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In this section English articles are published on neuropathy.

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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Focus on Palmitoylethanolamide in IASP journal PAIN

In the recent journal PAIN of the IASP ( number 3 march 2013) an editorial as well as a research paper is devoted to natural moleucles such as palmitoylethanolamide. In the editorial comment, by BK Taylor (N-acylethanolamine acid amidase (NAAA), a new path to unleash PPAR-mediated analgesia) he writes:

Antihyperalgesic effects are produced by endogenously-generated PPAR activators. Of particular importance to pain research are the fatty acid ethanolamides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), both of which bind with high affinity to PPARα.

In neurons, glia, and inflammatory cells, PEA and OEA are not stored, but rather are made on demand – endogenous levels are regulated by the relative activity of biosynthetic and degradative enzymes. Animal studies convincingly demonstrate that PEA exerts a broad spectrum pain inhibition that can be reversed with PPARα antagonists and this inhibition does not occur in deletion mutant mice lacking PPARα. 

Palmitoylethanolamide is approved in some countries  as a dietary supplement in humans, and preliminary but intriguing clinical trials and case studies suggest that oral PEA is effective for a variety of pain syndromes …

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Aldskogius H. Mechanisms and consequences of microglial responses to peripheral axotomy. Front Biosci (Schol Ed). 2011 Jun 1;3:857-68.

Antal A, Terney D, Kühnl S, Paulus W. Anodal transcranial direct current stimulation of the motor cortex ameliorates chronic pain and reduces short intracortical inhibition. J Pain Symptom Manage. 2010 May;39(5):890-903. 

De Alba J, Clayton NM, Collins SD, Colthup P, Chessell I, Knowles RG. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain. 2006 Jan;120(1-2):170-81. Epub 2005 Dec 19.

Anonymous. Drug Class Review: Neuropathic Pain: Final Update 1 Report [Internet].

Attal N, Bouhassira D. Chapter 47 Pain in syringomyelia/bulbia. Handb Clin Neurol. 2006;81:705-13. Schurch B, Wichmann W, Rossier AB. Post-traumatic syringomyelia (cystic myelopathy): a prospective study of 449 patients with spinal cord injury. J Neurol Neurosurg Psychiatry. 1996 Jan;60(1):61-7. 

Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain. 1994 Jan;56(1):51-7.

Barrera-Chacon JM, Mendez-Suarez JL, Jáuregui-Abrisqueta ML, Palazon R, Barbara-Bataller E, García-Obrero I. Oxycodone improves pain control and quality of life in anticonvulsant-pretreated spinal cord-injured patients with neuropathic pain. Spinal Cord. 2011 Jan;49(1):36-42. Epub 2010 Sep 7. 

Benvenuti F, Lattanzi F, De Gori A, Tarli P. [Activity of some derivatives of palmitoylethanolamide on carragenine-induced edema in the rat paw]. Boll Soc Ital Biol Sper. 1968 May 15;44(9):809-13. 

Bettoni I, Comelli F, Rossini C, Granucci F, Giagnoni G, Peri F, Costa B. Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice. Glia. 2008 Sep;56(12):1312-9.

Bishay P, Schmidt H, Marian C, Häussler A, Wijnvoord N, Ziebell S, Metzner J, Koch M, Myrczek T, Bechmann I, Kuner R, Costigan M, Dehghani F, Geisslinger G, Tegeder I. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids. PLoS One. 2010 May 13;5(5):e10628.

Broadley KE, Kurowska A, Tookman A. Ketamine injection used orally. Palliat Med. 1996 Jul;10(3):247-50. 

Bulanova E, Bulfone-Paus S. P2 receptor-mediated signaling in mast cell biology. Purinergic Signal. 2010 Mar;6(1):3-17. Epub 2009 Nov 17. 

Calignano A, La Rana G, Piomelli D. Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol. 2001 May 11;419(2-3):191-8.

Calignano A, La Rana G, Piomelli D. Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol. 2001 May 11;419(2-3):191-8. [116]: Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol. 1996 Apr 11;300(3):227-36. 

Chang YW, Waxman SG. Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury. J Pain. 2010 Nov;11(11):1146-54. Epub 2010 Apr 24.

Chen S, Hui H, Zhang D, Xue Y. The combination of morphine and minocycline may be a good treatment for intractable post-herpetic neuralgia. Med Hypotheses. 2010 Dec;75(6):663-5. Epub 2010 Sep 9.

Chiang CY, Li Z, Dostrovsky JO, Sessle BJ. Central sensitization in medullary dorsal horn involves gap junctions and hemichannels. Neuroreport. 2010 Feb 17;21(3):233-7.

Chu YX, Zhang Y, Zhang YQ, Zhao ZQ. Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses. Brain Behav Immun. 2010 Oct;24(7):1176-89. Epub 2010 Jun 8.

Cho Y, Crichlow GV, Vermeire JJ, Leng L, Du X, Hodsdon ME, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis EJ. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11313-8. Epub 2010 Jun 8.

Cohen SP, DeJesus M. Ketamine patient-controlled analgesia for dysesthetic central pain. Spinal Cord. 2004 Jul;42(7):425-8. 

Colburn RW, Rickman AJ, DeLeo JA. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol. 1999 Jun;157(2):289-304. [104]: Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci. 2006 Mar 29;26(13):3551-60. 

Cvrcek P. Side effects of ketamine in the long-term treatment of neuropathic pain. Pain Med. 2008 Mar;9(2):253-7. 

Defrin R, Grunhaus L, Zamir D, Zeilig G. The effect of a series of repetitive transcranial magnetic stimulations of the motor cortex on central pain after spinal cord injury. Arch Phys Med Rehabil. 2007 Dec;88(12):1574-80. 

Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007 Dec 5;132(3):237-51. Epub 2007 Oct 24.

Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J; IMMPACT. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005 Jan;113(1-2):9-19.

Eijkelkamp N, Heijnen CJ, Willemen HL, Deumens R, Joosten EA, Kleibeuker W, den Hartog IJ, van Velthoven CT, Nijboer C, Nassar MA, Dorn GW 2nd, Wood JN, Kavelaars A. GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. J Neurosci. 2010 Feb 10;30(6):2138-49.

Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-80. 

Falci SP, Indeck C, Lammertse DP. Posttraumatic spinal cord tethering and syringomyelia: surgical treatment and long-term outcome. J Neurosurg Spine. 2009 Oct;11(4):445-60.

Fattal C, Kong-A-Siou D, Gilbert C, Ventura M, Albert T. What is the efficacy of physical therapeutics for treating neuropathic pain in spinal cord injury patients? Ann Phys Rehabil Med. 2009 Mar;52(2):149-66. Epub 2009 Feb 14. 

Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010 Sep;150(3):573-81. 

Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005 Dec 5;118(3):289-305. Epub 2005 Oct 6.

Frech T, Novak K, Revelo MP, Murtaugh M, Markewitz B, Hatton N, Scholand MB, Frech E, Markewitz D, Sawitzke AD. Low-dose naltrexone for pruritus in systemic sclerosis. Int J Rheumatol. 2011;2011:804296. Epub 2011 Sep 12. 

Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, Castro AW, Souza DR, Riberto M, Freedman SD, Nitsche MA, Pascual-Leone A. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain. 2006 May;122(1-2):197-209. Epub 2006 Mar 27. 

Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010 Apr;126(1):56-68. Epub 2010 Feb 1.

Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009 Oct 10;374(9697):1252-61. Epub 2009 Sep 30.  

Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005 Mar 31;352(13):1324-34.

Giner-Pascual M, Alcanyis-Alberola M, Querol F, Salinas-Huertas S, García-Massó X, Gonzalez LM. Transdermal nitroglycerine treatment of shoulder tendinopathies in patients with spinal cord injuries. Spinal Cord. 2011 Sep;49(9):1014-9. doi: 10.1038/sc.2011.41. Epub 2011 May 3. 

Graeber MB. Changing face of microglia. Science. 2010 Nov 5;330(6005):783-8. 

Gautschi OP, Seule MA, Cadosch D, Gores M, Ewelt C, Hildebrandt G, Heilbronner R. Health-related quality of life following spinal cordectomy for syringomyelia. Acta Neurochir (Wien). 2011 Mar;153(3):575-9. Epub 2010 Nov 16. 

Garcia-Ovejero D, Arevalo-Martin A, Petrosino S, Docagne F, Hagen C, Bisogno T, Watanabe M, Guaza C, Di Marzo V, Molina-Holgado E. The endocannabinoid system is modulated in response to spinal cord injury in rats. Neurobiol Dis. 2009 Jan;33(1):57-71. Epub 2008 Sep 30. 

Guasti L, Richardson D, Jhaveri M, Eldeeb K, Barrett D, Elphick MR, Alexander SP, Kendall D, Michael GJ, Chapman V. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain. Mol Pain. 2009 Jul 1;5:35.

Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008 Aug;12(6):804-13. Epub 2008 Feb 8.

Hatem SM, Attal N, Ducreux D, Gautron M, Parker F, Plaghki L, Bouhassira D. Clinical, functional and structural determinants of central pain in syringomyelia. Brain. 2010 Nov;133(11):3409-22. Epub 2010 Sep 17.

Heutink M, Post MW, Bongers-Janssen HM, Dijkstra CA, Snoek GJ, Spijkerman DC, Lindeman E. The CONECSI trial: Results of a randomized controlled trial of a multidisciplinary cognitive behavioral program for coping with chronic neuropathic pain after spinal cord injury. Pain. 2011 Nov 17. Epub ahead of print 

Hojomat M, Kleven M, Wala EP. Effects of norketamine enantiomers in rodent models of persistent pain. Pharmacol Biochem Behav. 2008 Oct;90(4):676-85. 

Holtman JR Jr, Crooks PA, Johnson-Hardy JK, Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2011 May 1;4(3):379-388. 

Horvath RJ, Romero-Sandoval EA, De Leo JA. Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain. 2010 Sep;150(3):401-13. Epub 2010 Jun 22.

Harvey VL, Dickenson AH. Mechanisms of pain in nonmalignant disease. Curr Opin Support Palliat Care. 2008 Jun;2(2):133-9.

Inceoglu B, Jinks SL, Ulu A, Hegedus CM, Georgi K, Schmelzer KR, Wagner K, Jones PD, Morisseau C, Hammock BD. Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18901-6. Epub 2008 Nov 21.

Inceoglu B, Jinks SL, Schmelzer KR, Waite T, Kim IH, Hammock BD. Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain. Life Sci. 2006 Nov 10;79(24):2311-9. Epub 2006 Aug 2.

Keppel Hesselink, JM (2011) Syringomyelia in Cavalier spaniels treated succesfully with palmitoylethanolamide https://neuropathie.nu/research-development/syringomyelia-in-cavalier-spaniels-treated-succesfully-with-no.html  

Keppel Hesselink, JM (2011a) https://neuropathie.nu/treatment/palmitoylethanolamide-een PEA-houdend product-information-for-mds.html 

Kiefer RT, Rohr P, Ploppa A, Dieterich HJ, Grothusen J, Koffler S, Altemeyer KH, Unertl K, Schwartzman RJ. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Pain Med. 2008 Nov;9(8):1173-201. Epub 2008 Feb 5.

Knowler SP, McFadyen AK, Rusbridge C. Effectiveness of breeding guidelines for reducing the prevalence of syringomyelia. Vet Rec. 2011 Oct 13. [Epub ahead of print] 

Koch M, Kreutz S, Böttger C, Benz A, Maronde E, Ghadban C, Korf HW, Dehghani F. Palmitoylethanolamide protects dentate gyrus granule cells via peroxisome proliferator-activated receptor-alpha. Neurotox Res. 2011 Feb;19(2):330-40. Epub 2010 Mar 11.

Kopsky DJ, Keppel Hesselink JM. Multimodal Stepped Care Approach Involving Topical Analgesics for Severe Intractable Neuropathic Pain in CRPS Type 1: A Case Report. Case Report Med. 2011;2011:319750.

Kopsky DJ, Keppel Hesselink JM. High Doses of Topical Amitriptyline in Neuropathic Pain: Two Cases and Literature Review. Pain Pract. 2011 Jun 16. doi: 10.1111/j.1533-2500.2011.00477.x.  

Kopsky DJ, Keppel Hesselink JM.A new combination cream for the treatment of severe neuropathic pain. J Pain Symptom Manage. 2010 Feb;39(2):e9-e10.  

Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain. 2007 Nov;132(1-2):179-88. Epub 2007 Sep 12. 

Kumru H, Murillo N, Samso JV, Valls-Sole J, Edwards D, Pelayo R, Valero-Cabre A, Tormos JM, Pascual-Leone A. Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury. Neurorehabil Neural Repair. 2010 Jun;24(5):435-41. Epub 2010 Jan 6. 

LaBuda CJ, Koblish M, Tuthill P, Dolle RE, Little PJ. Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain. Eur J Pain. 2006 Aug;10(6):505-12. Epub 2005 Aug 24. [94]: Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011

Lambert DM, Vandevoorde S, Diependaele G, Govaerts SJ, Robert AR. Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice. Epilepsia. 2001 Mar;42(3):321-7.Mar;12(3):370-83.

Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ. The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem. 2002 Mar;9(6):663-74. 

Leung A, Donohue M, Xu R, Lee R, Lefaucheur JP, Khedr EM, Saitoh Y, André-Obadia N, Rollnik J, Wallace M, Chen R. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain. 2009 Dec;10(12):1205-16. Epub 2009 May 23.

Liebregts, R, Kopsky, D, Keppel Hesselink, JM. Topical Amitriptyline in Post-Traumatic Neuropathic Pain. J Pain Symptom Management Vol. 41, No. 4, April 2011: e6-e8 

Luongo L, Palazzo E, Tambaro S, Giordano C, Gatta L, Scafuro MA, Rossi FS, Lazzari P, Pani L, de Novellis V, Malcangio M, Maione S. 1-(2′,4′-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice. Neurobiol Dis. 2010 Jan;37(1):177-85. Epub 2009 Oct 3. 

Mao J, Price DD, Hayes RL, Lu J, Mayer DJ, Frenk H.Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy. Brain Res. 1993 Mar 5;605(1):164-8.

Mattioli TA, Milne B, Cahill CM. Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats. Mol Pain. 2010 Apr 16;6:22. 

Mei XP, Zhou Y, Wang W, Tang J, Wang W, Zhang H, Xu LX, Li YQ. Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain. Neurosignals. 2011;19(1):44-53. Epub 2011 Mar 9.

van Meeteren ME, Baron W, Beermann C, Dijkstra CD, van Tol EA. Polyunsaturated fatty acid supplementation stimulates differentiation of oligodendroglia cells. Dev Neurosci. 2006;28(3):196-208.

Mercadante S, Lodi F, Sapio M, Calligara M, Serretta R. Long-term ketamine subcutaneous continuous infusion in neuropathic cancer pain. J Pain Symptom Manage. 1995 Oct;10(7):564-8. [39]: Persson J, Hasselström J, Wiklund B, Heller A, Svensson JO, Gustafsson LL. The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans. Acta Anaesthesiol Scand. 1998 Aug;42(7):750-8. 

Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD007938.

Mori F, Codecà C, Kusayanagi H, Monteleone F, Buttari F, Fiore S, Bernardi G, Koch G, Centonze D. Effects of anodal transcranial direct current stimulation on chronic neuropathic pain in patients with multiple sclerosis. J Pain. 2010 May;11(5):436-42. Epub 2009 Dec 16. 

Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008 May-Jun;60(3):297-307.

Noordenbos, Willem. Pain: Problems Pertaining to the Transmission of Nerve Impulses Which Give Rise to Pain. Amsterdam: Elsevier, 1959 

Norrbrink C, Lundeberg T. Acupuncture and massage therapy for neuropathic pain following spinal cord injury: an exploratory study. Acupunct Med. 2011 Jun;29(2):108-15. Epub 2011 Apr 6.   

Nikolajsen L, Hansen PO, Jensen TS. Oral ketamine therapy in the treatment of postamputation stump pain. Acta Anaesthesiol Scand. 1997 Mar;41(3):427-9. [43]: Villanueva-Perez VL, Cerdá-Olmedo G, Samper JM, Mínguez A, Monsalve V, Bayona MJ, De Andrés JA. Oral ketamine for the treatment of type I complex regional pain syndrome. Pain Pract. 2007 Mar;7(1):39-43. 

Ohara PT, Vit JP, Bhargava A, Romero M, Sundberg C, Charles AC, Jasmin L.Gliopathic pain: when satellite glial cells go bad. Neuroscientist. 2009 Oct;15(5):450-63.

Paola FA, Arnold M. Acupuncture and spinal cord medicine. J Spinal Cord Med. 2003 Spring;26(1):12-20. 

Prévinaire JG, Nguyen JP, Perrouin-Verbe B, Fattal C. Chronic neuropathic pain in spinal cord injury: efficiency of deep brain and motor cortex stimulation therapies for neuropathic pain in spinal cord injury patients. Ann Phys Rehabil Med. 2009 Mar;52(2):188-93. Epub 2009 Jan 22.  

Persson J, Axelsson G, Hallin RG, Gustafsson LL. Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization. Pain. 1995 Feb;60(2):217-22.

Persson J, Axelsson G, Hallin RG, Gustafsson LL. Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization. Pain. 1995 Feb;60(2):217-22. [37]: Mathisen LC, Skjelbred P, Skoglund LA, Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain. 1995 May;61(2):215-20.

Roh DH, Yoon SY, Seo HS, Kang SY, Han HJ, Beitz AJ, Lee JH. Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats. Exp Neurol. 2010 Jul;224(1):123-32. Epub 2010 Mar 11.

Sabato AF. Idiopathic breakthrough pain: a new hypothesis. Clin Drug Investig. 2010;30 Suppl 2:27-9. doi: 10.2165/1158410-S0-000000000-00000. [99]: O’Callaghan JP, Miller DB. Spinal glia and chronic pain. Metabolism. 2010 Oct;59 Suppl 1:S21-6. [100]: Beggs S, Salter MW. Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0. Curr Opin Neurobiol. 2010 Aug;20(4):474-80.

Saito O, Svensson CI, Buczynski MW, Wegner K, Hua XY, Codeluppi S, Schaloske RH, Deems RA, Dennis EA, Yaksh TL. Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br J Pharmacol. 2010 Aug;160(7):1754-64. [81]: Buchanan MM, Hutchinson M, Watkins LR, Yin H. Toll-like receptor 4 in CNS pathologies. J Neurochem. 2010 Jul;114(1):13-27. Epub 2010 Apr 6.

Sampson SM, Kung S, McAlpine DE, Sandroni P. The use of slow-frequency prefrontal repetitive transcranial magnetic stimulation in refractory neuropathic pain. J ECT. 2011 Mar;27(1):33-7. 

Saulino M. Simultaneous treatment of intractable pain and spasticity: observations of combined intrathecal baclofen-morphine therapy over a 10-year clinical experience. Eur J Phys Rehabil Med. 2011 Apr 28. Epub ahead of print 

Staniland AA, Clark AK, Wodarski R, Sasso O, Maione F, D’Acquisto F, Malcangio M. Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J Neurochem. 2010 Aug;114(4):1143-57. Epub 2010 May 28.

Sweitzer S, De Leo J. Propentofylline: glial modulation, neuroprotection, and alleviation of chronic pain. Handb Exp Pharmacol. 2011;(200):235-50.

Swislocki A, Orth M, Bales M, Weisshaupt J, West C, Edrington J, Cooper B, Saputo L, Islas M, Miaskowski C. A randomized clinical trial of the effectiveness of photon stimulation on pain, sensation, and quality of life in patients with diabetic peripheral neuropathy. J Pain Symptom Manage. 2010 Jan;39(1):88-99. Epub 2009 Nov 5. 

Smith HS, Argoff CE. Pharmacological treatment of diabetic neuropathic pain. Drugs. 2011 Mar 26;71(5):557-89. doi: 10.2165/11588940-000000000-00000.

Tanei T, Kajita Y, Noda H, Takebayashi S, Nakatsubo D, Maesawa S, Wakabayashi T. Efficacy of motor cortex stimulation for intractable central neuropathic pain: comparison of stimulation parameters between post-stroke pain and other central pain. Neurol Med Chir (Tokyo). 2011;51(1):8-14. 

Tanenberg RJ, Irving GA, Risser RC, Ahl J, Robinson MJ, Skljarevski V, Malcolm SK. Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc. 2011 Jul;86(7):615-26.

Tronnier V, Baron R, Birklein F, Eckert S, Harke H, Horstkotte D, Hügler P, Hüppe M, Kniesel B, Maier C, Schütze G, Thoma R, Treede RD, Vadokas V; Arbeitsgruppe zur Erstellung der S3-Leitlinie. Epidural spinal cord stimulation for therapy of chronic pain. Summary of the S3 guidelines . Schmerz. 2011 Sep;25(5):484-92. 

Turk DC, Dworkin RH. What should be the core outcomes in chronic pain clinical trials? Arthritis Res Ther. 2004;6(4):151-4. Epub 2004 Jun 4.

Turk DC, Dworkin RH, McDermott MP, Bellamy N, Burke LB, Chandler JM, Cleeland CS, Cowan P, Dimitrova R, Farrar JT, Hertz S, Heyse JF, Iyengar S, Jadad AR, Jay GW, Jermano JA, Katz NP, Manning DC, Martin S, Max MB, McGrath P, McQuay HJ, Quessy S, Rappaport BA, Revicki DA, Rothman M, Stauffer JW, Svensson O, White RE, Witter J. Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. Pain. 2008 Oct 31;139(3):485-93. Epub 2008 Aug 15.

Walker JM, Krey JF, Chu CJ, Huang SM. Endocannabinoids and related fatty acid derivatives in pain modulation. Chem Phys Lipids. 2002 Dec 31;121(1-2):159-72. 

Wang KC, Wang SJ, Fan LW, Cai Z, Rhodes PG, Tien LT. Interleukin-1 receptor antagonist ameliorates neonatal lipopolysaccharide-induced long-lasting hyperalgesia in the adult rats. Toxicology. 2011 Jan 11;279(1-3):123-9. Epub 2010 Oct 19. [79]: Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011 Mar;12(3):370-83.

Watkins LR, Hutchinson MR, Rice KC, Maier SF. The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009 Nov;30(11):581-91. Epub 2009 Sep 15.

Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005452. Heutink M, Post MW, Wollaars MM, van Asbeck FW. Chronic spinal cord injury pain: pharmacological and non-pharmacological treatments and treatment effectiveness. Disabil Rehabil. 2011;33(5):433-40. Epub 2010 Aug 9.

Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD005451. Drug Class Review: Neuropathic Pain: Final Update 1 Report [Internet]. Chogtu B, Bairy KL, Smitha D, Dhar S, Himabindu P. | Comparison of the efficacy of carbamazepine, gabapentin and lamotrigine for neuropathic pain in rats. Indian J Pharmacol.2011 Sep;43(5):596-8.

Wiffen PJ, Derry S, Moore RA. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006044.

Williams KA, Gonzalez-Fernandez M, Hamzehzadeh S, Wilkinson I, Erdek MA, Plunkett A, Griffith S, Crooks M, Larkin T, Cohen SP. A multi-center analysis evaluating factors associated with spinal cord stimulation outcome in chronic pain patients. Pain Med. 2011 Aug;12(8):1142-53. doi: 10.1111/j.1526-4637.2011.01184.x. Epub 2011 Jul 12. 

Wu A, Green CR, Rupenthal ID, Moalem-Taylor G. Role of gap junctions in chronic pain. J Neurosci Res. 2011 Oct 4. doi: 10.1002/jnr.22764. Epub ahead of print 

Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009 Oct;6(4):713-37.

Rivers JR, Ashton JC. The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies. Cent Nerv Syst Agents Med Chem. 2010 Mar;10(1):47-64.

Teasell RW, Mehta S, Aubut JA, Foulon B, Wolfe DL, Hsieh JT, Townson AF, Short C; Spinal Cord Injury Rehabilitation Evidence Research Team. A systematic review of pharmacologic treatments of pain after spinal cord injury. | Arch Phys Med Rehabil. 2010 May;91(5):816-31.

Saadé NE, Jabbur SJ. Nociceptive behavior in animal models for peripheral neuropathy: spinal and supraspinal mechanisms. Prog Neurobiol. 2008 Sep;86(1):22-47. Epub 2008 Jun 18.

Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007 Nov;10(11):1361-8. [102]: Garrison CJ, Dougherty PM, Kajander KC, Carlton SM. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 1991 Nov 22;565(1):1-7. 

Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA. Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res. 1999 May 22;829(1-2):209-21.

Sigtermans MJ, van Hilten JJ, Bauer MC, Arbous MS, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-11. Epub 2009 Jul 14.

Stemler I. Advocating for the traumatically brain injured child. Chart. 1992 Oct;89(8):6.

Xu B, Zhang WS, Yang JL, Lû N, Deng XM, Xu H, Zhang YQ. Evidence for suppression of spinal glial activation by dexmedetomidine in a rat model of monoarthritis. Clin Exp Pharmacol Physiol. 2010 Oct;37(10):e158-66. doi: 10.1111/j.1440-1681.2010.05426.x.

 Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, Aoyama T, Yamamura Y, Yamada Y, Iga T. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003 Jan;24(1):37-43. 

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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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Occipital Neuralgia Responding to Palmitoylethanolamide

Under the titel ’Occipital Neuralgia Responding to Palmitoylethanolamide’ Rocco Salvatore Calabrò and Placido Bramanti reported a case in ‘Headache’, a female patient affected by occiptal-treatment-refractory-neuralgia that greatly improved after oral intake of palmitoylethanolamide (PEA).

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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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Why do so many drugs fail in phase II?

In the internet there is a big community of specialists involved in drug R&D and at LinkedIn there are quite some interesting discussions related to topics worth while considering. The question which haunts many drug developers is: Why is it that so many drugs flunk after phase II trials? That question is also immensly important for the development of drugs in the field of chronic pain. But it is a generic question. 

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Chronic pancreatitis: neuropathy of intrapancreatic nerves

In chronic pancreatitis (CP) severe back and belly pain with caracteristics of neuropathic pain can be found. In CP there are indications of intra-organ and central neuropathic and neuroplastic alterations.

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Low dose naltrexone for MS: a pilot trial

Presentation FP48-TH-05 of the 19th World Congress of Neurology, titel: "Study of low dose naltrexone modulation of the endocannabinoid system in patients with multiple sclerosis" from the studygroup from Italy (M. Gironi ety al) discussed the use of low dose naltrexone (LDN) in Multiple Sclerosis (MS. They showed that LDN (4 mg/day) administered daily for 6 months in 40 patients with primary progressive (PP) MS (Gironi et al., 2008) was safe, well tolerated and partially efficacious on spasticity. 

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Dalfampridine: old bird poison helps MS patients walking..

In Annels of neurology an editorial on 4-Aminopyridine: New Life For an Old Drug. Fampiridine we called in in the past, it was an old bird poising at one time long ago. I have reviewed clinical data of that old potassium channel inhibitor for symptomatic improvement of MS many years ago, in order to possibly licence it in for a certain pharmaceutical company. You could function a bit better, due to an improvement of impulse conductance of the nerves. At that time, many, many years ago, I felt that the symptomatic improvement was too little and the side effects to troublesome to put development energy into the drug. Since then various pharmaceutical industries must have looked into the files of fampiridine in MS. Now, the FDA approved the drug for walking difficulties in patients suffering from MS.

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Critical illness myopathy (CIM) or critical illness polyneuropathy (CIP): bad sign!

German anesthesiologists and neurologists analysed whether there is an association between the early differentiation ofcritical illness myopathy (CIM) versus critical illness polyneuropathy (CIP) and clinical prognosis. 

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Mutiple Target Analgesia

In Patent literature sometimes great insights can be found about how to proceed in pain treatment, such as in this patent,  and we enclose here the introductrion and a part of the summary. Pain clearly is especially influenced by non-neuronal cells, is the thesis of this patent.

The current theories and treatment options for persistent pain are not satisfactory. The population of patients with chronic pain and disrupted lives grows constantly. According to the American Pain Foundation, there are 75 million Americans who have chronic pain. Pain is the second most common reason for doctor visits. Unless we can understand how pain is generated, we cannot provide a solution. Our understanding of pain has not advanced since the 1965 publication of the gate theory of pain by Canadian psychologist Ronald Meizack and British physiologist Patrick Wall. In their paper titled “Pain Mechanisms: A New Theory,” Melzack and Wall suggested a gating mechanism within the spinal cord that closed in response to normal stimulation of the fast conducting “touch” nerve fibers; but opened when the slow conducting “pain” fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these signals were countered by renewed stimulation of the large fibers.

A recent model, known as Sota Omoigui’s Law, proposes that the origin of all pain is inflammation and the inflammatory response. This model is a dramatic and revolutionary shift from a focus on structural pathology to an understanding of the biochemical origin of Pain.

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Glia modulators for neuropathic pain

Since 1994 when Meller and colleagues for the first time demonstrated that by inhibiting astrocyte functions, neuropathic pain did not emerge, many glia modulators have been explored as new inroads in the treatment of neuropathic pain. Some specifically inhibit cytokines (like Il-18), others enhance anti-inflammatory cytokines, such as Il-10, and again others stabilize mastcell degranulation and are PARR agonists, such as palmitoylethanolamide. Here a summary:

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Pentoxyfilline as a gliamodulator

Pentoxifylline is a xantine derivate and can be given to patients with claudicatio intermittens. Because pentoxifylline inhibits cytokines (molecules that activate inflammation), this drug could be interessing for the treatment of neuropathic, and thus gliopathic pain.

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Palmitoylethanolamide and leucocyte inhibition

Palmitoylethanolamide (PEA) is a lipid amide that occurs in our bodies as well as in many mammalian tissues, and can when administered as a drug, inhibits inflammatory responses via the recent described nuclear receptor, the peroxisome proliferator-activated receptor-alpha (PPAR-alpha).

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Parkinson’s disease and modulation via endocannabinoids

Endocannabinoids are important molecules with a mutitude of actions. Endocannabinoids might play a role in Parkinon’s disease. Now that palmitoylethanolamide, a key endocannabinoid molecule, is available as a supplement, this topic seems quite important to adress. We quote from the hallmark TIPS paper The endocannabinoid system in targeting inflammatory neurodegenerative diseases.

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Ketamin might have glia as target for neuropathic pain

Glia is a new target in the treatment of neuropathic pain. Ketamine might have a mode of action related to glia hyperactivity.

The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. The authors explored the possible effect of ketamine on spinal microglia. They found that  S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia.

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Honorary Consultants Institute Neuropathic Pain

The institute of neuropathic pain closely cooperates with the Ukrainian Association for the Study of Pain, in order to exchange scientific insights and new treatment modalities in the field of neuropathic pain.

In 2010 we welcomed two colleagues from the Ukraine and since 2010

Prof. Igor Romanenko MD, PhD, neurologist, President Ukrainian Association for the Study of Pain,

Dr Volodymyr Romanenko MD, neurologist, Ukrainian Association for the Study of Pain, Secretary
are our honorary external consultants.

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P38 MAP kinase inhibitor, losmapimod, fails in patients with neuropathic pain after injury

The P38 MAP kinase inhibitor, losmapimod, failed to be effective in treating patients in patients with neuropathic pain after nerve injury. GlaxoSmithKline’s losmapimod was tested in  a randomized, double-blind, placebo-controlled, parallel-group trial between September 2009 and July 2010. [1]

Patients were recruited from 20 clinical centres across the European Union. The trial consisted of a screening period lasting up to 3 weeks, a 1-week baseline period, a 4-week double-blind dosing period and a follow-up period of approximately 2 weeks.

The primary efficacy measure was the mean change in average daily pain score from baseline to week 4 of treatment based on the 11-point PI-NRS 

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Neuron-glia crosstalk gets serious: role in pain hypersensitivity

glia_jmkh.gifThis titel of a recent article demonstrates the increasing awareness in the scientific community about the relevence of the once seen as unimportant glia cells and the nervous tissue.  Glia and asterocytes play a very important role in the genesis of neuropathic pain. The word gliopathic pain is recently coined to capture this importance…A low-grade inflammation in the spinal cord and along the pain pathways to thalamus and the parietal cortex is the hallmark of chronic pain states and glia plays the key role!

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