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Research & Development

Drug Development Issues Related To New Compounds For Treating Neuropathic Pain And Neuropathy Are Presented Here.

Phenytoin cream normalizes neural overactivity in skin in neurogenic inflammation

Phenytoin cream is a newly developed cream by the Institute of Neuropathic Pain and protected by 2 patents, filed on December 6th, 2016. The cream contains 5 or 10% phenytoin and here we picture one of the mechanisms of action, via the keratinocyte.

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Low-grade inflammation in Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS); treatment by palmitoylethanolamide supplement

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a disorder difficult to understand for many, especially for doctors who too often think this disorder does not exist. Well it does! Modern neurobiological research clearly found new insights in the cause of this disease. New findings point out that inflammatory pathways and immunity derangements play an important role in the pathophysiology of Myalgic Encephalomyelitis […]

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Chronic prostatitis/chronic pelvic pain syndrome, neurologic inflammation and autoimmune disease and palmitoylethanolamide

In a recent review it was highlighted that symptoms of chronic prostatitis/CPPS appear to cluster into a group with primarily pelvic or localized disease,  as well as in a group with more systemic symptoms, such as generalized pain disorders. There seems to exist a cluster of chronic pain conditions related to chronic inflammation, and in this cluster we can […]

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Visceral pain: a forgotten topic

Prof. Fernando Cervero from Montreal, Canada discussed at the EFIC 2013 in Florence an underserved but very important topic: visceral pain. Visceral pain is very underserved, as patients visit often organ specialists not interested in pain itself, but directly focussing on the underlying illness. However, as visceral pain is a cinderella in the pain field, […]

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Visceral pain: basic mechanism and science

At the 2013 EFIC congress on pain in FLorence the Ulf Lindblom Special Lecture was dedicated to visceral pain, and presented by Prof. dr. F. Cervero from The Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada. Cervero pointed out that visceral pain is a prominent symptom of many clinical conditions. Visceral […]

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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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Capnellene from coral as a new lead for treating neuropathic pain

A Coral in the sea around Taiwan might produce a new lead for the treatment of neuropathic pain.

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Topical administration of ketamine and related compounds in neuropathic pain

wijze_creme_3.jpgIn our clinic we develop prototypes of transdermal creams to treat neuropathic pain. Currently we work on simple creams containing amitriptyline (5-10%) and ketamine (10%).

Here we quote from a clinical source and a patent analysis on various cream compositions for neuropathic pain, published in the VS. 

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KU-32 in diabetic neuropathy

KU-32 showed promessing effects in a mice model. KU-32 inhibits a specific member of a family of proteins, the socalled molecular chaperones. Diabetic mice were administered KU-32. The compound effectively stopped diabetic polyneuropathy and could even restore the sensory neuron functions of the damaged nerve tissue. 

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Adelmidrol: a new ALIAmide for chronic inflammation


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).

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Zinkvinger ligand SB-509 for diabetic neuropathy

The pharmaceutical company Sangamo BioSciences Inc. announced in January 2009 to start a new phase IIb study to analyse the efficacy and safety of their new compound, SB-509, a ligand for the so-called zinc finger proteins, for moderate to severe diabetic neuropathy.

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Measuring outcome in neuropathic pain trials

neupsig1.jpgDr. Nadine Attal from INSERM, discussed measurements in RCT’s of neuropathic pain and showed that there are great number of pain scales and questionnaires that have been used in clinical trials to assess the efficacy of interventions in neuropathic pain, varying from a simple visual analogue scale (VAS) or the numerical rating scale (NRS) to assess pain intensity to more complex multidimensional scales to assess pain, sleep, depression, quality or life or disability.NRS and VAS remain both the most suitable instruments to assess effects of treatment on pain intensity. Furthermore, clinical global impression of doctors (CGI) and responder rates are recommended for the assessment of overall change of neuropathic pain due to treatment.

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Antidepressants into low back pain: duloxetine (Cymbalta®)

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.  

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AZD 9272 from NPS Pharmaceutical for neuropathic pain

AZD 9272 from NPS Pharmaceutical for neuropathic pain in in phase I development. It is an mGluR1 antagonist. Its development might be discontinued in 2008.

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AZ11713908, a peripheral CB1 agonist for pain

Peripheral cannabinoid receptors are also clearly pathyways leading to analgesic effects, that is the lesson learned after exploring the analgesic effects of AZ11713908, a peripheral CB1 agonist for pain.

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Non-surgical treatment of syringomyelia pain

1.0. Introduction

Persistent neuropathic pain in syringomyelia is often quite refractory to conventional analgesic therapy, with most patients obtaining, at best, only partial relief of symptoms. The tendency still exists to treat these complex pains with one or a combination of two analgesics at the most. But as its pathogenesis is highly complicated, with many factors involved, this approach not often leads to relevant improvements. The famous Dutch surgeon Noordenbos wrote already  in 1959:

“One-one synaptic transmission must be the exception rather than the rule in the nervous system. Any nerve cell located in the anterior horn. . . could hardly be expected to synapse at higher level with one such similar cell only. It will probably send ramifications to many other locations, and in turn be acted upon by the ramifications of many other cells. . . Far from being a continuous chain of short neurons, these fibres must constitute links in an extremely complicated nerve net in which, within limits, everything synapses more or less with everything else.” (Noordenbos, W, 1959)

This old quotation is a crisp preview to the emergence of the modern concept of the hexapartite synaps, the synaps were 6 elements play a role in neurotransmission of pain: the two neurons making synaptic contact with each other, the microglia, the astrocyte, the T cell and the mast cell. Each of these elements play a role in the pathogenesis of pain, and too long we have been focussed on the first two elements of the synaps in our search for new analgesics only.

hexapartite_synaps.jpg

Figure 1. The hexapartite synaps: 6 cellular elements play a role in the genesis and maintenance of neuropathic pain: two neurons and the glia cell, astrocyte, mast cell and T cell. The non-neuronal cells play a much underestimated role in neuropathic pain and this is one of the major reasons for the clinical failure to satisfactory treat neuropathic painstates as in syronomyelia.

It is clear that more than half a century after Noordenbos, our therapy of pain starts slowly slowly to become in line with his early insights and multimodal therapy starts to become the hallmark in the treatment of neuropathic pain. However, there is scant literature on what would be the best regimen to follow. Although we follow different biological routes in treating pain, the focus still is on the modulation of functions of the nervous system itself, without taking other players into consideration, such as the glia, mastcells and other immune-competent cells. This is unfortunate, as the major players in the pathogenesis of chronic neuropathic pain most probably are these non-neuronal cells.

Generally there is an hierarchy of treatments for chronic neuropathic pain physicians will mostly follow, in- or explicitely, starting with monotherapy or the combination of various pharmacologic compounds, such as opioids, serotonin-noradrenaline uptake inhibitors, tricyclic antidepressants and anticonvulsants, Cannabis, endocannabinoids and topical analgesics, hand in hand with nonpharmacologic treatments like TENS and interventions which are in general seen as supportive, as well as cognitive, behavioral and physical therapies.

If patients are non-responders,  interventional approaches can be considered, such as dorsal cord stimulators, various nerve blocks, and intrathecal drug delivery systems. If this all does not help, invasive neuromodulation up to deep brain stimulation are last resort options. Some patients however, never achieve adequate pain control. And for syringomyelia none of the above strategies are routed on solid evidence.

1.0.1 Insufficient pharmacological efficacy

Most outcome studies are focussed on painful polyneuropathy, and most often due to diabetes, a good number two is postherpetic neuralgia. Studies in central neuropathic pain are rare, and even more rare are studies in spinal pain. Clearly studies in syrngomyelia are white ravens.

Most often tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids were studied and these drugs are proven to be of use in neuropathic pain in general. However, despite the 66% increase in published trials during the period 2005-2010, only a limited improvement in neuropathic pain treatment has been obtained. Most neuropathic pain patients are still left with insufficient pain relief, calling for other treatment options and modalities to target chronic neuropathic pain.

Although our understanding of neuropathic pain-generating mechanisms grew considerably since 2000, unfortunately this research did not result in similar improvement in treatment efficacy. Finnerup et al (2010) evaluated the 69 new randomized controlled trials published in the past 5 years and compared these with 105 published trials published in the preceding 39 years. Their conclusion: only a marginal improvement in the treatment of the patients with neuropathic pain has been achieved. The authors also point out that the clinical recommendations how to treat neuropathic pain usually depend on the simple assessments of the patients’ pain intensity and functionality without taking the possible underlying mechanisms into account.

Finnerup et al (2010) further datamined in the database for completed clinical trials to identify negative trials and found some very interesting facts. In addition to the published trials, this database presented one trial examining gabapentin 3600 mg, which relieved painful polyneuropathy with an NNT of 7.0 (4.3–20), and four positive and three negative trials with pregabalin, revealing a combined NNT of 9.5 (6.8–16.0). This implies that the tables most often quoted on NNT of analgesics are flawed and these analgesics might have much less efficacy as we thought. This fact, hand in hand with the numbers needed to harm makes one working in this field quite humble.

Figure 2 : Combined number-needed-to-treat (NNT) values for various drug classes in all central and peripheral neuroathic pain. The bigger the circle, the more patients were included in clinical trials assessing the efficacy of the drug. (IASP Pain Clinical Update November 2010) Due to bias NNT’s on this chart might look over optimistic.

 

nnt.gif

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Neuropathic pain research in Germany

The doctors and researchers working in the field of neuropathic pain in Germany, are bundling insights and resources in the German Research Network on Neuropathic Pain (DFNS). The DFNS focusses on research in the field of neuropathic pain by integrating the resources of the leading centers actively involved in neuropathic pain research in Germany.

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Epoxygenated fatty acids (EFAs) and neuropathic pain

Fatty acids might play a bigger role in neuropathic pain than previously thought. 

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Palmitoylethanolamide: for the treatment of cannabis dependence.

Drs M. Coppola and R. Mondola from the Department of Addiction, in Alba, Italy and the Department of Mental Health, Saluzzo, Italy published an interesting paper on the putative use of palmitoylethanolamide (PEA) in the treatment of Cannabis dependency. They bring forward this hypothesis based on a variety of findings,

They point out that like cannabis, evidences suggest that PEA, as THC, has anti-inflammatory and anti-nociceptive activity in humans as well as in animal models. PEA, an anandamide congener, might have PEA has anti-craving effects in cannabis dependent patients, is efficacious in the treatment of withdrawal symptoms, produces a reduction of cannabis consumption and is effective in the prevention of cannabis induced neurotoxicity and neuro-psychiatric disorders due to its pleotropic mechanism of action.

Source: Coppola M, Mondola R. Palmitoylethanolamide: From endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence. Med Hypotheses. 2013 Jul 26. doi:pii: S0306-9877(13)00338-1.

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Reduction of PEA- FAAH in medication-overuse headache

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.

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NGX-1998, a non-patch liquid formulation of capsaicin

NeurogesX, Inc. developed Qutenza, a dermal patch containing capsaicin, and proceeeds working in this field. They focus now on various other pain killers, and in the pipeline we find NGX-1998, a non-patch liquid formulation of capsaicin for neuropathic pain, NGX-1576, NGX-9674, and NGX-5752 prodrugs of acetaminophen for acute pain, NGX-6052, an opioid prodrug for chronic pain.

 

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Nerve cell regeneration and the receptor called DCC (Deleted in Colorectal Carcinoma)

Researchers from the university of Montreal published in Cell an article that gives some new insight in the issue of nerve cell regeneration. "We found an alternate way that helps nerve cells respond quickly and locally," sayd one of the authors of the paper, Philippe P. Roux, a professor of pathology and cell biology and a researcher at the University of Montreal Institute for Research in Immunology and Cancer (IRIC). He sees new therapeutic targets in future based on this principle:  "We can envisage manipulating this alternate mechanism to make cells respond locally to their environment. Our findings mean that scientists must consider a new way that cells organize themselves to perform essential functions."

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Fibromyalgia is linked to Inflammatory Back Pain

Fibromyalgia is linked to Inflammatory Back Pain, according to new findings from rheumatologists. This adds to the burden of proof that fibromyalgia is probably a very mild systemic inflammation of parts of the muscular system. Here the article:

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Botulinum toxin A from Allergan for neuropathic pain

Botulinum toxin A from Allergan in development, phase I, for neuropathic pain. But at the site of Allergan there is a remark: No Trials Currently Recruiting in the field of CNS. However, we do find an other pipeline-accent: Alpha Agonists for Neuropathic Pain licenced from ACADIA Pharmaceuticals currently in Phase II. And in March 2010 we heard a story about Bristol-Myers Squibb who is willing to pay $40 million up front for global development, manufacturing and commercialisation rights to Allergan’s neuropathic pain product AGN-209323.

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Neuromed’s NMED-160 in phase I

Neuromed Technologies focusses on developing new drugs based on calcium channel modulation. Neuromed has identified a selective N-type calcium channel blocker with analgesic effects, relevant for the treatment of neuropathic pain. 

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Clinical Trials with PEA: overview

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

Overview of all clinical trials:

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Neuropathic Pain Market booming: $5.2 billion by 2018

The market for drugs to be used for the treatment of neuropathic pain is suggested to become very significantand seems to be booming: the forcast is e doubling in 10 years time up to a dassling figure of $5.2 billion by 2018! Under the titel: Research and Markets: Forecast Insight: Neuropathic Pain – Brighter Future for Pipeline Drugs with Market to Double in Value to $5.2 Billion, a press release of Datamonitor dated Monday February 15, 2010 states.

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GRC 15300 from Glenmark in the hands of Sanovi-Aventis

Glenmark Pharmaceuticals Ltd. (GPL) announced in 2010 that the company has entered into an agreement with Sanofi-aventis to grant Sanofi-Aventis a license for the development and commercialization of the new class of agents called vanilloid receptor (TRPV3) antagonists. This includes Glenmark’s first-in-class clinical compound, GRC 15300, currently in phase I.

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Nanorobots interacting with neurons

Nerve cells break down: spinal damage and paralysis, parkinson’s disease and nigra cells…will nanorobots ever interact with our delicate and plastic nervous system like in this simulation?

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Palmitoylethanolamide: a natural protector against lipid peroxidation

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 

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