Tina Mainka

Peripheral Neuropathic Pain: A mechanism-related organizing principle based on sensory profiles

Abstract Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain.

Topical high‐dose capsaicin acting on TRPV1 receptors and inducing an intraepidermal decrease in the small nerve fibre count is effective in treating neuropathic pain (NP). Sensory changes after capsaicin application, their correlation with pain relief and their role as possible predictors of response have been insufficiently analysed. We hypothesized a positive correlation between pain relief and increase in the warmth detection threshold (WDT), indicating loss of C‐fibre function, and higher response rates in patients with preserved C‐fibre function or heat hyperalgesia before application.

Who is healthy? Aspects to consider when including healthy volunteers in QST-based studies - A consensus statement by the EUROPAIN and NEUROPAIN consortia

Abstract Clinical and human experimental pain studies often include so-called “healthy” controls in investigations of sensory abnormalities, using quantitative sensory testing (QST) as an outcome measure. However, the criteria for what is considered “healthy” vary among the different studies and between study centers and investigators, partly explaining the high variability of the results. Therefore, several aspects should be considered during inclusion of healthy volunteers in QST-based trials to have homogenous groups of healthy controls with less variability between human experimental studies, so that results are less likely to be false negative or false positive because of subject-related factors. The EUROPAIN and NEUROPAIN consortia aimed to define factors influencing the variability in selection of healthy subjects in QST-based studies before the start of both projects and to give recommendations how to minimize it based on the current literature and expertise of the participants. The present suggestions for inclusion criteria of healthy volunteers into QST-based trials describe a 2-level approach including standardized questionnaires enabling the collection of relevant information on sociodemographic data, medical history, current health status, coping strategies in dealing with pain, and the motivation of the volunteer to participate in the study. These suggestions are believed to help researchers interpret their results in comparison with others and improve the quality of clinical studies including healthy volunteers as controls or in human experimental pain studies. They aim to reduce any confounding factors. Furthermore, the acquired information will allow post hoc analyses of variance for different potential influencing factors.

Quality assurance for Quantitative Sensory Testing laboratories: development and validation of an automated evaluation tool for the analysis of declared healthy samples.

Abstract Quantitative Sensory Testing (QST) is a psychophysical method assessing the somatosensory nervous system. A premise for comparable results between laboratories is standardized testing. Its quality can be proven by analyzing healthy subjects, because their results should lie within confidence intervals estimated from large database samples. However, it is unclear how many abnormal values can be tolerated. Based on a binomial distribution, a tool for assessing samples of healthy subjects was developed to detect inclusion errors (inclusion of nonhealthy subjects) or measuring errors (inaccuracies in single QST parameters). Sensitivity and specificity of detecting inclusion errors were assessed in 431 healthy subjects and 833 patients with neuropathic pain syndromes from the German Research Network on Neuropathic Pain (DFNS) database. Measuring errors were simulated by raising all absolute values in a single parameter by 0.5 SD. We calculated optimal cutoff values for group sizes of 16 healthy subjects, as implemented in the DFNS certification procedures. The algorithm was applied in the certification process of 18 European QST laboratories. With a specificity of 95% and a sensitivity of 60%, inclusion errors can be assumed for ≥4 abnormal values per subject, whereas ≥6 abnormal values per QST parameter and laboratory indicate measuring errors. Subsequently, in the certification process of 5 of 18 centers, inclusion or measuring errors were detected. In most cases, inclusion errors were verified and reasons for measuring errors were illuminated by the centers. This underlines the usefulness and validity of our tool in quality assurance of QST laboratories using the DFNS protocol.

Comparison of muscle and joint pressure-pain thresholds in patients with complex regional pain syndrome and upper limb pain of other origin

Summary Pressure‐pain thresholds measured over distal hand joints are highly specific for complex regional pain syndrome and might be a clinical sign reflecting bone pathophysiology. ABSTRACT Pain localized in the deep tissues occurs frequently in complex regional pain syndrome (CRPS). In addition, hyperalgesia to blunt pressure over muscles is common in CRPS, but it often appears in limb pain of other origin as well. Considering that 3‐phase bone scintigraphy (TPBS) reveals periarticular enhanced bone metabolism in CRPS, joint‐associated hyperalgesia to blunt pressure might be a more specific finding than hyperalgesia over muscles. In 34 patients with upper limb pain (18 CRPS, 16 non‐CRPS; diagnosed in accordance to the Budapest criteria) and in 18 healthy controls, pressure‐pain thresholds (PPT) were assessed bilaterally over the thenar (PPTThenar), the metacarpophalangeal (PPTMCP), and the proximal interphalangeal (PPTPIP) joints using a pressure algometer (Somedic, Sweden). Beforehand, all patients had received TPBS for diagnostic purposes independently of the study. Region‐of‐interest (ROI) ratios (mineralization phase) for the MCP and PIP, excluding fracture sites, were correlated with the PPT. In CRPS, all ROI ratios were significantly increased and all PPT of the affected hand were decreased compared to non‐CRPS (PPTThenar: 243 ± 150 kPa vs 358 ± 197 kPa, PPTMCP: 80 ± 67 kPa vs 159 ± 93 kPa, PPTPIP: 80 ± 56 kPa vs 184 ± 110 kPa; P < .01) and controls (PPTThenar: 478 ± 106 kPa, PPTMCP: 254 ± 50 kPa, PPTPIP: 275 ± 76 kPa; P < .01). A PPTThenar below 293 kPa revealed 77% sensitivity but only 63% specificity, whereas a PPTPIP below 102 kPa had 82% sensitivity and 94% specificity to identify CRPS. Only in CRPS were PPTMCP and PPTPIP correlated significantly inversely with the ROI ratio (MCP: r = −0.439, PIP: r = −0.447). PPTPIP shows higher specificity for CRPS type I than PPTThenar without loss of sensitivity. Therefore, measurement of joint PPT could be a noninvasive diagnostic tool reflecting increased bone metabolism assessed by TPBS as a sign of bone pathophysiology.

Neuropathic pain assessment: update on laboratory diagnostic tools.

Purpose of review The purpose of this review was to provide an update on the diagnostic tools for neuropathic pain for clinical practice. Recent findings The new definition of neuropathic pain by the International Association for the Study of Pain requires confirmation of a lesion or disease affecting the somatosensory system. In addition to traditional diagnostic procedures, for example, nerve conduction studies, skin biopsies depict morphological alteration and/or rarefication of the small intraepidermal nerve fibers and were recently used to identify small fiber abnormalities, for example, in patients with fibromyalgia or sarcoidosis. Quantitative sensory testing assesses the somatosensory function including both peripheral and central pathways. A recent consensus statement discussed its diagnostic value. Corneal confocal microscopy is a noninvasive method enabling in-vivo assessment of the small nerve fibers in the cornea and also seems to identify patients at risk for developing diabetic neuropathy at an early stage and to reflect the improvement of neuropathy after treatment. Further promising methods are the microneurography and nociceptive evoked potentials; however, they are technically challenging and their diagnostic value for clinical practice has yet to be confirmed. Summary For diagnosing neuropathic pain, confirmation of a lesion or disease affecting the somatosensory system is needed. Better clinical phenotyping will hopefully enable individualized mechanism-based treatment of neuropathic pain.

Symptom profiles in the painDETECT Questionnaire in patients with peripheral neuropathic pain stratified according to sensory loss in quantitative sensory testing.

Abstract The painDETECT Questionnaire (PDQ) is commonly used as a screening tool to discriminate between neuropathic pain (NP) and nociceptive pain, based on the self-report of symptoms, including pain qualities, numbness, and pain to touch, cold, or heat. However, there are minimal data about whether the PDQ is differentially sensitive to different sensory phenotypes in NP. The aim of the study was to analyze whether the overall PDQ score or its items reflect phenotypes of sensory loss in NP as determined by quantitative sensory testing. An exploratory analysis in the Innovative Medicines Initiative Europain and Neuropain database was performed. Data records of 336 patients identified with NP were grouped into sensory profiles characterized by (1) no loss of sensation, (2) loss of thermal sensation, (3) loss of mechanical sensation, and (4) loss of thermal and mechanical sensation. painDETECT Questionnaire profiles were analyzed in a 2-factor analysis of variance. Patients with loss of thermal sensation (2 and 4) significantly more often reported pain evoked by light touch, and patients with loss of mechanical sensation (3 and 4) significantly more often reported numbness and significantly less often burning sensations and pain evoked by light touch. Although the PDQ was not designed to assess sensory loss, single items reflect thermal and/or mechanical sensory loss at group level, but because of substantial variability, the PDQ does not allow for individual allocation of patients into sensory profiles. It will be useful to develop screening tools according to the current definition of NP.

high-Frequency repetitive sensory stimulation as intervention to improve sensory loss in Patients with complex regional Pain syndrome i

Achieving perceptual gains in healthy individuals or facilitating rehabilitation in patients is generally considered to require intense training to engage neuronal plasticity mechanisms. Recent work, however, suggested that beneficial outcome similar to training can be effectively acquired by a complementary approach in which the learning occurs in response to mere exposure to repetitive sensory stimulation (rSS). For example, high-frequency repetitive sensory stimulation (HF-rSS) enhances tactile performance and induces cortical reorganization in healthy subjects and patients after stroke. Patients with complex regional pain syndrome (CRPS) show impaired tactile performance associated with shrinkage of cortical maps. We here investigated the feasibility and efficacy of HF-rSS, and low-frequency rSS (LF-rSS) to enhance tactile performance and reduce pain intensity in 20 patients with CRPS type I. Intermittent high- or low-frequency electrical stimuli were applied for 45 min/day to all fingertips of the affected hand for 5 days. Main outcome measures were spatial two-point-discrimination thresholds and mechanical detection thresholds measured on the tip of the index finger bilaterally. Secondary endpoint was current pain intensity. All measures were assessed before and on day 5 after the last stimulation session. HF-rSS applied in 16 patients improved tactile discrimination on the affected hand significantly without changes contralaterally. Current pain intensity remained unchanged on average, but decreased in four patients by ≥30%. This limited pain relief might be due to the short stimulation period of 5 days only. In contrast, after LF-rSS, tactile discrimination was impaired in all four patients, while detection thresholds and pain were not affected. Our data suggest that HF-rSS could be used as a novel approach in CRPS treatment to improve sensory loss. Longer treatment periods might be required to induce consistent pain relief.

Association between clinical signs assessed by manual segmental examination and findings of the lumbar facet joints on magnetic resonance scans in subjects with and without current low back pain: A prospective, single-blind study ☆

Summary Only the combination of the clinical sign pain and certain MRI findings seems to be adequate to identify patients with true facet joint arthropathy. ABSTRACT The relevance of magnetic resonance imaging (MRI) findings such as facet joint (FJ) effusion and edema in low back pain (LBP) is still unknown. Therefore, we prospectively evaluated the presence of these MRI findings in the lumbar spine (Th12‐S1) and their association with pain evoked by manual segmental FJ provocation tests (spinal percussion, springing, and segmental rotation tests) in 75 subjects with current LBP (≥30 days in the past 3 months) compared with 75 sex‐ and age‐matched control subjects. FJs were considered painful, if ≥1 provocation test triggered LBP. FJs were classified as true positives, if the same FJ was painful and showed effusion and/or edema. FJs with effusion and/or edema and painful FJs were present significantly more frequently in subjects with LBP, but these conditions were also common in control subjects (27% vs 21% and 50% vs 12%, respectively). Effusion and/or edema were present in 65 subjects with LBP (87%) and in 56 control subjects (75%, not significant); painful FJs were present in 68 (91%) and 29 (39%) (P < 0.01) LBP and control subjects, respectively. True‐positive findings occurred in 16% of LBP FJs and in 2% of control FJs (P < 0.01); 46 LBP subjects (61%) and 9 control subjects (12%, P < 0.01) had true‐positive findings. Pain on provocation and FJ effusion and/or edema were significantly correlated only in patients with LBP. In conclusion, only true‐positive findings (ie, concurrent effusion and/or edema and positive provocation test results in the same FJ) discriminate well enough between control subjects and subjects with current LBP, whereas neither effusion and/or edema nor FJ provocations tests alone are suitable to detect suspected FJ arthropathy.

Erweiterte Diagnostik neuropathischer Schmerzen erfasst kleine Nervenfasern

ZusammenfassungDie Diagnostik neuropathischer Schmerzen erfordert die Bestätigung einer Läsion oder Erkrankung, die das somatosensorische Nervensystem betrifft. Da die klassische Elektroneurografie oder somatosensorische evozierte Potenziale aber nur die dick-myelinisierten Aβ-Fasern, jedoch nicht die dünn- und unmyelinisierten Aδ- und C-Fasern erfassen, sollten auch andere Untersuchungsmethoden durchgeführt werden, die zusätzlich die Funktion und Morphologie der kleinen Nervenfasern erfassen.