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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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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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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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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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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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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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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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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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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 een PEA-houdend product and as a foodsupplement under the name PeaPure.

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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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Toll receptor 4 and glia in neuropathic pain

Toll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes and seems to play an important role in the regulation of pain signalling in neuropathic pain. Moreover, compounds like Trental (pentoxifylline) and low dose naltrexone are interesting instruments to modulate the Toll 4 receptor and perhaps these compounds will even help in the treatment of intractable neuropathic pain.

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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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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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Wise reactions of glia in neuropathic pain possible

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, een PEA-houdend product), 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:

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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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Adelmidrol: a novel glia modulator

adelmidrol.gifAdelmidrol is a novel chemical synthetized non-natural compound, and resembles in its biological effects palitoylethanolamide (PEA). PEA however is a natural molecule, adelmidrol as said is synthetical and cannot be found in living organisms. The father of this molecule is the Italian chemist  Dr Francesco della Valle, pupil 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 importance of these molecules as biological modulators.

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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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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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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: een PEA-houdend product and PaePure.

een PEA-houdend product 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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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 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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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 een Italiaans bedrijf 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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Obesity, chronic low grade inflammation, pain and low dose naltrexone

Obesity-associated health complications are thought to be in part due to the low-grade proinflammatory state that characterizes this disease. A quote from a recent article on obesity. In our clinic we regulary see obese diabetic patients, suffering from chronoc pain. Sometimes this pain resembles neuropathic pain, sometimes it is more of a fibrobyalgia sort. We gained some experience in treating chronic pain by using low dose naltrexone, sometimes together with low dose tramadol and would like to share this experience.

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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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Endocannabinoid, BDNF and inhibition

The neurotrophin brain-derived neurotrophic factor (BDNF) is a potent regulator of inhibitory synaptic transmission, and thus highly important for the central processes related to chronic pain experiences.

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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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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 een PEA-houdend product) 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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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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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 een PEA-houdend product 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 een PEA-houdend product 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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