any side effects at that level as she has a cold/flu and has had nausea and headaches. She does not have any sleep issues so far. K thought the Delsym was making her lightheaded. She will start it again as soon as she is feeling better.…

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Needless to say, it makes me very happy to know I am able to help someone in pain, especially a child.

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11/21/11: “We are thrilled too! The only things she is taking is the NAC and the naltrexone. When she tried 2mgs the pain receded to just the upper back of the leg. She also noticed the minor cut she had that day burned a lot. At 3mg all pain just vanished. I can’t tell you how excited we are. Her muscles are a bit sore in the leg as she is exerting herself more in physical therapy…. I am interested to see K’s next autoimmune text results in 6 months. I am wondering whether her Autoimmune test results will be negative from taking the naltrexone.”

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1/15/12, “K has been using the LDN at 4 mg and it is working better for her….Once K has recovered from the mononucleosis and is back on her feet again she will know for sure whether her leg pain is gone when standing in one position. If not, she will try the dose at 5 mg and let you know how that goes.”

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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:  
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Ketamine Intranasal for Rapid Relief of Pain and Depression

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Poorly managed pain can evolve into chronic disease of the nervous system

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Ketamine is an important analgesic, more important than opioids. It can dramatically reduce pain, and rapidly relieve depression and PTSD.  Please read my earlier posts here and here. And the NPR report here just after I posted this (skip to their last section). Yes, it is FDA approved and legal. One woman said:

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 ‘It was almost immediate, the sense of calmness and relaxation.

‘No more fogginess. No more heaviness. I feel like I’m a clean slate right now. I want to go home and see friends or, you know, go to the grocery store and cook the family dinner.’

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NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

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‘I Wanted To Live Life’

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Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.
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Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.
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About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.
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Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.

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It would be of interest to see a case report of the bladder problems they mention. Is this in a single drug addict who used many unknown medications on the street? Several physicians have infused IV ketamine for persons with pain for many years, in far higher doses than I prescribe, with no report of any but transient minor symptoms.

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David Barsook’s 2009 review, reference below, describes changes that cause memory loss and brain atrophy with chronic pain, in particular, Complex Regional Pain Syndrome (CRPS), and they also occur with chronic depression:

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With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death.

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Brain atrophy and memory loss has also been shown in chronic low back pain as well as in chronic depression.

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Barriers to management of chronic pain are many:

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Although opioids are effective for acute pain, effective treatment of chronic pain is often daunting, particularly neuropathic pain.

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Opioids have been shown to create pain causing imbalance in the glial cytokines that favor pain rather than relief of pain. Opioids carry the risk of opioid-induced hyperalgesia which is a severe pain sensitivity. They affect the brain and endocrine system. Opioids may fail to offer significant relief, fail to improve function, and risk misuse, abuse, diversion and death. Their costs are astronomic, insurance coverage is increasingly limited, the potential for complications may be life threatening in a hectic medical setting, side effects can be lethal, lack of physician training in use of opioids and alternatives to pain control lead to increasing deaths, addiction and diversion. It has become a national emergency and a trillion dollar war on drugs.

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Complications can be greatly reduced through use of a scrupulous history and physical examination, but reimbursement is directly proportional to the shortest time spent with a patient. Will that help assessment and care?

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Individuals may have dramatically different responses to opioid therapy; some may not tolerate any, and relief must be balanced with side effects that increase as the dose increases. Patient status may change and require IV, rectal or tube delivery instead of oral formulas; drug-drug interactions may require rapid changes, and disease of kidney, liver or brain may require modifications or stopping altogether. They may increase risk of falls and cause central sleep apnea with drop in oxygen because the brain fails to give a signal to breathe.

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Chronic pain can lead to loss of sleep, hopelessness, depression, anger and other mood disorders such as panic, anxiety, hypochondriasis and post traumatic stress disorder [PTSD]. Treatment of mood disorders are shown to profoundly reduce pain perception and/or ability to cope with pain.

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Ketamine is anti-inflammatory and can reduce the need for opioid use, thus reducing the pain and side effects caused by opioids.

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Nasal ketamine is more effective than oral ketamine for pain relief; oral dosing has no effect on depression.

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Nasal delivery of ketamine is now possible due to advances in metered nasal sprayers that deliver a precise dose. No needle is required, no IV access, no travel to a specialist needed.

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You can carry pain relief with you and use it as directed when it is needed.

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Ketamine is an NMDA antagonist: it antagonizes the NMDA receptor which plays a profound role in pain systems and centralization of pain.

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Ketamine is neuroprotective and it can help other disease states as noted by Barsook, 2009:

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Besides improvement in pain, “there may be lessons from other diseases that affect the brain; it is noteworthy that acute ketamine doses seem to reverse depression and ketamine decreased prevalence of post-traumatic stress disorder (PTSD) in soldiers receiving ketamine during their surgery for treatment of their burns. In addition ketamine attenuates post-operative cognitive dysfunction following cardiac surgery that has been known to produce significant changes in cognition. [emphasis mine] The data suggest that the drug can alter or prevent other conditions based on its NMDAR activity where other drugs NMDA receptor antagonists are perhaps not as effective in these or pain conditions. Lastly, NMDA antagonists have been used in degenerative disease (and pain may be considered a degenerative disease as defined by loss of gray matter volume, see above) with mixed effects perhaps relating to how they act on specific NMDA subtypes. Taken together, ketamine may act not only on sensory systems affecting pain intensity, but also on a constellation of brain regions that are involved in the pain phentype. [sic, phenotype]“

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Side Effects

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Ketamine is more frequently used in babies and children than in adults because high doses of ketamine can induce hallucinations in the adult. Importantly, it is used in high dose in adults for treatment of Complex Regional Pain Syndrome.

Low doses, cause little or no side effects in adults. If present, they are transient and often resolve in 20 minutes. Patient who respond to ketamine report good acceptance as they find the relief of pain and/or depression far outweighs any short term minimal discomfort.

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Pain care reform is urgently needed.

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Research funding for pain is less than half of one percent of the NIH budget. More research is needed, but research on low dose ketamine for treatment of pain and depression has gone on for twenty years.

The public health crisis of untreated pain, which often results in disability, parallels the country’s struggle to halt the cost of health care. The longer a person remains with untreated pain, the less likely they are to return to work or to be employable.

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Conclusion

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Pain control requires urgent attention. It is past time to put into practice the use of this valuable medication so people can get on with life instead of being mired in chronic pain that for many risks suicide and ensures continuing decades of disability. Academic studies are usually limited by defining a predetermined dose rather than clinically titrating to effect. Thus no surprise, they find no effect as every patient will have no response until they reach their dose. And that dose, in my experience, falls into a bell shaped curve. One size does not fit all. Some respond at very low dose, others require much more, and the majority fall between.

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In my experience prescribing ketamine for ten years, only a rare person has problems. Almost all find it has returned function or significantly relieved pain. Some have been able to entirely eliminate opioids that did nothing for their pain for decades, though they dutifully returned to the MD every month to chronicle that pain. Pain continued to be rated ten on a scale of ten; patient always compliant despite side effects of constipation and often depression. My patients find the benefits of nasal ketamine far outweigh the relief of oral ketamine and at much lower doses with fewer side effects.

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Further, while the pain relief may be short lived, some find it gets better with repeat dosing, and relief of depression may last one to two weeks with a single dose.

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References

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http://www.wjgnet.com/1007-9327/10/1028.asp  Ketamine suppresses intestinal NF-kappa B activation and proinflammatory cytokine in endotoxic rats.

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CONCLUSION: Ketamine can suppress endotoxin-induced production of proinflammatory cytokines such as TNF-a and IL-6 production in the intestine. This suppressive effect may act through inhibiting NF-kappa B.

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http://informahealthcare.com/doi/abs/10.1080/J354v16n03_03  Ketamine as an Analgesic Parenteral, Oral, Rectal, Subcutaneous, Transdermal and Intranasal Administration

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Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain. Because ketamine is a phencyclidine analogue, it has some of the psychological adverse effects found with that hallucinogen, especially in adults. Therefore, ketamine is not routinely used as an anesthetic in adult patients. It is a frequently used veterinary anesthetic, and is used more frequently in children than in adults. The psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III Controlled Substance. A review of the literature documents the analgesic use of ketamine by anesthesiologists and pain specialists in patients who have been refractory to standard analgesic medication regimens. Most reports demonstrate no or mild psychotomimetic effects when ketamine is dosed at sub-anesthetic doses. Patients who respond to ketamine tend to demonstrate dramatic pain relief that obviates the desire to stop treatment due to psychotomimetic effects (including hallucinations and extracorporeal experiences). Ketamine is approved by the FDA for intravenous and intramuscular administration. Use of this drug by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating nociceptive and neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pubmed/15109503  Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study  Daniel Carr, et al, 2004
Crossover, 20 patients. Ketamine reduced breakthrough pain within 10min of dosing, lasting up to 60min
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http://www.ncbi.nlm.nih.gov/pubmed/15288418  Safety and efficacy of intranasal ketamine in a mixed population with chronic pain
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The intranasal route for ketamine administration has been applied only for pain of dressing changes in a single case study (Kulbe, 1998). In this patient, oxycodone and acetaminophen were ineffective to control pain during burn dressing changes in a 96-year-old woman cared for at home. She tolerated the burn dressing changes after three intranasal sprays of 0.1 ml each, in rapid succession, each containing 5 mg ketamine (15 mg total) (Kulbe, 1998).
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http://www.acutepainjournal.com/article/S1366-0071%2807%2900167-2/abstract  Safety and efficacy of intranasal ketamine for acute postoperative pain
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Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics.
The safety profile following treatment with ketamine was comparable to that seen with placebo.
Although patients did report side effects of fatigue, dizziness and feelings of unreality more often following treatment with ketamine than following treatment with placebo, no patient reported hallucinations and the side effects were generally reported to be of mild or moderate severity, and transient. No serious adverse events were reported and the incidences of associated adverse events were comparable for ketamine and placebo. Although study medication was administered intranasally, nasal signs and symptoms were few and inconsequential. A distinctive taste, however, was reported more often following treatment with ketamine than following treatment with placebo.In conclusion this randomized, placebo-controlled, double-blind study, in 20 patients, has demonstrated that intranasal ketamine is safe and effective for BTP [breakthrough pain]. Our findings augment an early but promising literature documenting the effectiveness of nasal administration of a variety of opioids for pain management in adults (Dale et al., 2002) .
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~http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875542/  Ketamine and chronic pain – Going the distance, David Barsook, 2009

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This important paper covers essential points not mentioned by many, thus quoted at length below:

“Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic

With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations ; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially deleteriously affect neurons that may already be compromised but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity . Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia. However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects.

So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and/or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to be understood in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months. While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6weeks, they did show a level of efficacy based on NNT that equals or betters most drug trials for this condition.”

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“Conclusions

As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.”

 

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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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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 or contact your local psychiatrist.

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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!

RSD – CRPS – Complex Regional Pain Syndrome – Long Distance Patients

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I see long distance patients in my office who generally come for a two week stay, and I wish to encourage their comments on this page. I am sorry I did not post this page for them sooner.

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Most people I see have been tried on every common approach to treatment for Complex Regional Pain Syndrome, CRPS. I prescribe most of those therapies as well, but I also use an expanded number of neuropharmacology approaches. Some of these are outlined in the case report I filed in March 2010. Patients have sent comments on their progress, and others have made comments on spinal cord stimulators, below.

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In my opinion, it is important to use rational polypharmacy. When pain is intense, it is important to look at more than one mechanism. Once pain comes under control and remains at zero, then we can slowly begin to taper off one at a time.

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The following describe two of the several mechanisms of interest to me.

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NMDA Antagonists

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The glutamate-NMDA receptor is profoundly important in controlling pain pathways. It is responsible for tolerance to medication and centralization of pain. Research in France has shown that with chronic pain in persons with CRPS there is an increase in NMDA receptors in the central nervous system. After pain control, the increased number of NMDA receptors returns to normal.

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With persistent pain or chronic depression, glutamate increases and becomes excitotoxic. When it attaches to the NMDA receptor, it causes calcium to enter the neuron, creates free radicals, and kills neurons. This leads to brain atrophy and potentially memory loss.

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The goal is to block this mechanism. I use three medications that work at this level.

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Morphinans – Glial dysregulation of pain pathways

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Another important area of focus for me are the morphinans which means morphine-like. Their mechanism of action is at the microglia, the immune cells in the central nervous system. There is important new research on glial dysregulation of pain pathways. Once primed and activated by pain, the next pain insult causes glia to react harder, faster and longer perpetuating pain with cascades of pro-inflammatory molecules. Glial research on pain is very recent, very new, very important, and is a rapidly growing  body of science. It offers an entirely new paradigm for treatment of chronic pain.

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The Reflex Sympathetic Dystrophy Syndrome Association library has

many research articles that you may wish to read.

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I am grateful to be invited to their workshop on activated glia.

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Oth

Contributing Factors

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I look at the whole person, review all of their medications including their vitamins and botanicals, toxicity and adverse interactions with medication. I check the blood level for 25(OH) vitamin D (done at ARUP labs), parathyroid hormone (PTH) if not already done, and stress the importance of anti-inflammatory diet, fish oil, and adequate levels of vitamin D3.

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Spinal cord stimulators – controversy

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A recent Wall Street Journal article discusses some of the controversy of interventional techniques in this evolving specialty and mentions that some studies are underway to show efficacy. Implantable devices are controversial “and questions remain about the appropriateness of their use.”

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In April 2010, new guidelines were published, updating earlier ones from 1997: Practice Guidelines for Chronic Pain Management: An Updated Report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine.

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“Spinal cord stimulation: One randomized controlled trial reports effective pain relief for CRPS patients at follow-up assessment periods of 6 months to 2 yr when spinal cord stimulation in combination with physical therapy is compared with physical therapy alone (Category A3 evidence).”

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A3 evidence was defined as: “The literature contains a single randomized controlled trial.”

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The guidelines had no references, nor did it indicate how old that study was. A short two year followup and a single limited study after more than 32 years of implanting these devices should call for more research.

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I do not recommend spinal cord stimulators as there is no research showing long term efficacy and no quality evidence showing they are superior treatment. Success declines after placement and that may occur the first day. In fact, there is one long term 5 year European study showing no efficacy after two years. A surgical nurse offered her frightful surgical experiences in comments below. Any invasive procedure may trigger pain in a person with CRPS and removal of the device does not necessarily relieve pain.

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Often patients are not aware that alternatives exist and are not given fully informed consent on the stimulators. Those risks include increased pain with any invasive procedure in persons with CRPS, paralysis, spasticity, infection, scarring, potential flare into generalized CRPS pain. The fact that these leads may be permanent  - they can never be removed – means that person can never undergo MRI scans in future even if they should have cancer or stroke. The leads may become scarred into nerve tissue and tethered to the spinal cord.

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A colleague, a prominent Harvard trained anesthesia pain specialist in practice for 40 years, declines to recommend stimulators or pumps for that reason: there is no long term data proving efficacy.

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Complications of spinal cord stimulators should be published. Perhaps they exist. If anyone has seen them, please advise me. I tend to see the complications or the failures, but those who place them and the corporations that fund them should have a special obligation to study the complications and the long term benefits. Having a spinal cord stimulator does not prevent use of other medication but it may add to the burden of pain to overcome. Nationally there should be an audit of stimulators placed, with patient outcomes including complications and number of revisions made. The risks are too grave not to require this and the cost is too high if there is no lasting efficacy.

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The excerpt below is from a 2003 review on spinal cord stimulation (SCS) for Complex Regional Pain Syndrome. It may be outdated, however Medtronic failed to provide me with any long term studies when requested:

“The use of SCS for the treatment of pain in CRPS (including RSD and causalgia) has been reported in the literature for over 25 years. The consensus opinion from experts suggests that SCS should be considered in the treatment algorithm when conservative or traditional therapies have failed. However, such considerations are not based on reliable evidence generated through well-designed randomized controlled trials. To date, there has not been a systemic evaluation of the existing literature concerning the efficacy of SCS for patients with CRPS.”

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For those wishing to come to San Diego for two week stay, please see information on long distance patients in banner at top of page.

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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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RSD – Complex Regional Pain Syndrome – A Case Report

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Rational Polypharmacy

Naltrexone is a remarkable drug for intractable pain

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I first saw this RN in June 2006.

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She is now 60 years old.  She was an OR scrub nurse for almost 30 years, but was disabled for the last 5 years before seeing me. She had Reflex Sympathetic Dystrophy [RSD] of both legs with “arthritis” of the feet/ankle that felt like she was “90 years old” with cold allodynia. Allodynia is pain from a stimulus such as light touch or a breath or air that is not normally painful. Imagine a light touch that feels like severe nerve pain, one of the most disturbing pains a person could have. The temperature of her feet was 81 degrees, hands 92 degrees.

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Pain of both feet felt like a vise grip, gnawing, penetrating, “like broken bones in the feet,” variable at different times but always worse as the day progressed, with a crushing sensation that penetrated through foot and ankle. She was unable to tolerate socks or anything on her feet after 5 pm, unable even to tolerate air on the area, unable to tolerate coolness below waist, but felt hot above waist. She wore a blanket and covers on the hottest 120 degree days, and forced herself to tolerate touch at the legs in order to desensitize them, as we instruct patients to do. She felt constant tingling numbness of the soles of feet for 3 years, with weakness, stiffness “almost solid” like a block. Spasm in soles of feet had resolved the last 6 months before seeing me.

Pain ranged from 2 to 9 on a scale of 10, where 10 is the worst pain imaginable, worst after 5 pm. Average pain was 3. It interfered with sleep at times, and she used a tented frame to keep blankets off her feet, preheated the bed to avoid any coolness, and avoided cold under all circumstances. In the morning, the joints felt like she had a broken ankle. She would massage the feet with lotion, put on alpaca socks, and slowly begin to walk. Then tried to mobilize the joints. Walking made pain worse though walking had always been a favorite activity.~

Before seeing me she had had more than 10 sympathetic blocks, was hospitalized 11 days due to headache from prednisone 60 mg that had been trialed to relieve her pain. She had been prescribed Procardia to relieve the “vascular” disease that she did not have but the drug led to gangrene of the gall bladder; she had been prescribed almost every “adjuvant” used to relieve pain and as much as 9 grams of Neurontin daily, all of this to attempt to relieve the severe pain in her legs and feet.

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This is how she got better

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When I first saw her in 2006, I prescribed low dose oral ketamine that gave relief lasting up to 3 hours from each dose. She then requested referral to Dr. Schwartzman, chief of neurology at Drexel University in Philadelphia, for continuous 5 day ketamine infusion that was done May 2007. She was pain free but it completely lost effect after 8 months, despite booster infusions every 4 to 6 weeks for 4 hours daily over 2 days during those 8 months. After insurance the cost out of pocket was $45,000 in 2007 alone. Dr. Schwartzman had nothing more to offer after it failed and said most patients have relief for less than 6 months if at all.

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In March 2007, I started her on a combination of Namenda 55 mg daily with lamotrigine 350 mg daily that relieved 90% of the pain, but once every 6 to 8 weeks she needed 12.5 to 25 mg low dose oral ketamine for breakthrough pain. Even more rarely, she used oxycodone 10 to 20 mg.

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In October 2008, adding naltrexone 1 mg by mouth, she became pain free. Since then she has not needed anything for breakthrough pain and on 3/5/09, she reported that her last use of ketamine and oxycodone occurred with the addition of low dose naltrexone.

 

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In 2009, she hiked 30 miles down the Grand Canyon and back up in 3 days.

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Naltrexone was later increased to 4.5 mg as she completely tapered off lamotrigine.

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By December 2009, the RSD was 98% better and she reported that it was not pain anymore. Medications then were naltrexone 12.5 mg at bedtime and Namenda 55 mg daily in divided doses. She had just a “remnant” of a little buzz, but no crushing except when active, late in the day.

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A few months later she slowly tapered off Namenda with no increase in pain; and in October 2010, on my advice she tapered naltrexone 12.5 mg from daily to every third day. There has been no increase in pain but she is reluctant to discontinue naltrexone for fear that RSD may recur.

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She hikes 2 miles 3 to 4 times a week, does Iron Mountain once a week, does “Silver Sneekers” exercise 1 hour 3 times a week and sleeps well 8 to 10 hours a night without a sleeping pill.

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She remains on low dose naltrexone as her sole medication for this

previously disabling neuropathic pain syndrome~

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She has returned to part time work and spends a few weeks a month traveling the world, hiking, volunteering, sightseeing.

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Research funding is needed to view whether we can detect

activated glia in the spinal cord, as discussed here.

If there are no signs of activated glia, she may feel reassured that the condition has resolved.

Naltrexone is an immune modulator.

The site of action of naltrexone is at the Toll-like receptor (TLR4) attached to the cell surface membrane of glia.

The ability to view activated glia would help greatly in treatment of so many conditions including neuropathic pain.

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Naltrexone

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I have found that naltrexone is a remarkable medication for various pain conditions, and going through the steps of rational polypharmacy may be very rewarding for some patients though at times it may work all on its own. It has caused me to completely reassess how I approach the treatment of intractable pain – not just RSD or CRPS but arthritis, sciatica and various forms of mechanical pain. And it has led to further changes in the timing and dosing of naltrexone based upon the experiences patients have reported back to me over the years. It is hoped that further research will lead to better understanding of how naltrexone acts upon pain pathways. Surprisingly we already know quite a fair amount.

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My deepest gratitude to Dr. Jau-Shyong Hong, Chief of Neuropharmacology at NIH, whose many generous discussions, emails and research publications have helped me to understand it’s profound anti-inflammatory effect in the central nervous system through its actions on microglia. I previously posted a discussion of mechanisms of naltrexone and dextromethorphan in greater detail here. Naltrexone and dextromethorphan are classified as morphinans, morphine-like. They suppress Superoxide, a free radical that destroys neurons which may cause or contribute to Alzheimers and Parkinsons Disease. That research goes back to the late 1980′s and continues to grow. Phase II studies with morphinans are now being done on those conditions. Studies are also going on now with naltrexone/Wellbutrin combination for weight loss. The drug is called Contrave, from Orexigen Therapeutics Inc. and the dose I believe is 32 mg naltrexone – I do not know how they decided upon that dosage.

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In my experience, naltrexone is a very benign drug at these low doses, though colleagues who prescribe 400 mg for the FDA approved use at that high dose may see some liver toxicity. I always begin at 1 mg or 4.5 mg, depending upon whether or not the patient is a slow drug metabolizer, i.e. may lack one of the CYP P450 chromosomes for metabolizing drugs. I have long suspected it also has an effect on the hypothalamus because a few patients with profound postmenopausal hot flashes have reported that is no longer a problem and that their husbands simply cannot believe the bonus, and this may explain the effect upon appetite that Orexigen has found. At higher doses than I generally use there may be some constipation which is treatable. It may cause vivid dreaming in some, and a small percentage may have insomnia for a few days. Pharmacology and safety is discussed here.

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Stay tuned. I’ll be adding more case reports of different pain conditions in the near future. They are truly fascinating. It has changed my entire approach to treating pain.

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Cost

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Wouldn’t it be nice if NIH funded more for pain research? Imagine how much money that would save the country and save the lives of each person with disability who could recover? As I posted here, the American Pain Society has shown that NIH spends 0.67% of its budget on pain research – less than 1% – though 10 to 20% of the population in the US suffers from chronic pain, an estimated 60 million Americans, and pain conditions are more prevalent among the elderly.

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I am told by my pharmacist that perhaps 70% of the time insurance will approve coverage for compounded low dose naltrexone. It is very affordable but some insurance carriers deny payment for naltrexone. Medicare will not pay for compounded medication either. Compare this low cost compound to the wholesale price for 100 tablets of Oxycontin, $1300, which may not be relieving pain – then multiple that by 2 or 3 each month for one patient. Imagine if the $22 billion of federal money for health insurance technology, for software which is untested and will expire in a few years, instead went into NIH funding for pain research. What a lovely thought.

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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.

~

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

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Ketamine

Ketamine for persons with severe pain

cancerIn special circumstances, I may suggest a trial of low dose oral ketamine. It is formulated by a compounding pharmacist as an oral suspension. It is safe to use without significant adverse effects, though you may experience transient symptoms lasting 20 to 40 minutes after the first few doses. For most people, it may relieve pain when all other methods have failed, possibly including total pain relief with no side effects in patients who have then been able to discontinue all opioids.

Keep all your medicine, opioids and ketamine, in a lock box to prevent abuse by others. This is a Schedule III drug like Vicodin.

Achieving control of chronic pain requires a partnership

based upon trust and effort

Requirements: I will work closely with you on ketamine and ask you to keep a log of pain before each dose and 30 minutes after. In addition, for the first week I ask that you log blood pressure and heart rate before each dose and 30 minutes after. This requires that you see me in the office one week later. If you have any questions or problems, I ask that you call me the same day, whether it be weekend or holiday. If you are unable to keep these logs before and after the dose, and the appointment one week later, the trial will be discontinued. You have no authority to continue without my consent.

Blood Pressure: Usually no change occurs in blood pressure. Some have reported that ketamine lowers their blood pressure and they are lightheaded when they stand up. If your blood pressure drops or if you are lightheaded, be very cautious as that may lead to fainting and brief loss of consciousness. Anytime a person faints, that could result in potentially serious injury such as hip fracture, other fractures, bleeding or brain injury if you strike your head. Your blood pressure should be above 100 when standing.  Ketamine has been reported to increase blood pressure and pulse, but I have not found that to occur with these doses.

Side Effects: Ketamine has a very narrow therapeutic window for pain control. This means that once you find the dose that relieves pain, a very slight increase in dose may produce intolerable side effects. Unfortunately some patients reach a dose that produces side effects before they experience any pain relief.

Most patients have no side effects with the low doses used by this protocol, though some may have mild symptoms lasting up to 40 minutes. If you do, then try decreasing the dose a small amount.

It is possible but rare that you may experience severe, frightening hallucinations or may feel you are outside the body observing it do things, called a dissociative reaction.

These side effects are dose related and have been short lasting, usually no longer than 40 minutes.  The antidote is Ativan.

Steps to follow: Read all steps carefully before you begin

  • Take ketamine 30 minutes prior to your other pain medication
  • For the first dose, remain seated or lie down for 20 minutes after you take the dose to avoid risk of falling. Do not take the dose and walk around.
  • A few persons have had severe imbalance lasting 10 or 20 minutes. This has resolved after the first few doses in those persons. It may not happen to you, so test with caution. If it has not occurred at the first dose, it is unlikely to occur at all.
  • Follow the dosing guidelines in the log I give you and which I repeat in this next step:
    Begin with 0.25 mL and increase by increments of 0.25 mL every 6 hours or longer than 6 hours, until you have some pain relief. Do not increase that dose or dosing interval.

Example: begin 0.25 mL, then 0.5, next 0.75, 1.0, 1.25, 1.5, 1.75, 2.0

If you have had no effect on pain by 2.0 mL, schedule an appointment for further instructions.
If your pain decreases only 1 or 2 points, that is your dose.  It will NOT get better by increasing the dose.  Stop increasing.

  • If you have intolerable side effects, you may use 1 or 2 Ativan tablets immediately as an antidote, and every 30 minutes, up to 5 of them.
  • CAUTION: Be alert to the opioid-sparing effects of ketamine!

This means that if ketamine relieves your pain, you do not need to take the opioid as that would be an opioid overdose and may cause serious side effects.

Reduce or temporarily stop your opioid medication if pain is gone after using ketamine.

This is why you take ketamine 30 minutes before the opioid. Some people have been able to completely stop all opioid medication due to pain relief from ketamine alone.

  • CAUTION: Do not drive for 6 hours after a dose.

This is for the protection of you and others. You may not be aware of very subtle side effects.

  • You may take a dose every 6 hours, or longer than 6 hours. Less is more.

If ketamine loses its effect, stop use for 2 or 3 days, then resume. It can be a fickle drug.  That is why increasing the dose causes loss of effect.

Some take ketamine only before sleep. If you do that, use it 30 minutes before sleep in order to log its effect and take blood pressure/pulse before and after. Continue this initially until further changes are approved.

Ketamine was approved for use as an anesthetic by the FDA in 1970

It’s use for pain is “off label” as it was approved only in high doses for anesthesia. It has been used safely in babies. Unlike opioids, it does not depress breathing or bowel function, and usually does not depress cardiovascular function. Since the late 1980′s, numerous scientific articles have been published on its use as a third line choice for some pain conditions; there are few double blind control studies, one is listed below. If you search ketamine on various internet search engines you find it is abused by addicts just as other drugs are. You find medical articles when you search the literature using Google Scholar or PubMed in the National Library of Medicine. If you find a medical article with adverse effects, let me know. I have spoken to leading brain and psychiatric researchers who have verified there are no lasting side effects from its use.

Many publications on ketamine use multi-day infusions at much higher dosages than the oral dosages in my protocol. Drexel University has treated over 3,000 patients with infusions of 40 mg/hour for 5 days with no lasting adverse effects. Even higher doses than that are used for surgical anesthesia. Ketamine is a powerful tool for treating pain.

Medical Publications


You can click and download each reference in blue below

High dose ketamine improves neurological outcome after stroke in rats, Reeker et al, Canadian J Anesth 47:572-578, 2000

Ketamine, Pasero C, McCaffery M, Amer J Nursing, 105:60-64, 2005
An excellent review, more clinical, easier to read than some more technical papers

Ketamine in Chronic Pain Management: An Evidence Based Review, Hocking & Cousins, Anesth Analg, 97(6):1730-1739, 2003This nine page article is the best comprehensive review of ketamine’s use in almost every known pain condition including post stroke pain.  Easier to read; a catalogue of pain syndromes and references.

Ketamine Stops Aura in Familial Hemiplegic Migraine, Neurology, 55:139-141, 2000 Two mechanisms may account for this. First, ketamine can increase cerebral blood flow, which may counteract the marked hypoperfusion induced by cortical spreading depression, as observed in migraine with aura. Second, in experimental animals, ketamine accelerates the  restitution of neuronal function after hypoxia.

Ketamine oral use in 8 chronic pain patients, Canadian J. of Anesthesia, 2004


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The Reflex Sympathetic Dystrophy Association library has many articles on RSD, CRPS and ketamine. Remember most of the articles are written for scientists and physicians.

From their library I particularly recommend the first article, below.  The last two are very technical but important new research.


Expectations of Pain: I Think, Therefore I Am, Jones-London M, National Institute of Neurological Disorders and Stroke

For pain mechanisms, read
Beyond Neurons: Evidence that Immune and Glial Cells Contribute to Pathological Pain States, Watkins L and Maier SF, Physiology Review. 2003;82:981-1011.

For pain mechanisms, read
Complex Regional Pain Syndrome (CRPS): Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy),  Oaklander AL et al., Pain. 2006;120:235-243.

There is no link to the following double blind controlled research publication:

Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous Ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000;20:246-252. Mercadante et al compared intravenous infusions of Ketamine (0.25 and 0.5 mg/kg) with placebo in a double-blind, crossover study of 10 cancer patients with neuropathic pain.

Please note that the free Adobe Acrobat Reader is needed to read some references.

You can download the free reader now.

~~~~~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. ~~~~~

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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