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In this section English articles are published on neuropathy.

Neuropathic low blood pressure: Droxidopa

Patients suffering from small fibre neuropathy sometimes also suffer from difficult to treat low bloodpressure. In the Orient there is a registered drug for this dindication: L-DOPS (L-threo-dihydroxyphenylserine; Droxidopa; SM-5688). Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Unlike norepinephrine and epinephrine themselves, L-DOPS is capable of crossing the protective blood-brain barrier (BBB).

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Hereditary Sensory Neuropathy: pain and instability

erfelijke-sensibele-neuropathie-hsn.jpgHereditary sensory neuropathy: this patient suffers from neuropathic pain and instability in walking, but does not have other nasty symptoms you sometimes find in HSN type 1, or HSAN. We treated her with our treatment protocol, consisting of amongst others isosorbide dinitrate cream and lidocaine cream, against pain and specific physiotherapy, with focus on condition, muscle strenght and balance. Het QOL improved much and the pain decreased from 8 over 10 to 2 over 10. Her balance improved too.

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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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Burning mouth syndrome (BMS), burning lip and tongue

Burning mouth syndrome (BMS), burning lip and burning tongue. Very unpleasant. Penza and colleagues from the *Neuromuscular Diseases Unit, IRCCS Foundation "Carlo Besta" National Neurological Institute, University of Brescia, in Italy interviewed more than 50 patients and correlated the symptoms with the results of a tongue biopsy.

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Topical low dose clonidine gel to treat Diabetic Neuropathy: phase 2 results

A phase 2b double-blind, randomized, placebo-controlled clinical trial, involving topical gel candidate ARC-4558 for the treatment of painful diabetic neuropathy produced effective results in relieving the pain, according to a press release of the company in july 2010.

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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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Beveiligd: een PEA-houdend product e PeaPure: informazioni palmitoilethanolamide

Er is geen samenvatting, omdat dit een beveiligd bericht is.

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R-flurbiprofen reduces glutamate in neuropathic pain

R-flurbiprofen, an enantiomer of flurbiprofen racemate, is inactive with respect to cyclooxygenase (COX) inhibition, but in vivo it shows analgesic properties. Its mechanism of analgesic action is unknown, but R-flurbiprofen reduced glutamate release in the dorsal horn of the spinal cord evoked in a sciatic nerve injury models of neuropathic pain.

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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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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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Axonal painful neuropathy treated with palmitoylethanolamide and alpha lipoic acid

ciap-lipoic-acid.jpg This patient was diagnosed with axonal painful neuropathy in one of the Dutch academic hospitals. His pain was severe and the neuropathic changes on the EMG moderate to severe. The hospital physicians tried the obvious, amitriptyline and pregabalin, but due to side effects both analgesics had to be stopped. We started a treatment regime with PEA and alpha lipoic acid. The pain decreased more than 50% and the patient was able to return to his work and stand for longer periods of time with much less pain. Furthermore, the slowly deteriorating CIAP did stabilize and furthermore the functionality, as measured by the physiotherapist on different objective tests improved in time! For CIAP this is remarkable, as functionality mostly decreases by time.

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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.


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.



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New insights at world congress on pain, 2012: acute and presistant pains

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.

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Palmitoylethanolamide protects mitochondria against toxic stress

Palmitoyethanolamide (PEA) is a remarkable lipid. In 1973 HANA OBERMAJEROV and colleagues from the Institute of Pharmacology, Czechoslovak Academy of Sciences, published a paper were they discussed a number of experiments, using mitochondria, stressed by different toxins, were they detected a protective effect of PEA.

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