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Research & Development

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

Low-grade inflammation and chronic pain

Low-grade inflammation is thought to play a role in the pathophysiology of chronic pain conditions. This is the reason why increasing numbers of pain physicians use the anti-inflammatory compound palmitoylethanolamide. Previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have only looked at a few predetermined cytokine candidates. The aim of a number of researchers […]

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PERIPHERAL INFLAMMATION IN FIBROMYALGIA

Drs N. Groven and his colleagues from Norway presented a poster at the EFIC in 2017 in Copenhagen, were they explored the peripheral inflammatory character of fibromyalgia. We often recommend palmitoylethanolamide for the treatment of fibromyalgia. This is a supplement based on an endogenous molecule inhibiting inflammation (PeaPlex, Glialia). Fibromyalgia (FM) patients often experience symptoms […]

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Topical Phenytoin cream and the identification of responders and placebo responders

At the European Pain Federation (EFIC) at Copenhagen, September 2017, we could present our placebo response test at the workshop on placebo and nocebo responders. This workshop on ‘the state of the art, prediction and ethical considerations’, chaired by Dr Vase, the first presenter dr Colloca from the USA reinforced such response system to identify […]

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Topical TV-45070 8% ointment in herpes zoster pain not effective

Teva Pharmaceutical Industries Ltd. at the end of June 2017 disclosed the results of a Phase II study analysing topical TV-45070 4% and 8% oil in patients with post-herpetic neuralgia (PHN). The ointment treatment (twice a day) did not reduce the primary endpoint, pain measured via the NRS, at week four compared to placebo. However, there were […]

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Chronic Pain Trials considerations

Chronic Pain Trials are not easy to conduct: some relevant issues are discussed.

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Neuropathic Itch, its neurophysiology and putative treatment

At the plenary session at the NeuPSIG 2017 at Gothenburg, Sweden a topic discussed was Neuropathic Itch. A state of the art lecture was given by  Sarah Ross, USA In PubMed only few entries can be found on neuropathic itch, and no clear therapies are known. Many neuropathic pain conditions have an itch component, such as post […]

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Neuropathic Pain Treatment Update at NeuPSIG 2017

Neuropathic Pain Treatment Update : an overview of recent neuropathic pain treatments show especially sodium channel blockers are hot in the early clinic.

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Topical treatment in Chronic Pelvic Pain

Chronic Pelvic Pain: difficult to treat! At the poster sessions atthe NeuPSIG 2017 at Gothenburg, Sweden a poster was presented from the Albany Medical Centre, claiming that in chronic pelvic pain local small fibre neuropathic changes could be detected. This was concluded based on biopsies of the skin. SFPN was suggested to be screened as […]

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Global Burden of Neuropathic Pain

Global Burden of Disease discussed in the light of neuropathic pain.

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Sodium channel function in neuropathic pain

Sodium channels were discussed as new inroads for reducing neuropathic pain.

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Repositioning of Amantadine and phenytoin: patent protected strategies

Repositioning (or repurposing) of old not-patent protected drugs in new, off label indications leads to quick development times and cheaper developments. However, one needs to overcome a number of hurdles to reach a successful repurposing of such old drugs. Athors are quite experienced in repositioning phenytoin anno 2017 as a topical analgesic. In the enclosed […]

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CR845 (Difelikefalin), A Kappa Receptors Agonist In Phase III By CARA Therapeutics

CR845: (difelikefalin), a peripheral opioid agonist currently developed by Cara Therapeutics, an analysis.

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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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Nerve Growth Factors as new inroads in chronic and neuropathic pain

Stakeholder Opinions: Targeting Nerve Growth Factor for Pain Therapy – Groundbreaking class to breathe new life into saturated market – this is the somewhat pompous and overdone title a new market research report from companiesandmarkets.com, published in 2010, on a new potential class of analgesics for neuropathic pain.

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JNJ 42160443 from Johnson in neuropathic pain

JNJ 42160443 from Johnson in neuropathic pain, phase II. Hereunder the update of clinical trials running for this compound, as of April 2010. The Janssen compound is a monoclonal antibody directed against nerve growth factor (NGF). In animal models it demonstrates potential analgesic activity. Anti-nerve growth factor monoclonal antibody JNJ-42160443 binds to NGF, and prevents its binding to the NGF receptors TrkA and p75NTR. Inhibition of this pathway may prevent neuropathic pain.

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CNSB015 at Third International Congress on Neuropathic Pain in Athens, Greece

Relevare Pharmaceuticals Ltd. presented results for CNSB015 (flupirtine), at the Third International Congress on Neuropathic Pain on May 27 -30 in Athens, Greece, which we visited. Flupirtine belongs to the class of aminopyridines, like fampyridine used in MS, and is a centrally acting nonopioid analgesic. It is on the market in Europe since 1984 under the names Katadolon and Trancolong. It is a non-opioid, non-NSAID, non-steroidal analgesic. Flupirtine therefore is an already established clinical analgesic for musculoskeletal pain. 

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AstraZeneca and neuropathic pain

AstraZeneca, a pharmaceutical company, has three compounds in clinical development for neuropathic pain:

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Il-17: new target in neuropathic pain

Il-17 is a pro-inflammatory cytokine and this molecule plays a certain role in neuropathic pain.

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Natrium channel disruption in small fibre neuropathy

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). 

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Taurine for painful diabetic neuropathy

taurine.jpegTaurine 3,000 mg/day (3 capsules) orally vs placebo 3 capsules daily for 12 weeks is evaluated currently in a RCT in the UK. The idea of the trial is that taurine depletion contributes to the development of painful Diabetic Neuropathy (DN). This rationale is based on:  

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Beta-blockers for Cachexia

It sounds strange, but the treatment of caridac  failure and cachexia is currently also explored via prescribing beta-blockers. [1] This seems to be a therapeutic inroad not only for cachexia related to cardiac failure.

Already in the last century internists have experimemented prescribing beta-blockers such as propranolol for cachexia related to cancer. Propranolol seemed in that indication to correct the autonomic nervous system dysfunction responsible for the elevated metabolism in elderly cancer patients, leading to cachexia. [2]  The cachexia and loss of weight in cancer patients is by some authors explained via the increased beta(1) and beta(2)-adrenoceptor activity, in part secondary to elevated cardiovascular activity compensating for anaemia, and loss of cardiac contractility. This argumentation supports the use the use of beta-blockers in the indication cardiac waisting.

 

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KRN5500 Kirin Brewery and Massachusetts General Hospital, DARA Biosciences

KRN5500 Kirin Brewery and Massachusetts General Hospital, is licenced to DARA Biosciences, and currently in phase II for neuropathic pain. KRN5500 (6-[4-Deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-ß-L-manno-heptopyranosyl]amino-9H-purine) has been targeted for specific indications: Neuropathic Pain in cancer patients, in particular, chemotherapy-induced peripheral neuropathy (CIPN). KRN5500 is a novel non-opioid analgesic agent, a semi-synthetic derivative of spicamycin.

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Retigabine (D-23129)

Retigabine, a anticonvulsant, known already sinds 1995, activates Kv7 (KCNQ/M) channels in the axonal/nodal membrane of peripheral myelinated axons. 

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Axonal regeneration: the ‘signaling endosome’ model

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.     

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Mast cells and nerve endings in the heart: clinical significance?

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:

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