Human Experimental Pain Models Research Articles

Priming of the autonomic nervous system after an experimental human pain model.

Modulated autonomic responses to noxious stimulation have been reported in experimental and clinical pain. These effects are likely mediated by nociceptive sensitization, but may also, more simply reflect increased stimulus-associated arousal. To disentangle between sensitization- and arousal-mediated effects on autonomic responses to noxious input, we recorded sympathetic skin responses (SSRs) in response to 10 pinprick and heat stimuli before (PRE) and after (POST) an experimental heat pain model to induce secondary hyperalgesia (EXP) and a control model (CTRL) in 20 healthy females. Pinprick and heat stimuli were individually adapted for pain perception (4/10) across all assessments. Heart rate (HR), heart rate variability (HRV) and skin conductance (SCL) were assessed before, during, and after the experimental pain model. Both pinprick- and heat-induced SSRs habituated from PRE to POST in CTRL, but not EXP (p=0.033). Background SCL (during stimuli application) was heightened in EXP compared to CTRL condition during pinprick and heat stimuli (p=0.009). Our findings indicate that enhanced SSRs after an experimental pain model are neither fully related to subjective pain, as SSRs dissociated from perceptual responses, nor to nociceptive sensitization, as SSRs were enhanced after both modalities. Our findings can, however, be explained by priming of the autonomic nervous system during the experimental pain model, which makes the autonomic nervous system more susceptible to noxious input. Taken together, autonomic readouts have the potential to objectively assess not only nociceptive sensitization, but also priming of the autonomic nervous system, which may be involved in the generation of distinct clinical pain phenotypes.

Effects of High-Definition Transcranial Direct Current Stimulation Over the Primary Motor Cortex on Cold Pain Sensitivity Among Healthy Adults.

Some clinical studies have shown promising effects of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) on pain relief. Nevertheless, a few studies reported no significant analgesic effects of tDCS, likely due to the complexity of clinical pain conditions. Human experimental pain models that utilize indices of pain in response to well-controlled noxious stimuli can avoid many confounds that are present in the clinical data. This study aimed to investigate the effects of high-definition tDCS (HD-tDCS) stimulation over M1 on sensitivity to experimental pain and assess whether these effects could be influenced by the pain-related cognitions and emotions. A randomized, double-blinded, crossover, and sham-controlled design was adopted. A total of 28 healthy participants received anodal, cathodal, or sham HD-tDCS over M1 (1 mA for 20 min) in different sessions, in which montage has the advantage of producing more focal stimulation. Using a cold pressor test, several indices reflecting the sensitivity to cold pain were measured immediately after HD-tDCS stimulation, such as cold pain threshold and tolerance and cold pain intensity and unpleasantness ratings. Results showed that only anodal HD-tDCS significantly increased cold pain threshold when compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain tolerance, pain intensity, and unpleasantness ratings. Correlation analysis revealed that individuals that a had lower level of attentional bias to negative information benefited more from attenuating pain intensity rating induced by anodal HD-tDCS. Therefore, single-session anodal HD-tDCS modulates the sensory-discriminative aspect of pain perception as indexed by the increased pain threshold. In addition, the modulating effects of HD-tDCS on attenuating pain intensity to suprathreshold pain could be influenced by the participant’s negative attentional bias, which deserves to be taken into consideration in the clinical applications.

Blue-light treatment reduces spontaneous and evoked pain in a human experimental pain model.

Chronic pain is a frequent severe disease and often associated with anxiety, depression, insomnia, disability, and reduced quality of life. This maladaptive condition is further characterized by sensory loss, hyperalgesia, and allodynia. Blue light has been hypothesized to modulate sensory neurons and thereby influence nociception. Here, we compared the effects of blue light vs red light and thermal control on pain sensation in a human experimental pain model. Pain, hyperalgesia, and allodynia were induced in 30 healthy volunteers through high-density transcutaneous electrical stimulation. Subsequently, blue light, red light, or thermal control treatment was applied in a cross-over design. The nonvisual effects of the respective light treatments were examined using a well-established quantitative sensory testing protocol. Somatosensory parameters as well as pain intensity and quality were scored. Blue light substantially reduced spontaneous pain as assessed by numeric rating scale pain scoring. Similarly, pain quality was significantly altered as assessed by the German counterpart of the McGill Pain Questionnaire. Furthermore, blue light showed antihyperalgesic, antiallodynic, and antihypesthesic effects in contrast to red light or thermal control treatment. Blue-light phototherapy ameliorates pain intensity and quality in a human experimental pain model and reveals antihyperalgesic, antiallodynic, and antihypesthesic effects. Therefore, blue-light phototherapy may be a novel approach to treat pain in multiple conditions.

Effect of Pregabalin on the Median Effective Plasma Concentration of Intravenous Alfentanil in Capsaicin-Induced Pain.

To apply the sequential up-down method to a human experimental pain model in order to examine the opioid-sparing effect of oral pregabalin on intravenous alfentanil. Double-blind, randomized, crossover. Academic university medical center. Thirty-one healthy males. The median effective plasma concentration of intravenous alfentanil was determined under two conditions: alfentanil alone (phase I) and alfentanil+ pregabalin (300 mg orally) (phase II). The alfentanil plasma level (after a computer-controlled infusion) producing a success criterion (at least 30% intradermal capsaicin-induced pain reduction compared with placebo) was used to determine higher or lower doses for each sequential subject. The median dose producing a success criterion and its confidence interval were determined. On the basis of the t test for a difference across phase and regression coefficients across groups, there was no opioid-sparing effect of pregabalin on alfentanil. Four subjects in phase I and five subjects in phase II did not complete the study. Two in phase I were technical failures, with the rest in both phases stopped because of side effects. Of the subjects who completed the study, six of 19 subjects in phase I and 11 of 12 subjects in phase II reported side effects. When the intradermal capsaicin-induced pain model was used in healthy volunteers, oral pregabalin had no opioid-sparing effects on intravenous alfentanil. This experimental model may be useful in studying analgesic interactions.

CGRP release in an experimental human trigeminal pain model.

BackgroundMigraine and trigemino-autonomic cephalalgia attacks are associated with an increase of α-calcitonin-gene related peptide levels in the ipsilateral jugular vein. It is however unknown whether trigeminal pain stimulation in healthy subjects without headache disorders also induces increase of calcitonin-gene related peptide levels.FindingsWe measured α-calcitonin-gene related peptide levels in eight healthy subjects after subcutaneous injection of capsaicin in the forehead and in the mandibular region and after injection of sodium chloride in the forehead. We observed a significant increase of α-calcitonin-gene related peptide level only after injection of capsaicin in the forehead (i.e. first trigeminal branch). We also observed trigemino-autonomic activation (lacrimation, rhinorrhea etc.) only after injection of capsaicin in the forehead.ConclusionIncrease of α-calcitonin-gene related peptide levels do not only occur in primary headache attacks but also after experimental trigeminal pain of the first branch. This finding suggests that α-calcitonin-gene related peptide elevation is, at least an additional, unspecific effect of first trigeminal branch stimulation following pain activation and not a specific mechanism of idiopathic headache disorders.

Effects of transcranial direct current stimulation on experimental pain perception: A systematic review and meta-analysis

ObjectiveMany studies have examined the effectiveness of transcranial direct current stimulation (tDCS) on human pain perception in both healthy populations and pain patients. Nevertheless, studies have yielded conflicting results, likely due to differences in stimulation parameters, experimental paradigms, and outcome measures. Human experimental pain models that utilize indices of pain in response to well-controlled noxious stimuli can avoid many confounds present in clinical data. This study aimed to assess the robustness of tDCS effects on experimental pain perception among healthy populations. MethodsWe conducted three meta-analyses that analyzed tDCS effects on ratings of perceived pain intensity to suprathreshold noxious stimuli, pain threshold and tolerance. ResultsThe meta-analyses showed a statically significant tDCS effect on attenuating pain-intensity ratings to suprathreshold noxious stimuli. In contrast, tDCS effects on pain threshold and pain tolerance were statistically non-significant. Moderator analysis further suggested that stimulation parameters (active electrode size and current density) and experimental pain modality moderated the effectiveness of tDCS in attenuating pain-intensity ratings. ConclusionThe effectiveness of tDCS on attenuating experimental pain perception depends on both stimulation parameters of tDCS and the modality of experimental pain. SignificanceThis study provides some theoretical basis for the application of tDCS in pain management.

Sterile water; a novel and promising human experimental craniofacial muscle pain model.

The aim of this study was to investigate if intramuscular injection of sterile water can be used as a human experimental pain model that resembles clinical craniofacial muscle pain and to analyse if the effects differ between sexes. This randomised, double-blind, placebo-controlled cross-over study included 30 healthy age-matched women and men (23.6±2.4years). At three sessions, with at least one week of washout in between, 0.2mL of either sterile water (test-substance), hypertonic saline (58.5mg/mL; active control) or isotonic saline (0.9mg/mL; passive control) was randomly injected into the right masseter muscle. Pain intensity (VAS) was continuously assessed during 5min whereafter pain duration (s) and pain area (au) were calculated; pressure pain thresholds (PPT;kPa) were recorded every 5minutes during 30minutes. Sterile water evoked pain of similar intensity (74.5±49.9) as hypertonic saline (74.0±50.5); whereas, isotonic saline evoked low-intensity pain (11.4±23.4). The pain induced by sterile water and hypertonic saline had higher intensity (P<0.001), longer duration (P<0.001) and larger pain area (P<0.001) than isotonic saline. There were no significant differences in any pain variable between sterile water and hypertonic saline. The PPT did not change significantly after any substance, except for in women 5minutes after sterile water injection (P<0.002). Pain duration was longer in the men for all substances (P<0.006), while the pain area was larger in women after injection of hypertonic saline (P<0.003). These results indicate that pain evoked by sterile water resembles clinical muscle pain and may offer a novel and simpler alternative to hypertonic saline injections.

ZNRD1-AS and RP11-819C21.1 long non-coding RNA changes following painful laser stimulation correlate with laser-evoked potential amplitude and habituation in healthy subjects: A pilot study.

Non-coding RNAs (lncRNAs) are a group of non-coding RNAs that act as regulators of gene expression; they are implicated in various human diseases and have been reported to be involved in the modulation of pain. We aimed to study whether: (a) lncRNAs modifications could be found in an experimental model of pain; (b) there was a correlation between lncRNA changes and laser evoked potential (LEP) amplitude/laser-pain rating. Laser evoked potentials were recorded from 11 healthy subjects to both left hand and perioral region stimulation. Three consecutive averages were calculated for each stimulation site in order to investigate the LEP amplitude habituation. Blood samples were obtained immediately before LEP recording (pre-pain) and 30-min after the recording of the last LEP average (post-pain). Eighty-four lncRNAs, involved in autoimmunity and human inflammatory response, were screened. The criteria used for lncRNAs analysis were fold change >2 and p<.05. By Real-Time PCR, we identified two lncRNAs up-regulated at the post-pain time, as compared to the pre-pain time: RP11-819C21.1 (fold change=8.2; p=.038) and ZNRD1 antisense RNA 1 non-protein coding (ZNRD1-AS; fold change=6.3; p=.037). The ZNRD1-AS up-regulation was directly correlated with the N1 amplitude, while the RP11-819C21.1 increase after pain showed a correlation with the reduced N2/P2 amplitude and laser-pain habituation. IncRNA changes in a human experimental phasic pain model. The correlation between lncRNA changes and LEP amplitude and habituation suggests that RP11-819C21.1 and ZNRD1-AS could be involved in the pathophysiology of painful diseases characterized by abnormal excitability of the cerebral cortex. Long non-coding RNAs are upregulated after experimental pain. RP11-819C21.1 and ZNRD1 could be involved in the pathophysiology of diseases characterized by reduced habituation to pain.

Humani modeli eksperimentalnog bola

Pain is an unpleasant sensory experience, associated with existing or potential tissue damage. It has also strong cognitive and emotional components. Stimuli that causes pain goes through process of nociception, which includes transduction, transmission, modulation and perception of said stimuli. Depending on the type of stimuli, we can classify human experimental pain models into mechanical, electrical, thermal and chemical. Information about pain mechanisms can be obtained from the following: 1) in vitro studies, 2) animal experiments, 3) human experimental pain studies and 4) clinical studies. Chosing the appropriate method for pain evaluation is a key step in the design of pain studies. Combining it with different electro-physiological and imaging methods, it can provide better objectivity and quantification of pain mechanisms. Focus in experimental pain studies is slowly shifting from static parameters of pain, such as pain threshold and maximum tolerance, to dynamic parameters, which can give us valuable insight in function of endogenous analgesic systems. This can be done using conditioned pain modulation. Using experimental pain on healthy voulenteers is key step in switching from animal models to clinical studies, foremost for validization of data from animals, making them important in translational research. Results from experimental pain studies can help us in understanding nociceptive mechanisms of acute and chronic pain, alongside development of new therapeutic modalities.

A data science approach to the selection of most informative readouts of the human intradermal capsaicin pain model to assess pregabalin effects.

Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin-based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo-controlled, randomized cross-over study, seven different pain-related readouts were acquired in 16 healthy individuals before and after oral administration of 300mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain-related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.

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.

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.

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.

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.

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.

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.

Effects of Different Anesthetics on Pain Processing in an Experimental Human Pain Model.

After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus. Forty-eight healthy volunteers underwent conditioning noxious stimulation (CS) over 5days. On day 2, the volunteers were randomized into 4 groups: control group (no anesthesia) and 3 groups receiving anesthesia before CS in anesthetic doses: propofol (P), propofol/remifentanil (PR), and propofol/remifentanil/S-ketamine (PRK). Quantitative sensory testing was performed on days 1 through 5 and on day 22. In every group, CS was associated with short- and long-term habituation to the electrical stimulus. Repetitive CS resulted in unmodified short-term sensitization with stable areas of hyperalgesia. Although the PR group showed a trend toward increased areas of hyperalgesia on day 2, no significant differences were detectable between the groups. In contrast, anesthesia resulted in decreased intensity of the electrically evoked pain on day 2. Finally, the mechanical pain threshold before CS on day 5 was increased in all groups and remained elevated 3weeks after the first CS, consistent with a long-term antinociceptive effect after CS. The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems.