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In this section English articles are published on neuropathy.

New treatment options neuropathic pain urgently needed

More and more randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are published, and it seems there is a surge! Will this help the patient? Some top pain experts analysed one hundred and seventy-four studies, a twothird increase in published randomised, placebo-controlled trials in the last 5 years. What did they find out?

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Low dose naltrexone for neuropathic pain

Low dose naltrexone is popular in the alternative treatment world. It is a bit strange, as this molecule is quite non-alternative. But low dose naltrexone (LDN) is recommended on lay internetsites for a multitude of diseases, from MS to cancer. That always provokes anti-bodies by doctors, but naltrexone indeed has anti-inflammatory properties. It might be an interesting treatment option for  treatment refractory neuropathic pain patients.

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Low dose Intravenous Ketamine in Refractory Neuropathic Pain

Treatment of refractory neuropathic pain is a clinical challenge. However, many new case reports and small clinical trials suggest that the N-methyl-D-aspartic acid (NMDA) receptor antagonists ketamine may be clinically useful in treating cases of neuropathic pain. Here a case report. This case report supports the idea that ketamine can be useful in the reduction of refractory chronic neuropathic pain and that the effect of ketamine can persist for many weeks after treatment.

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Post-stroke shoulder pain and DN4

Classifying post-stroke shoulder pain: Can the DN4 be helpful?  Under this titel the dutch investigators Roosink and collegaues from the Biomedical Signals & Systems, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, The Netherlands analysed the usefulness of the DN 4 scale in post stroke pain. The shoulderpain after a stroke has both neuropathic as well as nociceptive elements combined. 

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Dexpramipexole, and dose-dependent slowing of decline in ALS

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).

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Belief systems in the treatment of neuropathic pain

There are many misconceptions that may hamper the treatment of patients suffering neuropathic pain. These misconceptions are all parts of belief systems. Your belief system is the actual set of precepts from which you live your daily life, those which govern your thoughts, words, and actions. For a doctor these belief system are defining the way he explores medical problems, and how he treats and prescribes. Belief systems have a strong impact on behaviour! 

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Milestone in pain treatment: Leriche’s surgery of pain

"Physical pain is not a simple affair of an impulse, travelling at a fixed rate along a nerve. It is the resultant of a conflict between a stimulus and the whole individual", a quote from the French professor René Leriche, born October 12, 1879, in Roanne at the Loire; he died December 28, 1955. 

In 1938 dr Leriche moved to Paris after he was called on the chair of experimental medicine at the Collège de France, the first surgeon to be named to this the prestigious chair in France. However, he did not operate at those facilities, Leriche operated at the American Hospital at Neuilly. As professor of experimental medicine he was required to gve lectures each year and ‘La chirurgie de la Douleur’, The Surgery of Pain, published in 1939 was the first publication based on these lectures.

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Bladder pain syndrome (BPS) and glia cells

The urothelium, the epithelial lining of the lower urinary tract (LUT), most probably plays an important role in bladder function due to its intercations with bladder nerves, smooth muscle, and cells of the immune systems.

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Gliopathic modulators

Gliopathic pain and gliopathic modulators: Introduction into the field of glia and neuropathic pain

Glia is the new target for treating neuropathic pain. The positive feedback loop between overactive neurons and overstimulated glia and asterocytes create a winding up phenomena. Regular therapy tries to cut this winding up positive feedback loop by inhibiting the fire frequency of the neurons. The glia and asterocytes interprete the neurotransmitters of the neurons as emergency signals, and start pooring out nerve growth factors and all kinds of other molecules. This good intention leads to the further winding up phenomena. Therefore, modulating or inhibiting the nervous activity only is not enough for many patients suffering from neuropathic pain. We need additional gliopathic modulators.

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Selected pharmacology of palmitoylethanolamide

The discovery of our own ‘Cannabis", the molecule anandamide, as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides.  N-palmitoylethanolamine (PEA) is a sistermolecule of anandamide, a shorter and fully saturated analogue, and this molecule has been known since the fifties. In the sixties and seventies much research supported its use as prophylactic treatment for the flu, and the compound was on the market available as Impulsin.

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Angina pectoris pain decreases after palmitoylethanolamide

In our clinic we saw a 79-old lady, with a history of myocardial infarctions, a pacemaker was implanted, and severe artrosis in various joints as well as a knee replacement. She suffered from angina attacks and was treated with a betablocker and nitroglycerin under the tongue. She came under our care due to severe pain based on a herniated disk at two levels, L4/L5 and L5/S1. We prescribed palmitoylethanolamide 600 mg bid. On the sciatic pain the efects were very modest, but since the beginning of palmitoylethanolamide, now 7 weeks ago, no attacks of angina were seen. She explicitely asked us whether the attacks vanished due to palmitoylethanolamide. The attacks before our treatment were quite frequent, couple of times each week. Due to the fact that mast cells have been found in the coronary system and around nerve endings this by accident therapeutic effect might be a result of the pharmacological action of palmitoylethanolamide on the mast cells.

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Palmitoylethanolamide (PEA): information for MD’s

pea.jpeg

Palmitoylethanolamide (‘PEA’) is a endogenous compound and is in Europe available for the treatment of chronic pain and chronic inflammation. Most clinical data have been gathered and published around its efficacy in various neuropathic painstates, such as in diabetes, carpal tunnel syndrome, sciatic pain, and we outline these indications and the clinical and preclinical data below. 

Under the follow link an extensive review for specialists can be downloaded. The article appeared in The Open Pain Journal (2012) 

Palmitoylethanolamide has be described as an endogenous fatty acid amide, belonging to the class of lipid signaling molecules (autocoids). Since 50 years of research around this molecule, the last decade the number of scientific papers on PEA’s biological and clinical activity has been expanded to nearly 400.

PEA has been demonstrated to bind to a receptor in the cell-nucleus (a nuclear receptor, PPAR), a number of other receptors, and therefore it exerts a great varity of biological functions related to chronic pain and inflammation. It is considered as a breakthourgh in the treament of chonic pain, and with PEA a new mechanism of action in the world of analgesics has been introduced and validated in a great number of studies.

PEA can be seen as a glia modulator and proof of principle (POP) as well as proof of concept (POC) has been generated via PEA studies of glia as an important factor in the genesis of neuropathic pain.

Brandnames of drugs containing PEA 

PEA is available under various brandnames: een PEA-houdend product and een PEA-houdend product in Italy and Spain, and as PeaPure (JP Russell Science Ltd) for the rest or the world. PeaPure is available in Europe as a food supplement. 

In een PEA-houdend product and the active ingredient is palmitoylethanolamide. In een PEA-houdend product and een PEA-houdend product excipients like magnesium stearate, povidone and polisorbate are added. In the een PEA-houdend product sachets a sweetener has been added, sorbitol.

In PeaPure the sole content is palmitoylethanolamide (no excipients). 

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Combination PEA and creme

A patient from Australia asked us to support her physician in treating her neuropathic pain She wrote the following letter after a few months:

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Interstitial cystitis, the role of the mast cell and treatment with palmitoylethanolamide (PEA)

Non-infectious cystitis can be due to a variety of causes, such as medication, radiation, foreign bodies, autoimmune response, and but cases of non-infectious cystitis end as being idiopathic in nature; we call this interstitial cystitis (IC). IC is a pain-syndrome characterized by urinary bladder pain and irritative voiding symptoms of more than 6 months duration. The European Society for the study of Interstitial Cystitis (ESSIC) proposed a diffirent name for IC, ‘bladder pain syndrome’ (BPS). Pelvic pain syndrome is also sometimes used. IC is characterized by infiltration of mast cells and other inflammatory white blood cells, and due to mast cell activation a chronic inflammatory cascade developes, leading to irreversible tissue destruction, dysfunctional pathology such as fibrosis and due to enhanced tissue levels of NGF detrusor overactivity, and hyperalgesia. All the symptoms, voiding problems and pain are characterized by chronic waxing and waning of these symptoms and sadly enough sometimes to generalization the local painsyndrome into a pelvic painsyndrome, or even to irritable bowel disorder or fibromyalgia. Fibromyalgia, irritable bowel syndrome (IBS; 35% cases) and vulvodynia (vulvodynia in 20–51.4% of patients) are often seen hand in hand with IC. Central in the pathogenesis of IC is the mast cell.  The central role of inflammation  and the mast cell have been confirmed in both human as well as in animal models.

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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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Extended release oxymorphone may help treating chronic neuropathic pain

Extended release oxymorphone may help treating chronic neuropathic pain due to a small pilot trial published during a congress.

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AL-309: Efficacy in animal models of neuropathy and neuropathic pain

AL-309: Efficacy in animal models of neuropathy and neuropathic pain. According to a press release of the company, and we quote:

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Bupropion for the treatment of neuropathic pain.

Bupropion for the treatment of neuropathic pain. A short review.

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Syringomyelia, pain and its treatment

syringomyelia.jpg Although pain is a prominent symptom in patients suffering from syringomyelia, and this central neuropathic pain is very difficult to treat. However, more than half of all patients with syringomyelia suffer from symptoms related to central neuropathic pain. In the video you can see one of our patients, suffering from syringomyelia telling his story and reporting the effect of our treatment of the neuropathic pain:

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Flupirtine from CNSBio in neuropathic pain

Flupirtine from CNSBio is in phase I for the development in neuropathic pain. However, flupirtine is an old molecule, aminopyridine. It has been used as an analgesic in the past and is still on the market in various countries.

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Physiotherapy for polyneuropathy

keppel_hesselink_polyneuropathy_physiotherapy.jpg We use physiotherapy and physiofitness as a part of an integrative medicine treatment concept to treat neuropathy or polyneuropathy including HMSN such as the disease of Charcot Marie Tooth: training on muscular strenght, compensation, stability and balance as well as condition in general. In this field we speak of Neurological Physiotherapy, and this can be of important help individuals with neuropathies. Physiotherapy treatment will control your symptoms improving your quality of life.  A Physiotherapy treatment program may involve:A structured exercise program increasing muscle strength and endurance. Advice on hand and foot orthotics to help with muscle weakness and pain. Active and passive movement to reduce muscle cramps, improve muscle and prevent muscle wasting.Improving stability, gait and coordination.

A presentation by the director R&D for the institute for the treatment of neuropathy and neuropathic pain in the Netherlands, Jan M. Keppel Hesselink, MD, PhD. www.neuropathy.nl 

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Melatonin: protective in chemotherapy for neuropathy?

Melatonin demonstrated neuroprotective effects in a variety of animal studies and has been suggested to decrease adverse reactions of chemotherapy including neuropathy. In a pilot trial melatonin, 21 mg before sleep, given during taxane chemotherapy for breast cancer, decreased the incidence and severity of neuropathy.

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Clinical relevant and electrophysiological effect of Palmitoylethanolamide

At the Third International Congress on Neuropathic Pain, Athens, Greece, May 27 – 30, 2010 A. Biasiotta, S. et al presented a poster which demonstrated a clinical relevant and electrophysiological measurable effect from a rather unknown compound, in some European countries registered as food for medical purposes, a body own molecule, palmitoylethanolamide (PEA, een PEA-houdend product© or PeaPure©).

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Nitrates in neuropathic pain

The Indian group of Agrawal and collegues (2007) explored the analgesic effects of glyceryl trinitrate spray in neuropathic pain. They suggested that impaired nitric oxide (NO) synthesis may play an important role in the pathogenesis of painful diabetic neuropathy. Some studies demonstrated impaired neuronal nitric oxide generation in diabetic rats induces hyperalgesia and in other studies a decreased nitric oxide production was seen to to a reduction in endoneural blood flow in type 2 diabetic patients with neuropathy. Both iso-sorbide dinitrate as well as glyceryl trinitrate may act as potent nitric oxide donor and have similar pharmacological activity compared to endothelial derived relaxing factor, a nitric oxide dependent enzyme with vasodilator capacity. In our institute we have now gathered quite some experience using isosorbide dinitrate cream in neuropathic pain, with good results.

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Glia Acitivation Inhibitors in neuropathic pain

Glial activation inhibitors have become hot once the neurological cimmunity understood that neurons are not solely responsable for neuropathic pain. Meanwhile it has been widely recognized that glia and asterocytes play an important role in the upregulation of neuropathic pain (winding up). These non neural cells release neuroexcitatory, pain-enhancing substances such as pro-inflammatory cytokines, and these cytokines dysregulate the actions of our own endogenious opioids.

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Bias in preclinical pharmacology: the abstract deceives!

Preclinical researchers do not fully understand clinical studies and clinicans fail to grasp preclinical work. One of the reasons is the mistake many of us make in reading scientific papers. We start screening the abstract in Pubmed and jump to conclusions, sometimes or most of the time without reading the full paper. This happens frequently and will be demonstrated by an recent example, the publication of a key paper on pain treatment using opioids together with an opioid antagonist in the peer reviewed journal Molecular Pain.

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Palmitoylethanolamide protects against side-effects anticancer drugs

Kahler’s disease is cancer of certain white blood cells, the plasma cells, and leads to death, mostly within 3-4 years. It is the second most frequent occuring forms of blood cancer, after non-Hodgkin’s disease. Initially patients can respond to chemotherapy, but treatment resistance often occurs. Furthermore, side effects such as nerve pain and nerve disfunctions (painful neuropathy) are dose limiting and thus optimal treatment of patients is not possible, as the chemotherapy needs to be stopped or reduced. Therfore patients cannot finish the course of chemotherapy and run a higher risk of relapse or recurrence of their cancer. Since years science searches for compounds to protect the nerve function, in order to enable patients suffering from MM to proceed being treated with chemotherapy.

Therefore it is highly important to point out that recently a natural occuring compound palmitoylethanolamide (PEA) has been identified in a clinical trial in MM patients, which indeed counteracts the side-effects of chemotherapy in blood cancer and restores nerve functions.

Italian neurologists from the neurological department of professor Cruccu, of the university of Rome, assessed the effect of PEA on pain and nerve function in patients with chemotherapy-induced painful neuropathy. 

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Carpal tunnel syndrome treated with PEA

median_nerve_in_ct.gifCarpal Tunnel Syndrome (CTS) is the most common compression neuropathy. It is the reason for pain and functional impairment. On the picture we see in yellow the median nerve, being compressed under a ligament in the wrist. This gives rise to chronic pain. Pain normally can be reduced with oral neuropathic analgesics. However, the side effects of most of the NSAIDS limit its use.  

Palmitoylethanolamide (PEA), a fatty acid occuring naturally in our body, has also neuropathic pain reducing properties. Furthermore, it stabilizes mast cells, present in the carpal tunnel. Besides the pain reducing effect, PEA has also neuroprotective properties. To evaluate the clinical effects of PEA in CTS, Italian researchers randomised 28 diabetic patients with CTS, in two groups: one group received PEA twice daily 600mg and the other group received placebo.

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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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Palmitoylethanolamide analogue, palmitoylallylamide (L-29) in a pain model

Cannabis and the endogenous cannabinoids are associated with analgesia in acute and chronic pain states. The analgesic effect of the palmitoylethanolamide (PEA) has ben described in many different animal models, and meanhile also in a number of clinical trials. This has prompted to look for analogues of PEA. Palmitoylallylamide (L-29) is such a analogue.

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