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Gliopathic pain

Gliopathic Pain Is A Brand New Term For What We Always Thought To Be Neuropathic Pain. It Refers To Pain Related To Neuropathic Pain, However, The Primary Driver Of This Pain Is Most Probably More Linked To Glia And Asterocytes. The Mechanism Of Gliopathic Pain Is The Hyperactivation Of Glia Cells, Which Results In Neuropathic Pain.

Neuropathic pain: microglia controls neuronal network excitability

Microglia-neuron interactions are leading to altered neural network excitability, the pathogenetic base of neuropathic pain. Modern research demonstrates that one of the key factors driving neurons nuts in neuropathic pain is the inflammatory compound ‘Brain-derived neurotrophic factor (BDNF)’, released by microglia. [1] Microglial BDNF plays a key role in controlling neuronal excitability by causing disinhibition. This […]

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Gliopathic pain in orofacial pain

Chiang CY, Dostrovsky JO, and colleagues from the Department of Oral Physiology, Faculty of Dentistry, University of Toronto, Canada, adress the role of glia in orofacial pain in the Neuroscientist of June 2011.

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Ketamin might have glia as target for neuropathic pain

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.

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Endocannabinoids and palmitoylethanolamide in chronic inflammation

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.

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Gliopathic modulators

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.

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Neuron-glia crosstalk gets serious: role in pain hypersensitivity

glia_jmkh.gifThis titel of a recent article demonstrates the increasing awareness in the scientific community about the relevence of the once seen as unimportant glia cells and the nervous tissue.  Glia and asterocytes play a very important role in the genesis of neuropathic pain. The word gliopathic pain is recently coined to capture this importance…A low-grade inflammation in the spinal cord and along the pain pathways to thalamus and the parietal cortex is the hallmark of chronic pain states and glia plays the key role!

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Glia modulator propentofyllin not active on human non-neuronal cells

Glial cells are involved in neuropathic pain conditions. Several glial-targeted agents are in development for the treatment of pain conditions. The glial modulating agent, propentofylline, did however not decrease pain reported in association with post-herpetic neuralgia. Why? Because the human non-neuronal cells do not listen to this glia modulator, although rat non neuronal cells do….

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Palmitoylethanolamide in neuropathic sciatic pain: clinical results


Palmitoylethanolamide (PEA) is an natural and 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 a nutraceutical (dietfood for medical purposes)  in Italy and Spain under the brandname Normast and in the Netherlands and elsewhere as a foodsupplement under the brandname PeaPure. 

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

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) and were based on a double blind placebo contriolled study.

TWe conducted a furher analysis of the Numbers Needed to Treat we presented at the SIAARTI in 2011 for around 1000 pain specialists, the efficacy of PEA based on the NNT analysis we presented was impressive: 1.5! For details see link.

The presentation at the SIAARTI was moderated and introduced by professor G. Varrassi. 

In various different clinical nerve compression studies, conducted up to 2011, a total of more than 1300 patients  wre treated all confirming positive effects for PEA in sciatic pain (see under)  

PEA is a safe compound, with virtually no side effects, and a robust efficacy (NNT=1.5, see graph: NNT at week 3 for 50% pain reduction on NRS). 


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Pentoxyfilline as a gliamodulator

Pentoxifylline is a xantine derivate and can be given to patients with claudicatio intermittens. Because pentoxifylline inhibits cytokines (molecules that activate inflammation), this drug could be interessing for the treatment of neuropathic, and thus gliopathic pain.

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Glia as target for new analgesics and palmitoylethanolamide: PEA in sciatic pain

In 2011 our institute was present at the SIAARTI, in Perugia, Italie, at the biggest Italian congres for anesthesiologists and pain specialists (SIAARTI, Società Italiana di Anestesia, Analgesia, Rianimazione e Terapia Intensiva). siaarti_2011_sciatic_pain_.png
At this congress we had the honor and pleasure to talk extensively on the efficacy of palmitoylethanolamide (PEA) and present for the first time our analysis of the efficacy and safety of this compound related to its Numbers Needed to Treat, based on a RCT with 636 patients.

We will discuss the results of this analysis based on the presentation at the SIAARTI.The entire presentation under the link, start at 1 minute 53 to skipp the Italian introduction.

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New Targets in pain, non-neuronal cells, and the role of palmitoylethanolamide: A Prezi!

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 purposeunder the name Peavera and Normast and as a foodsupplement under the name PeaPure.

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Pentoxifylline, tocopherol, and clodronate in radiation-induced lumbosacral polyradiculopathy

Pentoxifylline, tocopherol, and clodronate seem to be effective in radiation-induced lumbosacral polyradiculopathy, as reported by a case study. This is important, although the evidence is weak (case report), as to date there is not one single therapy found to be of use in this late complication of radiation induced polyradiculopathy.

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Trigeminus neuralgia treated with palmitoylethanolamide

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 palmitoylethanolamide 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 PEA.

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Propentofylline, a glia modulator

Glia modulators are the new kids on the block for the treatment of intractable neuropathic pain. Gliopathic pain is perhaps a better term for this pain, as the winding up phenomena is very much driven by activated glia. The search for glia modulators therefore is quite exciting. We work in our clinic with a number of glia modulators in treatment refractory neuropathic pain and sometimes with amazing results. 

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New insights in mast cell modulation by palmitoylethanolamide

New Insights in Mast Cell Modulation by Palmitoylethanolamide

was the title of a review of drs De Filippis, Iuvone and collaegues in CNS & Neurological Disorders – Drug Targets, 2013, 12, 78-83. 

The authors discussed the findings of Levi-Montalcini and the mechanism proposed by her group to explain PEA action, first identified in the 1990s,  the so called ALIA mechanismor the ““Autacoid LocalInflammation Antagonism””. They pointed out that later this terminology was modified into ““Autacoid Local Injury Antagonism””.
The change in acronym was based on the observation that ““the pharmacological effects of PEA appear to reflect the consequences of supplying the tissue with a sufficient quantity of its physiological regulators of cellular homeostasis”” (Aloe, L.; Leon, A.; Levi-Montalcini, R. A proposed autacoids mechanism controlling mastocyte behavior. Agents Actions 1993; 39: C145-7). Thus, De Fillipis et al point out that
PEA needs to be being viewed as a broad bioactive ““protector”” instead of limiting its field of action to the inflammation response.

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Mutiple Target Analgesia

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.

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Depression: a gliopathic disorder?

Antidepressants in our culture: an expanding wave. Although scientific studies do not support the use of antidepressants in mild to moderate depression, prescriptions for anti-depressants are soaring high. We want to share to contemporary critics on our use of anti-depressants. The first is dr. Helen Fischer, a well known antropologist from the VS. She warns for chronic use with seronin-uptake inhibitors. By increasing the serotonin in the brain during months to years, other neurotransmittersystems tend to collaps, such as the dopaminergic system. And, as she vividly points out, the dopamine system is key for a healthy love life and for the kick in life. The second scientist is dr. Vladimir Maletic, who recently argued depression is not a nerve cell disorder, but a glia cell disorder, a gliopathic pathology, just as neuropathic pain is!

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Neuroinflammation explains aspects of chronic pain: what about naltrexone?

‘Neuroinflammation explains aspects of chronic pain and opens new avenues for therapeutic interventions’ is the titel of an editorial of Harald Breivik and Torsten Gordh, in the Scandinavian Journal of Pain, Volume 1, Issue 2, April 2010, Pages 65-66. These editors raise important issues, as current drugs for chronic pain exclusively target neuronal mechanisms, and these drugs appear only partly effective. Therefore, new treatment strategies via the manipulation of the neuron–glia interactions in pain may lead to new break through approaches. It seems that more than one basic neuroscientist claims that inhibition of immune function might become a major avenue for treating neuropathic pain in the future.

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Gliopathic pain, asteropathic pain..


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. 

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Palmitoylethanolamide, PPAR-alpha and glia

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.

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Proinflammatory cytokines in small fiber neuropathy

Proinflammatory cytokines in small fiber neuropathy can be found in the skin of patients suffering from Small fiber neuropathy (SFN). SNF is a sensory neuropathy with neuropathic pain in feet and hands, and normal findings in routine EMG/nerve conduction studies. These results make patients very uneasy, as they tend to believe their pain is between the ears. Now new findings show a crisp pathological disturbance in the skin of the affected area. SFN is as many other neuropathic pain states a chronic inflammation.

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Opioids activate Glia: counterproductive in neuropathic pain…

Opioids can cause chronic pain, especially neuropathic pain, were glia and asterocytes are happy to become over activated.  After chronic opiate exposure, this excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia, and the glia are key in this negative pain cascade.

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Palmitoylethanolamide analogue, palmitoylallylamide (L-29) in a pain model

Cannabis and the endogenous cannabinoids are associated with analgesia in acute and chronic pain states. The analgesic effect of the palmitoylethanolamide (PEA) has ben described in many different animal models, and meanhile also in a number of clinical trials. This has prompted to look for analogues of PEA. Palmitoylallylamide (L-29) is such a analogue.

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Neuropathic pain, glia and cannabis

Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. These are the opening words of a brand new article on ‘Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain’ from the hand of Cory C Toth and colleagues. 

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Bladder pain syndrome (BPS) and glia cells

The urothelium, the epithelial lining of the lower urinary tract (LUT), most probably plays an important role in bladder function due to its intercations with bladder nerves, smooth muscle, and cells of the immune systems.

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Palmitoylethanolamide and leucocyte inhibition

Palmitoylethanolamide (PEA) is a lipid amide that occurs in our bodies as well as in many mammalian tissues, and can when administered as a drug, inhibits inflammatory responses via the recent described nuclear receptor, the peroxisome proliferator-activated receptor-alpha (PPAR-alpha).

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Palmitoylethanolamide for sciatic pain

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. 

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Glia modulators for neuropathic pain

Since 1994 when Meller and colleagues for the first time demonstrated that by inhibiting astrocyte functions, neuropathic pain did not emerge, many glia modulators have been explored as new inroads in the treatment of neuropathic pain. Some specifically inhibit cytokines (like Il-18), others enhance anti-inflammatory cytokines, such as Il-10, and again others stabilize mastcell degranulation and are PARR agonists, such as palmitoylethanolamide. Here a summary:

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Metabolism, Mast cells, neuropathic pain and palmitoylethanolamide

mast_cell2.gifInfluencing 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.

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Glia Acitivation Inhibitors in neuropathic pain

Glial activation inhibitors have become hot once the neurological cimmunity understood that neurons are not solely responsable for neuropathic pain. Meanwhile it has been widely recognized that glia and asterocytes play an important role in the upregulation of neuropathic pain (winding up). These non neural cells release neuroexcitatory, pain-enhancing substances such as pro-inflammatory cytokines, and these cytokines dysregulate the actions of our own endogenious opioids.

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