Neuropathic Pain: Redefinition and a grading system for clinical and research purposes

Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Mainz, Germany.
Neurology (Impact Factor: 8.29). 05/2008; 70(18):1630-5. DOI: 10.1212/01.wnl.0000282763.29778.59
Source: PubMed


Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes.

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Available from: Jonathan O Dostrovsky, Feb 02, 2015
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    • "Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al., 2008). Voltage-gated sodium channel have a major role in the generation and conduction of the electrical pain information in the central and peripheral nervous system (Dib-Hajj et al., 2010; Catterall, 2012). "
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    ABSTRACT: Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal sodium channels, hNav1.7-1.9, cause human painful diseases. Thus while treatment of chronic pain remains an unmet clinical need, sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the analgesic activity of sumatriptan, an agonist of serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse. Interestingly, we observed that the analgesic effectiveness was not necessarily correlated to serotonin agonism. In this study, we evaluated whether sumatriptan and its congeners may inhibit heterologously expressed hNav1.7 sodium channels using the patch-clamp method. We show that sumatriptan blocks hNav1.7 channels only at very high, supratherapeutic concentrations. In contrast, its three analogs, namely 20b, (R)-31b, and (S)-22b, exert a dose and use-dependent sodium channel block. At 0.1 and 10 Hz stimulation frequencies, the most potent compound, (S)-22b, was 4.4 and 1.7 fold more potent than the well-known sodium channel blocker mexiletine. The compound induces a negative shift of voltage dependence of fast inactivation, suggesting higher affinity to the inactivated channel. Accordingly, we show that (S)-22b likely binds the conserved local anesthetic receptor within voltage-gated sodium channels. Combining these results with the previous ones, we hypothesize that use-dependent sodium channel blockade contributes to the analgesic activity of (R)-31b and (S)-22b. These later compounds represent promising lead compounds for the development of efficient analgesics, the mechanism of action of which may include a dual action on sodium channels and 5HT1D receptors.
    Frontiers in Pharmacology 08/2015; 6:155. DOI:10.3389/fphar.2015.00155 · 3.80 Impact Factor
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    • "Pathological pain, including neuropathic pain and fibromyalgia, is a frequent condition and is very challenging to manage. Neuropathic pain is described as " pain arising as a direct consequence of a lesion or disease affecting the somatosensory system " (Treede et al., 2008). The definition and causes of fibromyalgia are vague. "
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    ABSTRACT: Antidepressant drugs of the SSRI family are used as a third-line treatment for neuropathic pain. In contrast MAOi antidepressants, that also increase extracellular serotonin bioavailability have little or no effects on this condition. In addition to their action of the serotonin transporter, some SSRI have been shown to inhibit voltage gated sodium channels. Here we investigated the potential inhibition of SSRIs and MAOi antidepressants on Nav1.7 or Nav1.8, which are expressed in sensory neurons and play an important role in pain sensation. We used the whole-cell patch-clamp technique on HEK293 cells expressing either Nav1.7 or Nav1.8, and evaluated the effects of the SSRIs fluoxetine, paroxetine, and citalopram as well as one MAOi antidepressants on the electrophysiological properties of the Na(+) channels. Paroxetine exhibited the greatest affinity for Na(+) channels. In ascending order of affinity for Nav1.7 were paroxetine (IC50=10µM), followed by fluoxetine (IC50=66µM), then citalopram (IC50=174µM). In ascending order of affinity for Nav1.8 were paroxetine (IC50=9µM), followed by fluoxetine (IC50=49µM), then citalopram (IC50=100µM). Paroxetine and fluoxetine accelerated the onset of slow-inactivation and delayed the time-course of recovery from inactivation for both channels. Paroxetine and fluoxetine also had a prominent effect on the frequency-dependent inhibition, with a greater effect on Nav1.7. In contrast to SSRIs, MAOi did not affect Na(+) channels currents. These results suggest that, in certain conditions, the analgesic effect of SSRIs may in part be due to their interactions with Na(+) channels. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 07/2015; 764. DOI:10.1016/j.ejphar.2015.06.053 · 2.53 Impact Factor
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    • "Together with the present study, this strongly points to a pathological process involving C-fibres in fibromyalgia syndrome. Neuropathic pain is defined as pain caused by a disease or a lesion of the somatosensory nervous system (Treede et al., 2008). "
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    ABSTRACT: Recent studies have provided evidence of pathology and functional abnormalities of small nerve fibers as a potential correlate of pain in the fibromyalgia syndrome. Here, we aimed to quantify dermal unmyelinated nerve fiber diameter at the electron microscopic level to find a potential morphological correlate of the functional disturbance. Thirty-two patients with fibromyalgia syndrome, twelve patients with small fiber neuropathy and twenty-four healthy controls were prospectively recruited. Skin biopsies of the distal and proximal leg and index finger were taken and processed for immunofluorescence and for electron microscopy. We determined the diameter of small unmyelinated nerve fibers by measuring ten transversely cut axons of each biopsy. The mean axon diameter was reduced in patients with fibromyalgia syndrome compared to patients with small fiber neuropathy and to controls (p<0.05). Furthermore, we confirmed previous findings of disturbed small fiber function in quantitative sensory testing and of reduced intraepidermal nerve fiber density in fibromyalgia patients. Our study provides further evidence of small fiber pathology in fibromyalgia syndrome and discloses differences compared to small fiber neuropathy, indicating that different pathomechanisms may lead to small fiber loss in the two disorders.
    Pain 07/2015; DOI:10.1097/j.pain.0000000000000285 · 5.21 Impact Factor
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