79 WORKSHOP SUMMARY: SENSORY TESTING BY PRIMARY CARE DOCTORS

79 WORKSHOP SUMMARY: SENSORY TESTING BY PRIMARY CARE DOCTORS

24 Oral presentations / European Journal of Pain Supplements 4 (2010) 1–46 socks). Nav 1.7 mutations that impair fast-inactivation are associated wi...

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Oral presentations / European Journal of Pain Supplements 4 (2010) 1–46

socks). Nav 1.7 mutations that impair fast-inactivation are associated with Paroxysmal Extreme Pain Disorder characterized by perirectal, perimandibular and periocular pain, triggered by bowel movement and perineal pressure. It is not known why the different types of gain-of-function mutations produce different phenotypes. Finally, loss-of-function mutations of Nav 1.7 have been identified in patients with congenital insensitivity to pain. Interestingly, while Nav1.7 is normally present within sympathetic ganglion neurons as well as DRG neurons, Nav 1.7-related CIP patients do not display apparent autonomic dysfunction. Together with the dynamic regulation of this channel in diabetic and inflammatory injury models in rodents, and its accumulation within painful neuromas in humans, these data from Nav 1.7related heritable pain syndromes provide compelling evidence that Nav 1.7 acts as a threshold channel DRG neurons, and suggest that Nav 1.7-specific blockade may provide a new approach for effective treatment of chronic pain. 77 SELECTIVE ABOLITION OF ABNORMAL IMPULSES BY A NON-CHANNEL SELECTIVE BLOCKER, LIDOCAINE G. Strichartz. Pain Research Center, Harvard Medical School, Boston, MA, USA Both in vivo and in vitro experimental results show that lidocaine, at 1–10 micromolar concentrations, can reversibly abolish the abnormal impulse activity that results from changes in Na channel function. Isolated nerve can be manipulated by peptide toxins that slow Na+ channel activation, such that the action potentials (APs), which are normally 1–2 msec long depolarizations to single, brief electrical stimuli, are changed to repetitive firing, slowly (>20& msec) repolarizing, sometimes spontaneously occurring depolarizations. Lidocaine, with its state-dependent binding to Open and Inactivated conformations of Na+ channels, at 5–10uM concentrations, effectively abolishes these “abnormal” signs while preserving the normal, early spike of the AP. In contrast, tetrodotoxin, a Na+ channel specific blocker that binds equally to all states of the channels, suppresses the APs spike at the same concentrations that reduce the abnormal firing. Computer simulations, with squid axons and with C-fiber models, show that the addition of a few percent of “slowly inactivating” Na channels, e.g. Nav1.8, can reproduce the repetitive impulse aspect of abnormal firing, and also induce sub-threshold membrane potential oscillations that occur between APs in a burst. The introduction of reversible binding of lidocaine to Na channels, with a selective affinity for Open and Inactivated conformations, effectively abolishes the repetitive firing and blunts the subthreshold oscillations while sparing the initial spike, recapitulating the biological effects of this drug. Further investigations in silico show that altering the channel selectivity for lidocaine binding between normal “fast” and the introduced “slow” channels has little effect on the overall potency for abnormal impulses. In contrast, when lidocaine binding is restricted to the Inactivated conformation, which is often designated as the the primary binding target of such drugs, the potency for reducing the abnormal firing activity is reduced about 25-fold. Repetitive firing that is induced in silico by a reduction in the delayed outward K+ current is susceptible to lidocaine like that caused by changes in Na+ channel gating, suggesting that the mechanism for the “disease state” is not indicated by its susceptibility to a (Na+ ) channel-selective blocker.

78 SODIUM CHANNELS AND ECTOPIC REPETITIVE FIRING IN PAINFUL NEUROPATHY M. Devor1,2 . 1 Department of Cell and Developmental Biology, 2 Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem, Israel Sodium channels carry the inward current that is responsible for the upstroke of action potentials in all mammalian sensory neurons. As such, they are essential for impulse propagation. Their contribution to impulse generation (electrogenesis) in the sensory ending of normal afferent neurons, and at ectopic locations in the event of neuropathy, is more complex. In the large majority of intact sensory neurons the cell soma, as well as the mid-nerve axon, fires a single spike, or at most a brief burst of spikes upon delivery of step a depolarization. Slow ramp depolarization typically yields no spiking at all. However, after axotomy, many afferents acquire enhanced electrogenic properties, expressed as repetitive firing to prolonged step and slow ramp depolarization and in some neurons spontaneous discharge at resting membrane potential. This change is believed to be due to altered gene expression, particularly of Na+ channel transcripts, combined with abnormal marshalling of gene expression products to the cell membrane. But no single Na+ channel type appears to be critical. Numerical simulation of the repetitive firing process shows that an altered spectrum of Na+ conductances can yield membrane resonance, subthreshold oscillations and enhanced repetitive firing. This effect appears to be due mostly to a small change in a delayed component of the overall Na+ conductance that occurs at a latency of about 20 msec. The 20 msec delayed current, which is not a “persistent” Na+ current, might be associated with a variety of different Na+ channel types. Selective suppression of this current might normalize exaggerated repetitive firing in injured afferents and hence resolve neuropathic pain, without interfering with normal impulse propagation.

A4. Clinical and Quantitative Sensory Testing by Primary Care Doctors 79 WORKSHOP SUMMARY: SENSORY TESTING BY PRIMARY CARE DOCTORS M. Backonja1 , M. Ware2 , P. Squire3 , G. Mick4 , V. Guastella5 . 1 Neurology, University to Wisconsin – Madison, Madison, WI, USA; 2 MUHC Pain Clinic, Montreal General Hospital, Montreal, QC, 3 Department of Family Practice, Lion’s Gate Hospital, Vancouver, BC, Canada; 4 Centre d’evaluation et traitement de la douleur, Hˆ opital Neurologique, Hospices civils de Lyon, Lyon, 5 Centre d’´evaluation et traitement de la douleur, CHU de Clermont-Ferrand, Clermont-Ferrand, France The majority of the patients with neuropathic pain will receive most of their care by primary care doctors. Complexity of neuropathic pain poses challenge to pain specialists and disproportionately to primary care clinicians. Primary care doctors face incredible pressure to provide standard of care in a very fast paced practice, and patients with chronic pain disorders, especially in case of neuropathic pain, are usually treated in primary care with traditional analgesics, according to most of the survey, thought there is no evidence to support this and other similar treatment approachs. There are international efforts to assist primary care physicians in reaching more specific neuropathic pain diagnosis. There are relatively simple symptoms based tools which can aid in this process, and this presentation will discuss efforts to bring additional tools, such as quantitative sensory testing, to primary care. The first step in evaluation in determining the role of quantitative sensory testing to be undertaken is feasibility of such testing within the time constraints and cognitive demands

Oral presentations / European Journal of Pain Supplements 4 (2010) 1–46

in primary care practice setting. Consequently, procedure of the exam would be focused and limited not to more than a couple of minutes. Attention to the problem of neuropathic pain, its severity and location, would be aided by simple symptoms assessment tools such as ID Pain or Neuropathic Pain Questionnaire and pain diagram, which could be administered by the nursing staff. This workshop will discuss the need for standardizing and validating a bedside clinical examination. Complex and technologically-intensive quantitative sensory testing protocols have been developed and used for detailed phenotyping in research contexts. However, this sort of examination is not possible in primary care. We will explore methods to develop and teach primary care physicians how to do a rapid and effective bedside sensory examination. In addition to Canadian and US experiences, we will discuss French experience, that although the diagnosis of neuropathic pain appears to be easier today by means of validated screening tools, the clinical examination of putative sensory abnormalities remains a problem for non neurologists in daily practice. We will present proposals for a guide pertaining with the objectives of demonstration of sensory abnormalities suitable for general practitioners (GPs) and specialists (SPs) that are not neurologists but have to face daily with patients presenting with neuropathic pain (orthopedic surgeons, rheumatologists). Use of the DN4 as a primary diagnostic tool will be proposed through an evaluation of its daily use by French GPs and SPs. An algorithm for the choice of a convenient multimodal treatment (pharmacological and non pharmacological) will summarize the basis regarding safety and evaluation. With the advent of new therapies for pharmacological treatment of neuropathic pain, it is increasingly important to teach primary care physicians how to diagnose and initiate treatment of neuropathic pain. 80 BASIS FOR A SIMPLE CLINICAL SENSORY EXAMINATION IN NON SPECIALIZED PRACTICE G. Mick1 , V. Guastella2 . 1 Pain Center, Neurological Hospital, Bron, 2 Pain Center, University Hospital, Clermont-Ferrand, France We will first show, through a survey performed in France in 2009– 2010, that although the diagnosis of neuropathic pain appears to be easier today by means of validated screening tools, the clinical examination of putative sensory abnormalities remains a problem for non neurologists in daily practice. We will subsequently present proposals for a guide pertaining with the objective demonstration of sensory abnormalities suitable for general practitioners (GPs) and specialists (SPs) that are not neurologists but have to face daily with patients presenting with neuropathic pain (orthopedic surgeons, rheumatologists). Use of the DN4 as a primary diagnostic tool will be proposed through an evaluation of its daily use by French GPs and SPs. Reliable examination of sensory modalities will be proposed by means of a simple set of tools, including body diagrams. An algorithm for the choice of a convenient multimodal treatment (pharmacological and non pharmacological) will summarize the basis regarding safety and evaluation. Finally, the idea of a “pocket guide” including all the previous data will be challenged with the audience.

S4. The Spinothalamic Tract and its Role in Pain 81 WORKSHOP SUMMARY: THE SPINOTHALAMIC TRACT AND ITS ROLE IN PAIN N.B. Finnerup. Danish Pain Research Center, Aarhus University, Aarhus, Denmark The spinothalamic tract (STT) represents a major ascending pathway conveying nociceptive information from the dorsal horn via the

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thalamus to brain regions involved in pain. This workshop will discuss the assessment of STT function and possible roles of STT dysfunction in hyperalgesia and neuropathic pain based on findings from basic science and clinical studies. Jurgen ¨ Sandkuhler ¨ will address synaptic plasticity in lamina I projection neurons and how long-term potentiation (LTP) in neurokinin 1 expressing neurons at the first synapse in the pain pathways may underlie some forms of hyperalgesia following nerve injury and inflammation. Jurgen ¨ Sandkuhler ¨ will also present new observations showing that activity-dependent LTP and opioidwithdrawal LTP share induction protocols, pharmacology, and signal transduction pathways with afferent-induced forms of hyperalgesia and opioid-withdrawal hyperalgesia. Luis Garcia-Larrea will address the use of laser-evoked potentials (LEPs) for the assessment of the STT in humans. The study of discrete STT lesions of similar sizes at different points of the STT (medulla, mesencephalon, thalamus) has shown that thalamic VPL lesions cause minimal distortion of LEPs suggesting that a sizeable part of the STT in humans goes to other non-VPL/VPI thalamic nuclei. Alteration of the STT is a common rule in central neuropathic pain patients, and subtle alterations in remnant STT transmission have been associated with a greater probability of provoked pain (allodynia, hyperalgesia). Nevertheless, even small lesions restricted to the VPL (and altering relatively little the LEPs) seem to be able to generate strong central pain, and data will be presented showing that neuropathic pain can exist in patients with large peripheral fiber or dorsal column lesions and normal STT conduction. Nanna Finnerup will review the role of STT dysfunction for central pain. While lesions of the STT have been considered a prerequisite for central pain, such lesions have been found to be equally frequent in patients without central pain. Recent experimental and human studies suggest that dysfunction of residual STT neurons is important in patients with spinal cord injury pain. Studies will be presented suggesting that the STT may trigger neuronal hyperexcitability and central pain by spontaneous activity in residual neurons or by signaling remote neuroimmune activation. 82 THE SPINOTHALAMIC TRACT AND ITS ROLE IN PAIN: SPINOTHALAMIC TRACT DYSFUNCTION IN CENTRAL PAIN N.B. Finnerup. Danish Pain Research Center, Aarhus University, Aarhus, Denmark Both preclinical and human studies suggest that a central nervous system lesion causes major structural and biochemical changes in widespread areas of the central nervous system remote from the initial lesion. Plastic changes taking place around the level of a central nervous system lesion are considered important for the development of neuronal hyperexcitability and central pain. However, the spinothalamic tract (STT) and remote changes in the thalamus are also thought to play important roles in central pain. Clinical studies suggest that in patients with incomplete or discomplete spinal cord injury, residual STT neurons can become the source of neuronal hyperexcitability and abnormal impulse generation, causing evoked and spontaneous pain. Experimental studies have also suggested that afferent barrage from the STT may trigger remote changes, causing microglia activation and abnormal expression of sodium channels in the thalamus, contributing to neuronal hyperexcitability and central pain. Case series with (11C)PK11195 and positron emission tomography (PET) in spinal cord injury pain patients with the purpose of studying thalamic microglia activation will be presented. Central pain may also be seen following complete interruption of the STT. In these patients with complete spinal cord injury, central pain has been suggested to arise from bursting neuronal activity in the deafferented thalamus. However, various clinical studies using quantitative sensory testing, spinal anesthesia, MRI, or electrophysiological recordings suggest a relation between at-level neuronal changes and below-level