Palmitoylethanolamide (Normast) is now registered as medical food in various European countries (It, Sp) and as a food supplement (NL) and is one of the major existing new non-ionchannel tools to target the glia and the neurons in neuropathic and chronic pain. The availability of this compound leads to this discussion on how to influence chronic pain states with this endocannabinoid. 

Chronic pain can disrupt brain function and cause many somatic and psychological problems. When neurons fire too much they may change their connections with other neurons and may even die. Crucial to understanding chronic pain are insights in the function of neuronal networks and the role of the all-invading glia cells. But: 'Glia are nervous system caretakers whose nurturing can go too far. 

Taming them holds promise for alleviating pain that current medications cannot ease.' ^[1]

Taming the glia cells and quitening the nerve cells can be done by hacking into the neurobiological system via the ancient endocannabinoid system. 

Current treatment options for chronic painconditions are frequently ineffective or are limited by adverse side effects. Therefore new think-out-off-the-box treatments are needed. We need to target the gla and the nerve cells hand in hand. The endocannabinoid system holds a great promise to better treat pain and a variety of other disorders.

Glia as new target for chronic pain treatment

Glia is the new target for treating neuropathic pain. The positive feedback loop in chronic pain between overactive neurons and overstimulated glia and asterocytes create a winding up phenomena. Regular therapy tries to cut this winding up positive feedback loop by inhibiting the fire frequency of the neurons. The glia and asterocytes interprete the neurotransmitters of the neurons as emergency signals, and start pooring out nerve growth factors and all kinds of other molecules. This good intention leads to the further winding up phenomena. Therefore, modulating or inhibiting the nervous activity only is not enough for many patients suffering from neuropathic pain. We need to focus on nerve cells & gliopathic modulators.  

More and more articles indeed can be found on glial cells, such as microglia and astrocytes in the CNS, as well as on mast cells, as important players in the development and maintenance of chronic pain.^[2]Activated astrocytes in neuropathic pain are releasing pro-inflammatory cytokines (e.g., interleukin [IL]-1β) as well as chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1]/also called CCL2) in the spinal cord leading to chronic pain states. Nerve injury and chronic low grade inflammation activate the c-Jun N-terminal kinase in spinal astrocytes, leading to the expression and release of MCP-1. The MCP-1 increases pain sensitivity via direct activation of NMDA receptors in the spinal cord. 

Pharmacological inhibition in animal models of the IL-1β, c-Jun N-terminal kinase, MCP-1, or matrix metalloprotease-2 signaling all seems to be able to attenuate neuropathic pain. Microglia is rapidly reactive in response to injury of peripheral nerve axons (axotomy). Microglia activated by axotomy are major contributors to CNS pathology, e.g. in models of neuropathic pain. ^[3]

Neurohacking into the chronic pain state via the endocannabinoids

The discovery of our own 'Cannabis', the molecule anandamide, as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides. N-palmitoylethanolamine (PEA) is a sistermolecule of anandamide, a shorter and fully saturated analogue, and this molecule has been known since the fifties of last century. In the sixties and seventies much research supported its use as prophylactic treatment for the flu, and the compound was on the market available as Impulsin for some years, till the comany producing palmitoylethanolamide went broke.

Anandamide (arachidonoylethanolamide, AEA) and palmitoylethanolamide (PEA) both are modulators of nerves as well as of glia, and these molecules have positive influences in chronic and neuropathic pain and in various inflammatory states. 

We are convinced that we can hack the pain-neurobiology via our body-own compound palmitoylethanolamide (PEA). Especially since PEA is avaiable now in Europe as a foodsupplement under the name Normast (via www.ergomax.nl).

PEA is a lipidergic messenger and is known to mimic several endocannabinoid-induced biological responses via novel mechanism of action, without binding to CB1, CB2, and the abormal-CBD receptors.

During the last decades many impressive biological actions of PEA have been described, such as influence on immune cells such as inhibition of mast cell degranulation, attenuation of leukocyte extravasation, and modulation of cytokine release from macrophages. Furthermore PEA acts not only on a variety of peripheral immunocompetent cell types but also seems to inhibit activated microglial cells.

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. ^[4]

In certain cell-lines, PEA inhibits cAMP accumulation in nanomolar range, and this response is independent of CB1 mechanism. ^[5]

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. ^[6][7][8]

PEA can influence anandaminde efficacy via inhibition of anandamide degeneration due to the so called entourage effect. PEA also has neuroprotective and inflammation inhibiting effects mediated through PPAR-alpha. ^[9][10]

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 as well as via nuclear receptors, on immune cell function which provides promise for targeted therapy of a variety of neuroinflammatory states, including neuropathic pain.^[11]  

PEA as an inhibitor of inflammation

PEA can be found in most mammalian and human tissues. PEA tissue concentration increase during inflammation and acts as a body-own modulator with anti-inflammatory properties. This has been substantiated in various relevant animal models of inflammation and inflammatory pain. ^[12]  Its precise mechanism of action has ben a debate since the last 40 years, and major shifts in understanding can be documented if publications are analysed in a chronological sequence.

PEA was comnpared to the synthetic cannabinoid nabilone in the rat model of carrageenan-induced acute hindpaw inflammation together with the nonsteroidal antiinflammatory drug indomethacin. Nabilone 2.5 mg kg(-1), PEA 10 mg kg(-1) and indomethacin 5 mg kg(-1), given p.o. 1 h before carrageenan, all reduced the inflammatory parameters in a time-dependent manner. ^[13] This anti-infalmmatory effect of PEA has been duplicated in many different experiments ^[14]  

The resemblance between PEA and anandamide became known in the nineties of last century, and in that time people started to believe the biological actions of PEA were mediated via the Cannabis receptors, CB1 and/or CB2 ^[15] Especially the CB 2 receptor was seen as the major inroad for PEA's biological actions, as the CB2 receptor is expressed in many while blood cells and the mast cells. The CB(2) receptor selective agonist AM1241 also diminishes edema produced as a result of mast cell degranulation in vivo. 

Due to PEA's activity in chronic inflammatory disorders and animal models, various clinical entities have been mentioned as targets for PEA, such as psoriasis, topical dermatitis, inflammatory bowel disorder, multiple sclerosis to mention just a few. Therefore is reasonable to that various authors suggest that PEA and other cannabinomimetic compounds could represent possible candidates for treating several of these chronic inflammatory diseases.^[16]  

PEA as an analgesic compound 

When PEA and anandamide are administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage.

These pharmacological experiments lead invstigators to believe that peripheral CB1-like and CB2-like receptors participate in pain initiation and control and that that locally generated anandamide and PEA may mediate analgesic effects via these receptors.^[20] Anandamide (via CB1 receptors) and PEA (putatively via CB2 receptors) attenuated hyperalgesia in a dose-dependent fashion.^[21] 

Both anandamide (at a dose of 25 mg/kg) and PEA (at doses of 10-30 mg/kg) were able to attenuate the viscero-visceral hyper-reflexia (VVH) induced by inflammation of the urinary bladder. ^[22] Later new findings pointed out that the mechanism of action of PEA might also be found via the PPAR pathway. The PPAR-alpha agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and PEA both reduced nocifensive behaviors elicited in mice by intraplantar injection of formalin. These effects were absent in PPAR-alpha-null mice. PPAR-alpha is expressed in dorsal root ganglia neurons of wild-type but not PPAR-alpha-null mice. PEA also reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain, and were dependent on the PPAR mechanism of action. ^[23] 

In an experimental spinal cord injury (SCI) model in mice repeated PEA administration (10 mg/kg i.p.; 30 min before and 1 and 6 h after SCI) significantly reduced the degree of spinal cord inflammation and tissue injury, the neutrophil infiltration, the proinflammatory cytokine expression, the nuclear transcription factor activation-kappaB activation, the inducible nitric-oxide synthase expression, and apoptosis. Moreover, PEA also significantly ameliorated the recovery of motor limb function.^[24]   

Clinical trial of PEA in sciatic pain

All this exciting pharmacology led to a great many clinical trials, and we will focus on one, in sciatic pain. 

Hacking into chonic pain neurobiology with palmitoylethanolamide (Normast)

This all made it quite clear that the PEA as the supplement Normast, containing pure palmitoylethanolamide, can open a whole new chapter in the treatment of chronic painstates. However, clinicians need to take off their paradigm-glasses that only big pharma can produce drugs against chronic pain. Off patent natural molecules, such as PEA can offer sometimes much more!

In our clinic we treated more than 200 patients succesfully with Normast, and all were given no hope anymore by their treating physicians. 

It is our hope that more and more enlighthened neurobiologists, neurohackers, patients and physicians will understand the clinical relevant role of palmitoylethanolamide in the treatment of chronic pain.

And mind you, no relevant side effects, no drug-drug interactions and quite safe in the elderly!

Jan M. Keppel Hesselink, MD, PhD, juli 2011, rev octover 2011

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