Immune Biomarker Response Depends on Choice of Experimental Pain Stimulus in Healthy Adults: A Preliminary Study

Few studies in healthy subjects have examined the neuroimmune responses associated with specific experimental pain stimuli, while none has measured multiple biomarkers simultaneously. The aim of the present study was to compare the neuro-immune responses following two common experimental pain stimuli: cold pressor test (CPT) and focal heat pain (FHP). Eight adults participated in two counterbalanced experimental sessions of FHP or CPT with continuous pain ratings and blood sampling before and 30 minutes after the sessions. Despite similar pain intensity ratings (FHP = 42.2±15.3; CPT = 44.5±34.1; P=0.871), CPT and FHP induced different neuro-immune biomarker responses. CPT was accompanied by significant increases in cortisol (P=0.046) and anti-inflammatory cytokine IL-10 (P=0.043) with significant decreases in several pro-inflammatory mediators (IL-1β (P=0.028), IL-12 (P=0.012), TNF-α (P=0.039), and MCP-1 (P=0.038)). There were nonsignificant biomarker changes during the FHP session. There were close to significant differences between the sessions for IL-1β (P=0.081), IFN-γ (P=0.072), and IL-12 (P=0.053) with biomarkers decreasing after CPT and increasing after FHP. There were stronger associations between catastrophizing and most biomarkers after CPT compared to FHP. Our results suggest that CPT is a stressful and painful stimulus, while FHP is mostly a painful stimulus. Thus, each experimental pain stimulus can activate different neuro-immune cascades, which are likely relevant for the interpretation of studies in chronic pain conditions.

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Muscle stretching – the potential role of endogenous pain inhibitory modulation on stretch tolerance

Scandinavian Journal of Pain ◽

10.1515/sjpain-2018-0334 ◽

2019 ◽

Vol 19 (2) ◽

pp. 415-422 ◽

Cited By ~ 3

Author(s):

Morten Pallisgaard Støve ◽

Rogerio Pessoto Hirata ◽

Thorvaldur Skuli Palsson

Keyword(s):

Range Of Motion ◽

Cold Pressor Test ◽

Experimental Pain ◽

Cold Pressor ◽

Knee Extension ◽

Painful Stimulus ◽

Control Group ◽

Inhibitory System ◽

Pain Group ◽

Resistive Torque

Abstract Background and aims The effect of stretching on joint range of motion is well documented and is primarily related to changes in the tolerance to stretch, but the mechanisms underlying this change are still largely unknown. The aim of this study was to investigate the influence of a remote, painful stimulus on stretch tolerance. Methods Thirty-four healthy male subjects were recruited and randomly assigned to an experimental pain group (n=17) or a control group (n=17). Passive knee extension range of motion, the activity of hamstring muscles and passive resistive torque were measured with subjects in a seated position. Three consecutive measures were performed with a 5-min interval between. A static stretch protocol was utilized in both groups to examine the effect of stretching and differences in stretch tolerance between groups. Following this, the pain-group performed a cold pressor test which is known to engage the endogenous pain inhibitory system after which measurements were repeated. Results A significant increase in knee extension range of motion was found in the pain group compared with controls (ANCOVA: p<0.05). No difference was found in muscle activity or passive resistive torque between groups (ANCOVA p>0.091). Conclusions Passive knee extension range of motion following stretching increased when following a distant, painful stimulus, potentially engaging the endogenous pain inhibitory systems. Current findings indicate a link between increased tolerance to stretch and endogenous pain inhibition. Implications The current findings may have implications for clinical practice as they indicate that a distant painful stimulus can influence range of motion in healthy individuals. This implies that the modulation of pain has significance for the efficacy of stretching which is important knowledge when prescribing stretching as part of rehabilitation.

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Does experimental pain response vary across the menstrual cycle? A methodological review

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00920.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. R245-R256 ◽

Cited By ~ 111

Author(s):

Jeffrey J. Sherman ◽

Linda LeResche

Keyword(s):

Sex Differences ◽

Menstrual Cycle ◽

Pain Sensitivity ◽

Experimental Pain ◽

Pain Response ◽

Methodological Review ◽

Pain Stimulus ◽

Hormonal Cycle ◽

Methodological Problems ◽

Pain Stimuli

The findings on sex differences in human experimental pain research are inconsistent. One possible factor contributing to the inconsistent findings is the female hormonal cycle, as hormone levels may affect pain sensitivity. A number of studies suggest that women's responses to experimentally evoked pain vary across the menstrual cycle. However, at least an equal number of studies suggest a lack of variability. The purpose of this article is to review the literature with emphasis on what we believe could be the reasons for the inconsistent findings, namely, differences in populations sampled, timing of experimental sessions across the menstrual cycle, and nomenclature used to identify the time (phases) in the cycle when measurements were done, nature of the pain stimuli chosen, and outcomes measured. These inconsistencies and other methodological problems associated with most experimental pain studies make it difficult to draw inferences from this literature. For the science to improve, replication of significant findings using standardized timing of sessions, pain stimulus procedures, outcomes, and hormonal assessment is necessary.

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Classification of Game Demand and the Presence of Experimental Pain Using Functional Near-Infrared Spectroscopy

Frontiers in Neuroergonomics ◽

10.3389/fnrgo.2021.695309 ◽

2021 ◽

Vol 2 ◽

Author(s):

Stephen H. Fairclough ◽

Chelsea Dobbins ◽

Kellyann Stamp

Keyword(s):

Infrared Spectroscopy ◽

Near Infrared Spectroscopy ◽

Near Infrared ◽

Cold Pressor Test ◽

Experimental Pain ◽

Cold Pressor ◽

Pain Tolerance ◽

Support Vector ◽

Test Protocol ◽

Functional Near Infrared Spectroscopy

Pain tolerance can be increased by the introduction of an active distraction, such as a computer game. This effect has been found to be moderated by game demand, i.e., increased game demand = higher pain tolerance. A study was performed to classify the level of game demand and the presence of pain using implicit measures from functional Near-InfraRed Spectroscopy (fNIRS) and heart rate features from an electrocardiogram (ECG). Twenty participants played a racing game that was configured to induce low (Easy) or high (Hard) levels of demand. Both Easy and Hard levels of game demand were played with or without the presence of experimental pain using the cold pressor test protocol. Eight channels of fNIRS data were recorded from a montage of frontal and central-parietal sites located on the midline. Features were generated from these data, a subset of which were selected for classification using the RELIEFF method. Classifiers for game demand (Easy vs. Hard) and pain (pain vs. no-pain) were developed using five methods: Support Vector Machine (SVM), k-Nearest Neighbour (kNN), Naive Bayes (NB) and Random Forest (RF). These models were validated using a ten fold cross-validation procedure. The SVM approach using features derived from fNIRS was the only method that classified game demand at higher than chance levels (accuracy = 0.66, F1 = 0.68). It was not possible to classify pain vs. no-pain at higher than chance level. The results demonstrate the viability of utilising fNIRS data to classify levels of game demand and the difficulty of classifying pain when another task is present.

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Aging Independently of the Hormonal Status Changes Pain Responses in Young Postmenopausal Women

Pain Research and Treatment ◽

10.1155/2012/693912 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Yannick Tousignant-Laflamme ◽

Serge Marchand

Keyword(s):

Postmenopausal Women ◽

Pain Threshold ◽

Pain Perception ◽

Cold Pressor Test ◽

Cold Pressor ◽

Pain Tolerance ◽

Hormonal Status ◽

Pain Pathways ◽

Pain Ratings ◽

The Mean

Both aging and hormonal status have an effect on pain perception. The goal of this study was to isolate as much as possible the effect of aging in postmenopausal women. Thirty-two women with regular menstrual cycles (RMW) and 18 postmenopausal women (PMW) underwent a 2-minute cold pressor test (CPT) to activate DNIC with a series of tonic heat pain stimulations with a contact thermode to assess ascending pain pathways. We found that this procedure induced much less pain during the first 15 seconds of stimulation the PMW group (P=0.03), while the mean thermode pain ratings, pain tolerance, pain threshold, and DNIC analgesia were similar for both groups (P>0.05). The absence of the peak pain in the PMW was probably due to reduced function of the myelinated Aδ fibers that naturally occurs with age.

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A 5-HT Antagonist (UP 26-91) versus Codeine and Placebo in a Human Experimental Pain Study

Pain Research and Management ◽

10.1155/2000/842198 ◽

2000 ◽

Vol 5 (2) ◽

pp. 135-140 ◽

Cited By ~ 2

Author(s):

Lars Arendt-Nielsen ◽

Poul Pedersen ◽

Lars Poulsen ◽

Ole Kæseler Andersen ◽

Peter Bjerring ◽

...

Keyword(s):

Serotonin Receptor ◽

Pain Threshold ◽

Statistical Significance ◽

Cold Pressor Test ◽

Experimental Pain ◽

Cold Pressor ◽

Double Blind ◽

Stimulus Response ◽

Pressor Test ◽

Pain Models

BACKGROUND: This double-blind, randomized, crossover study compared the potential analgesic effect of the serotonin receptor antagonist UP 26-91 (50 mg, 150 mg and 300 mg) with that of codeine (100 mg) and placebo by use of different human experimental pain models.SUBJECTS AND METHODS: In experiment 1, pain detection and tolerance thresholds to heat, pressure and pain ratings during the cold pressor test were measured. In experiment 2, the pain threshold to single and repetitive (temporal summation) electrical sural nerve stimulation, and the pain intensity on a visual analogue scale to supra pain threshold electrical stimulation (stimulus-response-function) were measured. Tests were performed before, and 1, 2 and 6 h after drug administration.RESULTS: UP 26-91 did not show a marked effect on the experimental pain tests. Most of the variables tended to show a better effect from codeine than from placebo, but statistical significance for peak pain was only reached during the cold pressor test (P=0.011).CONCLUSIONS: In the present doses, the serotonin antagonist UP 26-91 had no effect on the experimental pain models applied.

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The Influence of Examiner Gender on Responses to Tonic Heat Pain Assessments: A Preliminary Investigation

Frontiers in Pain Research ◽

10.3389/fpain.2021.729860 ◽

2021 ◽

Vol 2 ◽

Author(s):

Jessica F. McDougall ◽

Nicole G. N. Bailey ◽

Rohan Banga ◽

Lukas D. Linde ◽

John L. K. Kramer

Keyword(s):

Preliminary Investigation ◽

Cold Pressor Test ◽

Cold Pressor ◽

Assessment Method ◽

Gender Effects ◽

Heat Pain ◽

Sex And Gender ◽

Pain Thresholds ◽

Pain Ratings ◽

The Impact

Background: The influence of examiner gender on pain reporting has been previously explored in both research and clinical settings. However, previous investigations have been limited, with the majority of studies employing single, static assessments of pain (e.g., cold pressor test, verbal pain ratings). The impact of examiner gender on both static and dynamic heat-based pain assessments is currently unknown.Methods: Thirty eight participants (20 females aged 24.1 ± 4.44, and 18 males, aged 24.8 ± 4.54) completed two identical testing sessions, randomized to a male and female examiner in a cross-over design. Pain sensitivity was examined using heat pain thresholds, verbal pain ratings to tonic heat, computerized visual analog scale (CoVAS) rating to tonic heat, and participant-controlled temperature (PCT) heat pain assessments.Results: Female participants reported higher verbal pain to tonic heat with a female examiner compared to male participants, with similar trends for CoVAS responses to tonic heat. Conversely heat pain thresholds and PCT were not significantly influenced by experimenter gender.Conclusions: Overall, verbal ratings were the most impacted by examiner gender, with temperature-based methods such as PCT and pain thresholds showing little to no examiner gender effects. While the gender of the examiner may be an important consideration in the measurement of sex and gender differences in pain research, the choice of pain assessment method may be of similar consequence.

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Pregabalin Has Analgesic, Ventilatory, and Cognitive Effects in Combination with Remifentanil

Anesthesiology ◽

10.1097/aln.0000000000000913 ◽

2016 ◽

Vol 124 (1) ◽

pp. 141-149 ◽

Cited By ~ 37

Author(s):

Marianne Myhre ◽

Lien My Diep ◽

Audun Stubhaug

Keyword(s):

Pain Score ◽

Cold Pressor Test ◽

Experimental Pain ◽

Cold Pressor ◽

Analgesic Effects ◽

Rapid Information Processing ◽

End Tidal ◽

Double Blinded ◽

Dose Dependent ◽

Higher Doses

Abstract Background Pregabalin is widely used perioperatively. The authors explored the effects of pregabalin, remifentanil, and their combination on experimental pain, ventilatory, and cognitive function. Methods In a randomized, double-blinded crossover study, 12 volunteers received (1) pregabalin + placebo, (2) placebo + remifentanil, (3) pregabalin + remifentanil, and (4) placebo + placebo. Pregabalin 150 mg/placebo was administered twice orally. After baseline, remifentanil/placebo was given as effect-site target-controlled infusion (TCI): 0.6, 1.2, and 2.4 ng/ml. Pain during cold pressor test was scored on visual analog scale (0 to 100 mm). Ventilation was measured by spirometry and cognition tested with Color-Word Interference and Rapid Information Processing tests. Results Pain intensity after placebo was (mean) 72 mm (95% CI, 62 to 83). Pregabalin reduced pain score by −10 mm (−14 to −7, P < 0.001). Remifentanil had dose-dependent analgesic effect, reducing pain score by −47 mm (−54 to −39, P < 0.001) on highest TCI level, whereas pregabalin + remifentanil exerted additive effect, reducing pain score by −57 mm (−64 to −50, P < 0.001). Respiratory depression was potentiated by adding pregabalin to remifentanil; end-tidal carbon dioxide was 39.3 mmHg (37.2 to 41.3) with placebo, increased 1.8 mmHg (−0.9 to 4.6, P = 0.4) with pregabalin, 10.1 mmHg (4.9 to 15.4, P < 0.001) with remifentanil, and 16.4 mmHg (11.3 to 21.5, P < 0.001) with pregabalin + remifentanil on highest TCI level. The combination pregabalin + remifentanil, but not either drug alone, adversely affected all cognitive tests. Conclusions The combination of pregabalin and remifentanil had additive analgesic effects, pregabalin potentiated remifentanil ventilatory depression, and the combination adversely affected cognition. These results question the clinical benefit of the combination compared with higher doses of opioids.

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The Role of Musical Attributes in Music-induced Analgesia: A Preliminary Brief Report

10.31234/osf.io/3n7kp ◽

2018 ◽

Author(s):

Krzysztof Basiński ◽

Agata Zdun-Ryżewska ◽

Mikołaj Majkowicz

Keyword(s):

Pain Perception ◽

Experimental Pain ◽

Cold Pressor ◽

Pain Modulation ◽

Pain Tolerance ◽

Cold Pressor Task ◽

Novel Approach ◽

Pain Ratings ◽

Musical Characteristics ◽

Average Pain

Music-induced analgesia (MIA) is the ability of music to influence pain perception. Although this phenomenon has been extensively studied in recent years, only a few studies have addressed what musical characteristics are optimal for MIA. Here, we present a novel approach to this topic, using a recently proposed model of music attribute preferences. The model addresses three musical dimensions: arousal, valence, and depth. Thirty participants (fifteen women and fifteen men, M age = 37.1 years, standard deviation = 15.7) were subjected to experimental pain stimulation (cold-pressor task) while listening to music characteristic of the three attribute dimensions. There was also a control condition, where participants listened to white noise. Results showed that average pain ratings were significantly lower in arousal (p = .002) and depth (p = .01) conditions in comparison to the control condition. Furthermore, participants showed increased pain tolerance in musical conditions in comparison to the control condition (p = .04). The results contribute to better understanding of the mechanisms of pain modulation, and to the development of novel evidence-based therapies of chronic pain. In the advent of on-line music streaming services, this research opens new possibilities for music-based pain interventions.

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The effects of gabapentin in human experimental pain models

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2010.04.001 ◽

2010 ◽

Vol 1 (3) ◽

pp. 143-148 ◽

Cited By ~ 8

Author(s):

Thomas P. Enggaard ◽

Søren S. Mikkelsen ◽

Stine T. Zwisler ◽

Niels A. Klitgaard ◽

Søren H. Sindrup

Keyword(s):

Neuropathic Pain ◽

Nerve Stimulation ◽

Sural Nerve ◽

Cold Pressor Test ◽

Experimental Pain ◽

Cold Pressor ◽

Pain Model ◽

Pressor Test ◽

Pain Models ◽

Pain Detection

AbstractBackgroundThe antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain and have been shown to increase pain thresholds in healthy volunteers during repetitive electrical sural nerve stimulation causing temporal pain summation, whereas pain during the cold pressor test is unaltered by these drugs. If this pattern of effect in experimental pain models reflects potential efficacy in clinical neuropathic pain, the pain summation model may potentially be used to identify new drugs for such pain conditions. Gabapentinoids are evidence-based treatments of clinical neuropathic pain and could contribute with additional knowledge of the usefulness of the pain summation model.The aim of this studyTo test the analgesic effect of the gabapentinoid gabapentin in a sural nerve stimulation pain model including temporal pain summation and the cold pressor test.Method18 healthy volunteers completed a randomized, double-blind, cross-over trial with medication of 600 mg gabapentin orally dosed 3 times over 24 h against placebo. Pain tests were performed before and 24 h after medication including pain detection and tolerance to single sural nerve stimulation and pain summation threshold to repetitive stimulation (3 Hz). Peak pain intensity and discomfort were rated during a cold pressor test.ResultsCompared to placebo, gabapentin had a highly significant effect on the threshold of pain summation to repetitive electrical sural nerve stimulation (P = 0.009). Gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the pain detection threshold to single electrical sural nerve stimulation tended to be increased (P = 0.06). No significant differences were found on pain ratings during the cold pressor test.ConclusionGabapentin had a selective hypoalgesic effect in a human experimental pain model of temporal pain summation and the results lend further support to the usefulness of the pain summation model to identify drugs for neuropathic pain.

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Influence of memory on experienced pain during Virtual Reality analgesia

Polish Journal of Applied Psychology ◽

10.1515/pjap-2015-0020 ◽

2014 ◽

Vol 12 (4) ◽

pp. 41-52 ◽

Cited By ~ 2

Author(s):

Marcin Czub ◽

Joanna Piskorz ◽

Mateusz Misiewicz ◽

Paweł Hodowaniec ◽

Małgorzata Mrula ◽

...

Keyword(s):

Virtual Reality ◽

Pain Intensity ◽

Virtual Environments ◽

Pain Treatment ◽

Cold Water ◽

Cold Pressor Test ◽

Cold Pressor ◽

Pain Tolerance ◽

Intensity Measures ◽

Pain Stimuli

Abstract Virtual Reality (VR) technology can be applied during pain treatment, acting as an effective distractor from pain stimuli. In our paper we investigate how memory influences experienced intensity of thermal pain stimuli. An experiment (within subject design) was conducted on 35 students from various Wroclaw universities. A cold pressor test was used for pain stimulation. Participants were immersed in customized virtual environments, created for this particular study. The environments differed at the level of memory engagement while playing a game. Pain measures were determined by the length of time participants kept their hands in cold water (pain tolerance), and their pain rating intensity was measured on the VAS scale (pain intensity). Participants were asked to put their hand in a container with cold water and keep it there until the pain became difficult to bear. In both VR conditions participants kept their hands in the cold water significantly longer than in a non-VR (control) condition. Results of pain intensity measures were in conclusive. We did not find any significant differences in effectiveness in the virtual environments that were used.

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