Experimental Pain Sensitivity Research Articles

Persistent post-surgical pain and experimental pain sensitivity in the Tromsø study: Comorbid pain matters

In a large survey incorporating medical examination (N=12,981), information on chronic pain and surgery was collected, and sensitivity to different pain modalities was tested. Tolerance to the cold pressor test was analysed with survival statistics for 10,486 individuals, perceived cold pressor pain intensity was calculated for 10,367 individuals, heat pain threshold was assessed for 4,054 individuals, and pressure pain sensitivity for 4,689 individuals. Persistent post-surgical pain, defined by self-report, was associated with lower cold pressor tolerance (sex-adjusted hazard ratio=1.34, 95% confidence interval=1.08–1.66), but not when adjusting for other chronic pain. Other experimental pain modalities did not differentiate between individuals with or without post-surgical pain. Of the individuals with chronic pain (N=3352), 6.2% indicated surgery as a cause, although only 0.5% indicated surgery as the only cause. The associations found between persistent post-surgical pain and cold pressor tolerance is largely explained by the co-existence of chronic pain from other causes. We conclude that most cases of persistent post-surgical pain are coexistent with other chronic pain, and that, in an unselected post-surgical population, persistent post-surgical pain is not significantly associated with pain sensitivity when controlling for comorbid pain from other causes. A low prevalence of self-reported persistent pain from surgery attenuates statistically significant associations. We hypothesize that general chronic pain is associated with central changes in pain processing as expressed by reduced tolerance for the cold pressor test.

The behavioral impact of baroreflex function: A review

The baroreflex consists of a negative feedback loop adjusting heart activity to blood pressure fluctuations. This review is concerned with interactions between baroreflex function and behavior. In addition to changes in baroreflex cardiac control subject to behavioral manipulations, interindividual differences in reflex function predicted psychological and central nervous features. The sensitivity of the reflex was inversely related to cognitive performance, evoked potential amplitudes, experimental pain sensitivity, and the severity of clinical pain. Possible variables moderating the strength of the associations are tonic blood pressure, gender, and psychiatric disease. It is suggested that these observations reflect inhibition of higher brain function by baroreceptor afferents. While in many cases increased baroreflex function implies stronger inhibition, individual and situational factors modulate the behavioral impact of cardiac regulation.

Experimental pain sensitivity differs as a function of clinical pain severity in symptomatic knee osteoarthritis

Pain in knee osteoarthritis (OA) has historically been attributed to peripheral pathophysiology; however, the poor correspondence between objective measures of disease severity and clinical symptoms suggests that non-local factors, such as altered central processing of painful stimuli, also contribute to clinical pain in knee OA. Consistent with this notion, recent evidence demonstrates that patients with knee OA exhibit increased sensitivity to painful stimuli at body sites unaffected by clinical pain. In order to further investigate the contribution of altered pain processing to knee OA pain, the current study tested the hypothesis that symptomatic knee OA is associated with enhanced sensitivity to experimental pain stimuli at the knee and at remote body sites unaffected by clinical pain. We further anticipated that pain sensitivity would differ as a function of the OA symptom severity. Older adults with and without symptomatic knee OA completed a series of experimental pain assessments. A median split of the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) was used to stratify participants into low vs high OA symptom severity. Compared to controls and the low symptom group, individuals in the high symptom group were more sensitive to suprathreshold heat stimuli, blunt pressure, punctuate mechanical, and cold stimuli. Individuals in the low symptomatic OA group subgroup exhibited experimental pain responses similar to the pain-free group on most measures. No group differences in endogenous pain inhibition emerged. These findings suggest that altered central processing of pain is particularly characteristic of individuals with moderate to severe symptomatic knee OA.

Beta-Adrenergic Receptor Mechanisms and Pain Sensitivity in Women With Menstrually Related Mood Disorders

Somatic symptoms experienced by women with a menstrually related mood disorder (MRMD) during their premenstrual luteal phase contribute to functional impairment. Yet, investigations on pathophysiological mechanisms contributing to heightened pain sensitivity in MRMD are sparse. During the luteal phase, 61 women with an MRMD and 61 non-MRMD controls were evaluated for β-adrenergic receptor (β-AR) responsivity using the isoproterenol sensitivity test. A subset (43 MRMD and 50 non-MRMD) then entered a double-blind, placebo-controlled, crossover protocol to examine the effect of β-AR blockade with intravenous propranolol on sensitivity to experimental (cold pressor and ischemic) and clinical (McGill Pain Questionnaire score) pain. Women with an MRMD exhibited greater β1- and β2-AR responsivity, ischemic pain intensity, and affective clinical pain ratings than controls. Propranolol increased cold pressor pain tolerance in both groups, but it decreased cold pain intensity and ischemic pain unpleasantness ratings only in non-MRMD women. In contrast, propranolol decreased affective ratings of clinical pain in women with MRMD. Exploratory analyses indicated that only in MRMD women did greater β-AR responsivity predict greater sensitivity to cold pressor and ischemic pain. This study provides the first evidence for a role of β-AR mechanisms in the hyperalgesia and clinical pain experienced by women with MRMDs. PerspectiveThis article describes the effects of β-adrenergic receptor stimulation and blockade on experimental and clinical pain sensitivity in women with an MRMD. The results of this study may have implications for the management of the substantial somatic premenstrual symptomatology experienced by women with an MRMD.

The role of race and sex on experimental pain sensitivity in individuals with symptomatic knee osteoarthritis

Evidence suggests that experimental pain sensitivity varies across race and sex, with African Americans exhibiting increased perceptual responses to noxious stimuli when compared to non-Hispanic whites, and women demonstrating greater pain sensitivity than men. However, few studies have systematically assessed these differences in individuals with knee osteoarthritis (OA). Therefore, the aim of this study was to examine differences in experimental pain sensitivity across race (African Americans vs.

Experimental pain sensitivity in opioid dependent patients: a preliminary examination of opioid-induced hyperalgesia

Experimental pain sensitivity in opioid dependent patients: a preliminary examination of opioid-induced hyperalgesia

Is heart rate variability associated with experimental pain sensitivity assessed across the menstrual cycle phases?

Heart Rate Variability (HRV) is a measure of autonomic control over the heart, and high resting parasympthetically mediated HRV measures have been shown to be associated with reduced pain. But, it is unclear whether the relationship between HRV and pain varies across menstrual phases. The present study examined whether HRV was associated with experimental pain sensitivity during the different phases of the menstrual cycle. Fifty-three healthy women attended 3 laboratory testing sessions during the mid-follicular, ovulatory, and late-luteal phases (testing order counterbalanced).

Five-factor personality traits and pain sensitivity: A twin study

Factors underlying individual differences in pain responding are incompletely understood, but are likely to include genetic influences on basal pain sensitivity in addition to demographic characteristics such as age, sex, and ethnicity, and psychological factors including personality. This study sought to explore the relationship between personality traits and experimental pain sensitivity, and to determine to what extent the covariances between these phenotypes are mediated by common genetic and environmental factors. A sample composed of 188 twins, aged 23 to 35years, was included in the study. Heat pain intensity (HPI) and cold-pressor pain intensity (CPI) ratings were obtained using standardized pain testing procedures, and personality traits were assessed with the NEO Personality Inventory, Revised. Associations between personality and the pain sensitivity indices were examined using zero-order correlations and generalized estimating equations. Bivariate Cholesky models were used in the biometric analyses. The most robust finding was a significant phenotypic association between CPI and the personality facets Impulsiveness (a facet of Neuroticism) and Excitement-Seeking (a facet of Extraversion), and estimates of the genetic correlation were .37 (P<.05) and .43 (P<.05), respectively. In contrast, associations between HPI and personality seemed weak and unstable, but a significant effect of Angry Hostility (a facet of Neuroticism) emerged in generalized estimating equations analysis. Although the genetic correlation between these phenotypes was essentially zero, a weak but significant individual-specific environmental correlation emerged (re=.21, P<.05). Taken together, these findings suggest that CPI is more consistently related to personality dispositions than HPI, both phenotypically and genetically.

Fibromyalgia interacts with age to change the brain

Although brain plasticity in the form of gray matter increases and decreases has been observed in chronic pain, factors determining the patterns of directionality are largely unknown. Here we tested the hypothesis that fibromyalgia interacts with age to produce distinct patterns of gray matter differences, specifically increases in younger and decreases in older patients, when compared to age-matched healthy controls. The relative contribution of pain duration was also investigated. Regional gray matter was measured in younger (n = 14, mean age 43, range 29–49) and older (n = 14; mean age 55, range 51–60) female fibromyalgia patients and matched controls using voxel-based morphometry and cortical thickness analysis of T1-weighted magnetic resonance images. To examine their functional significance, gray matter differences were compared with experimental pain sensitivity. Diffusion-tensor imaging was used to assess whether white matter changed in parallel with gray matter, and resting-state fMRI was acquired to examine whether pain-related gray matter changes are associated with altered functional connectivity. Older patients showed exclusively decreased gray matter, accompanied by compromised white matter integrity. In contrast, younger patients showed exclusively gray matter increases, namely in the basal ganglia and insula, which were independent of pain duration. Associated white matter changes in younger patients were compatible with gray matter hypertrophy. In both age groups, structural brain alterations were associated with experimental pain sensitivity, which was increased in older patients but normal in younger patients. Whereas more pronounced gray matter decreases in the posterior cingulate cortex were related to increased experimental pain sensitivity in older patients, insular gray matter increases in younger patients correlated with lower pain sensitivity, possibly indicating the recruitment of endogenous pain modulatory mechanisms. This is supported by the finding that the insula in younger patients showed functional decoupling from an important pain-processing region, the dorsal anterior cingulate cortex. These results suggest that brain structure and function shift from being adaptive in younger to being maladaptive in older patients, which might have important treatment implications.

Gender, Variation in Opioid Receptor Genes and Sensitivity to Experimental Pain

BackgroundPain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included.ResultsNineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain.ConclusionThis is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

Relationship Between Temporomandibular Disorders, Widespread Palpation Tenderness, and Multiple Pain Conditions: A Case-Control Study

The multiple bodily pain conditions in temporomandibular disorders (TMD) have been associated with generalized alterations in pain processing. The purpose of this study was to examine the relationship between the presence of widespread body palpation tenderness (WPT) and the likelihood of multiple comorbid pain conditions in TMD patients and controls. This case-control study was conducted in 76 TMD subjects with WPT, 83 TMD subjects without WPT, and 181 non-TMD matched control subjects. The study population was also characterized for clinical pain, experimental pain sensitivity, and related psychological phenotypes. Results showed that: 1) TMD subjects reported an average of 1.7 comorbid pain conditions compared to .3 reported by the control subjects (P < .001); 2) Compared to control subjects, the odds ratio (OR) for multiple comorbid pain conditions is higher for TMD subjects with WPT [OR 8.4 (95% CI 3.1–22.8) for TMD with WPT versus OR 3.3 (95% CI 1.3–8.4) for TMD without WPT]; 3) TMD subjects with WPT presented with reduced pressure pain thresholds (PPTs) in both cranial and extracranial regions compared to TMD subjects without WPT; and 4) TMD subjects with WPT reported increased somatic symptoms. These findings suggest that pain assessment outside of the orofacial region may prove valuable for the classification, diagnosis, and management of TMD patients. PerspectiveTMD subjects with WPT experience a greater level of multiple comorbid pain conditions, compared to TMD subjects without WPT and non-TMD controls. Integration of bodily pain assessments can be informative for evaluation, diagnosis, and management of TMD.

Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity

Robust interindividual variation in pain sensitivity has been observed, and recent evidence suggests that some of the variability may be genetically mediated. Our previous data revealed significantly higher pressure pain thresholds among individuals possessing the minor G allele of the A118G SNP of the mu-opioid receptor gene (OPRM1) compared with those with 2 consensus alleles. Moreover, ethnic differences in pain sensitivity have been widely reported. Yet, little is known about the potential interactive associations of ethnicity and genotype with pain perception. This study aimed to identify ethnic differences in OPRM1 allelic associations with experimental pain responses. A total of 247 healthy young adults from three ethnic groups (81 African Americans; 79 non-white Hispanics; and 87 non-Hispanic whites) underwent multiple experimental pain modalities (thermal, pressure, ischemic, cold pressor). Few African Americans (7.4%) expressed the rare allele of OPRM1 compared to non-Hispanic whites and Hispanics (28.7% vs. 27.8%, respectively). Across the entire sample, OPRM1 genotype did not significantly affect pain sensitivity. However, analysis in each ethnic group separately revealed significant genotype effects for most pain modalities among non-Hispanic-whites (P<.05) but not Hispanics or African Americans. The G allele was associated with decreased pain sensitivity among whites only; a trend in the opposite direction emerged in Hispanics. The reasons for this dichotomy are unclear; they may involve ethnic differences in haplotypic structure, or A118G may be a tag-SNP linked to other functional polymorphisms. These findings demonstrate an ethnicity-dependent association of OPRM1 genotype with pain sensitivity. Additional research is warranted to uncover the mechanisms influencing these relationships.

Affect Balance Style, Experimental Pain Sensitivity, and Pain-related Responses

Affect is neurobiologically based, influences emotions, contributes to temperamental characteristics, and can be evaluated from both state and trait perspectives. Associations between state-related positive affect (PA), negative affect (NA), and chronic pain have been investigated. However, little is known about the relationship between trait affect patterns and pain-related experiences. Affect balance style (ABS) provides a framework to assess the combined contribution of trait PA and NA. Psychological factors and experimental pain sensitivity are indicated as predictors of chronic pain onset. The current study investigated the relationship between ABS, pain sensitivity, and pain-related measures in healthy adults. Participants (n=372) completed quantitative sensory testing, pain-related questionnaires, and the Positive and Negative Affect Scale. ABS groups were categorized as Healthy (high PA, low NA), Low (low PA, low NA), Depressive (low PA, high NA), and Reactive (high PA, high NA). Z-scores were computed for 3 experimental pain measures: ischemic, pressure, and heat. ABS groups significantly differed on ischemic pain sensitivity and pain-related measures. Specifically, the Healthy group demonstrated lower ischemic pain sensitivity compared with the Reactive group (P=0.02); the Depressive and Reactive groups endorsed higher somatic symptoms compared with the Healthy group (P<0.02); the Low and Depressive groups reported more physical stimuli sensitivity than the Healthy group (P<0.02); and the Reactive group indicated more passive coping strategies then the Low and Healthy groups (P=0.001). Findings from the study suggest that among healthy adults, trait affect patterns are associated with ischemic experimental pain sensitivity and other pain-related measures.

Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects

Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BPND) with μ-opioid receptor selective radiotracer [11C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects. Later, we recruited these subjects to participate in a separate psychophysical testing session to measure cold pressor pain threshold, cold pressor pain tolerance and tactile sensitivity with von Frey monofilaments. We used both voxel-by-voxel and region-of-interest image analyses to examine the potential associations between μ-opioid receptor BPND and psychophysical measures. The results show that striatal μ-opioid receptor BPND predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density is involved in setting individual pain threshold.

Experimental pain and depression: differences between Sickle Cell Disease patients, other chronic pain populations and healthy controls

Sickle Cell Disease (SCD) affects approximately 100,000 Americans, decreases life expectancy by 2 to 3 decades, causes chronic pain, and reduces quality of life. The underlying mechanisms involved in this population's experience of pain are still largely unknown. The present study sought to compare depressive symptomatology and experimental pain sensitivity in SCD patients to patients with Temporomandibular Joint Disorder (TMD), Arthritis and healthy controls. Forty-four SCD participants (62.2% female; age x=37.2, SD=11.7), forty-nine TMD participants (41.6% female; age x=33.9, SD=12.02), forty-two Arthritis participants (25.7% female, age x=54.57, SD=9.72), and eighty-five healthy controls (25.7%; age x=34.00, SD=14.59) completed quantitative sensory testing.

Sleep and conditioned pain modulation in sickle cell disease patients

Pain is one of the most prevalent symptoms associated with Sickle Cell Disease (SCD). Despite the prominence of pain, little is known regarding the experience of pain in this population, and few studies have explored experimental pain sensitivity in SCD patients. Sleep has become an increasingly recognized factor in determining pain perception. Although poor sleep is a consequence of pain, sleep disturbance reciprocally exacerbates clinical pain. Conceptual models of the chronic pain and sleep disturbance relationship implicate alterations in endogenous opioid peptides.

Clinical pain severity and experimental pain sensitivity in osteoarthritis

Pain is the most common presenting symptom of osteoarthritis and an important outcome in most osteoarthritis intervention trials. However, the causes of pain among osteoarthritis patients are not well-understood, and studies of pain mechanisms have been limited. To date, most studies have relied on visual analog scales of overall pain or patient-reported pain at joint sites, but these measurements are subjective and prone to bias. Although osteoarthritis is often defined structurally by cartilage loss and joint space narrowing, population-based studies have indicated that the association between joint space narrowing and patient-reported pain is weak. Recent studies, however, suggest that correlations between structural changes and pain may be masked by other factors, such as central pain processing mechanisms, which differ between patients. To examine pain mechanisms, some studies have utilized quantitative sensory testing techniques, which rely on the application of defined, noxious, experimental stimuli to determine pain threshold and tolerance levels. These studies suggest that, compared to pain-free controls, osteoarthritis patients are more sensitive to experimental noxious stimuli at both joint and non-joint sites, indicating diffuse hyperalgesia, characteristic of central pain syndromes. Studies using quantitative sensory testing methods and functional neuroimaging have also indicated that osteoarthritis patients have impairments in conditioned pain modulation, also known as descending analgesia or diffuse noxious inhibitory controls. This talk will give an overview of the study of pain mechanisms in osteoarthritis, focusing on studies of experimental pain sensitivity in osteoarthritis patients, and the implications of these studies for future research and for the development of pain management strategies in osteoarthritis.

Clinical pain and experimental pain sensitivity in progressive supranuclear palsy

ObjectiveWe aimed to assess spinal nociception and experimental pain sensitivity in progressive supranuclear palsy-Richardson’s syndrome (PSP-R) compared to patients with Parkinson’s disease (PD) and healthy controls (HC). MethodsSpinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in non-demented, non-depressed, probable PSP-R patients (N = 8), PD patients (N = 19) and 17 HC. ResultsPSP-R patients exhibited lower electrical pain thresholds and a tendency for lower NFR thresholds as compared to HC. No significant differences between PSP-R and PD patients were found with respect to experimentally-induced pain. However, significantly less PSP-R than PD patients reported disease-related pain. ConclusionsDegeneration of the descending inhibitory control system within the brainstem in PSP-R might lead to increased experimental pain sensitivity while frontal cortical deterioration may alter self-estimation of pain.

Pain Sensitivity Risk Factors for Chronic TMD: Descriptive Data and Empirically Identified Domains from the OPPERA Case Control Study

Many studies report that people with temporomandibular disorders (TMD) are more sensitive to experimental pain stimuli than TMD-free controls. Such differences in sensitivity are observed in remote body sites as well as in the orofacial region, suggesting a generalized upregulation of nociceptive processing in TMD cases. This large case-control study of 185 adults with TMD and 1,633 TMD-free controls measured sensitivity to painful pressure, mechanical cutaneous, and heat stimuli, using multiple testing protocols. Based on an unprecedented 36 experimental pain measures, 28 showed statistically significantly greater pain sensitivity in TMD cases than controls. The largest effects were seen for pressure pain thresholds at multiple body sites and cutaneous mechanical pain threshold. The other mechanical cutaneous pain measures and many of the heat pain measures showed significant differences, but with lesser effect sizes. Principal component analysis (PCA) of the pain measures derived from 1,633 controls identified 5 components labeled: 1) heat pain ratings; 2) heat pain aftersensations and tolerance; 3) mechanical cutaneous pain sensitivity; 4) pressure pain thresholds; and 5) heat pain temporal summation. These results demonstrate that compared to TMD-free controls, chronic TMD cases are more sensitive to many experimental noxious stimuli at extracranial body sites, and provide for the first time the ability to directly compare the case-control effect sizes of a wide range of pain sensitivity measures. Perspective This article describes experimental pain sensitivity differences between a large sample of people with chronic TMD and non-TMD controls, using multiple stimulus modalities and measures. Variability in the magnitude and consistency of case-control differences highlight the need to consider multiple testing measures to adequately assess pain processing alterations in chronic pain conditions.

Pain sensitivity and clinical progression in Parkinson's disease

Pain sensitivity in Parkinson's disease is known to be altered in an L-dopa-dependent manner with increased spinal nociception and experimental pain perception in the medication-defined "off" state. As Parkinson's disease-related pain can be an early symptom in Parkinson's disease, the present study aimed to investigate experimental pain sensitivity and spinal nociception during clinical progression. The nociceptive flexion reflex as a marker of spinal nociception as well as electrical and heat pain thresholds were assessed during the medication-defined "off" state in 29 patients with Parkinson's disease divided into 3 severity groups (according to their Unified Parkinson's Disease Rating Scale motor score) and compared with 27 healthy elderly subjects. Parkinson's disease-related pain was also quantified. Data provided evidence that spinal nociception and pain sensitivity are preserved during the early phase of Parkinson's disease. Following increased spinal nociception (F(1,36) = 6.838, P = .013), experimental thermal and electrical pain sensitivity were augmented during the course of Parkinson's disease (F(1,34) = 5.397, P = .014; F(1,34) = 6.038, P = 0.053), whereas spinal nociception further increased (F(1,34) = 5.397, P < .001). Increased experimental pain sensitivity was observed in patients exhibiting Parkinson's disease-related pain. Spinal alterations either on the local level or induced by diminished dopaminergic descending inhibition probably led to increased pain sensitivity in later stages. Because Parkinson's disease-related pain is correlated with experimental pain sensitivity these 2 observations likely reflect a causal relation.