The Astra-Zeneca compound AZD2423, a novel chemokine receptor 2 (CCR2) antagonist, fails in treating neuropathic pain in posttraumatic neuralgia. This is the result of a phase II trial dose-finding in 133 patients with posttraumatic neuralgia. Patients were equally randomized to 28days' oral administration of 20mg AZD2423, 150mg AZD2423 or placebo.

In the recent journal PAIN of the IASP ( number 3 march 2013) an editorial as well as a research paper is devoted to natural moleucles such as palmitoylethanolamide. In the editorial comment, by BK Taylor (N-acylethanolamine acid amidase (NAAA), a new path to unleash PPAR-mediated analgesia) he writes:

Antihyperalgesic effects are produced by endogenously-generated PPAR activators. Of particular importance to pain research are the fatty acid ethanolamides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), both of which bind with high affinity to PPARα.

In neurons, glia, and inflammatory cells, PEA and OEA are not stored, but rather are made on demand – endogenous levels are regulated by the relative activity of biosynthetic and degradative enzymes. Animal studies convincingly demonstrate that PEA exerts a broad spectrum pain inhibition that can be reversed with PPARα antagonists and this inhibition does not occur in deletion mutant mice lacking PPARα. 

Palmitoylethanolamide is approved in some countries  as a dietary supplement in humans, and preliminary but intriguing clinical trials and case studies suggest that oral PEA is effective for a variety of pain syndromes ...

An acute reduction of the endocannabinoid-hydrolase fatty acid amide hydrolase (FAAH) is coupled with an improvement of the facilitation of the nociceptive pathways in medication-overuse headache is the total title of a poster presentation by A. Perrotta and colleagues from a series of scientific institutions in Italy.

Medication overuse headache (MOH) is quite a problem for patients. The headaches are terrible and the idea that these hadaches increases if painkillers are ingested is couter-intuitive. Now there are clear indications Palmitoylethanolamide might be a good idea in the substitution of less painkillers and during the period of weaning off painkillers.

N-Acylethanolamines (NAEs) (fatty acid ethanolamides) are naturally occurring hydrophobic molecules usually present in a very small amount in many mammalian tissues and cells [1] and [2]. Moreover, NAEs are normally present in biological fluids, such as blood [2], in very low concentrations. The physiological levels of important NAEs in mammalian blood plasma are in the range 2.8–5.2 pmol/ml for anandamide (AEA); 9.4–16.7 pmol/ml for PEA; 8.1–10.3 pmol/ml for oleylethanolamide (OEA) [2], [3] and [4]. However, the NAEs levels in blood plasma could be modified in pathological conditions, e.g., the physiological concentrations of AEA in human plasma are 4 pmol/ml, but these concentrations are increased up to 18–30 pmol/ml in sera of patients with endotoxic shocks [5]. In vivo studies demonstrated that NAEs could accumulate in injured tissues, such as, e.g., in myocardium infarcted areas [6], and in post decapitative brain ischemia [7].

And 

Since 1993, after the work of the Nobel price laureate Rita Levi-Montalcini on palmitoylethanolamide and its inhibiting effects on inflammation, much happened. It seems that all Montalcini said in 1993 about inflammation, the role of the mastcell and the modulation of the mastcell by the endogenous modulator palmitoylethanolamide has been substantiated by new research.

Recently, a number of pharmacologists reviewed the literature and found new experimental data supporting the role of the mastcell in our central nervous system. They state that their experimental data strongly suggest the participation of mastcells in the processes which eventually lead to autoimmune demyelination, a kind of neuroinflammation, which is of relevance for e.g. multiple sclerosis.

ADELMIDROL: a new topical ALIAmide for chronic inflammation

Adelmidrol is the diethanolamide derivative of azelaic acid, i.e., naturally occurring dicarboxylic acid that has long proven to be an effective topical treatment for human inflammatory skin disorders (1), and whose mechanism of action have been recently and thoroughly investigated (2).

Similarly to the anti-inflammatory and anti-nociceptive compound palmitoylethanolamide (PEA) (3-17), adelmidrol belongs to the aliamide family, a group of fatty acid derivatives with cannabimimetic properties, able to control the event of mast cell (MC) hyper-reactivity in several pathophysiological and pathological conditions (5).

Michael W. Salter, MD, PhD, Neurosciences & Mental Health Program, Hospital for Sick Children presented: AN UPDATE ON THE NEUROBIOLOGY OF ACUTE AND PERSISTENT PAIN

Major advances have been made recently in understanding the pathobiology of acute and persistent pain at the molecular, cellular and neural systems levels. Thus, chronic pain may be conceptualized not as a symptom of disease but rather a disease unto itself.

The speaker elucidated on peripheral and spinal cord mechanisms of pain neuroplasticity through illuminating neuron-neuron synaptic plasticity and the emergent role of neuron-glia signaling, particularly in neuropathic pain.

He discussed the roles of plasticity and signaling in brain nociceptive networks in pain hypersensitivity. Furthermore he described the critical role of descending inhibitory and facilitatory modulation in gating persistent pain.

GPR55 receptor is highly expressed in large dorsal root ganglion neurons of spinal cord.

Several mechanisms have been suggested for the antinociceptive and anti-inflammatory actions of PEA. The relative contribution of cannabinoid CB1, vanilloid and PPARγ to PEA-induced antinociception effects has been shown in previous studies. 

The antinociceptive effect of PEA as a selective GPR55 agonist/weak cannabinoid receptor agonist was studied in a rat model. Based on the results the authors suggested that GPR55 receptors are involved in pain modulation and could be considered as an important target for antinociceptive therapies. 

Topical treatment of neuropathic pain

Topical analgesic creams to treat pain and tingling may have many advantages over systemic treatment with analgesics: 

8 analgesic creams and one paste in INP base

In the institute for neuropathic pain we developed various topical analgesic creams for the treatment of neuropathic pains. The development team working on these creams consisted of two pain physicians and one specialized compounding pharmacists. Creams were developed based in literature search and were optimized using superior formulations, leading to creams with optimal physical chemical properties and clear analgesia. 

The principle of these creams have been described in the literature below and have been prescribed to many hunderds of patients, without any bothersome side effect. The institute is constantly working to developed new creams.

The creams we developed are all specifically formulized based on the experience with drug development in our institute in a special Institute for Neuropathic Pain base (INP base) and those creams consist of:

1. Amitriptyline cream 5 % and 10% in INP base

2. Gabapentine cream 10% in INP base

3. Baclofen cream 1%, 2 % and 5% in INP base

3. Ketamine cream 10% in INP base

5. Isosorbide dinitrate  cream 0,4% and lidocaine cream 3% in INP base

6. Toothpaste baclofen 5% for dental neuropathic pains  in INP base

Most patients report a decrease of pain within 15-30 minutes after application. 

All these creams have a special formulation enabling optimal efficacy with minimal side effects. 

We will sent a prescription form to the physician.  

The Na(V)1.7 sodium channel can be found in the dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. The so called 'gain-of-function' variants of the Na(V)1.7 channel have recently been described in patients with painful small fibre neuropathy.

It is probably that a novel syndrome of pain, dysautonomia, small hands and small feet can be understood from a novel Na(V)1.7 mutation.

A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). 

Welcome to our Institute for neuropathy and neuropathic pain, and our Website. We gathered here for you many articles in the field of neuropathy and neuropathic pain. In our centre we are specialised in treating patients suffering from neuropathic pain and neuropathy following an Integrative Medicine concept. Part of our activities are within the field of consultation. We assist pharmaceutical companies in R&D strategies related to finding new drugs to treat neuropathic pain and neuropathy. 

Many patients suffering from neuropathic pain are currently not optimal treated using the drugs on the market. The total value of the neuropathic pain market is supposed to double from 2006 to reach over $7 billion by 2016. There is a lot of space in the marketplace for  improved pain management.

In our institute we are specialized in the treatment of neuropathic pain and adbvising R&D processes related to the identification of new potential painkillers for neuropathic pain. A short explanation of the experience we have in helping pharmaceutical companies developing new drugs, by professor Jan M. Keppel Hesselink, MD, PhD, consultant.

Recent review of palmitoylethanolamide including many clinical trials via this link. 

Overview of all clinical trials:

Syringomyelia is characterized by the presence of spinal cord cavitation and is most commonly seen in association with Chiari I malformation. Central neuropathic pain is a prominent feature in 50 to 90% of adult human patients with syringomyelia. The treatment of this neuropathic pain is not an easy task. Methodological sound clinical trials in the treatment of central neuropathic pain are not available. Treatment recommendations for this variety of pain are heavily depending on clinical trials conducted in peripheral neuropathic pain.

Neuroinflammation in inflammatory bowel disease, the titel of a leading article on the role of amongst others the mast cell in IBD. ( Journal of Neuroinflammation 2010, 7:37). We quote from this open access article several parts related to the impact of the mast cell on IBD. These quotations demonstrate that the use of the natural anti-inflammatory agent palmitoylethanolamide might be a very useful to treat patients suffering from these disorders.

In our clinic we saw a clear therapeutic effect when we prescribed PEA in a patient suffering from colitis ulcerosa combined with severe neuropathic pain. Not only was the neuropathic pain reduced in severeity by more than 50%, the same holds true for the symptoms of the IBD, diarrhoea and fecal incontinence.

Identification of palmitoylethanolamide (PEA) as regulatory mechanism for the metabolism of mast cells by Nobel Price Laureate Rita Levi Montalcini in 1993, and it's use as a analgesic and anti-inflammatory compound

Searching for non psychoactive Cannabinoids our clinic identified in 2010 the small molecule palmitoylethanolamide (PEA) as a potent novel and promising analgesic and anti-inflammatory agent. This molecule has been developed based on the work and insights of Rita Levi Montalcini, as an off spin of her work with nerve growth factors.

As PEA, trade names PeaPure and Normast, is gaining more and more international recognition as a break through molecule in the treatment of chronic pain and inflammation, it is worth while to shortly analyze how the mast cell modulation concept, palmitoylethanolamide and the ALIA concepts came into existence.

Adenosine is a neuromodulator that interacs with four adenosine receptors, A(1), A(2A), A(2B) and A(3). Adenosine receptors are new inroads in treating neuropathic pain. Even better, these compounds are inroads to treating gliopathic pain. Gliopathic pain is a new name for the chronic wind-up state of glia and neurons in chronic painstates we see in diabetic neuropathy, herpes zoster and many related painstates.

Given the fact that most antidepressants are not active in mild to moderate depression, it is a bit odd that the Food and Drug Administration has approved in 2010 the anti-depressant Cymbalta® for a different use, which is just as vague as mild and moderate depression: low back pain and osteoarthritis.  

In our continuing debate with international colleagues we received a letter with the following statement related to our articles on gliopathic pain:

Indeed I believe this new glial field in pain research highly exciting. Furthermore, the aspect you mentioned regarding the mast cells is also very promising as possible potent modulators of peripheral modulation of nerve endings in multiple organs.

This prompted us to look for further support to use and evaluate mast cell stabilisers in clinical practice. One indication we came across was myocardial infarction:

In a recent press release (18-10-2010) it was communicated that the company NeurogesX  U.S.will try to broaden the indications for Qutenza® (capsaicin) 8% patch to include patients with painful HIV-associated neuropathy (HIV-AN, also referred to as HIV-distal sensory polyneuropathy (HIV-DSP)). Following a recent meeting with the U.S. Food and Drug Administration (FDA), NeurogesX plans to submit a supplemental new drug application (sNDA) in the first half of 2011.

Palmitoylethanolamide is hot. It is a body-own compound which seems quite interesting for a number of clinical reasons, and most importantly for its analgesic properties in neuropathic pain. But how does it work? 

The search for the palmitoylethanolamide receptor was the title of a publication in Life Sciences, written by pharmacologists from the Department of Experimental Pharmacology, University of Naples, and the Department of Pharmacology, University of California, Irvine, USA.

Distal axonal degeneration is a hallmark of many neuropathies. Traditionally we tended to think in a simpel degeneration-regeneration model. The celbody of each neuron, based on the functions of its residing nucleus, is key in regeneration, and all regeneration processes are anterograde. Failure of metabolic support for the cellbody causes an impairement in the function of the axon, due to the fact that the axon itself is poorly inhabited by ribosomes and mitochondia and thus the axon is totally dependent on support from its master, the cellbody. In 1997 Spencer at all described the degeneration proces using an analogy of the farthest meaddow, which is the first to be drowned from water support, if the waterpump fails. These analogies and metaphors always play a big role in our understanding and our apporach of scientific problems and clinical problems.     

Most people and neurologist view nerves as 'copper ropes' conducting electricity. If the copper rope breaks, the nerve is damaged, and the damage is for the rest of our life. This creates great nihilism for therapeutic innovations. And even more disturbing, patients feel this metaphore is a desription of reality. The message patients often get from their neurologist is: nothing can be done, what is dead remains dead....

Dexpramipexole is an enantiomer, of the dopamine agonist pramipexole, used in Parkinson disease. It is the right-handed isomere and it is practically devoid from all the dopaminergic effect. Preclinical work indicates dexpramipexole might have neuroprotective properties, probably due to its ability to prevent mitochondria from developing leaky membranes when under stress. Therefore it has been taken into development in an orphan indication, amyotrophic lateral sclerosis, ALS, or Lou Gehring disease as the Americans call it. (Should actually been called Charcot's disease, as he first described ALS more than 100 years ago).

In the internet there is a big community of specialists involved in drug R&D and at LinkedIn there are quite some interesting discussions related to topics worth while considering. The question which haunts many drug developers is: Why is it that so many drugs flunk after phase II trials? That question is also immensly important for the development of drugs in the field of chronic pain. But it is a generic question.