Assessing the Influence of Nonischemic A-Fiber Conduction Blockade on Offset Analgesia: An Experimental Study.

Offset analgesia (OA) is believed to reflect the efficiency of the endogenous pain modulatory system. However, the underlying mechanisms are still being debated. Previous research suggested both, central and peripheral mechanisms, with the latter involving the influence of specific A-delta-fibers. Therefore, this study aimed to investigate the influence of a nonischemic A-fiber conduction blockade on the OA response in healthy participants. A total of 52 participants were recruited for an A-fiber conduction blockade via compression of the superficial radial nerve. To monitor fiber-specific peripheral nerve conduction capacity, quantitative sensory testing was performed continuously. Before, during, and after the A-fiber block, an individualized OA paradigm was applied to the dorsum of both hands (blocked and control sides were randomized). The pain intensity of each heat stimulus was evaluated by an electronic visual analog scale. A successful A-fiber conduction blockade was achieved in thirty participants. OA has been verified within time (before, during, and after blockade) and condition (blocked and control side) (P < .01, d > .5). Repeated measurements analysis of variance showed no significant interaction effects between OA within condition and time (P = .24, η²p = .05). Hence, no significant effect of A-fiber blockade was detected on OA during noxious heat stimulation. The results suggest that peripheral A-fiber afferents may play a minor role in OA compared with alternative central mechanisms or other fibers. However, further studies are needed to substantiate a central rather than peripheral influence on OA. PERSPECTIVE: This article presents the observation of OA before, during, and after a successful A-fiber conduction blockade in healthy volunteers. A better understanding of the mechanisms of OA and endogenous pain modulation, in general, may help to explain the underlying aspects of pain disorders.

Glucose attenuates the long-term adverse neurodevelopment effect of neonate pain stimulus via CRF/GR in rats.

BACKGROUND: Neonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated. METHODS: Neonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0-7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed. RESULTS: Oral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement. CONCLUSION: Exposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis.

Analgesic Electrical Stimulation Combined with Wrist-Ankle Acupuncture Reduces the Cortical Response to Pain in Patients with Myofasciitis: A Randomized Clinical Trial.

OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS) based on wrist-ankle acupuncture has been shown to relieve pain levels in patients with myofascial pain syndrome (MPS). However, its efficacy is highly subjective. The purpose of this study was to evaluate the feasibility and effectiveness of TENS based on wrist-ankle acupuncture for pain management in patients with MPS from the perspective of cerebral cortex hemodynamics. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: We designed a double-blind, randomized, controlled clinical trial. Thirty-one male patients with MPS were randomly assigned to two parallel groups. The experimental group (n = 16) received TENS based on wrist-ankle acupuncture for analgesic treatment, while the control group (n = 15) did not. The pain was induced by mechanically pressurized at acupoint Jianjing. The multichannel functional near-infrared spectroscopy (fNIRS) equipment was utilized for measuring oxyhemoglobin (HbO) levels in the cerebral cortex during the tasks. RESULTS: After the intervention, visual analog scale (VAS), the activation degree and activation area of pain perception cortices were significantly reduced in the experimental group compared to the baseline values (P < .05). Particularly, Frontopolar Area (FPA), and Dorsolateral Prefrontal Cortex (DLPFC) are highly involved in the pain process and pain modulation. CONCLUSION: Compared to no intervention, TENS based on wrist-ankle acupuncture can be effective in relieving pain in patients with MPS in terms of cerebral cortical hemodynamics. However, further studies are necessary to quantify the analgesic effect in terms of cerebral hemodynamics and brain activation.

Objective pain stimulation intensity and pain sensation assessment using machine learning classification and regression based on electrodermal activity.

An objective measure of pain remains an unmet need of people with chronic pain, estimated to be 1/3 of the adult population in the United States. The current gold standard to quantify pain is highly subjective, based upon self-reporting with numerical or visual analog scale (VAS). This subjectivity complicates pain management and exacerbates the epidemic of opioid abuse. We have tested classification and regression machine learning models to objectively estimate pain sensation in healthy subjects using electrodermal activity (EDA). Twenty-three volunteers underwent pain stimulation using thermal grills. Three different "pain stimulation intensities" were induced for each subject, who reported the "pain sensation" right after each stimulus using a VAS (0-10). EDA data were collected throughout the experiment. For machine learning, we computed validated features of EDA based on time-domain decomposition, spectral analysis, and differential features. Models for estimation of pain stimulation intensity and pain sensation achieved maximum macroaveraged geometric mean scores of 69.7% and 69.2%, respectively, when three classes were considered ("No," "Low," and "High"). Regression of levels of stimulation intensity and pain sensation achieved R2 values of 0.357 and 0.47, respectively. Overall, the high variance and inconsistency of VAS scores led to lower performance of pain sensation classification, but regression was better for pain sensation than stimulation intensity. Our results provide that three levels of pain can be quantified with good accuracy and physiological evidence that sympathetic responses recorded by EDA are more correlated to the applied stimuli's intensity than to the pain sensation reported by the subject.

Offset analgesia and onset hyperalgesia with different stimulus ranges.

INTRODUCTION: Offset analgesia (OA), a large reduction in pain after a brief increase in intensity of an otherwise stable painful stimulus, has been established by a large body of research. But the opposite effect, onset hyperalgesia (OH), a disproportional hyperalgesic response after a briefly decreased intensity of a painful stimulus, has only been investigated in one previous study. OBJECTIVES: The aim of this study was to induce OA and OH in healthy participants and explore the effects of different stimulus ranges (increase/decrease of temperature) on OA and OH. METHODS: A total of 62 participants were tested in 2 identical experiments. Offset analgesia and OH conditions included 2 different temperature deviations (±1°C/±2°C) from initial temperature and were compared with a constant temperature (control). RESULTS: Offset analgesia was successfully elicited in OA1°C in experiment 1, and in OA1°C and OA2°C in experiment 2. Results indicate a continuous stimulus-response relationship between the stimulus range and the resulting hypoalgesic response. Onset hyperalgesia was only elicited in OH2°C in experiment 1. Exploratory analysis showed that the lack of OH response in experiment 2 could be explained by sex differences, and that OA and OH responses were only weakly correlated. CONCLUSIONS: The asymmetry between pain responses after a brief temperature increase and decrease suggests that different mechanisms are involved in the pain responses to increasing and decreasing temperature. This asymmetry may also be explained by high temperatures in OA condition (+1°C/+2°C above baseline) that could be seen as salient "learning signals," which augment the response to following changes in temperature.

A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept.

Background and aims In recent years, focus on assessing descending pain modulation or conditioning pain modulation (CPM) has emerged in patients with chronic pain. This requires reliable and simple to use bed-side tools to be applied in the clinic. The aim of the present pilot study was to develop and provide proof-of-concept of a simple clinically applicable bed-side tool for assessing CPM. Methods A group of 26 healthy volunteers participated in the experiment. Pressure pain thresholds (PPT) were assessed as test stimuli from the lower leg before, during and 5 min after delivering the conditioning tonic painful pressure stimulation. The tonic stimulus was delivered for 2 min by a custom-made spring-loaded finger pressure device applying a fixed pressure (2.2 kg) to the index finger nail. The pain intensity provoked by the tonic stimulus was continuously recorded on a 0-10 cm Visual Analog Scale (VAS). Results The median tonic pain stimulus intensity was 6.7 cm (interquartile range: 4.6-8.4 cm) on the 10 cm VAS. The mean PPT increased significantly (P = 0.034) by 55 ± 126 kPa from 518 ± 173 kPa before to 573 ± 228 kPa during conditioning stimulation. When analyzing the individual CPM responses (increases in PPT), a distribution of positive and negative CPM responders was observed with 69% of the individuals classified as positive CPM responders (increased PPTs = anti-nociceptive) and the rest as negative CPM responders (no or decreased PPTs = Pro-nociceptive). This particular responder distribution explains the large variation in the averaged CPM responses observed in many CPM studies. The strongest positive CPM response was an increase of 418 kPa and the strongest negative CPM response was a decrease of 140 kPa. Conclusions The present newly developed conditioning pain stimulator provides a simple, applicable tool for routine CPM assessment in clinical practice. Further, reporting averaged CPM effects should be replaced by categorizing volunteers/patients into anti-nociceptive and pro-nociceptive CPM groups. Implications The finger pressure device provided moderate-to-high pain intensities and was useful for inducing conditioning stimuli. Therefore, the finger pressure device could be a useful bed-side method for measuring CPM in clinical settings with limited time available. Future bed-side studies involving patient populations are warranted to determine the usefulness of the method.

Scrambler therapy efficacy and safety for neuropathic pain correlated with chemotherapy-induced peripheral neuropathy in adolescents: A preliminary study.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, in need of effective treatment. Preliminary data support the efficacy of scrambler therapy (ST), a noninvasive cutaneous electrostimulation device, in adults with CIPN. We test the efficacy, safety, and durability of ST for neuropathic pain in adolescents with CIPN. PATIENTS AND METHODS: We studied nine pediatric patients with cancer and CIPN who received ST for pain control. Each patient received 45-min daily sessions for 10 consecutive days as a first step, but some of them required additional treatment. RESULTS: Pain significantly improved comparing Numeric Rate Scale after 10 days of ST (9.22 ± 0.83 vs. 2.33 ± 2.34; P < 0.001) and at the end of the optimized cycle (EOC) (9.22 ± 0.83 vs. 0.11 ± 0.33, P < 0.001). The improvement in quality of life was significantly reached on pain interference with general activity (8.67 ± 1.66 vs. 3.33 ± 2.12, P < 0.0001), mood (8.33 ± 3.32 vs. 2.78 ± 2.82, P < 0.0005), walking ability (10.00 vs. 2.78 ± 1.22, P < 0.0001), sleep (7.56 ± 2.24 vs. 2.67 ± 1.41, P < 0.001), and relations with people (7.89 ± 2.03 vs. 2.11 ± 2.03, P < 0.0002; Lansky score 26.7 ± 13.2 vs. 10 days of ST 57.8 ± 13.9, P < 0.001; 26.7 ± 13.2 vs. EOC 71.1 ± 16.2, P < 0.001). CONCLUSION: Based on these preliminary data, ST could be a good choice for adolescents with CIPN for whom pain control is difficult. ST caused total relief or dramatic reduction in CIPN pain and an improvement in quality of life, durable in follow-up. It caused no detected side effects, and can be retrained successfully. Further larger studies should be performed to confirm our promising preliminary data in pediatric patients with cancer.

Treatment of Postherpetic Pain With Scrambler Therapy, a Patient-Specific Neurocutaneous Electrical Stimulation Device.

OBJECTIVES: Postherpetic neuropathy (PHN) is common, severe, and often refractory to treatment. We treated 10 patients with refractory PHN using Scrambler therapy, a neurocutaneous stimulation device that delivers "nonpain" information with surface electrodes. METHODS: Scrambler therapy was given as 30-minute sessions daily for 10 days. Pain was recorded before and after treatment. Two centers. RESULT: The average pain score rapidly diminished from 7.64 ± 1.46 at baseline to 0.42 ± 0.89 at 1 month, a 95% reduction, with continued relief at 2 and 3 months. Patients achieved maximum pain relief with less than 5 treatments. DISCUSSION: Scrambler therapy appears to have a promising effect on PHN, with prompt and continued relief and no side effects. Further research is warranted.

Finite element method simulating temperature distribution in skin induced by 980-nm pulsed laser based on pain stimulation.

For predicting the temperature distribution within skin tissue in 980-nm laser-evoked potentials (LEPs) experiments, a five-layer finite element model (FEM-5) was constructed based on Pennes bio-heat conduction equation and the Lambert-Beer law. The prediction results of the FEM-5 model were verified by ex vivo pig skin and in vivo rat experiments. Thirty ex vivo pig skin samples were used to verify the temperature distribution predicted by the model. The output energy of the laser was 1.8, 3, and 4.4 J. The laser spot radius was 1 mm. The experiment time was 30 s. The laser stimulated the surface of the ex vivo pig skin beginning at 10 s and lasted for 40 ms. A thermocouple thermometer was used to measure the temperature of the surface and internal layers of the ex vivo pig skin, and the sampling frequency was set to 60 Hz. For the in vivo experiments, nine adult male Wistar rats weighing 180 ± 10 g were used to verify the prediction results of the model by tail-flick latency. The output energy of the laser was 1.4 and 2.08 J. The pulsed width was 40 ms. The laser spot radius was 1 mm. The Pearson product-moment correlation and Kruskal-Wallis test were used to analyze the correlation and the difference of data. The results of all experiments showed that the measured and predicted data had no significant difference (P > 0.05) and good correlation (r > 0.9). The safe laser output energy range (1.8-3 J) was also predicted. Using the FEM-5 model prediction, the effective pain depth could be accurately controlled, and the nociceptors could be selectively activated. The FEM-5 model can be extended to guide experimental research and clinical applications for humans.

Scrambler Therapy(®) MC-5A for Complex Regional Pain Syndrome: Case Reports.

BACKGROUND: Complex regional pain syndrome (CRPS) is a disorder that is often challenging to treat and can be associated with a prolonged course of severe pain. Therapy of CRPS remains controversial; the pain often can be very difficult to control, and treatment includes medications, physical therapy, regional anesthesia, and neuromodulation. AIM: We evaluated Scrambler Therapy(®) (ST) in terms of efficacy, safety, and durability of treatment effect in patients suffering from CRPS. MATERIALS AND METHODS: We report the response to ST in four patients with CRPS referred to the Pain Center of Bambino Gesù Children's Hospital. The patients previously did not respond to conventional and nonconventional medical treatments. RESULTS: The treatment with ST was found effective in all four of our patients; they obtained pain relief for long periods and an improvement in their quality of life. We observed a progressive improvement with complete disappearance of neuropathic pain. Patients also reported a muscle strength increase that allowed them to resume normal daily activities. DISCUSSION AND CONCLUSION: We conclude that ST may offer a therapeutic opportunity for patients with neuropathic pain resulting from CRPS, without side effects and with minimal discomfort during treatment. The observed pain relief indicates that ST could be an effective option for such patients.

Complex regional pain syndrome (CRPS) or continuous unilateral distal experimental pain stimulation in healthy subjects does not bias visual attention towards one hemifield.

In natural life pain automatically draws attention towards the painful body part suggesting that it interacts with different attentional mechanisms such as visual attention. Complex regional pain syndrome (CRPS) patients who typically report on chronic distally located pain of one extremity may suffer from so-called neglect-like symptoms, which have also been linked to attentional mechanisms. The purpose of the study was to further evaluate how continuous pain conditions influence visual attention. Saccade latencies were recorded in two experiments using a common visual attention paradigm whereby orientating saccades to cued or uncued lateral visual targets had to be performed. In the first experiment saccade latencies of healthy subjects were measured under two conditions: one in which continuous experimental pain stimulation was applied to the index finger to imitate a continuous pain situation, and one without pain stimulation. In the second experiment saccade latencies of patients suffering from CRPS were compared to controls. The results showed that neither the continuous experimental pain stimulation during the experiment nor the chronic pain in CRPS led to an unilateral increase of saccade latencies or to a unilateral increase of the cue effect on latency. The results show that unilateral, continuously applied pain stimuli or chronic pain have no or only very limited influence on visual attention. Differently from patients with visual neglect, patients with CRPS did not show strong side asymmetries of saccade latencies or of cue effects on saccade latencies. Thus, neglect-like clinical symptoms of CRPS patients do not involve the allocation of visual attention.

Prediction of postoperative pain by preoperative pain response to heat stimulation in total knee arthroplasty.

It has been estimated that up to 54% of the variance in postoperative pain experience may be predicted with preoperative pain responses to experimental stimuli, with suprathreshold heat pain as the most consistent test modality. This study aimed to explore whether 2 heat test paradigms could predict postoperative pain after total knee arthroplasty (TKA). Patients scheduled for elective, unilateral, primary TKA under spinal anesthesia were consecutively included in this prospective, observational study. Perioperative analgesia was standardized for all patients. Outcomes were postoperative pain during walk: from 6 to 24 hours (primary), from postoperative day (POD) 1 to 7 (secondary), and from POD 14 to 30 (tertiary). Two preoperative tonic heat stimuli with 47°C were used; short (5 seconds) and long (7 minutes) stimulation upon which patients rated their pain response on an electronic visual analog scale. Multivariate stepwise linear and logistic regressions analyses were carried out, including 8 potential preoperative explanatory variables (among these anxiety, depression, preoperative pain, and pain catastrophizing) to assess pain response to preoperative heat pain stimulation as an independent predictor for postoperative pain. A total of 100 patients were included, and 3 were later excluded. A weak correlation [rho (95% confidence interval); P value] was observed between pain from POD 1 to 7 and pain response to short [rho=0.25(0.04 to 0.44); P=.02] and to long [rho=0.27 (0.07 to 0.46); P=.01] heat pain stimulation. However, these positive correlations were not supported by the linear and logistic regression analyses, in which only anxiety, preoperative pain, and pain catastrophizing were significant explanatory variables (but with low R-squares; 0.05 to 0.08). Pain responses to 2 types of preoperative heat stimuli were not independent clinically relevant predictors for postoperative pain after TKA.

Comparing neural response to painful electrical stimulation with functional MRI at 3 and 7 T.

Progressing from 3T to 7 T functional MRI enables marked improvements of human brain imaging in vivo. Although direct comparisons demonstrated advantages concerning blood oxygen level dependent (BOLD) signal response and spatial specificity, these mostly focused on single brain regions with rather simple tasks. Considering that physiological noise also increases with higher field strength, it is not entirely clear whether the advantages of 7T translate equally to the entire brain during tasks which elicit more complex neuronal processing. Therefore, we investigated the difference between 3T and 7 T in response to transcutaneous electrical painful and non-painful stimulation in 22 healthy subjects. For painful stimuli vs. baseline, stronger activations were observed at 7 T in several brain regions including the insula and supplementary motor area, but not the secondary somatosensory cortex (p<0.05 FWE-corrected). Contrasting painful vs. non-painful stimulation limited the differences between the field strengths to the periaqueductal gray (PAG, p<0.001 uncorrected) due to a similar signal increase at 7 T for both the target and specific control condition in most brain regions. This regional specificity obtained for the PAG at higher field strengths was confirmed by an additional spatial normalization strategy optimized for the brainstem. Here, robust BOLD responses were obtained in the dorsal PAG at 7 T (p<0.05 FWE-corrected), whereas at 3T activation was completely missing for the contrast against non-painful stimuli. To summarize, our findings support previously reported benefits obtained at ultra-high field strengths also for complex activation patterns elicited by painful electrical stimulation. However, this advantage depends on the region and even more on the contrast of interest. The greatest gain at 7 T was observed within the small brainstem region of the PAG, where the increased field strength offered marked improvement for the localization of activation foci with high spatial specificity.

Validation of a Brazilian quantitative sensory testing (QST) device for the diagnosis of small fiber neuropathies / Validação de um aparelho brasileiro de teste de quantificação sensitiva brasileiro para o diagnóstico de neuropatia de fibras finas

Quantitative sensory testing (QST) is defined as the determination of thresholds for sensory perception under controlled stimulus. Our aim was to validate a new QST device for Brazilian sample. In 20 healthy adults, thermoalgesic thresholds were assessed using a QST prototype (Heat Pain Stimulator-1.1.10; Brazil). A 30 × 30 mm² thermode with a 1°C/s stimulus change rate were applied. Thresholds of three consecutive stimuli were averaged in two different sessions separated by at least two weeks. Additionally long thermal heat pain stimulus was performed. To evaluate the consistency of our method we also analyzed 11 patients with small fiber neuropathy. Results showed good reproducibility of thermal perception thresholds in normal individuals and plausible abnormal thresholds in patients. We conclude that our QST device is reliable when analyzing the nociceptive pathway in controls and patients.

Teste de quantificação sensitiva (TQS) significa determinação de limiares de percepção sensitiva frente a um estímulo de intensidade controlada. Nosso objetivo foi validar um novo equipamento de TQS adaptado à população brasileira. Em 20 adultos saudáveis, limiares termoalgésicos foram avaliados, utilizando um aparelho protótipo do TQS (Heat Pain Stimulator-1.1.10; Brazil). Foi utilizado um termodo de 30 × 30 mm², com estímulo térmico de 1°C/s. A média dos limiares de três estímulos consecutivos foi obtida em duas sessões diferentes, separadas por pelo menos 2 semanas. Adicionalmente, foram aplicados estímulos térmicos dolorosos de longa duração. Para avaliar a consistência do nosso método, foram também analisados 11 pacientes com neuropatia de fibras finas. Os resultados mostraram boa reprodutibilidade dos limiares de percepção nos indivíduos saudáveis, assim como limiares anormais nos pacientes. Em conclusão, nosso aparelho de TQS apresentou boa confiabilidade ao analisar a via nociceptiva de controles e pacientes.

Psychophysiological responses to pain stimulation and cognitive tasks in female temporomandibular disorder patients.

Background and purpose Psychophysiological factors may contribute to the development of temporomandibular disorders (TMD). Both local orofacial and systemic responses have been investigated. However, most studies have concentrated on physiological responding during cognitive challenges, while responses during painful tasks may be highly relevant for the development of chronic pain conditions. Moreover, the relationship between experimental challenges and physiological responding may be influenced by affective responses during the experimental tasks, an issue not often considered in the literature. Methods This study compared electromyography (EMG) of the left masseter and left trapezius muscles, orofacial and digital skin blood-flow (SBF), mean arterial pressure (MAP), and heart rate (HR) at rest, during orofacial isometric contraction, electrocutaneous pain stimulation of the left hand, pressure pain stimulation of the masseter muscle and the sternum, and three cognitive tasks (reading aloud, a simulated job interview, and visuomotoric tracking). The participants were 25 TMD patients and 25 matched pain-free controls, all females. Affective responses were assessed with the State part of the State-Trait Personality Inventory and with Visual Analogue Scales. Results Masseter EMG levels were significantly lower in the TMD group relative to the control group during jaw contraction, pressure pain stimulation, the relaxation periods, and cognitive tasks. SBF, MAP, and HR responses were largely similar in the two groups, with SBF responses to pain stimulation evident at lower levels of stimulation than previously found. The TMD patients reported significantly higher levels of negative affect during the experiment. Conclusions and implications The low EMG responses in the TMD group may be taken in support of the Pain Adaptation Model of musculoskeletal pain, in which reduced muscular activity serves to protect a painful area. However, it may also be supportive of the Integrated Pain Adaptation Model, where higher central nervous structures influence local muscular output. The group similarities in systemic physiological responding in combination with the elevated levels of negative state affect in the TMD patients confirm previous reports of psychosocial differences being more reliable indicators of TMD than generalized physiological responding.