Gia cells play an important role in neuropathic pain. So important that some scientists prefer to speak about gliopathic pain in stead of neuropathic pain. These cells produce their own modulators we could even say, their own endogeneous 'painkillers'. These modulators play an important role in decreasing winding up mechanisms in neuropathic pain. Anandamide (arachidonoylethanolamide, AEA) and its sistermolecule palmitoylethanolamide (PEA, Normast), both are such modulators, and these molecules have positive influences  in neuropathic pain and inflammation related to neuropathic pain. Both molecules are classical autocoids, and they fulfill the three criteria required for autocoids of lipid transmitters:

1. stimulus-dependent production,

2. interaction with specific receptors and

3. enzymatic inactivation. ^[1]

Palmitoylethanolamide and anandamide: guard molecules in glia and neurons 

AEA and PEA are both are present in the CNS as well as in peripheral tissues, and PEA concentrations are often ten times higher than those of anandamide. In animal models of tissue stress and/or inflammation, such as in the experimental autoimmune encephalomylitis, concentrations of molecules synthesized by glia such as PEA often increase up to 30-fold. ^[2]

In certain cell-lines, PEA inhibits cAMP accumulation in nanomolar range, and this response is independent of CB1 mechanism. ^[3]

PEA binds to the nuclear factor PPAR-a and blocks inflammation in wild-type but not PPAR-a knockout mice. Its activity via these Alpha-Type Peroxisome Proliferator-Activated Receptors is an explanation of many of its neuroprotective properties. ^[4][5][6]

PEA can influence anandaminde efficacy via inhibition of anandamide degeneration due to the so called entourage effect. ^[7][8]

Palmitoylethanolamide also has neuroprotective and inflammation inhibiting effects mediated through PPAR-alpha. Other endocannabinoids that activate PPAR-alpha include anandamide, virodhamine and noladin ether. Thus there is a convergence of effects of cannabinoids, acting via cell surface and nuclear receptors, on immune cell function which provides promise for targeted therapy of a variety of neuroinflammatory states, including neuropathic pain.^[9] 

Anandaminde especially mediates most of its biological effects by activating CB1 and CB2 receptors.

Both autocoids, palmitoylethanolamide and anandaminde thus function as a functional unity, although it is also quite clear that there are independent PEA and AEA signaling pathways in microglia.

PEA and anandamide both are produced in situations of stress for glia and neurons, and for instance PEA is found in significant levels in whole mouse or rat brains (100- 550 pmol/g)

All kinds of pathological stimuli may selectively increase its levels. And these autocoids can be produced not only by glia, but also by neurons.^[10]

This all leads to an interesting clinical view on palmitoylethalonamide (PEA)^{[11][12][13][14]} 

Treatment of neuropathic and chronic pain using our own 'wise molecules' 

Neuropathic pain is difficult to treat. Many classical compounds such as pregabaline, amitriptyline and gabapentine are limited in its use, due to side effects, peak dose sedation and interactions, comtraindications as well as difficulties administring these molecules to elderly patients.

These drawbacks do not exist if we make use of our body-own 'wise molecules or analgesics' such as palmitoylethanolamide. Many thousands of patients have already been treated with PEA, with clinical efficacy in for instance in sciatic pain, pain in diabeteic neuropathy and pain in carpal tunnel syndrome. In our clinic we have used PEA succesfully in various treatment refractory neuropathic pain patients, such as in diabetic pain, small fibre neuropathy and CIAP.

Furthermore many elderly patients have been treated without side effect or dose limiting problems, or interaction problems. More then 350 elderly patients have been treated with palmitoylethanolamide without clinical problems, and also in our hands, we did not see clinical relevant side effects, even not in a patient aged 90. To date the following numbers of elderly patients treated with palmitoylethanolamide (Normast) have been evaluated: 

- 111  between 65 and 70 years old

- 116  between 71 and 75 y.o.

-  63  between 76 and 80 y.o.

-  45  between 81 and 85 y.o.

-  20  between 86 and 90 y.o.  (Epitech data on file)

To use our onw body defense system molecules in neuropathic pain (gliopathic pain) seems a new important and clever inroad in the treatment of such debilitating painstates as neuropathic pain.

In the next videos from our institute we demonstrate the clinical efficacy of PEA in some patients suffering from different neuropathic pain states: acute sciatic pain, chronic diabetic neuropathic pain, small fibre neuropathic pain and CIAP, chronic idiopathic axonal polyneuropathy and pain.

For us it was impressive to see that patients refractory to treatment with gabapentine and pregabeline (maximal dosage) were full responders to the treatment with Normast, the preparation containing palmitoylethanolamide, in European market registered as food for medical purposes, to be administered under guidance of an MD.  

Acute pregabaline refractpory severe sciatic pain: 

Severe small fibre neuropathic pain, gabapentine resistant:

90 year old patient with CIAP:

Chronic polyneuropathy, burning feet and impossibility to walk:

In all these patients, most classical analgesics were not effective, or created too many side effects. Treatment with palmitoylethanolamide helped decreasing pain, in the first patient already within 1 week, and in most patients we see, between 2 to 3 weeks. 

Normast is registered as food for medical purposes and should be used under guidance of a medical doctor. 

November 2010, prof. dr. Jan M. Keppel Hesselink, MD 

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