Reference values of conditioned pain modulation.

Background and aims Endogenous pain modulation can be studied in humans by conditioned pain modulation (CPM): pain induced by a test stimulus is attenuated by a distantly applied noxious conditioning stimulus. The detection of impaired CPM in individual patients is of potential importance to understand the pathophysiology and predict outcomes. However, it requires the availability of reference values. Methods We determined reference values of CPM in 146 pain-free subjects. Pressure and electrical stimulation were the test stimuli. For electrical stimuli, we recorded both pain threshold and threshold for the nociceptive withdrawal reflex. Cold pressor test was the conditioning stimulus. The 5th, 10th and 25th percentiles for the three tests were computed by quantile regression analyses. Results The average thresholds increased after the conditioning stimulus for all three tests. However, a subset of subjects displayed a decrease in thresholds during the conditioning stimulus. This produced negative values for most of the computed percentiles. Conclusions This study determined percentile reference values of CPM that can be used to better phenotype patients for clinical and research purposes. The negative value of percentiles suggests that a slightly negative CPM effect can be observed in pain-free volunteers. Implications Pain facilitation rather than inhibition during the conditioning stimulus occurs in some pain-free volunteers and may not necessarily represent an abnormal finding.

The Role of Complex Analysis in Modelling Economic Growth.

Development and growth are complex and tumultuous processes. Modern economic growth theories identify some key determinants of economic growth. However, the relative importance of the determinants remains unknown, and additional variables may help clarify the directions and dimensions of the interactions. The novel stream of literature on economic complexity goes beyond aggregate measures of productive inputs and considers instead a more granular and structural view of the productive possibilities of countries, i.e., their capabilities. Different endowments of capabilities are crucial ingredients in explaining differences in economic performances. In this paper we employ economic fitness, a measure of productive capabilities obtained through complex network techniques. Focusing on the combined roles of fitness and some more traditional drivers of growth-GDP per capita, capital intensity, employment ratio, life expectancy, human capital and total factor productivity-we build a bridge between economic growth theories and the economic complexity literature. Our findings show that fitness plays a crucial role in fostering economic growth and, when it is included in the analysis, can be either complementary to traditional drivers of growth or can completely overshadow them. Notably, for the most complex countries, which have the most diversified export baskets and the largest endowments of capabilities, fitness is complementary to the chosen growth determinants in enhancing economic growth. The empirical findings are in agreement with neoclassical and endogenous growth theories. By contrast, for countries with intermediate and low capability levels, fitness emerges as the key growth driver. This suggests that economic models should account for capabilities; in fact, describing the technological possibilities of countries solely in terms of their production functions may lead to a misinterpretation of the roles of factors.

Percentile normative values of parameters of electrical pain and reflex thresholds.

Aabstract Background and purpose Central hypersensitivity, defined as an increased excitability of the central nervous system, is considered as the main factor behind facilitation of central pain processes and is probably a very important factor in the induction and maintenance of chronic pain. Widespread hyposensitivity is less studied than hypersensitivity states, but recent work indicates that hypoesthesia may be present in chronic non-neuropathic pain conditions and could have negative prognostic value. Electrical pain and reflex thresholds are well established measures of central pain sensitivity in human pain research. One potential application of these assessments in clinical practice is the detection of central hyper- or hyposensitivity in individual patients. In order to identify these disturbances in the central pain processing of individual patients, knowledge of reference values is essential. We computed percentile normative values of nociceptive withdrawal reflex (NWR) and pain thresholds to different electrical stimulation paradigms. The aim was to provide reference values for the assessment of widespread central hyper- and hyposensitivity in individual patients. Methods 300 pain-free subjects (150 males and 150 females, 18-80 years) were studied. Pain and reflex thresholds to single and repeated electrical stimulation (applied on the innervations area of the sural nerve), and the area of reflex receptive fields (RRF) were recorded. The RRF area was defined as the skin area of the sole of the foot from which a NWR could be evoked in the tibialis anterior muscle, expressed as proportion of the foot sole. For the threshold assessments, quantile regressions were performed to compute critical normative values for widespread central hypersensitivity (5th, 10th and 25th percentiles) and hyposensitivity (75th, 90th and 95th percentiles). For the RRF the opposite applied, computing normative values for widespread central hypersensitivity as 75th, 90th and 95th percentiles, and normative values for hyposensitivity as 5th, 10th and 25th percentiles. The following covariates were included in the regression analyses: gender, age, height, weight, body mass index, body side of testing, depression (Beck Depression Inventory), anxiety (State-Trait-Anxiety-Inventory), catastrophizing (Catastrophizing Scale of the Coping Strategies Questionnaire) and Short-Form 36. Results Age had a significant impact on the subjective pain threshold to single electrical stimuli. The reflex threshold to single electrical stimuli was lower on the dominant compared to the non-dominant side. Therefore, the percentiles for single stimulus pain threshold have been stratified by age and the percentiles for single stimulus reflex threshold by body side (dominant vs. non-dominant). Critical normative values of all tests were computed for widespread central hypersensitivity (5th, 10th and 25th percentiles) and hyposensitivity (75th, 90th and 95th percentiles). The values are provided in the table of the manuscript. Conclusions and implications The computed estimates of critical normative values for the electrical pain test can be used in clinical practice for the assessment of widespread central hypersensitivity and hyposensitivity in individual patients, and in future research on mechanism-based treatment of chronic pain.

Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients.

The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 ± 14 years) and 15 men (aged 48 ± 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2mg, and tropisetron 5mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity.

Factor analysis of responses to thermal, electrical, and mechanical painful stimuli supports the importance of multi-modal pain assessment.

During the last decade, a multi-modal approach has been established in human experimental pain research for assessing pain thresholds and responses to various experimental pain modalities. Studies have concluded that differences in responses to pain stimuli are mainly related to variation between individuals rather than variation in response to different stimulus modalities. In a factor analysis of 272 consecutive volunteers (137 men and 135 women) who underwent tests with different experimental pain modalities, it was determined whether responses to different pain modalities represent distinct individual uncorrelated dimensions of pain perception. Volunteers underwent single painful electrical stimulation, repeated painful electrical stimulation (temporal summation), test for reflex receptive field, pressure pain stimulation, heat pain stimulation, cold pain stimulation, and a cold pressor test (ice water test). Five distinct factors were found representing responses to 5 distinct experimental pain modalities: pressure, heat, cold, electrical stimulation, and reflex-receptive fields. Each of the factors explained approximately 8% to 35% of the observed variance, and the 5 factors cumulatively explained 94% of the variance. The correlation between the 5 factors was near null (median ρ=0.00, range -0.03 to 0.05), with 95% confidence intervals for pairwise correlations between 2 factors excluding any relevant correlation. Results were almost similar for analyses stratified according to gender and age. Responses to different experimental pain modalities represent different specific dimensions and should be assessed in combination in future pharmacological and clinical studies to represent the complexity of nociception and pain experience.

Reference values of mechanical and thermal pain tests in a pain-free population.

Quantitative sensory tests are widely used in human research to evaluate the effect of analgesics and explore altered pain mechanisms, such as central sensitization. In order to apply these tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 pain-free subjects. Pain detection and pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the pain measures. Women were more pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the tests for detecting abnormal pain reactions in individual patients.

The nociceptive withdrawal reflex: normative values of thresholds and reflex receptive fields.

Assessments of spinal nociceptive withdrawal reflexes can be used in human research both to evaluate the effect of analgesics and explore pain mechanisms related to sensitization. Before the reflex can be used as a clinical tool, normative values need to be determined in large scale studies. The aim of this study was to determine the reference values of spinal nociceptive reflexes and subjective pain thresholds (to single and repeated stimulation), and of the area of the reflex receptive fields (RRF) in 300 pain-free volunteers. The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. The 95% confidence intervals were determined for all the tests as normative values. Age had a statistically and quantitatively significant impact on the subjective pain threshold to single stimuli. The reflex threshold to single stimulus was lower on the dominant compared to the non-dominant side. Depression had a negative impact on the subjective pain threshold to single stimuli. All the other analyses either did not reveal statistical significance or displayed quantitatively insignificant correlations. In conclusion, normative values of parameters related to the spinal nociceptive reflex were determined. This allows their clinical application for assessing central hyperexcitability in individual patients. The parameters investigated explore different aspects of sensitization processes that are largely independent of demographic characteristics, cognitive and affective factors.