LDN – Low Dose Naltrexone – Prescribing Doctor Videos

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Prescribing Doctor Videos

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This website, click on link above, 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 – is a scientist with research background in the innate immune system, glia, cytokines. She discusses Toll-Like Receptors which is where naltrexone acts.

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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, MD, they have published on it, acknowledging my contribution in teaching him my experience using LDN for years in many persons with intractable 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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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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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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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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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.

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

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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!

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. ~~~~~

Vitamin D – A Steroid Hormone, Anti-inflammatory

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The Sunshine Vitamin Controversy

What should normal values  be for calcium homeostasis?

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

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

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

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

Vitamin D Metabolism - click to enlarge

Vitamin D Metabolism

The Controversy –  How Do We Determine Normal Values?

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

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

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

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

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

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

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

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

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

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

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

Evidence for Optimizing Vitamin D Concentrations

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

great-western-divide-wp1

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

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

To quote from their article:

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

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

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

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

Summary:

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

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

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

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

Do not make changes in your dosage without careful evaluation.

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

The material on this site is for informational purposes only, and

is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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