Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: A laser-evoked potential study

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. The CMT1A type can be considered the typical phenotype of this disease. Although pain is not considered a relevant symptom in CMT patients by physicians and no study assessed it comprehensively, this symptom is frequently complained by patients. The objective of the present study was to investigate the nociceptive system in a sample of CMT1A patients suffering from pain by laser-evoked potentials (LEPs). Moreover, we also used a pain specific questionnaire in order to obtain patient-oriented data about their painful symptoms, the Neuropathic Pain Diagnostic Questionnaire (DN4). We evaluated 16 patients affected by CMT1A and 14 controls. All subjects underwent a standard LEP recording session (foot, hand, and face stimulation) and filled in the DN4. While the N2/P2 amplitude to foot stimulation was lower in CMT patients than in controls (p = 0.003), no difference in LEP amplitude to both hand and face stimulation was found between patients and healthy subjects (p > 0.05). This result is probably due to a length-dependent Aδ-fiber loss which involves mostly the longer fibers coming from the lower limb. In our patients, there was a significant association between a reduced N2/P2 amplitude to foot stimulation and a high DN4 score (p = 0.03), meaning that patients with highly probable neuropathic pain had also low N2/P2 amplitude values to painful foot stimulation. This suggests that in our CMT1A patients neuropathic pain is probably related to a reduction of the Aδ afferents.     

Mechanisms of pain in multiple sclerosis: A combined clinical and neurophysiological study

In this clinical and neurophysiological study, we examined the clinical characteristics and underlying mechanisms of neuropathic pain related to multiple sclerosis. A total of 302 consecutive patients with multiple sclerosis were screened for neuropathic pain by clinical examination and the DN4 tool. In patients selected for having ongoing extremity pain or Lhermitte's phenomenon, we recorded somatosensory evoked potentials, mediated by Aβ non-nociceptive fibres, and laser evoked potentials, mediated by Aδ nociceptive fibres. Of the 302 patients, 92 had pain (30%), and 42 (14%) neuropathic pain. Patients with neuropathic pain had more severe multiple sclerosis, as assessed by the expanded disability severity score, than those without pain. Whereas, in patients with ongoing neuropathic pain, laser evoked potentials were more frequently abnormal than somatosensory evoked potentials, we found the opposite in patients with Lhermitte's phenomenon. Our data underline the clinical importance of pain in multiple sclerosis and indicate that a more severe disease is associated with a higher risk of developing neuropathic pain. The prevalence of pain that we found, which was lower than that reported in previous studies, may reflect the lesser disease severity in our patients. Neurophysiological data show that whereas ongoing extremity pain is associated with spinothalamic pathway damage, Lhermitte's phenomenon is related to damage of non-nociceptive pathways. These findings may be useful in designing a new therapeutic approach to neuropathic pain related to multiple sclerosis.     

Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome

Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS.We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Aβ-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Aδ-fibres. In 40 patients (75 CTS hands) we also recorded laser-evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive Aδ-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI.We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain.Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Aβ-fibres, spontaneous constant pain arises from damage to nociceptive Aδ-fibres.     

A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy

Although many pharmacological agents are used in the therapy of neuropathic pain (NeP) due to polyneuropathy (PN), there are limited comparison studies comparing these agents. We evaluated patients with PN and related NeP in a tertiary care neuromuscular clinic with prospective follow-up after 3 and 6 months for degree of NeP using a Visual Analog Score (VAS). Clinical response to specific open-label pharmacotherapies was measured and compared for those patients not receiving pharmacotherapy. The severity of PN was quantified by the Toronto Clinical Scoring System (TCSS), with patients classified according to etiology of PN. Of a total of 408 patients referred for diagnosis and/or management of PN, NeP was identified in 182 patients (45%). NeP was most prevalent in patients with alcohol-associated PN. Pharmacotherapy management was provided in 91% of cases at first visit, and for 87% of cases after 6 months of follow-up. There were no serious adverse events for patients related to any medications, which included gabapentinoids, tricyclic antidepressants, anticonvulsants, cannabinoids and topical agents. Prevalence of intolerable side effects was similar amongst groups of medications. Approximated numbers needed to treat were similar between different individual oral pharmacotherapies, trending towards greater treatment efficacy with combination therapy. NeP is common in patients with PN and frequently requires pharmacotherapy management, which may be more effective with combination therapy. Future studies assessing longer duration of follow-up and quality of life changes with the use of various pharmacotherapies for management of NeP due to PN will be important.     

Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study

Postherpetic neuralgia is an exceptionally drug-resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11-point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non-nociceptive myelinated Aβ-fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Aδ- and unmyelinated C-fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P < 0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Aδ- and C-LEP amplitude reduction correlated with the intensity of constant pain (P < 0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological-clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Aβ-fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia.     

The impact of pain in patients with polyneuropathy

Peripheral neuropathy (PN) is a common impairment which may impact upon quality of life (QoL). Neuropathic pain (NeP) occurs in up to 50% of patients with PN. We hypothesized that disability and impaired quality of life resulting from PN is primarily associated with presence of NeP. Our aim was to determine using prospectively identified PN patients presenting to a tertiary care neuromuscular clinic if presence of NeP (PN + NeP) had greater impact upon QoL than with absence of NeP (PN − NeP). A second aim was to identify if QoL varied based upon etiology of PN. We analyzed neuropathy severity (Toronto Clinical Neuropathy Score (TCSS)), pain quantity and quality (Visual Analogue Scale (VAS) pain score, Brief Pain Inventory (BPI)), QoL and health status measures (EuroQol Instrument 5 Domains (EQ-5D), Medical Outcomes Sleep Study Scale (MOSSS), Hospital Anxiety and Depression Scale (HADS), Short Form 36 Health Survey (SF-36)) and Health Assessment Questionnaire (HAQ) to determine impact of NeP. Although both cohorts were epidemiologically similar and had similar severity of PN, PN + NeP patients had considerably greater impairment for QoL, sleep efficacy, and features of anxiety and depression, leading to substantially greater health care resources utilization when compared to PN − NeP patients. The magnitude of NeP severity was the only explaining variable for increased impact upon QoL measures and diminishing overall wellbeing. Our results confirm that NeP is a primary indicator for worsening QoL and diminished overall wellbeing in PN patients. The etiology of PN did not influence levels of NeP-related compromise of QoL. Further studies are needed to determine optimal methods for management of PN + NeP patients subjected to a significant physiological, psychological and functional burden.     

Psychophysical and electrophysiological evidence for nociceptive dysfunction in complex regional pain syndrome

The aim of this study was to assess the function of the thermo-nociceptive system in 25 patients with long-lasting, medium-to-severe refractory complex regional pain syndrome (CRPS)-1 using behavioral (detection rates and reaction times) and electrophysiological (event-related brain potentials) responses to brief (50 milliseconds) and intense (suprathreshold for Aδ-nociceptors) carbon dioxide laser stimuli delivered to the affected and contralateral limbs, and by comparing these responses to the responses obtained in the left and right limbs of age- and sex-matched healthy controls. Compared with healthy controls and compared with the contralateral limb, the detection rate of pricking pain related to the activation of Aδ-fibers was markedly reduced at the affected limb. Furthermore, reaction times were substantially prolonged (>100 milliseconds in 84% of patients and >300 milliseconds in 50% of patients). Finally, the N2 and P2 waves of laser-evoked brain potentials were significantly reduced in amplitude, and their latencies were significantly increased. Taken together, our results show that in the majority of patients with chronic CRPS-1, thermo-nociceptive pathways are dysfunctional. A number of pathological mechanisms involving the peripheral nervous system and/or the central nervous system could explain our results. However, the primary or secondary nature of these observed changes remains an open question.     

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.     

Identification of neuropathic pain in patients with neck/upper limb pain: Application of a grading system and screening tools

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain has proposed a grading system for the presence of neuropathic pain (NeP) using the following categories: no NeP, possible, probable, or definite NeP. To further evaluate this system, we investigated patients with neck/upper limb pain with a suspected nerve lesion, to explore: (i) the clinical application of this grading system; (ii) the suitability of 2 NeP questionnaires (Leeds Assessment of Neuropathic Symptoms and Signs pain scale [LANSS] and the painDETECT questionnaire [PD-Q]) in identifying NeP in this patient cohort; and (iii) the level of agreement in identifying NeP between the NeuPSIG classification system and 2 NeP questionnaires. Patients (n = 152; age 52 ± 12 years; 53% male) completed the PD-Q and LANSS questionnaire and underwent a comprehensive clinical examination. The NeuPSIG grading system proved feasible for application in this patient cohort, although it required considerable time and expertise. Both questionnaires failed to identify a large number of patients with clinically classified definite NeP (LANSS sensitivity 22%, specificity 88%; PD-Q sensitivity 64%, specificity 62%). These lowered sensitivity scores contrast with those from the original PD-Q and LANSS validation studies and may reflect differences in the clinical characteristics of the study populations. The diagnostic accuracy of LANSS and PD-Q for the identification of NeP in patients with neck/upper limb pain appears limited.     

Investigation of neuropathic pain in treated leprosy patients in Ethiopia: a cross-sectional study

Pain can be a significant problem for treated leprosy patients. It can be nociceptive due to tissue inflammation occurring during episodes of immune mediated reactions, or neuropathic due to leprosy affecting the somatosensory system. There are sparse epidemiological data on the prevalence and impact of neuropathic pain in treated leprosy patients. Tools for assessing neuropathic pain have not been validated in leprosy. We have examined nature of pain in a cross-sectional study to determine the prevalence of neuropathic pain (NP) in 80 recently treated leprosy patients in Ethiopia. Pain and depression were evaluated using the General Health Questionnaire (GHQ-12) and the Brief Pain Inventory (BPI) questionnaire. The Douleur Neuropathique en 4 Questions (DN4) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used as screening tools for NP. Pain of any type was experienced by 60% of the patients. Pure nociceptive pain was experienced by 43%, pure NP by 11%, and mixed pain by 6%. Of the 14 patients who had NP either alone or in combination with nociceptive pain, 12 had high GHQ-12 scores, indicating possible depression. The DN4 had sensitivity and specificity of 100% and 45%, whereas the LANSS had 85% and 42%, respectively. This is the first study to differentiate nociceptive from NP in leprosy patients. The prevalence of NP is high in recently treated Ethiopian leprosy patients. We have validated the use of DN4 in leprosy and it is easier to use than LANSS. Depression is a common co-morbidity in patients with NP. The high prevalence and morbidity of NP in treated leprosy patients warrant clinical trials to assess the efficacy of pain therapies for leprosy-associated NP.     

A prospective study of neuropathic pain induced by thoracotomy: incidence, clinical description, and diagnosis

This study evaluated prospectively the incidence of neuropathic pain after thoracotomy, described its clinical characteristics, and delineated landmarks for its diagnosis in daily practice. We evaluated clinically painful symptoms and sensory deficits in 54 patients after lateral/posterolateral thoracotomy for broncho-pulmonary carcinoma with standardized surgical and analgesic procedures. At 2 months, 49 patients suffered from non malignant thoracic pain, and at 6 months 38 patients (loss to follow-up for 7) reported persisting pain. In 35 patients, painful symptoms and sensory deficits could be evaluated using a standardized clinical bedside procedure. According to the grading system proposed by Treede et al. [41], neuropathic pain was considered probable in 21 patients, while use of the DN4 questionnaire concluded that neuropathic pain was probable in 17 patients. The two diagnostic procedures provided similar conclusions in 16 patients. Morphine consumption during the early post-operative period (mean 111.3 ± 30.8 mg/day) and pain intensity (VAS: mean 5.71 ± 2.1) were significantly higher in patients suffering from neuropathic pain than in other patients with pain (mean 80 ± 21.4 mg/day; VAS: mean 3.9 ± 2.4). The clinical picture in most patients with neuropathic pain included electric shocks and severe multimodal hypoesthesia in the sensory area of 5th/6th intercostal nerves. Thus, our results indicate a minimal incidence of chronic post-thoracotomy pain at 70% and that of neuropathic pain at 29%, this latter being clinically suggested by a combination of certain symptoms and reinforced by the DN4 questionnaire when sensory deficit at scar is present.     

Chronic pain and sensorimotor deficits following peripheral nerve injury

Following upper limb peripheral nerve transection and surgical repair (PNIr) patients frequently exhibit sensory and motor deficits, but only some develop chronic neuropathic pain. Thus, the sensorimotor outcome of PNIr may be impacted by individual factors. Therefore, our aims were to determine if patients with chronic neuropathic pain (PNI-P) following PNIr (1) are distinguished from patients without pain (PNI-NP) and healthy controls (HCs) by the psychological factors of pain catastrophizing, neuroticism or extraversion, and (2) exhibit more severe sensorimotor deficits than patients who did not develop chronic pain (PNI-NP). Thirty-one patients with complete median and/or ulnar nerve transection (21 PNI-NP, 10 PNI-P) and 21 HCs completed questionnaires to assess pain characteristics, pain catastrophizing, neuroticism and extraversion and underwent sensorimotor evaluation. Nerve conduction studies revealed incomplete sensorimotor peripheral recovery based on abnormal sensory and motor latency and amplitude measures in transected nerves. The patients also had significant deficits of sensory function (two-point discrimination and vibration, touch, and warmth detection), sensorimotor integration, and fine motor dexterity. Compared to PNI-NP patients, PNI-P patients had higher vibration detection thresholds, performed worse on sensory-motor integration tasks, had greater motor impairment, and showed more impaired nerve conduction. Furthermore, PNI-P patients had reduced cold pain tolerance, elevated pain intensity and unpleasantness during the cold pressor test, and they scored higher on neuroticism and pain-catastrophizing scales. These data demonstrate that chronic neuropathic pain following PNIr is associated with impaired nerve regeneration, profound sensorimotor deficits and a different psychological profile that may be predictive of poor recovery after injury.     

The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised,double-blind,placebo-controlled phenotype-stratified study

In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment. This was a randomised, double-blind, placebo-controlled, and phenotype-stratified study with 2 6-week treatment periods of oxcarbazepine (1800-2400 mg) and placebo. The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11-point numeric rating scale, and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety-seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention-to-treat population comprised 83 patients: 31 with the irritable and 52 with the nonirritable nociceptor phenotype. In the total sample, oxcarbazepine relieved pain of 0.7 points (on a numeric rating scale 0-10; 95% confidence interval [CI] 0.4-1.4) more than placebo (P = 0.015) and there was a significant interaction between treatment and phenotype of 0.7 (95% CI 0.01-1.4, P = 0.047). The number needed to treat to obtain one patient with more than 50% pain relief was 6.9 (95% CI 4.2-22) in the total sample, 3.9 (95% CI 2.3-12) in the irritable, and 13 (95% CI 5.3-∞) in the nonirritable nociceptor phenotype. In conclusion, oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype.     

Postoperative patients’ perspectives on rating pain: A qualitative study

BackgroundIn postoperative pain treatment patients are asked to rate their pain experience on a single uni-dimensional pain scale. Such pain scores are also used as indicator to assess the quality of pain treatment. However, patients may differ in how they interpret the Numeric Rating Scale (NRS) score.ObjectivesThis study examines how patients assign a number to their currently experienced postoperative pain and which considerations influence this process.MethodsA qualitative approach according to grounded theory was used. Twenty-seven patients were interviewed one day after surgery.ResultsThree main themes emerged that influenced the Numeric Rating Scale scores (0–10) that patients actually reported to professionals: score-related factors, intrapersonal factors, and the anticipated consequences of a given pain score. Anticipated consequences were analgesic administration—which could be desired or undesired—and possible judgements by professionals. We also propose a conceptual model for the relationship between factors that influence the pain rating process. Based on patients’ score-related and intrapersonal factors, a preliminary pain score was “internally” set. Before reporting the pain score to the healthcare professional, patients considered the anticipated consequences (i.e., expected judgements by professionals and anticipation of analgesic administration) of current Numeric Rating Scale scores.ConclusionsThis study provides insight into the process of how patients translate their current postoperative pain into a numeric rating score. The proposed model may help professionals to understand the factors that influence a given Numeric Rating Scale score and suggest the most appropriate questions for clarification. In this way, patients and professionals may arrive at a shared understanding of the pain score, resulting in a tailored decision regarding the most appropriate treatment of current postoperative pain, particularly the dosing and timing of opioid administration.     

糖尿病患者下肢周围神经传导速度分析

目的　探讨下肢周围神经传导速度检测对糖尿病周围神经病变 (DPN )的早期诊断价值及评价DPN程度的意义。方法　对 5 3例糖尿病患者下肢F波、运动神经、感觉神经的传导速度检测 ,分析糖尿病患者中有、无神经系统自觉症状组 ,1型、2型糖尿病组的周围神经传导速度变化。结果　各观察组神经传导速度较正常值减慢 (P <0 .0 1) ;有症状组与无症状组比较 ,F波、运动神经传导速度减慢加重 (P <0 .0 1) ,感觉神经传导比较尚无统计学意义 (P >0 .0 5 ) ;1型糖尿病神经传导速度减慢较 2型为重 (P <0 .0 1)。结论　下肢周围神经传导速度减慢是DPN早期诊断及评价DPN程度的敏感指标。     

Pregabalin for peripheral neuropathic pain: results of a multicenter, non-comparative, open-label study in Indian patients

The aim of this study was to evaluate the tolerability, safety and efficacy of pregabalin in Indian patients with peripheral neuropathic pain. In this prospective, multicenter, non-comparative, open-label study, patients with peripheral neuropathic pain (n = 111) received pregabalin in doses ranging from 75 to 300 mg twice daily for 3 weeks. Primary efficacy measures included weekly pain score and the Visual Analogue Scale (VAS) score of the Short-Form McGill Pain Questionnaire (SF-MPQ). Despite a short study duration, a significant reduction was seen in weekly pain score (p < 0.0001), as well as VAS score of SF-MPQ (p < 0.0001). Significant improvements were also seen in other pain-related endpoints, weekly sleep interference score, quality of life measures, and patient and clinician ratings of global improvement. Pregabalin was well tolerated, and the most common adverse events were dizziness and somnolence. The short study duration precluded the assessment of longer term safety issues such as weight gain. This study has demonstrated the safety, tolerability and efficacy of pregabalin for peripheral neuropathic pain in Indian patients.     

Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy

Sensory neuropathy (HIV-SN) is a common cause of pain in HIV-infected people. Establishing a diagnosis of HIV-SN is important, especially when contemplating opioid use in high-risk populations. However physical findings of HIV-SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self-report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV-SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV-SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self-report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self-report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV-infected patients reporting symptoms consistent with HIV-SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV-SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history.