Effect of magnetic nanoparticles containing ropivacaine on ankle nerve block in rats

Ropivacaine (RVC), a common pain management drug used for clinical anesthesia and postoperative analgesia, inhibits peripheral nociceptive pain stimulation. However, the potential neurological damage resulting from RVC use must be considered. Developing a strategy to enhance the local anesthetic effect of RVC while reducing its potential acute toxicity to the central nervous system is urgently needed. In this study, a novel RVC nanocomposite drug, magnetic iron oxide/polyethylene glycol-carboxymethyl chitosan/ropivacaine nanoparticle (mCMCS-PEG/RVC NPs), was synthesized with magnetic iron oxide. The inherent shell–core structure of mCMCS-PEG retained core magnetic properties, improved the stability and biocompatibility of magnetic nanoparticles, and avoided excessive degradation. Thus, mCMCS-PEG/RVC NPs are expected to provide a new pain management strategy for perioperative patients.

An Investigation of Descending Pain Modulation in Women With Provoked Vestibulodynia: Alterations of Brain Connectivity

Provoked Vestibulodynia (PVD) is the most common vulvodynia subtype (idiopathic chronic vulvar pain). Functional magnetic resonance imaging (fMRI) studies indicate that women with PVD exhibit altered function in a number of pain modulatory regions in response to noxious stimulation, such as in the secondary somatosensory cortex, insula, dorsal midcingulate, posterior cingulate, and thalamus. However, previous neuroimaging studies of PVD have not examined periods of time before and after noxious stimulation or investigated functional connectivity among pain modulatory regions. Fourteen women with PVD and 14 matched Control participants underwent five fMRI runs with no painful stimuli interleaved randomly with five runs with calibrated, moderately painful heat stimuli applied to the thenar eminence. As recent findings indicate that pain processing begins before and continues after painful stimulation, 2-min periods were included in each run before and after the stimulus. Functional brain connectivity was assessed during both trials of Pain and No Pain stimulation for each group using structural equation modeling (SEM). Analyses of variance (ANOVAs) on connectivity values demonstrated significant main effects of study condition, and group, for connectivity among pain modulatory regions. Most of the differences between the Pain and No Pain conditions found only in the PVD group take place before (i.e., thalamus to INS, ACC to S1, thalamus to S1, and thalamus to S2) and after pain stimulation (i.e., INS to amygdala, PPC to S1, and thalamus to S2). Such differences were not observed in the Control group. These findings further support previous results indicating that women with PVD have altered pain processing compared to pain-free women.

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 US. The current gold standard to quantify pain is highly subjective, based upon self-reporting with numerical or visual analog scales (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 macro-averaged 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.

Real-Time High-Level Acute Pain Detection Using a Smartphone and a Wrist-Worn Electrodermal Activity Sensor

The subjectiveness of pain can lead to inaccurate prescribing of pain medication, which can exacerbate drug addiction and overdose. Given that pain is often experienced in patients’ homes, there is an urgent need for ambulatory devices that can quantify pain in real-time. We implemented three time- and frequency-domain electrodermal activity (EDA) indices in our smartphone application that collects EDA signals using a wrist-worn device. We then evaluated our computational algorithms using thermal grill data from ten subjects. The thermal grill delivered a level of pain that was calibrated for each subject to be 8 out of 10 on a visual analog scale (VAS). Furthermore, we simulated the real-time processing of the smartphone application using a dataset pre-collected from another group of fifteen subjects who underwent pain stimulation using electrical pulses, which elicited a VAS pain score level 7 out of 10. All EDA features showed significant difference between painless and pain segments, termed for the 5-s segments before and after each pain stimulus. Random forest showed the highest accuracy in detecting pain, 81.5%, with 78.9% sensitivity and 84.2% specificity with leave-one-subject-out cross-validation approach. Our results show the potential of a smartphone application to provide near real-time objective pain detection.

Preferred musical attribute dimensions underlie individual differences in music-induced analgesia

Music-induced analgesia (MIA) is a phenomenon that describes a situation in which listening to music influences pain perception. The heterogeneity of music used in MIA studies leads to a problem of a specific effect for an unspecified stimulus. To address this, we use a previously established model of musical preferences that categorizes the multidimensional sonic space of music into three basic dimensions: arousal, valence and depth. Participants entered an experimental pain stimulation while listening to compilations of short musical excerpts characteristic of each of the three attribute dimensions. The results showed an effect on the part of music attribute preferences on average pain, maximal pain, and pain tolerance after controlling for musical attributes and order effects. This suggests that individual preferences for music attributes play a significant role in MIA and that, in clinical contexts, music should not be chosen arbitrarily but according to individual preferences.

The autonomic pain relief response is dependent of self or social influence on pain

Pain relief is defined as the ease of pain and is thus highly relevant for clinical applications and everyday life. Given that pain relief is based on the cessation of an aversive pain experience, it is reasonable to assume that pain relief learning would also be shaped by factors that alter subjective and physiological pain responses, such as social presence or a feeling of control. To date, it remains unclear whether and how factors that shape autonomic pain responses might affect pain relief learning. Here, we investigated how pain relief learning is shaped by two important factors known to modulate pain responses, i.e. social influence and controllability of pain. Skin conductance responses (SCRs) were recorded while participants learned to associate a formerly neutral stimulus with pain relief under three different pain conditions. In the social-influence condition (N = 34), the pain stimulation could be influenced by another person’s decisions. In the self-influence condition (N = 31), the participants themselves could influence the pain stimulation. Finally, in the no-influence condition (N = 32), pain stimulation was simply delivered without any influence. According to our results, the SCRs elicited by the stimulus that was associated with pain relief were significantly smaller compared to the SCRs elicited by a neutral control stimulus, indicating pain relief learning. However, there was no difference in the pain relief learning effect across the groups. These results suggest that physiological pain relief learning in humans is independent of social influence and pain controllability.

Association of serotonin transporter-linked polymorphic region (5-HTTLPR) with heat pain stimulation and postoperative pain in gastric cancer patients

Background The aim of this study was to assess whether the genotype of the serotonin transporter-linked polymorphic region (5-HTTLPR) in gastric cancer patients is associated with postoperative pain and pain threshold. Methods We conducted a prospective cohort study of 251 patients scheduled for gastrectomy from May to September 2019. All patients enrolled in the study were asked to complete the Hospital Anxiety and Depression Scale questionnaire. Heat pain threshold (HPT), cold pain threshold (CPT) and Pressure pain threshold (PPT) were measured for all participants one day prior to surgery. Blood samples were collected for genetic testing. All patients were connected to a patient-controlled intravenous analgesia (PCIA) pump at the end of the surgery. After exclusion of 15 patients, the postoperative conditions of 236 patients were recorded. Results Distribution of homozygous long (L/L), heterozygous (L/S), and homozygous short (S/S) 5-HTTLPR genotypes among participants were 26 (11.0%), 91 (38.6%), and 119 (50.4%), respectively. Heat pain threshold ( P = 0.038) and Numerical rating scale (NRS) in the 1st postoperative 24 h ( P = 0.026) were significantly different between long (L/L) and short (S/S) genotype carriers. Conclusions In patients with gastric cancer, heat pain stimulation is associated with 5-HTTLPR polymorphism, and postoperative pain may be related to 5-HTTLPR polymorphism.

An Exploratory Study Testing Autonomic Reactivity to Pain in Women with Sensory Over-Responsiveness

Background: Difficulty modulating sensory input related to multi-sensory integration dysfunction, specifically the sensory over-responsive (SOR) type, is associated with psychological distress and hyperalgesia in children and adults. Scares reports suggest atypical autonomic nervous system (ANS) reactivity to innocuous sensory stimuli in children with SOR. Thus, the ANS may contribute to sensory stimuli responses and psychological distress. This exploratory study aimed to characterize the ANS reactivity to single and dual pain stimulation, and in relation to psychological distress in adults with SOR. Methods: Healthy women with SOR (n = 9) vs. without SOR (n = 9) underwent two runs of single pain stimulation and a third run comprised of dual pain stimulation. Pain was self-rated, while heart rate variability was measured and analyzed in the time and frequency domains. In addition, questionnaires assessing anxiety and somatization were utilized. Results: While controls demonstrated a vagal tone withdrawal (root mean square of successive differences in R-R-intervals; (RMSSD)) p = 0.029 from base-line to the third run, this was absent in the SOR group. However, no group differences were found in pain ratings. Furthermore, groups differed in the correlations between R-R mean and the level of both anxiety (p = 0.006) and somatization (p < 0.001); while in the SOR group, higher levels of anxiety and somatization correlated with shorter R-R intervals, the opposite was found in the control group. Conclusions: This is the first study to demonstrate in women with SOR atypical vagal tone reactivity to challenging pain load. Vagal tone reactivity is related to both pain ratings and psychological distress.