NeuPSIG guidelines on neuropathic pain assessment

This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level.Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes.Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction.The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.     

Évaluation quantitative des troubles sensitifs et des douleurs neuropathiques

Quantitative sensory testing (QST) may be defined as the analysis of perception of pain in response to thermal and mechanical stimuli of measured intensity. This method uses thermal, mechanical and vibratory stimuli, enabling the measurement of pain thresholds and sensations caused by suprathreshold stimulation. QST can quantify hypoesthesia (raised detection thresholds), allodynia (lowered pain thresholds) and hyperalgesia (increased response to suprathreshold stimuli). It is suitable for detecting or monitoring peripheral polyneuropathies characterized by fine fiber impairment, particularly diabetic peripheral neuropathies. It has also been used to analyse the pathophysiological mechanisms involved in certain neuropathic pain conditions and to assess the effects of treatments for neuropathic pain. In this paper the relevance and limitations of QST for the assessment of neuropathic pain and its treatment are discussed.     

神经源性疼痛的动物模型

神经源性疼痛的发病机理尚不完全清楚，虽有多种治疗方法蛤效果都不甚满意。为了探索神经源性疼痛的发病机理及检验新的治疗方法，基础研究者发展了一些神经源性疼痛的动物模型，这些研究模型的建立使人们可以应用在临床研究中不能采用的实验手段进行研究。但这些动物模型的价值则取决于它们与人类神经源性疼痛的痛觉症状及感觉变化上的相似程度。本文先介绍神经源性动物模型的感觉异常（痛觉过敏和痛觉超敏）及其检测，再介绍一外周     

Peripheral opioid analgesia for the treatment of neuropathic pain: Gene mutation to virus mediated gene transfer

Neuropathic pain can result from a number of different diseases, medical interventions and injuries. In addition to varying aetiologies, neuropathic pain may also differ in the anatomical location of the lesion – from peripheral nociceptors to the highest centres in the brain. The management of neuropathic pain continues to be a challenge for clinicians and despite taking prescribed medication for pain, patients with neuropathic pain continue to have pain of moderate severity. The use of opioids for the treatment of chronic neuropathic pain remains controversial. Recent studies demonstrate opioid analgesics are effective in neuropathic pain states but their use is often limited by unacceptable side effects that are mediated by opioid actions in the central nervous system. While it was once dogma that opioids exert their analgesic effects by binding to receptors in the central nervous system, there is a growing recognition of a potent peripheral analgesia in experimental models of inflammatory and neuropathic pains, and in clinical settings. The working model is that peripheral opioids can be used to treat neuropathic pain while avoiding the often dose-limiting and unacceptable central nervous system mediated side effects. Our work has focused on characterizing this peripheral opioid analgesia such that it can be exploited to develop novel and potent peripheral analgesics for the treatment of neuropathic pain. This article will set the clinical stage for the need for novel treatments for neuropathic pain, the use of gene mutation strategies to make the case for the use of opioids in treating neuropathic pain, the demonstration of peripheral opioid analgesia in neuropathic pain, and our work with virus mediated gene transfer to enhance peripheral opioid analgesia in neuropathic pain.     

Dynamic mechanical allodynia in neuropathic pain

Thirty-four patients with various forms of neuropathic pain have been examined with respect to two parameters of dynamic mechanical allodynia: the effect of repetitive stimulation on pain intensity; and refractory period. Pain intensity increased with repetitive stimulation ('windup') in most patients with neuropathic pain of peripheral origin, while it was not observed in patients with central neuropathic pain. While a non-responsive period occurs after tactile allodynic elicitation in patients with trigeminal neuralgia (Kugelberg and Lindblom, 1959), it was not seen in any case of neuropathic pain, including trigeminal neuropathy. The findings have implications for diagnosis, and require pathophysiological elucidation in terms of revealed differences.     

Quantitative sensory testing in pain states

The diagnosis and treatment of chronic pain presents a constant challenge for practicing physicians.There are numerous disorders of the peripheral and central nervous system that lead to chronic pain states.The pathophysiology of nerve injury in chronic pain states is highly complex and therefore leads to unpredictable response to treatment modalities. Standard diagnostic tools are often inadequate or equivocal in these conditions. Physical examination on the other hand is prone to examiner bias. Quantitative sensory testing of the nociceptive system consists of psychophysical methods used to measure intensity of stimuli needed to produce specific sensory perceptions. Measurements of subjective thresholds to thermal, mechanical, and electrical stimulation reflect the state of the peripheral and central nervous system responsible for pain processing.As opposed to standard diagnostic tools, quantitative sensory testing enables us to test specific components of the nociceptive system (such as unmyelinated C-fibers). In the clinical setting, quantitative sensory testing is becoming a clinical standard for evaluation of certain chronic pain conditions. Further clinical trials might enable us to use quantitative sensory testing as guidance for tailoring a therapeutic approach.     

Neurophatic Pain Treatment: The Challenge

Abstract : Neuropathic pain covers a heterogeneous group of pain conditions characterized by a primary lesion or dysfunction of the sensory nervous system. Its pathophysiology is not yet clear, but neuronal hyperexcitability in those neurons that have lost their normal patterned input seems to be a common denominator for neuropathic pain. A mechanism-based approach is being developed, but still the clinical workup is being based on the anatomical location and the determination of an underlying cause. In addition, clinicians are presented with a challenge because neuropathic pain does not respond well to traditional pain therapies and there are greater individual variations in pain responsiveness. A number of drug classes have been evaluated in the treatment of neuropathic pain syndromes; these are mainly drugs developed for other nervous system diseases, although their precise action and whether their action is central or peripheral remains unknown for the majority of them. First-line agents used in the treatment of neuropathic pain conditions are tricyclic antidepressants and anticonvulsants, especially carbamazepine and gabapentin. Novel therapies are currently being developed for neuropathic pain that are based in experimental models and theoretical frameworks on the pathosphysiological events that initiate this type of pain.     

Somatosensory function in patients with and without pain after traumatic peripheral nerve injury

Why traumatic injuries to the peripheral nervous system infrequently result in neuropathic pain is still unknown. The aim of this study was to examine the somatosensory system in patients with traumatic peripheral nerve injury with and without pain to try to unravel possible links to mechanisms underlying development and maintenance of pain. Eighteen patients with spontaneous ongoing pain and 16 patients without pain after unilateral partial peripheral traumatic nerve injury were studied. In the area of partial denervation and in the corresponding contralateral area perception thresholds to warmth, cold, light touch, pressure pain, cold‐ and heat pain were assessed as were pain intensities at suprathreshold heat pain stimulation. Comparing sides patients with pain reported allodynia to cold (p = 0.03) and pressure (p = 0.016) in conjunction with an increase in the perception threshold to non‐painful warmth (p = 0.024) on the injured side. Pain‐free patients reported hypoesthesia to light touch (p = 0.002), cold (p = 0.039) and warmth (p = 0.001) on the injured side. There were no side differences in stimulus–response functions using painful heat stimuli in any of the groups. In addition, no significant difference could be demonstrated in any sensory modality comparing side‐to‐side differences between the two groups. In conclusion, increased pain sensitivity to cold and pressure was found on the injured side in pain patients, pointing to hyperexcitability in the pain system, a finding not verified by a more challenging analysis of side‐to‐side differences between patients with and without pain.     

Comparison of autotomy behavior induced in rats by various clinically-used neurectomy methods

When a peripheral nerve is cut, a neuroma develops at its proximal end. Nerve-end neuromas are known to be a source of ectopic sensory input. In some humans this input may cause spontaneous and evoked neuropathic pain. There is currently no available animal model for developing better methods of cutting nerves that produce less painful neuromas than those currently in clinical use. Transection of the sciatic and saphenous nerves in rats also produces nerve-end neuromas. Afferent fibers in such neuromas spontaneously emit ectopic input that coincides with the outbreak of licking, scratching and self-mutilation of the denervated limb ('autotomy'). This behavior is considered to be the expression of spontaneous disagreeable sensations such as paresthesias, dysesthesias or neuropathic pain. We propose here that the autotomy model can be used as the first step for development of better neurectomy methods. As a demonstration, in this report we compared the course of autotomy expressed by rats following several methods of cutting peripheral nerves that are currently in clinical use. We found that the lowest extent of autotomy was caused by sciatic and saphenous neurectomy with a CO(2) laser. Tight ligation of the nerve, or a simple cut with scissors, also yielded significantly lower autotomy scores compared to cryoneurolysis and electrocut. The differing scores of autotomy caused by these neurectomy methods may derive from different properties of the injury discharge produced by these methods at the time of nerve cut. Our results raise the possibility that a higher incidence of neuropathic pain or related sensory disorders in humans may be expected following cryosurgical and electrocut neurectomies. If validated by further studies, neurectomy methods eliciting lower incidence of autotomy, and sensory disorders in models not based on autotomy may produce lower levels of neuropathic pain in humans.     

Thermal and tactile sensory deficits and allodynia in a nerve-injured patient: a multimodal psychophysical and functional magnetic resonance imaging study

OBJECTIVE: A case study was conducted to examine a patient with chronic neuropathic pain of the right foot following peripheral nerve injury and characterize associated sensory abnormalities. METHODS: Multimodal psychophysical examination of the patient's affected and nonaffected foot included thermal sensibility, dynamic touch, and directional sensibility. In addition, we used functional magnetic resonance imaging to study cortical representation of brush-evoked allodynia. RESULTS: Detailed psychophysical examination revealed substantial deficits in warm, cool, and tactile perception on the injured foot. These findings indicated severe dysfunction of perceptual processes mediated by A beta, A delta, and C fibers. Despite reduced tactile perception, light touch evoked a deep burning pain in the foot. Functional magnetic resonance imaging during brushing of the patient's injured foot showed that tactile allodynia led to activation of several cortical regions including secondary somatosensory cortex, anterior and posterior insular cortex, and anterior cingulate cortex. Brushing of the patient's nonaffected foot led to fewer activated regions. DISCUSSION: The profound sensory disturbances suggest a possible deafferentation type of tactile allodynia mediated by changes within the central nervous system, such as a disruption of normal tactile or thermal inhibition of nociception. The functional magnetic resonance imaging data suggest that tactile allodynia is represented in similar brain regions as experimental pain.     

Case reports - reversal of sensory deficit associated with pain relief after treatment with gabapentin

Many patients with neuropathic pain have coexistent sensory deficits. Neuropathic pain may be alleviated by a variety of drugs but sensory deficits are assumed to be permanent. In an audit of the effects of gabapentin therapy on patients with neuropathic pain, monthly detailed sensory examinations were performed during the first three months of treatment. Of five patients with sensory deficits who tolerated gabapentin therapy, three showed marked improvement of their sensory deficits associated with pain alleviation. The cases are presented and possible explanations for the observed sensory improvements are discussed. These findings raised exciting neurophysiological questions in addition to being of potential importance to the clinical problem of neurotrophic tissue injury.     

Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy

Central sensitization after peripheral nerve injury may result in ectopic neuronal activity in the spinal cord dorsal horn, implying a potential autonomous pain-generating mechanism. This study used peripheral nerve blockade and systemic lidocaine administration, with detailed somatosensory assessment, to determine the contribution of primary afferent input in maintaining peripheral neuropathic pain. Fourteen patients with neuropathic pain (7 with unilateral foot pain due to peripheral nerve injury and 7 with bilateral pain in the feet due to distal polyneuropathy) underwent comprehensive characterization of somatosensory function by quantitative sensory testing. Patients were then administered an ultrasound-guided peripheral nerve block with lidocaine and intravenous lidocaine infusion in randomized order. The effect of these interventions on spontaneous pain intensity and on evoked cold, warm, pinprick, and brush responses was assessed at each session. All patients had sensory disturbances at baseline. The peripheral nerve block resulted in a complete abolition of ipsilateral pain within 10 min (median) in all patients, with lidocaine plasma concentrations being too low to account for a systemic effect of the drug. Intravenous lidocaine infusion reduced the spontaneous pain by 45.5% (±31.7%), and it reduced mechanical and thermal hypersensitivity in most patients who displayed such signs. However, the improvement in evoked hypersensitivity was not related to the effect of the drug on spontaneous pain intensity. This study demonstrated that regardless of the individual somatosensory phenotype and signs of central sensitization, primary afferent input is critical for maintaining neuropathic pain in peripheral nerve injury and distal polyneuropathy.     

Hyperalgesia with reduced laser evoked potentials in neuropathic pain

Nociceptive evoked potentials to laser stimuli (LEPs) are able to detect lesions of pain and temperature pathways at peripheral, spinal and supraspinal levels. It is commonly accepted that LEP attenuation correlates with the loss of pain and temperature sensations, while pathological heat-pain hypersensitivity has been associated with increased LEP amplitude. Here we present two patients in whom increased pain sensation (hyperalgesia) to laser stimuli was, on the contrary, associated to delayed, desynchronized and attenuated LEPs. Both patients experienced increased unpleasantness and affective reactions to laser, associated to poor ability to localize the stimulus. In both cases the results may be explained by an overactivation of the 'medial pain system', in one patient due to deafferentation of cortical sensory areas by a capsular lesion, and in the other to imbalance between A-delta and C fiber excitation due to peripheral nerve injury. Our results suggest that LEPs, as currently recorded, reflect the activity of a 'lateral' pain system subserved by rapidly conducting fibers. They may therefore, assess the sensory and cognitive dimensions of pain, but may not index adequately the affective-emotional aspects of pain sensation conveyed by the 'medial' pain system. The dissociation between pain sensation and cortical EPs deserve to be added to the current semiology of LEPs, as the presence of abnormal pain to laser on the background of reduced LEPs substantiates the neuropathic nature of the pain.     

Chronic regional pain syndrome, type 1: Part I

Chronic regional pain syndrome refers to a class of disorders thought to involve common neuropathic and clinical features. These disorders usually are caused by injury, and they manifest in pain and sensory changes that are disproportionate in intensity, distribution, and duration to the underlying pathology. The result of these injuries is significant impairment of motor function over time. This article is divided into two parts. Part I discusses background information such as pain, pathophysiology, diagnosis, clinical stages, and the most common treatment modality, sympathetic nerve blocks. Part II, discusses alternate treatment modalities, such as sympathectomy, physical therapy, stimulators, trigger point injections, acupuncture, tourniquet effects, placebo effects, and amputation.