Human Experimental Pain Research Articles

The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects.

Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. Furthermore, fenobam showed no signs of analgesic tolerance with up to 2 weeks of daily dosing in mice. Analgesic effects of fenobam in humans have not been reported. The purpose of this investigation was to evaluate fenobam pharmacokinetics and analgesic effects in humans. We first evaluated single-dose oral fenobam disposition in a parallel-group dose-escalation study in healthy volunteers. A second investigation tested the analgesic effects of fenobam in an established experimental human pain model of cutaneous sensitization using capsaicin cream and heat, in a double-blind placebo-controlled study. The primary outcome measure was the area of hyperalgesia and allodynia around the area applied with heat/capsaicin. Secondary outcome measures included nociception, measured as pain rating on a visual analog scale, heat pain detection threshold, and effects on cognition and mood. Fenobam plasma exposures showed considerable interindividual variability and were not linear with dose. Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.

Neural oscillations and connectivity characterizing the state of tonic experimental pain in humans.

Pain is a complex phenomenon that is served by neural oscillations and connectivity involving different brain areas and frequencies. Here, we aimed to systematically and comprehensively assess the pattern of neural oscillations and connectivity characterizing the state of tonic experimental pain in humans. To this end, we applied 10‐min heat pain stimuli consecutively to the right and left hand of 39 healthy participants and recorded electroencephalography. We systematically analyzed global and local measures of oscillatory brain activity, connectivity, and graph theory‐based network measures during tonic pain and compared them to a nonpainful control condition. Local measures showed suppressions of oscillatory activity at alpha frequencies together with stronger connectivity at alpha and beta frequencies in sensorimotor areas during tonic pain. Furthermore, sensorimotor areas contralateral to stimulation showed significantly increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies. Together, these observations indicate that the state of tonic experimental pain is associated with a sensorimotor‐prefrontal network connected at alpha frequencies. These findings represent a step further toward understanding the brain mechanisms underlying long‐lasting pain states in health and disease.

Generating knowledge from complex data sets in human experimental pain research

Pain has acomplex pathophysiology that is expressed in multifaceted and heterogeneous clinical phenotypes. This makes research on pain and its treatment apotentially data-rich field as large amounts of complex data are generated. Typical sources of such data are investigations with functional magnetic resonance imaging, complex quantitative sensory testing, next-generation DNA sequencing and functional genomic research approaches, such as those aimed at analgesic drug discovery or repositioning of drugs known from other indications as new analgesics. Extracting information from these big data requires complex data scientific-based methods belonging more to computer science than to statistics. Aparticular interest is currently focused on machine learning, the methods of which are used for the detection of interesting and biologically meaningful structures in high-dimensional data. Subsequently, classifiers can be created that predict clinical phenotypes from, e.g. clinical or genetic features acquired from subjects. In addition, knowledge discovery in big data accessible in electronic knowledge bases, can be used to generate hypotheses and to exploit the accumulated knowledge about pain for the discovery of new analgesic drugs. This enables so-called data-information-knowledge-wisdom (DIKW) approaches to be followed in pain research. This article highlights current examples from pain research to provide an overview about contemporary data scientific methods used in this field of research.

Central Sensitization, N-methyl-D-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development.

Central Sensitization, N-methyl-D-aspartate Receptors, and Human Experimental Pain Models: Bridging the Gap between Target Discovery and Drug Development.

Static magnetic field exposure in 1.5 and 3Tesla MR scanners does not influence pain and touch perception in healthy volunteers.

Magnetic field therapy is a popular approach to pain therapy, but scientific evidence on treatment effects or even effects on sensory and pain perception in healthy controls is scarce. In the present randomized, placebo-controlled study, we investigated the influence of static magnetic field exposure on sensory (touch) and pain (pinprick, pressure and heat) perception. Eighteen healthy volunteers (age: 23±2years, nine women) underwent three 10-min static magnetic field exposures using field strengths of 0T (placebo), 1.5T and 3T within clinical MR scanners in randomized order on three separate days. Participants were blinded to magnetic field strength. Experimental sensory and pain testing was performed immediately before and after each magnetic field exposure. There was no significant effect of field strength on the assessed experimental sensory and pain testing parameters (mechanical detection threshold, pinprick threshold, pressure pain threshold, heat pain threshold and suprathreshold heat pain rating). We found no evidence that a 10-min 1.5T or 3T static magnetic field exposure affects experimental sensory or pain perception in young healthy volunteers. We used clinical MR scanners to investigate the effect of magnetic fields on pain perception. Using a rigorous, straightforward, placebo-controlled design, no effect of static magnetic fields on human experimental pain perception was detected. This provides a base for a more systematic investigation of magnetic field effects on pain.

Impact of suggestion on the human experimental model of cold hyperalgesia after topical application of high-concentration menthol [40%

Human experimental pain models in healthy subjects offer unique possibilities to study mechanisms of pain within a defined setting of expected pain symptoms, signs and mechanisms. Previous trials in healthy subjects demonstrated that topical application of 40% menthol is suitable to induce cold hyperalgesia. The objective of this study was to evaluate the impact of suggestion on this experimental human pain model. The study was performed within a single-centre, randomized, placebo-controlled, double-blind, two-period crossover trial in a cohort of 16 healthy subjects. Subjects were tested twice after topical menthol application (40% dissolved in ethanol) and twice after ethanol (as placebo) application. In the style of a balanced placebo trial design, the subjects received during half of the testing the correct information about the applied substance (topical menthol or ethanol) and during half of the testing the incorrect information, leading to four tested conditions (treatment conditions: menthol-told-menthol and menthol-told-ethanol; placebo conditions: ethanol-told-menthol and ethanol-told-ethanol). Cold but not mechanical hyperalgesia was reliably induced by the model. The cold pain threshold decreased in both treatment conditions regardless whether true or false information was given. Minor suggestion effects were found in subjects with prior ethanol application. The menthol model is a reliable, nonsuggestible model to induce cold hyperalgesia. Mechanical hyperalgesia is not as reliable to induce. Cold hyperalgesia may be investigated under unbiased and suggestion-free conditions using the menthol model of pain.

The effects of audiovisual distraction on the muscle sympathetic responses to experimental muscle pain.

Pain elicited by intramuscular infusion of hypertonic saline solution causes muscle sympathetic nerve activity (MSNA) to increase in some subjects, yet decrease in others. Although the direction of the response is not predictable based on baseline physiological and psychological parameters, we know that it results from sustained functional changes in specific brain regions that are responsible for the behavioral and cardiovascular responses to psychological stressors, as well as those involved in attention. The aim of this study was to investigate whether MSNA responses to experimental muscle pain in humans could be altered with an audiovisual stimulus that served to distract them from the pain. MSNA was recorded from the left common peroneal nerve of 20 young healthy individuals during a 45-min intramuscular infusion of hypertonic saline solution into the ipsilateral tibialis anterior muscle. The distracting stimulus commenced 15min after the start of the infusion and lasted for 15min. Fifteen subjects showed an increase in mean burst amplitude of MSNA (to 176.4 ± 7.9% of baseline), while five showed a decrease (to 73.1 ± 5.2% of baseline); distraction had no effect on these profiles. These results indicate that even though the subjects were attending to the audiovisual stimulus, and were presumably distracted from the pain, it failed to alter the MSNA responses to muscle pain.

A variant in the SCN10A enhancer may affect human mechanical pain sensitivity.

Expression of Nav1.8, encoded by SCN10A, can affect pain transmission and thus mediate the human pain phenotype. In the current study, we assessed whether the variant rs6801957, located in the SCN10A enhancer region, may have the potential to affect human pain. Through dual-luciferase reporter assays in 293T cells, we found that the SCN10A enhancer A (Enh-A) increased the activity of the SCN10A promoter (P < 0.05). Additionally, in a cohort of 309 healthy women, mutant rs6801957 A/A was found to have a significant association with decreased human experimental mechanical pain sensitivity (P < 0.05). We then found that mutant genotype A/A suppressed the increased effect of Enh-A compared with wild-type G/G (P < 0.05). The association between rs6801957 and human experimental mechanical pain sensitivity was further validated in a larger cohort of 1005 women (P < 0.05). In conclusion, these results demonstrated that the variant rs6801957 and Enh-A may affect SCN10A gene expression and play an important role in human mechanical pain sensitivity.

Acid-induced experimental knee pain and hyperalgesia in healthy humans.

Inflammation and the related acidity in peri-articular structures may be involved in pain generation and hyperalgesia in knee osteoarthritis. This study investigated pain and associated hyperalgesia provoked by infusion of acidic saline into the infrapatellar fat pad. Twenty-eight subjects participated in two sessions in which acidic saline (AS, pH 5) or neutral saline (NS, pH 7.4) were infused into the infrapatellar fat pad for 15min. Pain intensity, pain area, mechanical and thermal sensitivity, and maximal voluntary knee extension force were recorded. Repeated infusions were performed in 14 subjects. Infusion of AS caused significantly higher pain intensity, larger pain areas, induced hyperalgesia around the infused knee, and reduced extension force. No significant pain facilitation or spreading of hyperalgesia was found after repeated infusions as compared with single infusions. Acidic saline infused into the infrapatellar fat pad provoked pain and localized mechanical hyperalgesia. Thus, this acid-induced pain model may mimic the early-stage responses to tissue injury of knee osteoarthritis.

Characterization of a novel capsaicin/heat ongoing pain model.

Human experimental pain models provide an important translational link between pre-clinical models and clinical pain. Using topical capsaicin and continuous heat application, the novel capsaicin/heat ongoing pain (CHOP) model induces long-lasting experimental pain of which the perceived intensity can be individually adjusted. In the CHOP model, capsaicin or control cream is applied to a 10×10cm skin area and a heating pad is applied over the area after cream removal. Two experiments in healthy participants were performed for model characterization. In Experiment 1, a constant temperature was applied for 60min; in Experiment 2, temperature was adjusted to maintain a constant perceived intensity for 60min. Experiment 1: across participants, constant temperature induced initial habituation followed by an increase in sensation back to baseline. Cluster analysis revealed that half the participants sensitized to the constant temperature, while the other half did not. The degree of sensitization was related to the baseline pain unpleasantness, relative to pain intensity. Experiment 2: constant perceived intensity was achieved in the painful and a non-painful control condition. The two conditions did not differ regarding possibly confounding variables, including blood pressure, heart rate, inflammation or physiological stress as measured by surrogate markers. Secondary allodynia and hyperalgesia were reported more following painful compared to control stimulation. Sensitizers as determined in Experiment 1 were also more pain sensitive in Experiment 2. The CHOP model reproduces some aspects of clinical pain, such as longer duration, sensitization, secondary allodynia and hyperalgesia. Here we demonstrate a novel pain model that can be applied for up to an hour without tissue damage. The CHOP model allows for investigation of primary and secondary hyperalgesia as well as top-down influences on sensitization, thereby providing an experimental model that can be used to assess clinically-oriented questions.

Effect of Intravenous Alfentanil on Nonpainful Thermally Induced Hyperalgesia in Healthy Volunteers.

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses nonpainful heat to induce secondary hyperalgesia. This study evaluated the effect of intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo-controlled crossover study consisting of 2 sessions, 1 with alfentanil and 1 with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/mL for 1 hour followed by the application of a 40°C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1°C every 15 minutes until the subject reported pain or 45°C was reached. After the end point was reached, the temperature was maintained, and repeat testing was performed. The nonpainful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right vs untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (P < .05) but failed to reduce the area of secondary hyperalgesia created by nonpainful heat when compared to placebo (P = .06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a nonpainful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

P302 Search for optimal protocol of temporal summation of experimental heat pain in healthy volunteers

Question Experimental human pain models are often insufficient to detect moderate effect of non-opioid analgesic drugs or hypoalgesic neuromodulation. Measurement of temporal summation of pain (TSP) is a promising tool for this purpose. The aim was to find out optimal stimulation parameters for a new protocol that consistently reproduces the TSP phenomenon. Material & methods Twenty healthy volunteers (15 females) underwent 4 sessions with different stimulation parameters with an interval of at least 48 h in-between. After determining the individual pain threshold temperature, pulsating heat stimuli were applied to the left ventral forearm with a ramp rate of 20°C/s and a frequency of 0.33 Hz using a CHEPS thermode (Medoc, Israel). Stimulation temperature, pulse duration and number of stimuli were changed among the conditions I–IV ( Download high-res image (124KB) Download full-size image Table 1). Participants rated the perceived pain of the first and every 10th heat stimulation using a numeric rating scale 0–100. TSP was calculated as the difference between the lowest rating and the rating of the last stimulus and was compared among 4 conditions. Results Condition IV yielded the largest TSP effect (20 ± 3.1; mean ± SEM), which was higher than TSP effect of condition I (7.9 ± 2.2; p = 0.03) and II (6.8 ± 1.5; p = 0.012; Fig. 1). TSP effects of condition III and IV were comparable, however condition IV caused discomfort and intolerable pain in 9 participants; no one complained about discomfort during other conditions. Conclusion The protocol with high number of repeated stimuli and short pulse duration ( Download high-res image (237KB) Download full-size image

The interaction between NGF-induced hyperalgesia and acid-provoked pain in the infrapatellar fat pad and tibialis anterior muscle of healthy volunteers.

Tissue pH is lowered in inflamed tissues, and the increased proton concentration activates acid-sensing ion channels (ASICs), contributing to pain and hyperalgesia. ASICs can be upregulated by nerve growth factor (NGF). The aim of this study was to investigate two new human experimental pain models combining NGF- and acid-induced pain in a randomized, controlled, double-blind study. In experiment 1, volunteers (N=16) received an injection of either NGF or isotonic saline in each infrapatellar fat pad (IFP). One day after 5mL of phosphate-buffered acidic saline was infused into each IFP at a rate of 20mL/h. In experiment 2, the tibialis anterior (TA) muscle of additional volunteers (N=16) was examined, following the same procedure except that the volume and infusion rate of acid were different (10mL, 30mL/h). Continuous pain ratings were recorded during and after acid infusions. In addition, soreness scores on a Likert scale and pressure pain thresholds (PPTs) were assessed. The PPT of the IFP was significantly decreased at the NGF injection site on day 1, but acid-provoked pain ratings and the change in PPT from pre- to postinfusion between the knees were similar. In the muscle pain model, local mechanical hyperalgesia developed 3h after the NGF injection and a significant additional decrease in PPT was found after acid infusion compared to preinfusion. NGF sensitization in the IFP was not facilitated by acid, whereas an acid-provoked enhancement of muscle hyperalgesia was found. NGF sensitization of adipose tissue responds differently to acid provocation compared to muscle tissue. Quantification of two novel pain models combining NGF and acid. Hyperalgesia developed after NGF injection in the infrapatellar fat pad, but it was not facilitated by acid provocation. Contrary, NGF-induced hyperalgesia in muscle tissue was enhanced by acid.

A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.

This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

Acute analgesic effects of nicotine and tobacco in humans: a meta-analysis.

Although animal models have consistently demonstrated acute pain inhibitory effects of nicotine and tobacco, human experimental studies have yielded mixed results. The main goal of this meta-analysis was to quantify the effects of nicotine/tobacco administration on human experimental pain threshold and tolerance ratings. A search of PubMed and PsycINFO online databases identified 13 eligible articles, including k = 21 tests of pain tolerance (N = 393) and k = 15 tests of pain threshold (N = 339). Meta-analytic integration for both threshold and tolerance outcomes revealed that nicotine administered through tobacco smoke and other delivery systems (eg, patch, nasal spray) produced acute analgesic effects that may be characterized as small to medium in magnitude (Hedges g = 0.35, 95% confidence interval = 0.21-0.50). Publication bias-corrected estimates remained significant and indicated that these effects may be closer to small. Sex composition was observed to be a significant moderator, such that pain threshold effects were more robust among samples that included more men than women. These results help to clarify a mixed literature and may ultimately help to inform the treatment of both pain and nicotine dependence. Pain and tobacco smoking are both highly prevalent and comorbid conditions. Current smoking has been associated with more severe chronic pain and physical impairment. Acute nicotine-induced analgesia could make smoking more rewarding and harder to give up. Future research should use dynamic measures of experimental pain reactivity and further explore biopsychosocial mechanisms of action.

Activation of different cortical areas may be responsible for the divergent sympathetic responses to long-lasting experimental muscle pain in humans

Activation of different cortical areas may be responsible for the divergent sympathetic responses to long-lasting experimental muscle pain in humans

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

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.

Movement Evoked Pain and Mechanical Hyperalgesia after Intramuscular Injection of Nerve Growth Factor: A Model of Sustained Elbow Pain.

Lateral epicondylalgia presents as lateral elbow pain provoked by upper limb tasks. An experimental model of elbow pain provoked by movement/muscle contraction and maintained over several days is required to better understand the mechanisms underlying sustained elbow pain. This study investigated the time course and pain location induced by nerve growth factor (NGF) injection into a wrist extensor muscle, and whether movement and muscle contraction/stretch provoked pain. On Day 0 twenty-six painfree volunteers were injected with NGF (N = 13) or isotonic saline (randomized) into the extensor carpi radialis brevis (ECRB) muscle of the dominant arm. On Day 2 pain was induced in all participants by hypertonic saline injection into ECRB. A Likert scale and patient-rated tennis elbow evaluation (PRTEE) was used to assess pain and functional limitation (Days 0-10). Pain intensity during contraction/stretch of ECRB, and pressure pain thresholds (PPTs) were recorded before and after injections on Days 0 and 2, and Days 4 and 10. Compared with isotonic saline, NGF evoked: i) greater Likert pain ratings from 12 hours post-injection until Day 6, ii) greater PRTEE scores on Days 2 and 4, iii) greater pain during ECRB contraction/stretch on Day 2, and iv) lower PPTs on Day 4. This article presents a novel experimental human pain model suitable to study the sustained effects of lateral elbow pain on sensorimotor function and to probe the mechanisms underlying persistent musculoskeletal pain.

A small yet comprehensive subset of human experimental pain models emerging from correlation analysis with a clinical quantitative sensory testing protocol in healthy subjects.

Picturing the complexity of pain in human experimental settings has increased the predictivity for clinical pain but requires increasingly complex test batteries. This raises problems in studies in which time is objectively limited, for example by the course of action of an analgesic drug. We addressed the selection of a small yet comprehensive set of pain tests for the use in such a situation. Nineteen different pain measures from 'classical' pain models (n = 9) and a clinically established QST-pain test battery (n = 10), were obtained from 72 healthy volunteers (34 men). The nonparametric correlation structure among the various pain measures was analysed using Ward clustering. Four clusters emerged, each consisting of highly correlated pain measures. The pain model groups emerged comprised (I) pain thresholds and tolerances to blunt pressure or electrical pain; (II) pain thresholds to thermal stimuli; (III) pain measures obtained following application of punctate mechanical, intranasal CO2 chemical or cutaneous laser heat stimuli; and (IV) detection thresholds to thermal stimuli. The first three clusters agreed with an immediate mechanistic interpretation as reflecting C-fibre mediated pain, thermal pain and Aδ-fibre mediated pain, respectively, whereas the last cluster contained non-painful measures and was disregarded. When basing a selection of a small comprehensive set of pain models on the assumption that highly correlated pain measures account for redundant results and therefore, one member of each group suffices an economic yet comprehensive pain study, results suggest inclusion of established C-fibre, Aδ-fibre mediated and thermal pain measures.

Age differences in cytokine expression under conditions of health using experimental pain models

Older adults are at an increased risk to develop frequent and prolonged pain. Emerging evidence proposes a link between immune changes and pain, which is consistent with the inflammation theory of aging and the increased incidence of age-related diseases. This study tested the hypothesis that older adults show greater immune responses to experimental pain compared to younger individuals. Study subjects (8 younger and 9 older healthy adults) underwent 3 experimental sessions using well-validated human experimental pain models: the cold pressor task (CPT), focal heat pain (FHP), and a non-painful thermal control. Blood was collected through an indwelling catheter at baseline and 3, 15, 30, 45, 60, and 90min post-stimuli administration. Pro-inflammatory cytokines (TNF-α IL-6 and IL-8) peaked at the same time points for both groups, with greater elevations among older subjects for TNF-α and IL-8 in both pain models and elevations in IL-6 only for CPT. Anti-inflammatory cytokines (IL-4, IL-5, and IL-10) generally peaked later for the older subjects, with increased elevations for FHP but not the CPT. These data are consistent with the assertion that age-related immune system dysregulation may account for the increased prevalence of pain in older adults.