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In this section English articles are published on neuropathy.

The taller, the more change for getting neuropathy

The taller you are, the more change you have to get a neuropathy. It was already known that tall people with cancer, treated with chemotherapy have a higher chance on developing (painful) neuropathy. Now based on epidemiological data we know this is a general issue. It is a bit logical, because the taller you are, the longer your nerves are. And long nerves are more vulnerable. Here the story:

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Cannabis as treatment for intractable abdominal pain syndrome

Treatment resistent abdominal pain, with unknown etiology can sometimes be treated succesfully by Cannabis. It might be that this chronic pain syndrome has something to do with small fiber neuropathy in the innervation network around the gut. But, whatever its etiology, it is merely a hypothesis and very difficult to substantiate. However, having said that, there are patients suffering from for instance diabetic neuropthy, with severe gasterointestinal complaits, and we feel these pains and complaints can be due to small fiber neuropthy. As Cannabis appeared to be a useful drug for treating treatment resistant neuropathic pain, we sometimes prescribe Cannabis to patients suffering from treatment resistent abdominal pain, and we follow the so called ex juvantibus approach. This means we give the patient the befifit of the doubt, that the pain might be caused by an internal neuropathy, and if so, whether the patients responds favourable on a treatment regime withn Cannabis, orally taken.  

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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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Pentoxifylline, tocopherol, and clodronate in radiation-induced lumbosacral polyradiculopathy

Pentoxifylline, tocopherol, and clodronate seem to be effective in radiation-induced lumbosacral polyradiculopathy, as reported by a case study. This is important, although the evidence is weak (case report), as to date there is not one single therapy found to be of use in this late complication of radiation induced polyradiculopathy.

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PEA influences PPAR

One of the recent insights regarding the workingmechanism of PEA (palmitoylethanolamide) is that this molecule influences PPAR-alpha. PPAR-apha is a receptor located in the nucleus of the cel with a long name: peroxisome proliferator-activatedreceptor alpha. PEA is available in its purest form as PeaPure. PeaPure contains PEA only. een PEA-houdend product contains PEA too, but around 60%; Pevliven contains between 60-40% PEA.

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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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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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Metabolism and degradation of palmitoylethanolamide

Metabolism and degradation of palmitoylethanolamide, a short analysis of a special therapeutic enodcannabinoid.

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Evidence based medicine, patient centered medicine and the place of PEA

ebm.jpg Why the supplement PEA ( PeaPure) in chronic painstates? Is Evidence-Based Medicine Patient-Centered and Is Patient-Centered Care Evidence-Based? The patient should be the ultimate judge. Therfore Dr Painless points out that treating patients suffering chronic pain with the non-prescription drug een PEA-houdend product makes sense. Evidence-based medicine is a rather young concept that entered the scientific literature in the early 1990s.

It has basically a positivistic, biomedical perspective. Its focus is on offering clinicians the best available evidence about the most adequate treatment for their patients, considering medicine merely as a cognitive-rational enterprise. In this approach the uniqueness of patients, their individual needs and preferences, and their emotional status are easily neglected as relevant factors in decision-making. 

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Low Doses of Palmitoylethanolamide: a selective GPR55 agonist

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. 

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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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ARC-4558, transdermal clonidine gel for neuropathic pain

ARC-4558 is the code for a transdermal gel in  development for the treatment of neuropathic pain. The gel is being developed by Arcion Therapeutics, Inc. and the company received in february 2010 $8 million to further develop this innovative gel. Arcion is a socalled venture backed clinical biotechnology company, focussing on pain treatment.  

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What sorts of peripheral neuropathies?

There are a great number, probably more than 100 different types of peripheral neuropathy. And all these neuropathies have their specific characteristics, different causes, typical set of symptoms, different patterns of development, and prognosis. Peripheral neuropathies are in general classified on the basis of the nerves that are primarily affected.

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Regional analgesia, nerve block, in painful neuropathy

Until recently, regional anesthesia provided for the patient with a preexisting neuropathy has received scant attention. A review of major reference works dedicated to regional anesthesia spanning 87 years, and more than 4,700 total pages, found only 5 pages wherein the issue of central neuraxial anesthesia or PNB was discussed in the context of neuropathy. 

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iNOS inhibitor KD7040 topical for neuropathic pain

In our clinicl we have good results using a topical cream based on ISDN, isosorbine dinitrate, a NOS inhibitor. The company Kalypsys is currently developing molecules targeting iNOS, a member of the nitric oxide synthase (NOS) family of enzymes.

Nitric oxide (NO) in the skin has been implicated in the pathophysiology of pain and inflammation.The lead molecule in this area of Kalypsys is is KD7040, a potent, topically administered, inhibitor of iNOS.


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ADL-5859 in neuropathic pain

ADL-5859 is a delta agonist for the opiod receptor family, and it might be of use for the treatment of neuropathic pain, by inducing less side effects as the current opioids. The compound is developed by Adolor Corporation (this is alsoi the Originator) and the compound is in phase II.

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KRN 5500 presents phase II: weak efficacy?

KRN 5500  (6-[4-Deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-ß-L-manno-heptopyranosyl]amino-9H-purine) has been tested in a phase II trial and the results were presented on april 20 2010. More details will be presented in May in Athens, during the neuropathic pain congress.

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Patient-oriented evidence that matters (POEM): Lyrica® for AIDS neuropathy

Patient-oriented evidence that matters (POEM), a nice inroad into the relevance of clinical outcome. Not academic research, but answers to specifici patient related questions. POEM is an action from the JAAPA, the Journal of the Emerican Academy of physician assistants, and iot is a free access journal. Under the header POEMS many relevant topics. As an example the article on the relevance of Lyrica in painful neuropathy due to AIDS. The Clinical question: Is pregabalin effective in decreasing pain in patients with HIV-associated peripheral neuropathy?

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Moore with a cold and fishy eye on RCT’s in neuropathic pain


On the international congress of neuropathic pain (NeuPsig) 2010 in Athens professor A. Moore from the Nuffield Department of Anaesthetics, University of Oxford, UK, put a cold and fishy eye on what is really known about the efficacy of drugs in neuropathic pain. In his talk he pointed out: “The great thing about being right is that you don’t have to change your mind so often” And Moore cited in the beginning of his talk Ioannides: “The trouble with evidence based medicine I that most of it is wrong.” (Ioannides PLOS medicine 2005 “Most published research findings are false.”)

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The Relationship Between Peripheral Neuropathy and Diabetic Retinopathy

There is a clear relationship Between Peripheral Neuropathy and Diabetic Retinopathy, both are based on the the same pathogenesis. At the the World Ophthalmology Congress (WOC) 2010, June 7 the following data on the relationship were presented as a poster:

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Natalizumab in chronic inflammatory demyelinating polyneuropathy (CIDP)

Natalizumab, a humanized monoclonal antibody against the 4 integrin did not help in treating a patient suffering from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although experimental evidence in an animal model pointed out that targeting 4 integrins in the inflamed peripheral nervous system may have clinical relevant effects, this was not the case in a patient.

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CIAP and Palmitoylethanolamide (PEA) for neuropathic pain

pea.jpg We present a case of a 90-year old woman, born in 1920, suffering since years from axonal idiopathic neuropathy and neuropathic pain. Pain scored 7-9 on a 11-points Likert scale when I first saw her. Walking increased burining pain to a score of 9, and during resting the score was 7. On the DN-4 scale she scored 6, which is indicative for neuropathic pain. 

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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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Ibudilast, XT101 in neuropathic pain

The glial blocker XT101 demonstrated in the preclinical phase to be able to upregulates IL-10. It is developed by Xalud Therapeutics, Inc. Data on AV411 (ibudilast) has been presented by Paul Rolan, M.D., FRACP, Professor of Pharmacology, University of Adelaide, Australia, at the 10th International Conference on the Mechanisms and Treatment of Neuropathic Pain held in Salt Lake City, Utah, in 2007.

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Rise of a concept: neuropathic pain

Medical terminology seems stable. However, although terms and words seem not to change, the content of the concepts might be quite different in different periods of time. This is exactly the case with the concept ‘neuropathy’. In the nineteeth century for instantce its meaning referred to all diseases of the nervous system, including psychiatric disorders. In order to analyse the emergence of the concept ‘neuropathic pain’, as well as the change in its definitions, we analysed a number of publications since this concept was launched. Related concepts, such as neuralgia, neuritis and neuropathy will be discussed too.

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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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Pharmacologic Treatment of Central Post-Stroke Pain

Pharmacologic Treatment of Central Post-Stroke Pain By:  A. Frese, I.W. Husstedt, E.B. Ringelstein, and S. Evers:  ClinJ Pain 2006;22:252–260: 

Treatment Recommendation for CPSP Based on Evidence Level

Short term pain control:
Lidocaine IV 5 mg/kg over 5 minutes

Propofol IV (Gaba-ergic) 0.3 mg/kg per hour  

Oral treatment:
Drugs of first choice(based on controlled trials):  

amitriptyline(anti-depressant) at least 75 mg per day

lamotrigine(glutamatergic) (at least 200mg per day

Drugs of second choice(based on open studies and experts’ opinion):

Mexiletineupto10 mg/kg per day

Fluvoxamin up to 125mg per day

Gabapentinat least 1200mg per day

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Hacking into chronic painstates with the endocannabinoid palmitoylethanolamide

Palmitoylethanolamide (brandnames een PEA-houdend product and PeaPure) is now registered as a supplement in various European countries and is one of the major existing new non-ionchannel tools to target the glia and the neurons in neuropathic and chronic pain. The availability of this compound leads to this discussion on how to influence chronic pain states with this endocannabinoid.

Chronic pain can disrupt brain function and cause many somatic and psychological problems. When neurons fire too much they may change their connections with other neurons and may even die. Crucial to understanding chronic pain are insights in the function of neuronal networks and the role of the all-invading glia cells. But: ‘Glia are nervous system caretakers whose nurturing can go too far. 

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Neuronal damage leads to increase production palmitoylethanolamide and other endocannabinoids

Neuronal damage as assessed by transection of long-range projections apparently provides a strong time-dependent and area-confined signal for de novo synthesis of various endocannabinoids, presumably to restrict neuronal damage. In an elegant study Sonja Kallendrusch and colleagues pointed out some recent studies demonstrating the neuroprotective properties of endocannabinoids in various models of neuronal lesion in vitro and in vivo. Palmitoylethanolamide, they emphesised, mediates its neuroprotective effects via dual PPAR alpha activation on microglial cells and neurons.

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PeaPure: some differences and similarities

PeaPure: we will discuss some differences and similarities of these three nutraceuticals. Palmitoylethanolamide is the active ingredient in all three. een PEA-houdend product is the Italian branded nutraceutical, available in Italy probably since 2007. een PEA-houdend product was developed since the end of last year, and the name een PEA-houdend product refers to the normalization of mast cell hyperactvity. The brandname een PEA-houdend product has been created in 2005.

een PEA-houdend product is the brand name of the in Italy produced palmitoylethanolamide version, een PEA-houdend product consists of 400 and 200 mg tablets, and PeaPure is a brand introduced in 2012 by the company Russell Science Ltd, produced in the Netherlands.


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