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    You are here : Home » MS Research News » Pain Research

    Pain Research

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    Central neuropathic pain in a patient with MS treated successfully with topical Amitriptyline

    Neuropathic PainAbstract

    Central neuropathic pain in patients with multiple sclerosis (MS) is a common debilitating symptom, which is mostly treated with tricyclic antidepressants or antiepileptics.

    Unfortunately, the use of these drugs is often limited due to adverse events.

    We investigated the analgesic effect of topical amitriptyline 5% and 10% cream in a patient with central neuropathic pain due to MS.

    The analgesic effect of topical amitriptyline cream on neuropathic pain was dose related.

    To evaluate whether this analgesic effect is due to the active compound or placebo, we conducted a double-blind placebo-controlled n-of-1 study with amitriptyline 5% cream and placebo.

    The instruction was to alternate the creams every week following the pattern ABAB, with an escape possibility of amitriptyline 10% cream.

    The result was a complete pain reduction after application of cream B, while most of the time cream A did not reduce the pain.

    The patient could correctly unblind both creams, determining B as active. She noted that in the week of using the active cream no allodynia was present, with a carryover effect of one day.

    1. Introduction

    Central neuropathic pain in patients with multiple sclerosis (MS) is a common debilitating symptom, which is mostly treated with tricyclic antidepressants or antiepileptics [1]. Unfortunately, the use of these oral drugs may be limited due to accompanying adverse events, such as drowsiness, constipation, and/or urinary retention. Caution is advised with the use of these drugs, because constipation and urinary retention are common problems in MS patients [2, 3]. Topical antidepressants might reduce these dose-limiting adverse events, while still offering adequate analgesia [4, 5].

    We describe here a double blind placebo controlled n-of-1 study in a patient with MS suffering from severe central neuropathic pain, which was effectively treated with topical amitriptyline cream without any lasting dose-limiting adverse events.

    2. Case Report

    A 62-year old woman with 14 years of primary progressive MS has been wheelchair-bound for eight years and suffered from severe neuropathic pain in the upper arms and in the left foot. The pain was characterized by pricking, tingling, numbness, and sometimes electric shocks. The average pain score, 8 on the 11-point numerical rating scale (NRS), was reduced to 6 after the usage of oral pregabalin 450 mg daily.

    On previously prescribed oral amitriptyline 40 mg daily she experienced intolerable adverse events, such as continuous drowsiness and tiredness. Her other complaints, such as urine retention, constipation, and spasms were successfully treated with solifenacin, polyethylene glycol, and baclofen, respectively. In May 2010, while on pregabalin treatment, the patient developed a severe burning pain in her left foot, scoring 9 on NRS. The patient also experienced electric shocks and could not bear the contact with bed sheets (allodynia).

    We prescribed topical amitriptyline 5% cream to apply 3 mL once daily to the painful foot. Thirty minutes after application the patient did not experience allodynia anymore. However, when the initial pain score was higher than 5 on NRS, the burning pain was only partially reduced. Therefore, we prescribed amitriptyline 10% cream, which relieved the burning pain completely (from 9 to 0 on the NRS) already 10 minutes after each application. The relief lasted the entire day. The patient reported tiredness, as the only adverse event of the topical amitriptyline 10% cream, but even this symptom disappeared in two weeks.

    In order to determine whether pain alleviation was due to topical or to systemic effect, we suggested distant application. After application to the nonpainful foot, analgesia could also be observed in the painful foot, although 15 minutes later. Due to her physical impairments the patient was not able to apply the topical amitriptyline to her painful foot. Therefore, we advised her to apply topical amitriptyline cream to her inner forearms, which turned out to have the same effect as direct application to the nonpainful foot. Also the pricking and tingling neuropathic pain in her upper arms and her left leg responded to the topical amitriptyline 5% cream, though only partially. Then however, direct application of amitriptyline 5% cream, once a day on her upper arms and her left foots reduced this pricking and tingling pain from 8 to 0 on NRS during the second day.

    To further inquire into the magnitude of the placebo response, we designed a double blind placebo controlled crossover n-of-1 study, comparing topical placebo cream to amitriptyline 5%. The compounding pharmacist blinded the two creams in two separate tubes, and named the creams A and B, respectively. Successful treatment was defined based on the following criteria:
    (1) relevant clinical pain reduction measured on NRS,
    (2) successfully unblinding the treatment,
    (3) no or minimal need to use escape medication.

    The instruction was to apply once daily 3 mL cream to the arm from one tube during one week, with an escape possibility of amitriptyline 10%, and to alternate the tubes every week following the pattern ABAB. The result was that the pain disappeared after application of cream B, while most of the time cream A did not reduce the pain. The patient could correctly unblind both creams, determining B as active. She noted that in the week of using the active cream no allodynia was present, with a carryover effect of one day. She did not need to use the escape medication in the week of using the active cream, though she used frequently escape medication in the placebo weeks, especially when the pain scores were above 4 on NRS. As a matter of fact, the patient could correctly identify the active cream as 5%, based on her previous experiences with both 5% and 10% creams. Furthermore, the patient did not experience any adverse events.

    3. Discussion

    To our knowledge this is the first report of treating central neuropathic pain due to MS with topical amitriptyline cream. This double blind placebo controlled n-of-1 experiment demonstrates that most of the pain reduction could be attributed to the active compound. The use of amitriptyline 5% and amitriptyline 10% cream as escape medication was chosen, because of the profound pain reducing effect in former observations [6, 7]. The fact that the burning pain disappeared after distant application suggests a systemic effect. Despite that pregabalin 450 mg daily reduced the pricking and tingling pain, severe burning pain with allodynia developed. In contrast, a complete reduction of this burning neuropathic pain with allodynia was achieved after adding topical amitriptyline. This observation might suggest that distinct characteristics of the central neuropathic pain respond differently to different types of analgesics, supported by sparse research [8, 9]. Systematic clinical examination and research will clarify this issue in the future.

    Also a local analgesic effect might play a role, because the already existing neuropathic pain in arms and left leg (mainly pricking and tingling) vanished completely only after local application. Due to the refractory and chronic character of this pain, placebo effect is less likely to contribute considerably in the positive effect. The reduction of ectopic pulses from nociceptors could be the explanation of the complete disappearance after topical amitriptyline [10]. Degeneration of some spinothalamic tract neurons can trigger pathological activity in neighboring intact afferents through the release of inflammatory mediators and neurotrophic factors. In addition, also the loss of intraspinal and descending inhibitory pathways elicits neuronal hyperexcitability [11]. Moreover, the degeneration of myelinated efferent fibers could induce spontaneous activity in uninjured C-fiber afferents [12]. To clarify which part of the analgesic response can be attributed to either systemic or local effect, in future studies serum levels of amitriptyline should be measured.

    Due to controlled release characteristics of the amitriptyline cream, persistent peak-dose adverse events were absent.

    Only a few case reports are available on topical analgesics in central neuropathic pain, describing the use of lidocaine 5% patches; menthol cream, and the combination cream of capsaicin 0.075%, lidocaine 3%, and isosorbide dinitrate 0.4% [13–16]. In peripheral neuropathic pain topical amitriptyline, sometimes combined with ketamine, is evaluated with mixed results, probably due to the insufficient concentration and/or a suboptimal vehicle [17, 18].

    Our paper suggests a systemic as well as a local analgesic effect of topical amitriptyline cream. More research is urgently needed for this interesting therapeutic option in the treatment of central neuropathic pain.


    C. Solaro and M. Messmer Uccelli, “Pharmacological management of pain in patients with multiple sclerosis,” Drugs, vol. 70, no. 10, pp. 1245–1254, 2010.

    A. Manack, S. P. Motsko, C. Haag-Molkenteller et al., “Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database,” Neurourology and Urodynamics, vol. 30, no. 3, pp. 395–401, 2011.

    C. Norton and S. Chelvanayagam, “Bowel problems and coping strategies in people with multiple sclerosis,” British Journal of Nursing, vol. 19, no. 4, pp. 220–226, 2010.

    D. Strumper and M. E. Durieux, “Antidepressant as long-acting local anesthetics,” Regional Anesthesia and Pain Medicine, vol. 29, no. 3, pp. 277–285, 2004.

    P. Gerner, G. Kao, V. Srinivasa, S. Narang, and G. K. Wang, “Topical amitriptyline in healthy volunteers,” Regional Anesthesia and Pain Medicine, vol. 28, no. 4, pp. 289–293, 2003.

    D. J. Kopsky and J. M. Keppel Hesselink, “High doses of topical amitriptyline in neuropathic pain: two cases and literature review,” Pain Practice, vol. 12, no. 2, pp. 148–153, 2012.

    R. Liebregts, D. J. Kopsky, and J. M. Keppel Hesselink, “Topical amitriptyline in post-traumatic neuropathic pain.,” J Pain Symptom Manage, vol. 41, pp. 6–7, 2011.

    I. Decosterd, A. Allchorne, and C. J. Woolf, “Differential analgesic sensitivity of two distinct neuropathic pain models,” Anesthesia and Analgesia, vol. 99, no. 2, pp. 457–463, 2004.

    M. J. Field, S. McCleary, J. Hughes, and L. Singh, “Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat,” Pain, vol. 80, no. 1-2, pp. 391–398, 1999.

    O. A. de Leon-Casasola, “Multimodal approaches to the management of neuropathic pain: the role of topical analgesia,” Journal of Pain and Symptom Management, vol. 33, no. 3, pp. 356–364, 2007.

    G. Wasner, B. B. Lee, S. Engel, and E. McLachlan, “Residual spinothalamic tract pathways predict development of central pain after spinal cord injury,” Brain, vol. 131, no. 9, pp. 2387–2400, 2008.

    G. Wu, M. Ringkamp, B. B. Murinson et al., “Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents,” Journal of Neuroscience, vol. 22, no. 17, pp. 7746–7753, 2002.

    G. Wasner, D. Naleschinski, and R. Baron, “A role for peripheral afferents in the pathophysiology and treatment of at-level neuropathic pain in spinal cord injury? A case report,” Pain, vol. 131, no. 1-2, pp. 219–225, 2007.

    G. H. Hans, D. N. Robert, and K. N. Van Maldeghem, “Treatment of an acute severe central neuropathic pain syndrome by topical application of lidocaine 5% patch: a case report,” Spinal Cord, vol. 46, no. 4, pp. 311–313, 2008.

    G. Wasner, D. Naleschinski, A. Binder, J. Schattschneider, E. M. Mclachlan, and R. Baron, “The effect of menthol on cold allodynia in patients with neuropathic pain,” Pain Medicine, vol. 9, no. 3, pp. 354–358, 2008. View at Publisher · View at Google Scholar ·

    D. J. Kopsky, G. J. Amelink, and J. M. Keppel Hesselink, “Intractable neuropathic pain in spinal intramedullary cavernoma treated successfully with a novel combination cream,” Pain Medicine (United States), vol. 13, no. 5, pp. 729–730, 2012.

    D. Everton, D. Bhagwat, and M. Damask, “A multicenter, double-blind, randomized, placebo controlled study of the efficacy/safety of two doses of amitriptyline/ketamine topical cream in treating post-herpetic neuralgia (PHN),” The Journal of Pain, vol. 8, no. 4, supplement, p. S47, 2007.

    K. Y. Ho, B. K. Huh, W. D. White, C. C. Yeh, and E. J. Miller, “Topical amitriptyline versus lidocaine in the treatment of neuropathic pain,” Clinical Journal of Pain, vol. 24, no. 1, pp. 51–55, 2008.

    Source: Hindawi Copyright © 2012 David J. Kopsky et al. (19/07/12)

    Easing neuropathic pain for millions of sufferers

    Neuropathic PainNeuropathic pain, caused by nerve or tissue damage, is the culprit behind many cases of chronic pain. It can be the result of an accident or caused by a variety of medical conditions and diseases such as tumors, Multiple Sclerosis, and diabetes. Typically resistant to common types of pain management including ibuprofen and even morphine, neuropathic pain can lead to lifelong disability for many sufferers.

    Now a drug developed by Tel Aviv University researchers, known as BL-7050, is offering new hope to patients with neuropathic pain. Developed by Prof. Bernard Attali and Dr. Asher Peretz of TAU's Department of Physiology and Pharmacology at the Sackler Faculty of Medicine, the medication inhibits the transmission of pain signals throughout the body. In both in-vitro and in-vivo experiments measuring electrical activity of neurons, the compound has been shown to prevent the hyper-excitability of neurons - protecting not only against neuropathic pain, but epileptic seizures as well.

    The medication has been licensed by Ramot, TAU's technology transfer company, for development and commercialisation by BioLineRx, an Israeli biopharmaceutical development company.

    Targeting potassium for pain control

    According to Prof. Attali, the medication works by targeting a group of proteins which act as a channel for potassium. Potassium has a crucial role in the excitability of cells, specifically those in the nervous system and the heart. When potassium channels don't function properly, cells are prone to hyper-excitability, leading to neurological and cardiovascular disorders such as epilepsy and arrhythmias. These are also the channels that convey pain signals caused by nerve or tissue damage, known as neuropathic pain.

    With few treatment options available for neuropathic pain, Prof. Attali set out to develop a medication that could bind to and stabilize the body's potassium channels, controlling their hyper-excitability and preventing the occurrence of pain by keeping the channels open for the outflow of potassium. This novel targeting approach has been recently reported in the journal PNAS.

    Inducing calm in the neurons

    Understanding the mechanism that controls these channels has been crucial to the development of the drug. By successfully controlling the excitability of the neurons, Prof. Attali believes that BL-7050 could bring relief to hundreds of millions of patients around the world who suffer from neuropathic pain. The medication will reach the first phase of clinical trials in the near future.

    In pre-clinical trials, BL-7050 was tested in rats experiencing both epilepsy and neuropathic pain and was found to be efficient in protecting against both when taken as a pill. While on the medication, rats were no longer affected by stimuli that had previously caused pain. Measures in the electrical activities of neurons also revealed that the medication was able to induce "calm" in the neurons, inhibiting pain pathways.

    Source: Medical News Today MediLexicon International Ltd © 2004-2012 (03/05/12)

    Study shows why some pain drugs become less effective over time

    MS PainResearchers at the University of Montreal's Sainte-Justine Hospital have identified how neural cells like those in our bodies are able to build up resistance to opioid pain drugs within hours.

    Humans have known about the usefulness of opioids, which are often harvested from poppy plants, for centuries, but we have very little insight into how they lose their effectiveness in the hours, days and weeks following the first dose.

    "Our study revealed cellular and molecular mechanisms within our bodies that enables us to develop resistance to this medication, or what scientists call drug tolerance," lead author Dr. Graciela Pineyro explained. "A better understanding of these mechanisms will enable us to design drugs that avoid tolerance and produce longer therapeutic responses."

    The research team looked at how drug molecules would interact with molecules called "receptors" that exist in every cell in our body. Receptors, as the name would suggest, receive "signals" from the chemicals that they come into contact with, and the signals then cause the various cells to react in different ways. They sit on the cell wall, and wait for corresponding chemicals known as receptor ligands to interact with them.

    "Until now, scientists have believed that ligands acted as 'on- off' switches for these receptors, all of them producing the same kind of effect with variations in the magnitude of the response they elicit," Pineyro explained. "We now know that drugs that activate the same receptor do not always produce the same kind of effects in the body, as receptors do not always recognise drugs in the same way. Receptors will configure different drugs into specific signals that will have different effects on the body."

    Pineyro is attempting to tease the "painkilling" function of opioids from the part that triggers mechanisms that enable tolerance to build up. "My laboratory and my work are mostly structured around rational drug design, and trying to define how drugs produce their desired and non desired effects, so as to avoid the second", Pineyro said. "If we can understand the chemical mechanisms by which drugs produce therapeutic and undesired side effects, we will be able to design better drugs."

    Once activated by a drug, receptors move from the surface of the cell to its interior, and once they have completed this 'journey', they can either be destroyed or return to the surface and used again through a process known as "receptor recycling." By comparing two types of opioids – DPDPE and SNC-80 – the researchers found that the ligands that encouraged recycling produced less analgesic tolerance than those that didn't.

    "We propose that the development of opioid ligands that favour recycling could be away of producing longer-acting opioid analgesics," Pineyro said.

    More information: The study "Differential association of receptor-Gβγ complexes with β-arrestin2 determines recycling bias and potential for tolerance of delta opioid receptor (DOR) agonists" was published in The Journal of Neuroscience on April 3, 2012.

    Source: Medical Xpress © Medical Xpress 2011-2012 (05/04/12)

    Scientists provide new understanding of chronic pain

    Neuropathic PainMillions of people worldwide suffer from a type of chronic pain called neuropathic pain, which is triggered by nerve damage. Precisely how this pain persists has been a mystery, and current treatments are largely ineffective.

    But a team led by scientists from The Scripps Research Institute, using a new approach known as metabolomics, has now discovered a major clue: dimethylsphingosine (DMS), a small-molecule byproduct of cellular membranes in the nervous system.

    In their new study, the scientists found that DMS is produced at abnormally high levels in the spinal cords of rats with neuropathic pain and appears to cause pain when injected. The findings suggest inhibiting this molecule may be a fruitful target for drug development.

    "We think that this is a big step forward in understanding and treating neuropathic pain, and also a solid demonstration of the power of metabolomics," said Gary J. Patti, a research associate at Scripps Research during the study, and now an assistant professor of genetics, chemistry, and medicine at Washington University in St. Louis. Patti is a lead author of the report on the study, which appeared online in the journal Nature Chemical Biology on January 22, 2012.

    Scientists who want to understand what makes diseased cells different from healthy cells have often looked for differences in levels of gene expression or cellular proteins - approaches known respectively as genomics and proteomics. Metabolomics, by contrast, concerns differences in the levels of small-molecule metabolites, such as sugars, vitamins, and amino acids, that serve as the building blocks of basic cellular processes. "These are the molecules that are actually being transformed during cellular activity, and tracking them provides more direct information on what's happening at a biochemical level," Patti said.

    Metabolomics is increasingly used to find biochemical markers or signatures of diseases. One of the most relied-upon "metabolome" databases, METLIN, was set up at Scripps Research in 2005, and now contains data on thousands of metabolites found in humans and other organisms. However, in this case the research team hoped to do more than find a metabolic marker of neuropathic pain.

    "The idea was to apply metabolomic analysis to understand the biochemical basis of the neuropathic pain condition and reveal potential therapeutic targets," said Gary Siuzdak, a senior investigator in the study, who is professor of chemistry and molecular biology and director of the Scripps Research Center for Metabolomics. "We call this approach 'therapeutic metabolomics'."

    The scientists began with a standard model of neuropathic pain in lab rats. Patti, Siuzdak, and their colleagues sampled segments of a previously injured tibial leg nerve triggering neuropathic pain, as well as the rats' blood plasma and tissue from the rats' spinal cords. The scientists then determined the levels of metabolites in these tissues, and compared them to levels from control animals.

    Unexpectedly, the scientists found that nearly all the major abnormalities in metabolite levels were present not in the injured leg nerve fibre, nor in blood plasma, but in tissue from the "dorsal horn" region of the spinal cord which normally receives signals from the tibial nerve and relays them to the brain. "After the nerve is damaged, it degrades and rebuilds itself at the site of the injury, but remodeling also occurs, possibly over a longer period, at the terminus of the nerve where it connects to dorsal horn neurons," Patti said.

    Next, the researchers set up a test to see which of the abnormally altered metabolites in dorsal horn tissue could evoke signs of pain signaling in cultures of rat spinal cord tissue. One metabolite stood out - a small molecule that didn't appear in any of the metabolome databases. Patti eventually determined that the molecule was DMS, an apparent byproduct of cellular reactions involving sphingomyelin, a major building block for the insulating sheaths of nerve fibers. "This is the first characterization and quantitation of DMS as a naturally occurring compound," Patti noted. When the scientists injected it into healthy rats, at a dose similar to that found in the nerve-injured rats, it induced pain.

    DMS seems to cause pain at least in part by stimulating the release of pro-inflammatory molecules from neuron-supporting cells called astrocytes. Patti, Siuzdak, and their colleagues are now trying to find out more about DMS's pain-inducing mechanisms - and are testing inhibitors of DMS production that may prove to be effective treatments or preventives of neuropathic pain.

    "We're very excited about this therapeutic metabolomics approach," said Siuzdak. "In fact, we're already involved in several other projects in which metabolites are giving us a direct indication of disease biochemistry and potential treatments."

    Source: Medical News Today © MediLexicon International Ltd 2004-2012 (24/01/12)

    First patient enrolled in PRIME Study of AVP-923 in MS central neuropathic pain

    Avanir LogoAvanir Pharmaceuticals, Inc. AVNR -0.69% today announced the enrollment of the first patient in the PRIME study. The PRIME study is a Phase II clinical trial investigating the use of AVP-923 for the treatment of central neuropathic pain in patients with multiple sclerosis (MS).

    "With approximately 400,000 people in the U.S. suffering from MS, there is clearly a need for effective and safe therapies to treat symptoms associated with this disease such as central neuropathic pain," said Andrew Goodman, MD, professor of neurology at the University of Rochester. "Neuropathic pain remains inadequately treated in many people with MS and significantly interferes with daily functioning of those affected."

    About the PRIME Study

    The objectives of the PRIME (Pain Research In Multiple sclErosis) study are to evaluate the safety, tolerability, and efficacy of AVP-923 for the treatment of central neuropathic pain in patients with multiple sclerosis. The trial is a multicenter, randomized, double-blind, placebo-controlled, 4-arm parallel group study. Eligible patients will receive one of three dose levels of AVP-923 containing either 45mg DM/10 mg Q, 30mg DM/10mg Q, 20mg DM/10mg Q or placebo, daily for 12 weeks. The primary efficacy endpoint will be measured based on the Numeric Pain Rating Scale as recorded in patient diaries. Secondary assessments include measures of fatigue, impact of MS on daily life, sleep quality, cognition and depression. Safety will be assessed by monitoring adverse events, clinical laboratory tests, ECGs and physical examinations.

    Avanir expects to enroll approximately 400 patients both in the U.S. and internationally.

    "The initiation of this clinical study is an important step in the continued development of AVP-923," said Joao Siffert, MD, senior vice president of research and development at Avanir. "With no approved therapies for central neuropathic pain in MS, we are very excited about the potential application of AVP-923 as a safe and effective option treatment option. In addition, we look forward to exploring the potential of AVP-923 across a broad range of other CNS disorders."

    About Multiple Sclerosis and Central Neuropathic Pain

    Multiple sclerosis is an autoimmune demyelinating disease of the central nervous system (CNS) that causes abnormal function of the motor, sensory and visual systems. The initial disease course is often characterized by multiple exacerbations and remissions, with symptoms determined by the location and extent of the demyelinating areas in the brain and spinal cord.

    Chronic pain affects nearly half of all MS patients and has a substantial impact on daily life, further affecting their ability to function and work. MS patients experience pain of several types including musculoskeletal pain, painful tonic spasms and neuropathic pain, including trigeminal neuralgia, L'hermitte's sign and central neuropathic pain affecting the limbs. Central neuropathic pain is caused by lesions of sensory pathways in the brain and spinal cord and is estimated to affect approximately 30% of MS patients. It is characterised by moderate to severe painful sensations of burning, pricking, electric shocks and squeezing overlying areas of numbness. Common analgesics provide inadequate relief and there are no FDA-approved drugs for the treatment of central neuropathic pain.

    About AVP-923

    AVP-923 is a combination of two well-characterized compounds: the active ingredient dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist) and low dose quinidine sulfate (a CYP2D6 enzyme inhibitor), which serves to increase the bioavailability of dextromethorphan. The dosage form of AVP-923 of 20 mg DM/10 mg Q capsules (twice daily) is approved by the FDA under the brand name NUEDEXTA® which is indicated for the treatment of pseudobulbar affect (PBA).

    About NUEDEXTA

    NUEDEXTA® is the first and only FDA-approved treatment for pseudobulbar affect (PBA). NUEDEXTA is an innovative combination of two well-characterized components; dextromethorphan hydrobromide (20 mg), the ingredient active in the central nervous system, and quinidine sulfate (10 mg), a metabolic inhibitor enabling therapeutic dextromethorphan concentrations. NUEDEXTA acts on sigma-1 and NMDA receptors in the brain, although the mechanism by which NUEDEXTA exerts therapeutic effects in patients with PBA is unknown.

    NUEDEXTA is not approved for the treatment of central neuropathic pain.

    NUEDEXTA Important Safety Information

    NUEDEXTA can interact with other medications causing significant changes in blood levels of those medications and/or NUEDEXTA. NUEDEXTA is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide) and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine. NUEDEXTA is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days. NUEDEXTA is contraindicated in patients with a known hypersensitivity to its components.

    NUEDEXTA may cause serious side effects, including possible changes in heart rhythm. NUEDEXTA is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, in patients with heart failure as well as patients with, or at risk of, complete atrioventricular (AV) block, unless the patient has an implanted pacemaker.

    NUEDEXTA causes dose-dependent QTc prolongation. When initiating NUEDEXTA in patients at risk of QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3-4 hours after the first dose.

    The most common adverse reactions in patients taking NUEDEXTA are diarrhea, dizziness, cough, vomiting, weakness, swelling of feet and ankles, urinary tract infection, flu, elevated liver enzymes, and flatulence.

    NUEDEXTA may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls.

    Patients should take NUEDEXTA exactly as prescribed. Patients should not take more than 2 capsules in a 24-hour period, make sure that there is an approximate 12-hour interval between doses, and not take a double dose after they miss a dose.

    Source: Avanir Pharmaceuticals, Inc (03/11/11)

    Gene find could lead to therapy for neuropathic pain in MS

    Neuropathic PainA gene responsible for chronic pain has been identified, with scientists saying this could lead to drugs for treating long-lasting back pain.

    Writing in the journal Science, University of Cambridge researchers removed the HCN2 gene from pain-sensitive nerves in mice.

    Deleting the gene stopped any chronic pain but did not affect acute pain.

    About one in seven people in the UK suffer from chronic pain, which can also include multiple sclerosis, arthritis and headaches.

    The researchers say their findings open up the possibility that new drugs could be developed to block the protein produced by the HCN2 gene, which regulates chronic pain.

    The HCN2 gene, which is expressed in pain-sensitive nerve endings, has been known for several years, but its role in regulating pain was not understood.

    For the study, the researchers removed the HCN2 gene from pain-sensitive nerves. They then carried out studies using electrical stimuli on these nerves in cell cultures to determine how they were altered by the removal of HCN2.

    They then studied genetically modified mice in which the HCN2 gene had been deleted.

    By measuring the speed that the mice withdrew from different types of painful stimuli, the scientists were able to conclude that deleting the HCN2 gene abolished neuropathic pain.

    However, they found that deleting HCN2 did not affect normal acute pain - which occurs suddenly, for example when biting one's tongue.

    'No respite'

    Chronic pain comes in two main varieties. Inflammatory pain occurs when a persistent injury, such as a burn or arthritis, results in very sensitive nerve endings which increase the sensation of pain.

    Neuropathic pain occurs when nerves are damaged, causing ongoing pain. This type of chronic pain, which is often lifelong, is surprisingly common and is poorly treated by current drugs, the study says.

    It is often seen in patients with multiple sclerosis, diabetes and shingles, and in the aftermath of cancer chemotherapy. It is also common in lower back pain and other chronic painful conditions.

    Professor Peter McNaughton, lead author of the study and head of the department of pharmacology at the University of Cambridge, said there was now hope for these people.

    "Individuals suffering from neuropathic pain often have little or no respite because of the lack of effective medications. Our research lays the groundwork for the development of new drugs to treat chronic pain by blocking HCN2."

    He added: "Many genes play a critical role in pain sensation, but in most cases interfering with them simply abolishes all pain, or even all sensation.

    "What is exciting about the work on the HCN2 gene is that removing it - or blocking it pharmacologically - eliminates neuropathic pain without affecting normal acute pain. This finding could be very valuable clinically because normal pain sensation is essential for avoiding accidental damage."

    Dr Brian Hammond, chairman of charity BackCare, said the findings of the study were good news.

    "Any effective treatment which relieves the suffering of chronic pain is to be welcomed. Treatment which helps reduce pain but still leaves the body's warning mechanisms intact is a major breakthrough."

    The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), and the European Union.

    Source: BBC News © British Broadcasting Corporation 2011 (09/09/11)

    Pain common in Multiple Sclerosis, restricts function

    Pain In MSMore than half of patients with multiple sclerosis in a new study reported moderate to severe pain that limits function.

    "Pain is common in people with multiple sclerosis," lead investigator Denis Martin, DPhil, from Teeside University in Middlesbrough, the United Kingdom, told Medscape Medical News. "This should reinforce to clinicians to ask about pain and how it may be affecting the person. Too often that can be overlooked or dismissed."

    Presenting here at the American Pain Society annual meeting, the researchers showed that 54% of their sample experienced pain in 1 or more areas during the past 3 months. These patients had a statistically significant worse outcome on the World Health Organization Disability Assessment Schedule II (P < .05).

    The results are from a subanalysis of a study assessing function in patients with multiple sclerosis using textured insoles in footwear. The researchers did not present the results of the primary analysis, which they say are being prepared for publication.

    The subanalysis included 46 people with multiple sclerosis. Patients reported levels of pain in their wrist, hand, back, hip, knee, and foot using numeric rating scales ranging from 0 to 10. Investigators then compared function in patients with and those without pain.

    Although the research team did see more disability in patients experiencing pain, they did not observe a significant difference on the Multiple Sclerosis Walking Scale or in measures of balance and gait (P > .05).

    "A bigger study would be needed to address questions such as what particular type of person is most affected, which areas of the body are most affected, and what are the precise prevalence and incidence rates," Dr. Martin said. "The study did not try to establish the nature of pain, only its presence, so there is more work needed."

    Accepting the Pain

    In a separate presentation here at the meeting, investigators looked at the role of pain-related acceptance in improving quality of life.

    Previous studies of chronic pain have found that patients who are able to accept that discomfort is a part of their lives fare better than those who resist it.

    Adam Hirsh, PhD, and his team from the University of Washington in Seattle wanted to know whether the pain-related psychological experience of people with multiple sclerosis is different from that of people without the disease.

    Investigators studied 129 people with multiple sclerosis and chronic pain. Patients completed measures assessing pain acceptance, intensity, interference, depression, and quality of life.

    Compared with a previously published mixed chronic pain sample, the patients with multiple sclerosis reported significantly greater overall pain acceptance, activity engagement, and pain willingness (P < .001).

    After controlling for pain intensity, regression analysis suggested that activity engagement and pain willingness were significant predictors of pain interference and depression. Only activity engagement was a significant predictor of quality of life.

    "Since greater pain acceptance was associated with lower levels of pain interference and depression and better quality of life in patients with multiple sclerosis," the investigators reported, "rehabilitation providers should consider ways to enhance pain acceptance to maximize the clinical outcomes of these patients."

    The researchers have disclosed no relevant financial relationships.

    American Pain Society 30th Annual Scientific Meeting. Posters 202 and 403. Presented May 19 and 20, 2011

    Source: Medscape Today Copyright © 1994-2011 by WebMD LLC (24/05/11)

    Effect of microvascular decompression in patients with MS & Trigeminal Neuralgia

    Microvascular DecompressionSummary
    Trigeminal neuralgia (TN) in patients with multiple sclerosis (MS) is thought to be caused by demyelinating plaques within the nerve root entry zone, the trigeminal nucleus, or the trigeminal tracts.

    Authors review their experience of microvascular decompression (MVD) in patients with MS and symptomatic TN. Sandell T, Eide PK., Neurosurgery. 2010 Jul 21. [Epub ahead of print]

    All first-time MVDs for symptomatic trigeminal neuralgia in patients with MS performed by the senior author during an 8-year period (1999-2007) in this department were reviewed. The preoperative pain components were differentiated as being 100% episodic pain, > 50% episodic pain, or > 50% constant pain. At follow-up, pain relief was assessed with a standard mail questionnaire; those still having residual pain were further examined in the outpatient clinic or interviewed by phone.

    Of the 19 MS patients, 15 were available for follow-up. The median observation period was 55 months (range, 17-99 months). At follow-up, 7 of 15 patients (47%) were completely free of their episodic pain, and an additional 4 (27%) had significant relief of episodic pain (ie, worst pain marked as 0 to 3 cm on a 10-cm visual analog scale). Among the subgroup of 8 patients with a constant pain component, all were free of their constant pain, and 4 (50%) were free of their episodic pain.

    CONCLUSION: In an 8-year experience of doing MVD in MS patients with TN, authors found complete and significant relief of episodic TN in a large proportion of patients. Even those with a constant pain component before MVD were completely relieved of their constant pain. Thus, in patients with TN (with or without a constant pain component), the presence of MS should not prevent patients from being offered MVD.

    Source: MS Society Of Canada (06/08/10)

    NICE sets first clinical guidelines for neuropathic pain
    Neuropathic PainTwo antidepressants and an anticonvulsant have been singled out by the National Institute for Health and Clinical Excellence as drugs doctors should turn to in the first instance to treat neuropathic pain.

    In the first ever clinical guideline in this area, the cost watchdog for the National Health Service in England and Wales Healthcare says healthcare professionals should prescribe veteran antidepressant amitriptyline or Pfizer’s epilepsy drug Lyrica (pregabalin) as a first-line therapies for neuropathic pain, or Eli Lilly/Boehringer Ingelheim’s antidepressant Cymbalta (duloxetine) for painful diabetic neuropathy.

    Should first-line treatment with one of these options fail, doctors should try another either as monotherapy or in combination with the original drug as second-line therapy. If this is then also unsuccessful the patient should be referred to a specialist for further treatment, the guidance states, stressing that non-specialist healthcare professionals should only prescribe opioids such as morphine or oxycodone for neuropathic pain when patients have previously been assessed by a specialist pain or condition-specific service.

    Neuropathic pain is caused by damage or changes to nerves and is estimated to affect around 1%-2% of adults in the UK. The condition is associated with a variety of illnesses – including diabetes, MS, HIV and cancer - but can be difficult to treat “because it is resistant to certain medications and some of those that do work can have unpleasant side effects for the people that take them,” explained Dr Fergus Macbeth, Director of the Centre for Clinical Practice.

    “Around 95% of all patients with neuropathic pain are currently given medication to manage their pain, so it is important that health professionals are supported in providing the right treatments,” said Macbeth, adding that the Institute hopes the new guidance “will be of great use to health professionals in these settings”.

    According to Dr John Lee, a Consultant in Pain Medicine at the University College London Hospitals and Guideline Developer: “Having a framework in place for initiating treatments without the need for specialist advice, will help patients access care more quickly, and will improve the use of available resources”.

    Source: PharmaTimes (25/03/10)

    Ocean coral 'offers pain therapy' for neuropathic pain
    Kenya Tree Coral

    A compound harvested from soft coral off the coast of Taiwan could provide a new treatment for pain from intractable nerve damage, experts say.

    Traditional painkillers like aspirin and even morphine often do little to take the edge off neuropathic pain.

    But research in the British Journal of Pharmacology suggests Capnella imbricata, or Kenya Tree Coral, could provide relief.

    The Taiwanese scientists report promising early trial results in rats.

    Several important drugs have already been developed from chemicals found in coral reef organisms.

    Among these is the antiviral AZT, a treatment for people with HIV, which is based on chemicals extracted from a Caribbean reef sponge.

    Reefs have also yielded treatments for cardiovascular diseases, ulcers, leukaemia and skin cancer.

    Deep treasures

    Dr Zhi-Hong Wen and colleagues at the National Sun Yat-Sen University have been testing a chemical called capnellene, which is isolated from soft coral collected at Green Island, a small volcanic island in the Pacific Ocean about 33km off the eastern coast of Taiwan.

    The reef there is said to be home to more than 200 different types of coral.

    Capnellene appears to work on the supporting cells that surround nerve cells, which are thought to be responsible for neuropathic pain in some way.

    Recent research suggests inflammation plays a role, and inflammation activates supporting cells like microglia to release compounds that can excite nerves carrying pain signals.

    People with neuropathic pain experience severe pain from a stimulus or touch that would normally cause only slight discomfort or stimuli that would normally induce no pain at all.

    Some even get unpleasant or painful feelings even when there is no stimulus.

    It is estimated that about 1 in 100 people in the UK have persistent neuropathic pain - many are people with nerve damage caused by diabetes and multiple sclerosis.

    Dr Wen's team tested capnellene and a second very similar compound in isolated microglia cells and in experimental models of neuropathic pain in rats, with promising results.

    They say more studies are now needed to see if this could offer a new way to treat the condition.

    Dr Wen said: "Today there are few pharmacological agents that can help people suffering from neuropathic pain, but we believe that these marine-derived compounds could lead to the development of a new range of drugs of great potential."

    Source: BBC News © British Broadcasting Corporation 2009

    Blocking Protein May Help Ease Painful Nerve Condition

    Nerve pathways

    Scientists have identified the first gene that pulls the plug on ailing nerve cell branches from within the nerve cell, possibly helping to trigger the painful condition known as neuropathy or neuropathic pain.

    The condition is a side effect of some forms of chemotherapy and can also afflict patients with cancer, diabetes, kidney failure, viral infections, neurodegenerative disorders, such as Multiple Sclerosis and other ailments.

    Researchers at Washington University School of Medicine in St. Louis showed that blocking the dual leucine zipper kinase (DLK) gene inhibits degeneration of ailing nerve cell branches, possibly preventing neuropathy.

    "Neuropathy can become so extraordinarily painful that some patients stop taking their chemotherapy, regardless of the consequences in their fight against cancer,” says co-senior author Aaron DiAntonio, M.D., Ph.D., associate professor of developmental biology. “So we’re very excited about the possibilities this gene may offer for reducing that pain.”

    The findings were published online on March 15 in Nature Neuroscience.

    Scientists have known since 1850 that nerve cells have ways to prune branches (also known as axons) that are injured. Although axon pruning is also a normal part of early human development, inappropriate loss of axons in the adult nervous system causes painful sensations that have been compared to burning, freezing or electric shock and have come to be known as neuropathy.

    DiAntonio’s lab previously revealed that the fruit fly’s version of DLK helps establish synapses, junctures where two nerve cells communicate. But they found the gene doesn’t do the same thing in mice.

    Curious about DLK’s role in mammals, Bradley Miller, an M.D./Ph.D. student in DiAntonio’s lab, consulted with co-senior author Jeffrey Milbrandt, M.D., Ph.D., the David Clayson Professor of Neurology. Milbrandt studies the role of various proteins in neurodegeneration. With support from the University’s Hope Center for Neurological Disorders, they showed that the long axons of the sciatic nerve in mice with a mutated DLK gene resisted degeneration after it was surgically cut.

    In follow-up tests, Miller and Craig Press, an M.D./Ph.D. student in Milbrandt’s lab, took nerve cells in culture and treated their axons with the chemotherapy drug vincristine. Normal axons degenerated rapidly after exposure to the drug, but axons where DLK’s activity had been blocked were protected from degeneration.

    “The pain of neuropathy is often a key factor that limits the dose in cancer chemotherapy,” DiAntonio notes. “We know when patients are going to start their treatment, so one day it might be possible to start patients on a DLK-blocking drug before their chemotherapy and spare them considerable pain.”

    DLK appears to act like a contractor that calls in wrecking crews, DiAntonio notes. It helps make the decision to eradicate an axon, but the actual demolition is left to other processes called up by DLK.

    “We want to more fully understand the chain of molecular reactions that carry out DLK’s decision, because that might reveal a better opportunity to block the effect with a drug,” says DiAntonio.

    DiAntonio and Milbrandt also plan to test if blocking DLK stops neurodegeneration in other forms of injury and stress, including the harm inflicted on the optic nerve by glaucoma and central nervous system phenomena like stroke and Parkinson’s disease.

    Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A. A DLK-dependent axon self-destruction program promotes Wallerian degeneration. Nature Neuroscience, online March 15.

    Funding from the National Institutes of Health, the Hope Center for Neurological Disorders, the Washington University Alzheimer’s Disease Research Center and the Keck Foundation supported this research.

    Source: Washington University in St. Louis (16/03/09)

    Prevalence of complex regional pain syndrome in a cohort of multiple sclerosis patients


    BACKGROUND: More than 50% of multiple sclerosis patients experience chronic pain syndrome. We set out to determine the specific type of chronic pain that was seen in our multiple sclerosis patients.

    METHODS: Patients with multiple sclerosis were catalogued between January 2002 and April 2006 and identified by a search of the database. Only MS patients that met the 2005 revised McDonald criteria were included.

    RESULTS: We determined the prevalence rate of complex regional pain syndrome in a cohort of multiple sclerosis patients. In our sample of 205 multiple sclerosis patients, the prevalence of complex regional pain syndrome was 4 cases per 205 compared to an expected age and sex-adjusted total prevalence of 0.078 cases per 205

    CONCLUSION: This study suggests that multiple sclerosis patients are at a higher risk of developing complex regional pain syndrome than the general population.

    Source: RSDS / CRPS News & Information (05/06/08)

    OHSU Brings Relief To Trigeminal Neuralgia patients
    Trigeminal neuralgia, or TN, is a disorder affecting the areas of the face where the trigeminal nerve's branches are distributed, including the lips, eyes, nose, scalp, forehead, and upper and lower jaws. Often caused by an artery that compresses the nerve, the condition can bring about stabbing, mind-numbing, electric shock-like pain from just a light wind or a finger's glance of the cheek.

    Believed to be among the most severe types of pain known to humanity, the most common forms of TN affect 1 in 15,000 to 20,000, but 1 in 5,000 are thought to suffer from some type of facial pain.

    People with the condition "are begging to be killed," said Kim Burchiel, M.D., professor and chairman of neurological surgery at the Oregon Health & Science University School of Medicine who sees several new TN cases a week. "I'm telling you, it's total agony."

    Just ask James Kirkpatrick of Vancouver. "If I lightly touch my eyebrow, it feels like I stuck my finger in an electrical outlet," said the 47-year-old construction manager, who has suffered from TN for 16 months. "I'll go outside and the breeze hits my face and it feels like the most intense toothache I've ever had in my life. It drops me to my knees almost. I can totally understand why they call it the suicide disease. It affects so many aspects of your life."

    Then there's Melissa Hill, 55, a retired California attorney living in Charbonneau who suffered from TN for three years: "It's just very intense. Excruciating is a very good word for it. I would get it down to below my front teeth, on the right side, and right around my eye mostly. I'd get it under control and then it would flare up again, and every time it did, it would take longer and longer to get it under control."

    But there is hope. Burchiel has pioneered a new method for classifying and diagnosing TN, and much of the diagnosis can be done by patients themselves. Burchiel's team has developed the world's first online, artificial neural network to be used as a diagnostic tool for facial pain syndromes. It's an artificial intelligence-based computer program built around a classification scheme that categorizes forms of the disorder, and it can be trained to recognize patterns in facial pain data and continually improve its accuracy in predicting the correct diagnosis.

    "It's software designed to work the way the brain does," Burchiel said.

    An accurate diagnosis means patients can more quickly seek appropriate treatment, he said. "A patient comes in and says, 'I'm having pain,' so a dentist might give him a root canal. The pain comes back, so the tooth is pulled out. People have all kinds of unbelievable things done before somebody finally says, 'You know what? Maybe this isn't your tooth.' To prevent unnecessary procedures, people need to be told early on what they have."

    Since 2002, Burchiel has been using an 18-point questionnaire he developed to clinically diagnose facial pain using his novel classification scheme. Since facial pain types are based almost solely on a patient's medical history, the questionnaire is comprised of yes-or-no questions that tend to make a difference in establishing the target diagnosis, such as whether the patient has multiple sclerosis, has suffered a facial injury or has had surgery for facial pain, and whether the pain is on just one side of the face or manifests during certain daily activities, like shaving or eating.

    Burchiel uses the responses to place a patient into one of seven TN categories: Type 1, or spontaneous, but severe and brief pain; Type 2, or spontaneous, more constant pain; trigeminal neuropathic pain from facial trauma, oral surgery, stroke or other causes; trigeminal deafferentation pain from procedures that intentionally injure the trigeminal nerve system to relieve other pain; symptomatic trigeminal neuralgia from multiple sclerosis; postherpetic neuralgia from trigeminal shingles; and atypical facial pain, which is more psychological rather than physiological in origin.

    Burchiel doesn't think patients should have to wait until a clinic visit to get a diagnosis, so he developed the artificial neural network, which patients can easily, and confidentially, access on the OHSU Department of Neurological Surgery's Web site. Burchiel and neurosurgery department colleagues Farhad Limonadi, M.D., and Shirley McCartney, Ph.D., recently tested the network by asking 100 patients with facial pain to respond to the questionnaire during their first visits. They then interviewed each patient and made an independent diagnosis. Patients' responses and their diagnoses were input to the network, and a genetic algorithm was used to train the program.

    The network correctly diagnosed most of the patients. It also correctly diagnosed trigeminal neuralgia Type 1 with 84 percent sensitivity and 83 percent specificity among another 43 new patients who used the network before their clinic diagnosis. Sensitivity is a measure of a diagnostic tool's ability to make a correct diagnosis, and specificity describes its ability to avoid a misdiagnosis.

    "We hope that as people use this system, they become more and more informed, because they should be able to make informed choices before they actually get into treatment," Burchiel said.

    One treatment Burchiel offers, and which Hill has received, is a surgical therapy called microvascular decompression. The procedure involves entering the brain through a small incision behind the ear, finding and exposing the trigeminal nerve with a powerful surgical microscope, and positioning a piece of Teflon between the nerve and the artery that's touching it and causing the pain.

    In most cases, the procedure offers longer-term relief from facial pain than many, less-effective or inappropriate treatments people seek when they haven't been accurately diagnosed.

    "People who have this condition are desperate for answers for what they have, so now, anywhere in world, somebody can log onto our Web site and basically diagnose themselves and go to the right resources," Burchiel said. "And we put the resources right there on the Web site."

    To log onto the network, visit

    Source: Medical News Today © 2006 MediLexicon International Ltd (10/04/06)

    © Multiple Sclerosis Resource Centre (MSRC)

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