Rony-Reuven Nir

Contact heat-evoked temporal summation: Tonic versus repetitive-phasic stimulation

Abstract Temporal summation (TS) is usually evoked by repetitive mechanical or electrical stimuli, and less commonly by tonic heat pain. The present study aimed to examine the TS induction by repetitive‐phasic versus tonic heat pain stimuli. Using 27 normal volunteers, we compared the extent of summation by three calculation methods: start‐to‐end pain rating difference, percent change, and double‐logarithmic regression of successive ratings along the stimulation. Subjects were tested twice, and the reliability of each of the paradigms was obtained. In addition, personality factors related to pain catastrophizing and anxiety level were also correlated with the psychophysical results. Both paradigms induced significant TS, with similar increases for the repetitive‐phasic and the tonic paradigms, as measured on 0–100 numerical pain scale (from 52.9 ± 11.7 to 80.2 ± 15.5, p < 0.001; and from 38.5 ± 13.3 to 75.8 ± 18.3, p < 0.001, respectively). The extent of summation was significantly correlated between the two paradigms, when calculated by absolute change (r = 0.543, p = 0.004) and by regression (r = 0.438, p = 0.025). Session‐to‐session variability was similar for both paradigms, relatively large, yet not biased. As with other psychophysical parameters, this poses some limitations on TS assessment in individual patients over time. The extent of TS induced by both paradigms was found to be associated with anxiety level and pain catastrophizing. Despite some dissimilarity between the repetitive‐phasic and the tonic paradigms, the many similarities suggest that the two represent a similar physiological process, even if not precisely the same. Future clinical applications of these tests will determine the clinical relevance of the TS paradigms presented in this study.

A psychophysical study of endogenous analgesia: the role of the conditioning pain in the induction and magnitude of conditioned pain modulation.

Endogenous analgesia (EA) can be examined experimentally using a conditioned pain modulation (CPM) paradigm. While noxious conditioning stimulation intensities (CSIs) are mainly used, it has not been fully investigated in the same experimental design whether the experienced conditioning pain level affects CPM responses. The principal goal of the present study was to characterize CPM induction and magnitudes evoked by various conditioning pain levels. Furthermore, we explored associations between conditioning pain reports and CPM responses across various CSIs. Thirty healthy, young, right‐handed males were tested with a parallel CPM paradigm. Three different CSIs (hand water‐immersion) induced mild, moderate and intense pain levels, rated 12.41±7.85, 31.57±9.56 and 58.1±11.43, respectively (0–100 numerical pain scale) (P<0.0001). Contact‐heat ‘test‐stimulus’ levels were compared before and during conditioning. Within the group, (i) CPM was induced only by the moderate and intense CSIs (Ps≤0.001); (ii) no difference was demonstrated between the magnitudes of these CPM responses. Regression analysis revealed that CPM induction was independent of the perceived conditioning pain level, but associated with the absolute CSI (P<0.0001). Conditioning pain levels were correlated across all CSIs, as were CPM magnitudes (Ps≤0.01). We conclude that among males, (i) once a CPM response is evoked by a required conditioning pain experience, its magnitude is not further affected by increasing conditioning pain and (ii) CPM magnitudes are inter‐correlated, but unrelated to conditioning pain reports. These observations may suggest that CPM responses represent an intrinsic element of an individuals EA processes, which are not significantly affected by the experienced conditioning pain.

Conditioned pain modulation.

Purpose of reviewConditioned pain modulation (CPM) paradigms have been increasingly used over the past few years to assess endogenous analgesia capacity in healthy individuals and pain patients. The current review concentrates on selected recent literature advancing our understanding and practice of CPM. Recent findingsThe main themes covered by the present CPM review include underlying mechanisms, approaches to experimental investigation, practicality in clinical practice, neurophysiological and psychophysiological correlates, and pharmacological solutions to pain modulation dysfunction. SummaryThe reviewed literature refines the methodology used for eliciting CPM responses and characterizing their physiological attributes in healthy individuals and pain patients, and exemplifies the materializing concept of individualized pain medicine through targeting impaired mechanisms of pain modulation by designated drugs for optimal pain alleviation.

Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation.

Summary Cognitively decreasing the perceived conditioning stimulus (CS) pain attenuates conditioned pain modulation (CPM) magnitude, although a ceiling effect may limit CPM enhancement after a cognitively increased CS pain. ABSTRACT Although painfulness of the conditioning stimulus (CS) is required for the activation of conditioned pain modulation (CPM), it is still unclear whether CPM expression depends on the objective physical intensity of the CS or the subjective perception of its pain. Accordingly, we cognitively manipulated the perceived CS pain, rendering the physical aspects of the CPM paradigm untouched. Baseline CPM was measured among 48 young healthy male subjects using the parallel paradigm with contact heat as test pain and hand immersion in hot water as CS. Subjects were then randomized into 4 groups, all of which were cognitively manipulated as to the CS‐induced pain: group 1, placebo (CS less painful); group 2, nocebo (CS more painful); and groups 3 and 4, the informed control groups for groups 1 and 2, respectively. CPM was reassessed after the manipulation. Comparing the groups by MANCOVA (multivariate analysis of covariance) revealed that placebo exerted decreased CS pain and consequent attenuation of CPM magnitudes, while nocebo elicited increased CS pain, but without CPM elevation (P < .0001). Within the placebo group, the reduction in CS pain was associated with diminished CPM responses (r = 0.767; P = .001); however, no such relationship characterized the nocebo group. Pain inhibition under CPM seems to depend on the perceived level of the CS pain rather than solely its physical intensity. Cognitively decreasing the perceived CS pain attenuates CPM magnitude, although a ceiling effect may limit CPM enhancement after cognitively increased CS pain. These findings emphasize the relevance of cognitive mechanisms in determining endogenous analgesia processes in humans.

Pain assessment by continuous EEG: Association between subjective perception of tonic pain and peak frequency of alpha oscillations during stimulation and at rest

Recordings of neurophysiological brain responses to noxious stimuli have been traditionally based on short stimuli, in the order of milliseconds, which induce distinct event-related potentials (ERPs). However, using such stimuli in the experimental setting is disadvantageous as they are too brief to faithfully simulate clinical pain. We aimed at utilizing continuous EEG to investigate the properties of peak alpha frequency (PAF) as an objective cortical measure associated with subjective perception of tonic pain. Five minute long continuous EEG was recorded in 18 healthy volunteers under: (i) resting-state; (ii) innocuous temperature; and (iii) psychophysically-anchored noxious temperature. Numerical pain scores (NPSs) collected during the application of tonic noxious stimuli were tested for correlation with peak frequencies of alpha power-curves derived from central, temporal and frontal electrodes. NPSs and PAFs remained stable throughout the recording conditions (RM-ANOVAs; Ps>0.51). In the noxious condition, PAFs obtained at the bilateral temporal scalp were correlated with NPSs (Ps<0.001). Moreover, resting-state PAFs recorded at the bilateral temporal scalp were correlated with NPSs reported during the noxious condition (Ps<0.01). These psychophysical-neurophysiological relations attest to the properties of PAF as a novel cortical objective measure of subjective perception of tonic pain. Moreover, resting-state PAFs might hold inherent pain modulation attributes, possibly enabling the prediction of individual responsiveness to prolonged pain. The relevance of PAF to the neural processing of tonic pain may indicate its potential to advance pain research as well as clinical pain characterization.

Neurophysiology of the Cortical Pain Network: Revisiting the Role of S1 in Subjective Pain Perception Via Standardized Low-Resolution Brain Electromagnetic Tomography (sLORETA)

UNLABELLED Multiple studies have supported the usefulness of standardized low-resolution brain electromagnetic tomography (sLORETA) in localizing generators of scalp-recorded potentials. The current study implemented sLORETA on pain event-related potentials, primarily aiming at validating this technique for pain research by identifying well-known pain-related regions. Subsequently, we pointed at investigating the still-debated and ambiguous topic of pain intensity coding at these regions, focusing on their relative impact on subjective pain perception. sLORETA revealed significant activations of the bilateral primary somatosensory (SI) and anterior cingulate cortices and of the contralateral operculoinsular and dorsolateral prefrontal (DLPFC) cortices (P < .05 for each). Activity of these regions, excluding DLPFC, correlated with subjective numerical pain scores (P < .05 for each). However, a multivariate regression analysis (R = .80; P = .024) distinguished the contralateral SI as the only region whose activation magnitude significantly predicted the subjective perception of noxious stimuli (P = .020), further substantiated by a reduced regression model (R = .75, P = .008). Based on (1) correspondence of the pain-activated regions identified by sLORETA with the acknowledged imaging-based pain-network and (2) the contralateral SI proving to be the most contributing region in pain intensity coding, we found sLORETA to be an appropriate tool for relevant pain research and further substantiated the role of SI in pain perception. PERSPECTIVE Because the literature of pain intensity coding offers inconsistent findings, the current article used a novel tool for revisiting this controversial issue. Results suggest that it is the activation magnitude of SI, which solely establishes the significant correlation with subjective pain ratings, in accordance with the classical clinical thinking, relating SI lesions to diminished perception of pain. Although this study cannot support a causal relation between SI activation magnitude and pain perception, such relation might be insinuated.

Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial

The aim of this work was to assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine.

Psychological Factors and Conditioned Pain Modulation: A Meta-Analysis.

Objective:Conditioned pain modulation (CPM) responses may be affected by psychological factors such as anxiety, depression, and pain catastrophizing; however, most studies on CPM do not address these relations as their primary outcome. The aim of this meta-analysis was to analyze the findings regarding the associations between CPM responses and psychological factors in both pain-free individuals and pain patients. Materials and Methods:After a comprehensive PubMed search, 37 articles were found to be suitable for inclusion. Analyses used DerSimonian and Laird’s random-effects model on Fisher’s z-transforms of correlations; potential publication bias was tested using funnel plots and Egger’s regression test for funnel plot asymmetry. Six meta-analyses were performed examining the correlations between anxiety, depression, and pain catastrophizing, and CPM responses in healthy individuals and pain patients. Results:No significant correlations between CPM responses and any of the examined psychological factors were found. However, a secondary analysis, comparing modality-specific CPM responses and psychological factors in healthy individuals, revealed the following: (1) pressure-based CPM responses were correlated with anxiety (grand mean correlation in original units r=−0.1087; 95% confidence limits, –0.1752 to −0.0411); (2) heat-based CPM was correlated with depression (r=0.2443; 95% confidence limits, 0.0150 to 0.4492); and (3) electrical-based CPM was correlated with pain catastrophizing levels (r=−0.1501; 95% confidence limits, −0.2403 to −0.0574). Discussion:Certain psychological factors seem to be associated with modality-specific CPM responses in healthy individuals. This potentially supports the notion that CPM paradigms evoked by different stimulation modalities represent different underlying mechanisms.

Selective inhibition of trigeminovascular neurons by fremanezumab — a humanized monoclonal anti-CGRP antibody

A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways. To answer this question, we used single-unit recording to determine the effects of fremanezumab (30 mg/kg, IV) and its isotype control Ab on spontaneous and evoked activity in naive and cortical spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats. The study demonstrates that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. In addition, when given sufficient time, fremanezumab prevents the activation and sensitization of HT neurons by CSD. Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help to explain the therapeutic benefit of CGRP-mAb in reducing headaches of intracranial origin such as migraine with aura and why this therapeutic approach may not be effective for every migraine patient. SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are capable of preventing migraine. However, their mechanism of action is unknown. In the current study, we show that, if given enough time, a CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression, but not their activation from the skin or cornea, suggesting a potential explanation for selectivity to migraine headache, but not other pains, and a predominantly peripheral site of action.

Preoperative preemptive drug administration for acute postoperative pain: A systematic review and meta-analysis

Preoperative administration of pharmacological substances, such as non‐steroidal anti‐inflammatory drugs or opioids, has been gaining acclaim as a preemptive measure to minimize postoperative pain. This systematic review and meta‐analysis aimed at evaluating the effectiveness of this approach in adults undergoing surgical procedures. MEDLINE, EMBASE and the Cochrane Central Register were searched from inception through January 2015. Data from randomized placebo‐controlled trials were screened, extracted and assessed for risk of bias according to The Cochrane Collaborations Tool by two independent authors. The primary outcome measure was reduction in postoperative analgesic consumption during 24 h post surgery; effects were described as mean differences between the drug and placebo arms with corresponding 95% confidence intervals (CIs) and were pooled using random‐effects models. Potential publication bias was tested using funnel plots and Eggers regression test for funnel plot asymmetry. Screened were 511 records, of which 39 were included in the final synthesis with data from 3172 patients. A significant reduction in postoperative analgesic consumption was observed using preoperative administration of non‐steroidal anti‐inflammatory drugs (NSAIDs; 95% CI, −0.61 to −0.14; 31 comparisons), chiefly by the COX‐2 inhibitors class (95% CI, −0.95 to −0.33; 13 comparisons). Significant reduction was also observed for gabapentin (95% CI, −1.60 to −0.38; 6 comparisons). No significant effects were observed using opioids, propionic acids or oxicam derivatives.