Variability In Pain Response Research Articles

Inter-individual variability in mechanical pain sensation in patients with cervicogenic headache: an explorative study

Currently, evidence for effective physiotherapy interventions in patients with cervicogenic headache (CeH) is inconsistent. Although inter-individual variability in pain response is predictive for successful physiotherapy interventions, it was never explored in patients with CeH. Therefore the objective of the current study was to explore inter-individual variability in mechanical pain sensation, and its association with biopsychosocial-lifestyle (BPSL) characteristics in patients with CeH. A cross-sectional explorative analysis of inter-individual variability in mechanical pain sensation in 18 participants with CeH (29–51 years) was conducted. Inter-individual variability in mechanical pain sensation (standard deviations (SDs), F-statistics, Measurement System Analysis) was deducted from bilateral pressure pain thresholds of the suboccipitals, erector spine, tibialis anterior. BPSL-characteristics depression, anxiety, stress (Depression Anxiety Stress Scale-21), quality of life (Headache Impact Test-6), sleep-quality (Pittsburgh Sleep Quality Index), and sedentary time (hours/week) were questioned. Inter-individual variability in mechanical pain sensation explained 69.2% (suboccipital left), 86.8% (suboccipital right), 94.6% (erector spine left), 93.2% (erector spine right), 91.7% (tibialis anterior left), and 82% (tibialis anterior right) of the total variability in patients with CeH. The significant p-values and large F-statistic values indicate inter-individual differences in SDs. Significant associations between (1) lower quality of life and lower SDs of the suboccipital left PPT (p .005), and (2) longer sedentary time and higher SDs of the suboccipital left PPT (p .001) were observed. Results from our explorative study could suggest inter-individual variability in mechanical pain sensation at the left suboccipitals which associates with quality of life and sedentary time. These novel findings should be considered when phenotyping patients and ‘individually’ match interventions.

To Calibrate or not to Calibrate? A Methodological Dilemma in Experimental Pain Research

To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the nociceptive system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of “noxiousness” by the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the optimal approach for experimental pain studies and provides recommendations for different study designs. PerspectiveTo calibrate pain or not? This dilemma is related to almost every experimental pain research. The decision is a trade-off between statistical power and greater control of stimulus encoding. The article decomposes both approaches and presents the pros and cons of either approach supported by data and simulation experiment.

Acute pain measured with the modified Bernese Pain Scale for Neonates is influenced by individual contextual factors.

Individual contextual factors like gestational age (GA) or previous painful experiences have an influence on neonates' pain responses and may lead to inaccurate pain assessment when not appropriately considered. We set out to determine the influence of individual contextual factors on variability in pain response in neonates, measured with the modified Bernese Pain Scale for Neonates (BPSN), and, if necessary, to incorporate relevant individual factors into a revised version of the BPSN. We videotaped 154 full-term and preterm neonates of different GAs during 1-5 capillary heel sticks in their first 14days of life. For each heel stick, we produced three video sequences: baseline, heel stick, and recovery. The randomized sequences were rated on the BPSN by five blinded nurses. Individual contextual factors were retrospectively extracted from patient charts and from the video recordings. We analysed the data in single and multiple linear mixed models. Premature birth (b=-0.721), caffeine (b=-0.302), and the behavioural states quiet and awake (b=-0.283), active and asleep (b=-0.158), and quiet and asleep (b=-0.498) were associated with changes in behavioural pain scores. Premature birth (b=-0.232), mechanical ventilation (b=-0.196), and duration of the heel stick procedure (b=0.0004) were associated with changes in physiological pain scores. Premature birth (b=-0.907), Caffeine (b=-0.402), the behavioural states quiet and awake (b=-0.274), and quiet and asleep (b=-0.459), and duration of the heel stick procedure (b=0.001) were associated with changes in the modified BPSN total scores. Postmenstrual age, behavioural state, caffeine, and ventilation status have an influence on neonates' pain response and should be incorporated in the revised BPSN to enhance clinical pain assessment in neonates with different GAs. We identified individual contextual factors associated with dampened pain response in neonates and will incorporate them into a revised version of the Bernese Pain Scale for Neonates to provide clinicians with a tool they can use to more accurately assess and manage pain in this vulnerable population.

Systems biology-based approaches to summarize and identify novel genes and pathways associated with acute and chronic postsurgical pain

Study objectiveTo employ systems biology–based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain. DesignInformed systems biology based integrative computational analyses. SettingPediatric research and teaching institution. InterventionsPubmed search (01/01/2001–10/31/2017) was performed to identify “training” genes associated with postoperative pain in humans. Candidate genes were identified and prioritized using Toppgene suite, based on functional enrichment using several gene ontology annotations, and curated gene sets associated with mouse phenotype–knockout studies. MeasurementsComputationally top-ranked candidate genes and literature-curated genes were included in pathway enrichment analyses. Hierarchical clustering was used to visualize select functional enrichment results between the two phenotypes. Main resultsLiterature review identified 38 training genes associated with postoperative pain and 31 with CPSP. We identified 2610 prioritized novel candidate genes likely associated with acute and chronic postsurgical pain, the top 10th percentile jointly enriched (p 0.05; Benjamini-Hochberg correction) several pathways, topmost being cAMP response element-binding protein and ion channel pathways. Heat maps demonstrated enrichment of inflammatory/drug metabolism processes in acute postoperative pain and immune mechanisms in CPSP. ConclusionHigh interindividual variability in pain responses immediately after surgery and risk for CPSP suggests genetic susceptibility. Lack of large homogenous sample sizes have led to underpowered genetic association studies. Systems biology can be leveraged to integrate genetic-level data with biologic processes to generate prioritized candidate gene lists and understand novel biological pathways involved in acute postoperative pain and CPSP. Such data would be key to informing future polygenic studies with targeted genome wide profiling. This study demonstrates the utility of functional annotation - based prioritization and enrichment approaches and identifies novel genes and unique/shared biological processes involved in acute and chronic postoperative pain. Results provide framework for future targeted genetic profiling of CPSP risk, to enable preventive and therapeutic approaches.

(276) Acute Exercise Decreases Situational Pain Catastrophizing of a Noxious Stimulus

There is limited evidence regarding the variability in pain response following exercise, including the impact of pain catastrophizing. The purpose of this study was to investigate the relation of the pain response after exercise with pain catastrophizing levels in young healthy individuals. Fifty-seven participants (20.75±1.81 years, 29 women) completed two randomized sessions (exercise and quiet rest). Exercise consisted of sustained submaximal isometric contraction of the knee extensors, performed until task failure. Temporal summation (TS) was assessed before and after exercise and quiet rest, by applying a constant mechanical stimulus to the index finger for one minute after reported pain threshold. During the one minute, participants were asked to rate their pain every 15 seconds (0-10 Numerical Pain Rating Scale). TS was calculated as the last pain rating minus the first pain rating. Pain catastrophizing scale (PCS) was completed at the beginning of the first session. Situational catastrophizing (S-PCS) was completed after each TS protocol. Based on the change in pain following exercise, participants were divided into two groups, responders (hypoalgesia) and non-responders (no change or hyperalgesia). There was no difference in baseline PCS between groups (p=0.974). For S-PCS, there was a session x trial x group interaction (p

Contribution of genetic variants to pain susceptibility inParkinson disease

Pain is a one of the most disturbing non-motor symptoms of Parkinson disease (PD). The susceptibility to pain varies substantially among patients with PD. The aim of this study was to assess a potential association of genetic variants to PD-related pain. We analysed 20 candidate SNPs from 12 genes previously reported to be associated with various pain phenotypes in a homogeneous group of 229 Israeli Jewish PD patients, with and without pain (n = 165 and 64, respectively). The statistical analysis accounted for the potential influence of demographic and clinical factors. The non-synonymous rs6746030 single nucleotide polymorphism (SNP) of the SCN9A gene, which alters the coding sequence of the sodium channel Nav1.7 (arginine to tryptophan), was nominally associated with PD-related pain susceptibility (p = 0.037), as well as with central and musculoskeletal pain subtypes independently. The synonymous rs324419 SNP of the FAAH gene which encodes fatty acid amide hydrolase, a cannabinoid metabolizing enzyme, was associated with PD-related pain (p = 0.006) and specifically with the musculoskeletal subtype. The FAAH haplotype of rs324419 and rs2295633 SNPs, which was previously associated with the variability in pain response in humans, was also associated with PD-related pain (p = 0.012) and specifically with PD-related musculoskeletal pain. Variants within in the SCN9A and FAAH genes were associated with the risk of pain in PD patients. These findings may contribute to our understanding of pain mechanisms of PD and to direct future therapies.

Variability in pain response to a non‐pharmacological intervention across repeated routine pain exposure in preterm infants: a feasibility study

To explore the variability in pain response in preterm infants across time who received sucrose during routine heel stick. Single group, exploratory repeated measures design. Two tertiary level neonatal intensive care units (NICU) in Switzerland. Nine preterm infants born between 28 2/7 and 31 4/7 weeks of gestation during their first 14 days of life. Pain was assessed by the Bernese Pain Scale for Neonates (BPSN), the Premature Infant Pain Profile (PIPP) and the Visual Analogue Scale (VAS). Salivary cortisol was analysed. 72-94% of the variability was within-subject variability, indicating inconsistency of pain responses across the 5 heel sticks. Interrater agreement was highest during heel sticks 1-3 and decreased during heel stick 4 and 5, indicating a possible alteration of pain patterns. No significant differences in the amount of cortisol could be detected before and after the heel sticks (p = 0.55), indicating no stress-induced peak after the painful intervention. However, a general gradual decrease of cortisol levels across time could be detected. A high variability in pain response among preterm neonates across time could be described. Consistency of cortisol levels before and after the heel sticks could indicate the effectiveness of sucrose across time.

Genetic Polymorphisms in Monoamine Neurotransmitter Systems Show Only Weak Association with Acute Post-Surgical Pain in Humans

BackgroundCandidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans.ResultsVariations in the catecholamine metabolizing enzyme genes (MAOA and COMT) showed significant associations with the maximum post-operative pain rating while the serotonin transporter gene (SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene (SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample.ConclusionThese results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype.

μ-Opioid Receptor-Mediated Antinociceptive Responses Differ in Men and Women

Sex differences in the experience of clinical and experimental pain have been reported. However, the neurobiological sources underlying the variability in pain responses between sexes have not been adequately explored, especially in humans. The endogenous opioid neurotransmitters and mu-opioid receptors are centrally implicated in responses to stress, in the suppression of pain, and in the action of opiate analgesic drugs. Here we examined sex differences in the activation of the mu-opioid system in response to an intensity-controlled sustained deep-tissue pain challenge with positron emission tomography and a mu-opioid receptor-selective radiotracer. Twenty-eight young healthy volunteers (14 men and 14 women) were studied during saline control and pain conditions using a double-blind, randomized, and counterbalanced design. Women were scanned during the early follicular phase of their menstrual cycles after ovulatory cycles. Significant sex differences in the regional activation of the mu-opioid system in response to sustained pain were detected compared with saline controls. Men demonstrated larger magnitudes of mu-opioid system activation than women in the anterior thalamus, ventral basal ganglia, and amygdala. Conversely, women demonstrated reductions in the basal state of activation of the mu-opioid system during pain in the nucleus accumbens, an area previously associated with hyperalgesic responses to the blockade of opioid receptors in experimental animals. These data demonstrate that at matched levels of pain intensity, men and women during their follicular phase differ in the magnitude and direction of response of the mu-opioid system in distinct brain nuclei.

Perceived exertion responses to novel elbow flexor eccentric action in women and men.

The primary aim was to describe perceived exertion responses to different intensities of eccentric exercise in women and men. 42 adults (21 men and 21 women, 7 per condition) completed elbow extension exercises with a weight corresponding to 80%, 100%, or 120% of maximal voluntary concentric strength. Total work was equated by manipulating the number of repetitions in the 80% (N = 45), 100% (N = 36), and 120% (N = 30) conditions. A two-way ANOVA showed significant main effects for the intensity and sex factors. Perceived exertion ratings were strongly dependent on exercise intensity, and women reported lower RPEs than men. A separate three-way mixed model ANOVA that included a repetition factor showed that perceived exertion ratings increased similarly across the first 30 repetitions in all exercise conditions. Significant partial correlations were found between mean RPE during the eccentric exercise bout, and the mean intensity of delayed-onset muscle pain measured from 12- to 72-h postexercise after controlling for the relative exercise intensity (r12.3 = 0.28) or the maximum concentric strength of the elbow flexors (r12.3 = 0.33). 1) for both women and men, there is a positive association between the intensity of eccentric exercise performed with the elbow flexors and RPE; 2) perceived exertion ratings increase significantly then plateau when repeated eccentric muscle actions are performed at constant, submaximal absolute intensities; 3) women rate eccentric exercise performed at the same intensity (relativized to MVC-C) as being less effortful compared with men; and 4) RPE during eccentric exercise can account for a small but significant amount of variability in delayed-onset muscle pain after statistically controlling for differences in strength or relative intensity.