In Patent literature sometimes great insights can be found about how to proceed in pain treatment, such as in this patent,  and we enclose here the introductrion and a part of the summary. Pain clearly is especially influenced by non-neuronal cells, is the thesis of this patent.

The current theories and treatment options for persistent pain are not satisfactory. The population of patients with chronic pain and disrupted lives grows constantly. According to the American Pain Foundation, there are 75 million Americans who have chronic pain. Pain is the second most common reason for doctor visits. Unless we can understand how pain is generated, we cannot provide a solution. Our understanding of pain has not advanced since the 1965 publication of the gate theory of pain by Canadian psychologist Ronald Meizack and British physiologist Patrick Wall. In their paper titled “Pain Mechanisms: A New Theory,” Melzack and Wall suggested a gating mechanism within the spinal cord that closed in response to normal stimulation of the fast conducting “touch” nerve fibers; but opened when the slow conducting “pain” fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these signals were countered by renewed stimulation of the large fibers.

A recent model, known as Sota Omoigui's Law, proposes that the origin of all pain is inflammation and the inflammatory response. This model is a dramatic and revolutionary shift from a focus on structural pathology to an understanding of the biochemical origin of Pain.

Here, in this flshing Prezi, we will review some of the recent evidence to support non-neuronal cells as new targets for the treatment of neuropathic pain. As clinical proof of concept we will discuss the efficacy and safety of the endogenous molecule palmitoylethanolamide (PEA) in the treatment of various neuropathic painstates.

PEA is available as food for medical purposes under the name Normas t and as a foodsupplement under the name PeaPure.

Palmitoylethanolamide (brandnames Normast and PeaPure) is now registered as a supplement in various European countries 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. 

Gliopathic pain and gliopathic modulators: Introduction into the field of glia and neuropathic pain

Glia is the new target for treating neuropathic pain. The positive feedback loop 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 additional gliopathic modulators.

Glia and asterocytes play a central role in neuropathic pain, and gliopathic pain, or asteropathic pain will become new synonyms for neuropathic pain. In a recent hallmark paper the term 'Gliopathic pain' was coined.

This is a reason to put our magnifying glass on glia. Gliamodulating drugs will become a new class of neuropathic drugs, the so called gliopathic modulating drugs, and the first prototype, the endogenous fatty acid palmitoylethanolamide, has already been explored in positive proof of principle studies. 

For more than a century doctors are aware of the special properties of glia in response to injury. In Germany in 1894 professor Franz Nissl decribed the reaction of glial cells in relation to the nerve fibers in the spinal cord and highlighted their morphological changes after injury. Microglia becomes mores bigger and more abundant after injury and these glial responses can be seen as a biological reponse to promote nerve repair after injury. However, this response can go biserk and might be one of the most important mechanisms leading to neuropathic pain. 

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:

Glia is a new target in the treatment of neuropathic pain. Ketamine might have a mode of action related to glia hyperactivity.

The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. The authors explored the possible effect of ketamine on spinal microglia. They found that  S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia.

Influencing metabolism is a powerful way to treat various painstates and inflammatory diseases. In chronic painstates metabolic disturbances in tissue and immune cells forms the base of the pathogenesis of neuropathic pain. These metabolic disturbances we can find in glia as well as in neurons and overactive mast cells play a crucial role here. 

Mast cells are found in all human tissues. Their cytoplasm is loaded with granules containing many key mediators of inflammation.Their surface is coated with a great variety of receptors which can trigger exocytosis of the granules. Via this process mast cells influences local tissue metabolism and this leads to inflammation and pathological painstates. Activated mast cells release a whole cascade of potent mediators. Some of these molecules are immediately released, some others later as mast cell metabolism further changes and these cells start synthesizing these second wind mediators via new gene transcriptionprocesses. Modulators of pathological metabolism of mast cells are urgently needed to treat neuropathic pain states, were mast cell activatio play a role. Palmitoylethanolamide is such an endogenious modulator for mast cell metabolism and since 2010 this molecule can be administered as dietfood for medical purposes (brandname Normast®). First we will review briefly some neuropathic pain states and the role of mast cells. Secondly we will review shortly the changed metabolism of mast cells in inflammatory and chronic pain states.

The naturally occurring fatty acid of ethanolamine and palmitic acid, palmitoylethanolamide (PEA), is an important addition to our clinical armamentarium for the treatment of chonic neuropathic pain and related chronic painstates, such as the syndrome of Costen, diabetic and sciatic pain.

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 abn-CBD receptors.

During the last decades many imprssive 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. have been described. Furthermore PEA acts not only on a variety of peripheral immunocompetent cell types but also seems to inhibit activated microglial cells, and these cells play an important role in both neuropathic pain as well as in secondary neuronal damage.

Palmitoylethanolamide (PEA) is an endogenous endogenous compound. It is a fatty acid amide and present in many foodstuffs as well as in the human body. In Europe PEA is available as food supplement in Italy and Spain under the brandname Normast and in the Netherlands and elsewhere branded as PeaPure. 

PeaPure has the advantage of not containing farmaceutical and chemical excipients, nor sorbitol (present in Normast).

In 2010 a Spanish publication described clinical meaningful effects of the treatment of lumbosciatic pain with palmitoylethanolamide, PEA. These results were published in Dolor (2010;25:35-42). The final analysis of the Numbers Needed to Treat (less then 2!) as presented at the SIAARTI, was impressive: less then 2! For details see link.

In 2012 a separate study was published, also confirming positive effects for PEA in sciatic pain (see under)  

PEA is a safe compound, with virtually no side effects, and a ronus efficacy (NNT <2, see graph: NNT at week 3 is below 2). 

Treating trigeminal neuralgia can be quite troublesome. Meanwhile there is some experience treating patients suffering from trigeminal neuralgic pain.

The company Epitech is collecting these cases and we were informed about their data on file related to 9 patients, all affected by chronic trigeminal neuralgia, that have been treated with Normast 600mg for about two months and that all these patients experienced a marked pain relief (the NSR score mean decreased about 3point).

Furthermore 4 addditional cases have been documented with improvement after treatement with Normast.

Adelmidrol is a novel compound, and resembles in its biologoical effects palitoylethanolamide (PEA), although the two compounds have different physical-chemical properties.

The molecular structure of adelmidrol looks a bit as if 2 palmitoylethanolamide (PEA) molecules are fused. The father of this molecule is the Italian chemist  Dr francesco della Valle, colleague of professor Rita Levi-Montalchini, the Nobel laureate, praised due to her work on nerve growth factors (Died on December 2012, 103 years old). They started working on the group of Aliamides around 1990, and in 1993 Professor Montalcini published the first paper on the role of PEA as a mastcell modulator. The adelmidrol chapter adds to the importancde of these nmolecules as biological modluators.

Six hundred and thirty-six patients  affected by sciatic pain, participated in a double blind, controlled, randomised multi-centre clinical study with two doses of Palmitoylethanolamid in a non-branded formulation against a placebo, in nine hospital and university departments distributed in Italy. Palmitoylethanolamide is sold under two brandnames: Normast and PaePure.

Normast isavailable in Italy as a neurtraceutical, and as PeaPure in the Netherlands and elsewhere as a supplement. As a body own fatty compound it has minimal side effects and the analgesic effects have been evaluated in this big study. PeaPure has probably a slight advantage that it does not contain any chemical exciepient, it is pure PEA in a vetegarian capsule of 400 mg. 

CB2 receptors are mainly expressed by immune cells, where they modulate cytokine release and immune cell migration. Palmitoylethanolamide (PEA is available as a supplement under the brandnames PeaPure and Normast) exerts anti-inflammatory and analgesic actions via several molecular mechanisms, and probably most important is the direct activation of peroxisome proliferator-activated receptor-α (PPAR-α).

In addition to this mechanism of action indirect activation of cannabinoid receptors and of transient receptor potential vanilloid type-1 (TRPV1) channels have been described. Recently the analgesic activity of PEA in animal model of neuropathic pain have been explained not only via indirect activation of the CB1 and TRPV1 receptors but also via the PPAR-γ pathway.