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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Spine Fusions: No Better Than Cognitive Behavioral Therapy & Exercise

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Spine Fusions: no better than Cognitive Behavioral Therapy and Exercise

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This reportfrom the Academy of Neurology may help guide you in decision making: 

Deaths, Complications, Higher Costs Accompany Increase in Complex Spine Fusions Among Elderly.

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“Fusion is usually performed for degenerative disc disease for chronic low back pain, but a number of studies have shown that their outcomes are no better than a combination of graded exercise and cognitive behavioral therapy.”

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Tragically, dementia can result from extensive spine surgery. Many factors can contribute to that. If I were having spine surgery, I would look at the data of dementia following open heart surgery and the protective benefits of ketamine given prior to surgery. Ketamine can spare neuronal function. It is neuroprotective. I link to a publication on that in this post. The problem may be that so few physicians are willing to provide ketamine as they may lack information on its use, yet it is one of the safest medications we have, nontoxic and neuroprotective.

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The material on this site is for informational purposes only,

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

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For My Home Page, click here: 

Welcome to my Weblog on Pain Management!

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“Heavy NSAID Use Linked to Higher Dementia Risk” – Exercise, Antidepressants Both Help Neurogenesis

NSAIDs are anti-inflammatory drugs used to treat pain, inflammation, or fever.  The only NSAIDs that are NOT associated with increased risk of heart attack or arrhythmia are naproxen (Aleve) or aspirin.  Taking high doses of aspirin has a greater risk of GI bleed than naproxen, which is why I usually recommend naproxen.

Background:

Several past studies have shown NSAIDs delay or prevent dementia, but there have been contradictory results.  Last year Neurology published a study of 49,349 patients’ usage ranging from ≤1 year to ≥7 years done at Boston University and Bedford VA. They showed long term use of NSAIDs protects against Alzheimers:

Compared with no NSAID use, the relative risk of Alzheimer’s disease decreased from 0.98 for ≤1 year of use (95% CI 0.95 to 1.00) to 0.76 for >5 years of use (95% CI 0.68 to 0.85).

Among patients who specifically cited use of ibuprofen, the risk of Alzheimer’s disease declined from 1.03 (95% CI 1.00 to 1.06) to 0.56 (95% CI 0.42 to 0.75).

Ibuprofen came out ahead in that study perhaps because it is the most commonly used.

They also sought to answer whether NSAIDs known to suppress Aβ1-42 amyloid would more likely protect .  Aβ1-42 amyloid is a major component of plaques found in Alzheimer’s Disease.

Aβ1-42 amyloid suppressors include ibuprofen, diclofenac, flurbiprofen — but as for suppressing Alzheimer’s, these were found to be no different than other NSAIDs, putting that theory to rest.


methusala-tree

Risk of dementia and Alzheimer’s Disease with prior exposure to NSAIDs in an elderly community-based cohort:

This new study by Breitner  et al, from the University of Washington School of Medicine was published online April 22, 2009, before the print edition in Neurology.  

Their outcome contradicts earlier protective studies possibly because they started with an older cohort, healthy adults 65 and older, which “could be enriched for cases [of Alzheimer's] that would otherwise have appeared earlier.”

They prospectively followed 2,736 persons in a Seattle health plan.  Before starting the study, they reviewed pharmacy records as much as 17 years earlier.

Findings:

12.8% of the study participants [were] heavy NSAID users at baseline. Heavy use was defined as taking 500 or more standard daily doses over a two-year period.

Another 3.9% of participants became heavy users during follow-up.

Ibuprofen, naproxen, indomethacin, and sulindac accounted for about 80% of all NSAIDs used.

Through follow-up, 476 participants developed dementia; for 356 of them, it was Alzheimer’s disease.

After controlling for age, gender, education, APOE status, hypertension, diabetes, obesity, osteoarthritis, and physical activity, the risk of developing all-cause dementia was 66% higher among heavy users than among those with little or no NSAID use (HR 1.66, 95% CI 1.24 to 2.24).

The risk of developing Alzheimer’s disease was 57% higher (HR 1.57, 95% CI 1.10 to 2.23).

Strengths of the study: the community-based sample, biennial assessment of dementia, rigorous exposure classification, and large numbers of dementia cases, outweigh the limitations.

Limitations:  lack of generalizability to a younger patient population, the lack of exact dosing information, and the possibility of bias from unmeasured confounders.

Can we draw conclusions on one study alone? We know that exercise is protective against Alzheimer’s Disease and pain may have prevented this older age group from being active. Though they did control for that, this research needs to be supported by further studies. What is helpful is to remain as active as you can.  Keep and maintain every bit of function you can and get help for depression and anxiety as they may profoundly affect memory, morbidity and mortality.  For a review of the literature on the morbidity and mortality of stress and mood, refer to my post on Cognitive Behavioral Therapy and the importance of a positive outlook.

The brain makes new neurons – neurogenesis.  I will write more in the future on exercise, mood, stress, brain atrophy and memory loss.   Exercise improves depression and anxiety, and exercise stimulates neurogenesis.  It appears that the action of antidepressants also may be to stimulate neurogenesis.  Chronic low back pain has been reported to cause brain atrophy.  Chronic depression leads to brain atrophy and memory loss with atrophy occurring in the hippocampus, the area essential for memory.  This important publication from Vancouver reviews the topic in great detail and proposes a hypothesis:  Antidepressant effects of exercise: Evidence for an adult-neurogenesis hypothesis?

Further medication is being tested to reduce neuronal cell death that leads to Alzheimer’s Disease, using a very simple compound that blocks free radicals and inflammation.  More on this later.

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

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

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

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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