Experimental Pain Threshold Research Articles

Association Between Experimental Pain Thresholds and Trajectories of Postoperative Recovery Measures After Benign Hysterectomy.

Quantitative sensory testing (QST) can be applied to quantify the sensitivity to different painful stimuli. This study aims to evaluate the association between preoperative pressure and thermal pain thresholds and trajectories of measurements of postoperative recovery (patient-reported daily maximum and average pain intensity, sum score of symptoms, and analgesic consumption) after benign hysterectomy. A prospective, longitudinal single-blinded, observational multicenter study was conducted in five hospitals in the southeast of Sweden between 2011 and 2017. A total of 406 women scheduled for abdominal or vaginal hysterectomy for benign conditions were enrolled in the study. QST measuring pressure (PPT), heat (HPT), and cold pain thresholds (CPT) were performed preoperatively. The cut-off levels for dichotomizing the pain thresholds (low/high) were set at the 25-percentile for PPT and HPT and the 75-percentile for CPT. The Swedish Postoperative Symptom Questionnaire was used to measure postoperative pain and other symptoms of discomfort (symptom sum score) on 13 occasions for six weeks postoperatively. Daily analgesic consumption of opioids and non-opioids was registered. A CPT above the 75-percentile was associated with high postoperative maximum pain intensity (p = 0.04), high symptom sum score (p = 0.03) and greater consumption of non-opioids (p = 0.03). A HPT below the 25-percentile was only associated with greater consumption of non-opioids (p = 0.02). PPT was not associated with any of the outcome measures. CPT seemed to be predictive for postoperative pain and symptoms of discomfort after benign hysterectomy. Preoperative QST may be used to individualize the management of postoperative recovery for low pain threshold individuals.

Pain sensitivity is modulated by affective temperament: Results from the population-based CHRIS Affective Disorder (CHRIS-AD) study

BackgroundNociceptive pain modulation is related to psychological and psychiatric conditions. Evidence from clinical studies backs innate temperaments as potential precursors of mood symptoms and disorders, and pain sensitivity. Our study examines the modulation effect of affective temperaments on pain sensitivity in a general population adult sample, accounting for possible intervening mood symptoms, lifetime anxiety and depression, and pain treatments. MethodsThe sample is part of the CHRIS-AD study, Italy. Primary outcomes were the pain sensitivity questionnaire PSQ-total intensity score and the experimental pressure pain threshold (PPT). Affective temperaments were evaluated with the TEMPS-M. Lifetime depression, anxiety, current mood disorders, and treatments were self-reported via rating-scales. Directed acyclic graphs theory guided linear and mixed linear regression model analyses. ResultsAmong 3804 participants (aged 18–65; response rate 78.4 %, females 53.3 %, mean age 38.4 years) for any given temperament, both the PSQ-total and the PPT were associated with temperament. The TEMPS-M four cyclothymic-related temperaments aligned on the pain-sensitive pole and the hyperthymic on the pain-resilient pole. The inclusion of current or lifetime mood symptoms, or pain drug use, as possible intervening pathways only partly diluted these associations, with stronger evidence for an effect of trait anxiety. LimitationsThe main limitations were the lack of experimental measures of suprathreshold pain intensity perception, and detailed information on affective disorders in the study population. ConclusionsThese findings support the hypothesis of a biological dichotomous diathesis of affective temperaments towards pain sensitivity; hyperthymic suggesting protection, whereas cyclothymic suggesting predisposition.

Improving the Congruence between Knee Radiographs and Clinical/Experimental Pain: The Importance of Dispositional Traits

Knee osteoarthritis (OA) is a common progressive joint disease with increasing prevalence. There are inconsistent findings on the concordance between radiograph derived Kellgren-Lawrence (KL) scores and pain measures. We have previously reported that dispositional traits predict sensory sensitivity and psychosocial functioning. This study aims to determine whether consideration of a measure of dispositional trait, affect balance style (ABS), improves the congruence between KL scores and clinical and experimental pain. Adults between 45 and 85 years with knee pain with or at risk for osteoarthritis and who self-identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW) were recruited and enrolled in the study. Participants completed a health assessment and quantitative sensory testing (QST). Data collected included sociodemographics, knee radiographs, clinical pain and function, and affect. Punctate temporal summation and pressure pain threshold were assessed on the most painful knee. ABS was determined and protective traits (health/low) and vulnerable traits (reactive/depressive) identified. Unadjusted and adjusted regression analyses with and without dispositional trait groups were completed using SAS (9.4). A total of 218 individuals, 57.8 ± 8.0 years of age, 63.6% women, and 48.2% NHB were included. Participants with vulnerable dispositional traits reported higher clinical pain (p <0.0001) and lower experimental pain thresholds (p<0.05) than those with protective traits regardless of KL score. Dispositional traits and KL scores were predictive of all clinical pain measures (p<0.0001) and knee punctate temporal summation (p<0.0001) in regression models adjusted by age, sex, and ethnicity/race. Improvements in R2 were noted across all models with inclusion of dispositional traits. Previous findings between knee radiographs and clinical and experimental pain are mixed; consideration of dispositional traits may clarify incongruences. Further investigation is needed to determine if dispositional traits may serve as a key factor to elucidate the convoluted relationships between pathology and clinical pain experience. Grant support from NIH/NIA Grants R01AG054370 (KTS); R37AG033906 (RBF) and UF CTSA Grant UL1TR001427 and UAB CTSA Grant UL1TR001417 from the NIH Center for Advancing Translational Sciences.

Do Sex and Pain Characteristics Influence the Effectiveness of Pain Neuroscience Education in People Scheduled for Total Knee Arthroplasty? Secondary Analysis of a Randomized Controlled Trial.

This explorative study investigates the moderating effect of sex and baseline pain characteristics on the effectiveness of preoperative pain neuroscience education (PNE) plus knee joint mobilization versus biomedical education plus knee joint mobilization in patients who have knee osteoarthritis and are scheduled to undergo total knee arthroplasty (TKA). After baseline assessment of self-reported questionnaires (pain intensity, disability, symptoms of central sensitization and pain cognitions) and quantitative sensory testing, 44 participants with knee osteoarthritis were randomized into the PNE plus knee joint mobilization or biomedical education plus knee joint mobilization group. The questionnaires were retaken directly after and 1month after 4 sessions of treatment and at 3months after surgery. Based on baseline quantitative sensory testing results, the sample was subdivided into a high (showing high experimental pain levels and low pressure pain thresholds) and low pain cluster using principal components analysis and cluster analysis. Therapy effects over time were evaluated using 3-way analysis of variance, with time as the within factor and treatment, sex, and baseline pain cluster as between factors. Women benefited significantly more from the PNE intervention compared with the control intervention in terms of self-reported symptoms of central sensitization. For both pain clusters, differences in therapeutic effects concerning pain intensity and pain cognitions were found, with higher superiority of the PNE intervention in the high-pain cluster subgroup compared with the low-pain cluster. Based on these explorative analyses, it can be concluded that sex and preoperative pain measures may influence the effectiveness of preoperative PNE for some specific outcome measures in people scheduled to undergo TKA. Although further research on this topic is needed, the potential influence of sex and preoperative pain measures on the effectiveness of preoperative PNE should be considered when implementing this intervention in people undergoing TKA.

A placebo-controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans.

Preclinical studies demonstrate that cannabidiol (CBD) elicits an antinociceptive response in animal models of neuropathic pain; in humans, limited data are available to support such analgesic effects. Few studies have examined CBD's analgesic effects when administered without other compounds, and little is known regarding dose-dependent effects in noncannabis users. This double-blind, placebo-controlled, within-subject outpatient clinical laboratory study sought to determine the analgesic effects, abuse liability, safety and tolerability of acute CBD (0, 200, 400 and 800 mg orally) in healthy noncannabis-using volunteers (n = 17; 8 men, 9 women). Outcomes included experimental pain threshold and pain tolerance using the cold pressor test (CPT), subjective ratings of CPT painfulness and bothersomeness, subjective ratings of abuse liability and mood, and cardiovascular measures, which were assessed at baseline and several time points after drug administration. Data analyses included repeated measures analysis of variance (ANOVA) with planned comparisons. CBD failed to consistently affect pain threshold and tolerance in the CPT relative to placebo. All doses of CBD increased ratings of painfulness compared to placebo (P < .01). Further, CBD had dose-dependent, modest effects on mood and subjective drug effects associated with abuse liability. Oral CBD was safe and well tolerated, producing small decreases in blood pressure (P < .01). CBD did not elicit consistent dose-dependent analgesia and in fact increased pain on some measures. Future studies exploring CBD-induced pain relief should consider using a more extensive pain assessment paradigm in different participant populations.

Abnormal sensory thresholds of dystonic patients are not affected by deep brain stimulation.

Unlike motor symptoms, the effects of deep brain stimulation (DBS) on non-motor symptoms associated with dystonia remain unknown. The objective of this study was to assess the effects of DBS on evoked experimental pain and cutaneous sensory thresholds in a crossover, double-blind on/off study and compare these results with those of healthy volunteers (HV). Sixteen patients with idiopathic dystonia (39.9±13years old, n=14 generalized) with DBS of the globus pallidus internus underwent a battery of quantitative sensory testing and assessment using a pain top-down modulation system (conditioned pain modulation, CPM). Results for the more and less dystonic body regions were compared in on and off stimulation. The patients' results were compared to age- and sex-matched HV. Descending pain modulation CPM responses in dystonic patients (on-DBS, 11.8±40.7; off-DBS, 1.8±22.1) was abnormally low (defective) compared to HV (-15.6±23.5, respectively p=.006 and p=.042). Cold pain threshold and cold hyperalgesia were 54.8% and 95.7% higher in dystonic patients compared to HV. On-DBS CPM correlated with higher Burke-Fahn-Marsden disability score (r=0.598; p=.014). While sensory and pain thresholds were not affected by DBS on/off condition, pain modulation was abnormal in dystonic patients and tended to be aggravated by DBS. The analgesic effects after DBS do not seem to depend on short-duration changes in cutaneous sensory thresholds in dystonic patients and may be related to changes in the central processing of nociceptive inputs.

Differential alteration of fMRI signal variability in the ascending trigeminal somatosensory and pain modulatory pathways in migraine

BackgroundThe moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. Here, we investigated the regional blood-oxygen-level-dependent signal variability (BOLDSV) and inter-regional dynamic functional connectivity (dFC) in the interictal phase of migraine and its relationship with the attack severity.MethodsWe acquired resting-state functional magnetic resonance imaging from 20 migraine patients and 26 healthy controls (HC). We calculated the standard deviation (SD) of the BOLD time-series at each voxel as a measure of the BOLD signal variability (BOLDSV) and performed a whole-brain voxel-wise group comparison. The brain regions showing significant group differences in BOLDSV were used to define the regions of interest (ROIs). The SD and mean of the dynamic conditional correlation between those ROIs were calculated to measure the variability and strength of the dFC. Furthermore, patients’ experimental pain thresholds and headache pain area/intensity levels during the migraine ictal-phase were assessed for clinical correlations.ResultsWe found that migraineurs, compared to HCs, displayed greater BOLDSV in the ascending trigeminal spinal-thalamo-cortical pathways, including the spinal trigeminal nucleus, pulvinar/ventral posteromedial (VPM) nuclei of the thalamus, primary somatosensory cortex (S1), and posterior insula. Conversely, migraine patients exhibited lower BOLDSV in the top-down modulatory pathways, including the dorsolateral prefrontal (dlPFC) and inferior parietal (IPC) cortices compared to HCs. Importantly, abnormal interictal BOLDSV in the ascending trigeminal spinal-thalamo-cortical and frontoparietal pathways were associated with the patient’s headache severity and thermal pain sensitivity during the migraine attack. Migraineurs also had significantly lower variability and greater strength of dFC within the thalamo-cortical pathway (VPM-S1) than HCs. In contrast, migraine patients showed greater variability and lower strength of dFC within the frontoparietal pathway (dlPFC-IPC).ConclusionsMigraine is associated with alterations in temporal signal variability in the ascending trigeminal somatosensory and top-down modulatory pathways, which may explain migraine-related pain and allodynia. Contrasting patterns of time-varying connectivity within the thalamo-cortical and frontoparietal pathways could be linked to abnormal network integrity and instability for pain transmission and modulation.

The effect of two different types of electric current on experimental pain threshold in healthy individuals: A duble blind, randomized controlled trial

Objective: Physiotherapists often resort to electrophysical agents for pain management. The aim of this study is to determine the effect of acupuncture-like Transcutaneous Electrical Nerve Stimulation (TENS) and Neuromuscular Electrical Stimulation (NMES) on experimental pressure pain threshold (PPT) in healthy individuals. Method: Sixty one healthy participants (44 females, 17 males) aged 18-21 years were included in the study.The participants were divided into acupuncture-like TENS and NMES groups. The application was performed for 20 minutes from the right upper limb. The PPT changes of the participants were evaluated from the thenar part of both hands with an algometer before the current application, immediately after and 60 minutes after. Results: There was no difference in the PPT levels of the right and left extremities of the participants in both groups before the application (p>0.05). In both groups and intergroup comparisons, there was no difference in PPT levels measured from the right and left extremities of participants before the current application, immediately after and 60 minutes after the current application (p>0.05). Conclusions: In this study, it was concluded that acupuncture-like TENS and NMES had no effect on experimental PPT and therefore, the clinical use of currents should be questioned.

Connectivity Patterns of Subthalamic Stimulation Influence Pain Outcomes in Parkinson's Disease.

Background: Pain is highly prevalent in Parkinson's disease and is associated with significant reduction in health-related quality of life. Subthalamic deep brain stimulation can produce significant pain relief in a subset of patients after surgery. However, the mechanism by which deep brain stimulation modulates sensory function in Parkinson's disease remains uncertain.Objective: To describe the motor and pain outcomes of deep brain stimulation applied to a series of patients with Parkinson's disease and to determine whether the structural connectivity between the volume of tissue activated and different regions of the brain was associated with the changes of these outcomes after surgery.Methods: Data from a long-term prospective cohort of 32 Parkinson's disease patients with subthalamic stimulation were combined with available human connectome to identify connections consistently associated with clinical improvement (Unified Parkinson Disease Rating Scale), pain intensity, and experimental cold pain threshold after surgery.Results: The connectivity between the volume of tissue activated and a distributed network of sensory brain regions (prefrontal, insular and cingulate cortex, and postcentral gyrus) was inversely correlated with pain intensity improvement and reduced sensitivity to cold pain after surgery (p < 0.01). The connectivity strength with the supplementary motor area positively correlated with motor and pain threshold improvement (p < 0.05).Conclusions: These data suggest that the pattern of the connectivity between the region stimulated and specific brain cortical area might be responsible, in part, for the successful control of motor and pain symptoms by subthalamic deep brain stimulation in Parkinson's disease.

Acute Experimental Pain Responses in Methadone- and Buprenorphine/Naloxone-Maintained Patients Administered Additional Opioid or Gabapentin: A Double-Blind Crossover Pilot Study

The study objective was to identify the analgesic efficacy of three different pharmacological strategies in patients receiving methadone or buprenorphine as opioid agonist treatment (OAT). The three pharmacological approaches, a) increasing maintenance methadone/buprenorphine dose by 30%, b) adding oxycodone, or c) adding a single dose of gabapentin, were compared with a control condition of the participant's usual OAT dose. A randomized, controlled, double-blinded, double-dummy, within-subject crossover study. Nine participants on stable doses of methadone and eight participants on stable doses of buprenorphine were recruited. An outpatient opioid treatment clinic in inner city Sydney, Australia. The cold pressor tolerance test was used to examine experimental pain threshold and tolerance. Ratings of subjective drug effects and safety measures (physiological and cognitive) were assessed. There was no difference in the primary outcome measures of pain thresholds or tolerance between the conditions examined. Interindividual variability was evident. Differences in some subjective measures were identified, including lower pain recall, lower "bad effects," and higher global satisfaction in the additional methadone condition. In the buprenorphine arm, increased drug liking and "bad effects" were detected with oxycodone administration, while increased subjective intoxication was identified with gabapentin. There was no evidence of an objective improvement in analgesia with any condition compared with control. Further research is required to optimize pain management strategies in this population.

Thermal and Mechanical Pain Thresholds of Women With Provoked Localized Vulvodynia: A Pilot Study.

Vulvodynia is a chronic pain condition defined as vulvar pain lasting at least 3 months in the absence of gross anatomic or neurologic findings. Provoked, localized vulvodynia (PLV), a subtype of vulvodynia, is characterized by vestibular pain in response to light touch. The cause of PLV remains largely unknown, and triggering events have yet to be determined. To evaluate vestibular and peripheral experimental pain thresholds in patients with PLV to further define the somatosensory profile of these patients. After informed consent was provided, eligible participants completed a questionnaire and underwent quantitative sensory testing at the forearm and posterior vestibule. Detection and pain thresholds to thermal (cold and heat) and mechanical (pressure) stimuli were measured. Seventeen participants with PLV and 16 control participants were included. Participants in the PLV group scored lower on the patient health questionnaire 9 (PHQ-9) compared with those in the control group (P<.05) and had higher ratings of self-reported genital pain with sex (P<.001) and daily activity (P<.05). Forearm pain thresholds to cold (P<.01) and heat (P<.01) stimuli were also lower in the PLV group compared with those in the control group. Vestibular pain thresholds to cold (P<.05) and pressure (P<.01) stimuli were also lower in the PLV group. Lower scores on the PHQ-9 and higher self-reported genital pain ratings of patients with PLV highlight the significant impact of this poorly understood condition on quality of life. Quantitative sensory testing results demonstrated that vestibular cold allodynia may be a somatosensory feature of PLV. Reduced forearm pain thresholds in these patients suggest altered sensory processing at extrapelvic sites, although it is unclear whether these measurements are related to central sensitization.

Experimental neck muscle pain increase pressure pain threshold over cervical facet joints

Abstract Aims Evaluate pressure pain threshold (PPT) over cervical facet joints before and after injection of experimental pain in the trapezius and multifidus muscles. Methods Fourteen healthy subjects (6 women) received randomized ultrasound-guided injections of hypertonic saline (5.8%), in the right multifidus muscle medial to C4/C5 facet joint and in the right trapezius muscle at the midpoint between C7 spinous process and acromion. The saline-induced pain intensity was assessed on a VAS scale. Before and during saline-induced pain PPTs were assessed by pressure algometry bilaterally over C2/C3 and C5/C6 facet joints. Three-way repeated-measures ANOVA with factors PPT location, injection site, and time was used for analysis. Post-hoc analysis was done by Bonferroni. Results Saline-induced trapezius muscle pain increased PPTs over all facet joints (P &lt; 0.05) compared with before pain. Saline-induced multifidus muscle pain increased PPTs bilaterally over C2/C3 facet joints and over the left C5/C6 facet joint (P &lt; 0.05) compared with before pain. Conclusions Trapezius muscle pain increased PPT over assessed facet joints. Similar results were found for multifidus muscle pain except for the right C5/C6 facet joint, which was close to the injection site. Such findings may reflect descending inhibitory control acting on structures furthest away from the painful structure.

Validation of the Norwegian Pain Sensitivity Questionnaire.

Background and purposeThere is a large variation in people’s reactions to painful stimuli. Although some conditions are more painful, the variation between people is larger than the reaction to pain across conditions. Induced experimental pain is one way to assess some aspects of these differences in pain perception. Experimental nociceptive testing is time consuming and not always feasible in a clinical setting. In order to overcome the obstacles of assessing pain sensitivity using experimental stimulation, the Pain Sensitivity Questionnaire (PSQ) was developed. The purpose of this study is to validate the Norwegian version of the PSQ.MethodsConstruct validity was examined through an exploratory principal component factor analysis with varimax rotation. Internal consistency was measured by Cronbach’s alpha reliability for subscales and the total PSQ. As confounding variables such as age and gender may contribute to the experience of pain, a regression analysis was performed with demographic variables and PSQ scores as independent variables and the experimental measures of pain as the dependent variable.ResultsThe factor analysis yielded at two factor solution, with an eigenvalue greater than one, explain 58% of the variance. Cronbach’s alpha for the PSQ was 0.92. In the regression analysis, only PSQ scores contributed to explain the experimental pain intensity and tolerance. Gender only influenced the experimental pain threshold, as men had statistically significant higher heat pain threshold than women.ConclusionThis study shows that PSQ is a valid and reliable questionnaire and might be a promising instrument for assessing pain sensitivity in Norwegian clinical settings. Further studies are needed to examine whether the PSQ can be used in clinical settings to predict postoperative pain and the development of chronic pain.

To predict sufentanil requirement for postoperative pain control using a real-time method: A prospective observational cohort study.

Preoperative identification of individual sensitivity to opioid analgesics could improve the quality of postoperative analgesia. We explored the feasibility and utility of a real-time assessment of sufentanil sensitivity in predicting postoperative analgesic requirement.Our primary study included 111 patients who underwent measurements of pressure and quantitative pricking pain thresholds before and 5 minutes after sufentanil infusion. Pain intensity was assessed during the first 24-hour postsurgery, and patients who reported inadequate levels of analgesia were excluded from the study. The sufentanil requirement for patient-controlled analgesia was recorded, and a subsequent exploratory study of 20 patients facilitated the interpretation of the primary study results. In the primary study, experimental pain thresholds increased (P < 0.001) 5 minutes after sufentanil infusion, and the percent change in pricking pain threshold was positively associated with sufentanil requirement at 12 and 24 hours after surgery (β = 0.318, P = 0.001; and β = 0.335, P = 0.001). A receiver-operating characteristic curve analysis showed that patients with a change in pricking pain threshold >188% were >50% likely to require more sufentanil for postoperative pain control. In the exploratory study, experimental pain thresholds significantly decreased after the operation (P < 0.001), and we observed a positive correlation (P < 0.001) between the percent change in pricking pain threshold before and after surgery. Preoperative detection of individual sensitivity to sufentanil via the above described real-time method was effective in predicting postoperative sufentanil requirement. Thus, percent change in pricking pain threshold might be a feasible predictive marker of postoperative analgesia requirement.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity.

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

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

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

Impact of Psychological Covariates on Experimental Pain Sensitivity in Children and Adolescents with SCD

Background: Children with Sickle Cell Disease (SCD) have increased sensitivity to heat and cold pain (Brandow et al) during steady state. However, the role of psychological factors such as anxiety, depressive symptoms and catastrophizing on pain sensitivity is not known in SCD. Characterization of these factors may provide an insight into the study of their possible roles in the transition to chronic pain.Aim: To determine if psychological factors impact pain sensitivity in patients with SCD.Methods: Patients with SCD were offered quantitative sensory testing (QST) when at steady state (at least 2 weeks following a VOE). QST procedures included estimation of pressure, mechanical and thermal pain thresholds (minimum intensity of stimulus which is first perceived as painful) and tolerances (maximum intensity of a pain-producing stimulus that a participant is willing to accept in a given situation) as well as windup values (increased pain perception to repetitive painful stimuli). At each time point, participants completed the PROMIS measures of pain intensity, pain interference, anxiety, depressive symptoms, sleep, fatigue and peer relationships. Participants also completed the Pain Catastrophizing Scale ((PCS)-Sullivan et al), Child Somatization Inventory (Walker et al), Pain Coping Inventory (Varni et al)* as well as Peds QL Generic and SCD specific measures of Quality of life*.Results: We determined the experimental pain phenotype (sensitivity to pressure, mechanical and thermal pain) of 29 patients with SCD during steady state (> 2 weeks from a vaso-occlusive episode). These participants were not receiving long-term opioids or adjunctive medications for pain. The median age of participants was 15 (IQR 10-19) and majority (69%) were female. Approximately half of the study sample had HbSS. Three quarters of the study sample were prescribed hydroxyurea. The median Hb level was 11.1 (IQR 10.2-11.6). The median number of VOC's in the year prior to testing was 1(IQR 0-2) and in 3 years prior to testing was 3 (IQR 2-5). The median PROMIS pain intensity T-score was 37.8, PROMIS pain interference T-score was 48.75, PROMIS Depressive symptom T-score was 44.35 and PROMIS anxiety was 43.9; these scores were not higher than the average T-score of 50 described in the pediatric population. High catastrophizing scores were reported on the PCS, with median score being 29. The median cold pain threshold was 23.6 degrees C (IQR 15.8-26.7) and median heat pain threshold was 39.1 degrees C (IQR 37.5-40.9).We noted that increase in scores on PROMIS depressive symptoms was associated with lower heat (Spearman's rho= -0.55), cold (Spearman's rho= 0.57) and mechanical (Spearman's rho= -0.4) pain thresholds. Scores on PROMIS depressive symptoms predicted heat and cold pain thresholds independent of age and VOC's in the past 3 years. Increased PROMIS anxiety scores were associated with lower mechanical pain thresholds (Spearman's rho= -0.43) and lower cold detection thresholds (Spearman's rho= 0.46). Increased scores on PCS were associated with lower heat detection thresholds (Spearman's' rho= -0.39). (All p-values were<0.05) Table 1OutcomeDepressive symptomsVOCs in 3 years prior to studyAge (years)Model signCoeffp-valueCoeffp-valueCoeffp-valueCold Pain Threshold0.40.003-0.190.6-0.410.16<0.0127Heat Pain Threshold-0.120.0130.380.0120.20.068<0.00128Conclusions: Depressive symptoms and anxiety are associated with lower experimental pain thresholds in patients with SCD. Higher scores on PROMIS depressive symptoms predict increased sensitivity to heat and cold pain independent of age and number of VOCs experienced in the past 3 years. Further studies are needed to determine the contribution of psychological factors in the transition to chronic pain in SCD.Acknowledgments: 1-Sickle Cell Disease Association of America 2- *PedsQL™ contact information and permission to use: Mapi Research Trust, Lyon, France. E-mail: PROinformation@mapi-trust.org - Internet: www.Mapi-trust.org and http://www.pedsql.org/index.html DisclosuresNo relevant conflicts of interest to declare.

Effects of Transcutaneous Electrical Nerve Stimulation on Experimental Blunt Pressure Pain in Healthy Participants in Randomized Controlled Trial: Pulse Frequency and Pad Size

Transcutaneous electrical nerve stimulation (TENS) is extensively utilized for antalgic effects in clinical practice but the optimal parameters and techniques for TENS treatment effect remain unknown. This study uses a randomized controlled design to examine the effects of the summation of temporal and spatial stimulations of TENS on a peripheral stimulation site. The aim was to investigate the hypoalgesia of pulse frequency (temporal stimulation) and pad size (spatial stimulation) using TENS on the forearm area for meaningful treatment effect. A hundred and eighty qualified healthy participants (equal numbers of males and females) were randomly divided into six groups (n = 30 per group): (1) control/standard pad (5 cm × 5 cm) group, (2) sham/standard pad group, (3) high frequency [80 pulses per second (pps)]/large pad (5 cm × 10 cm) group, (4) low frequency (3 pps)/large pad group, (5) high frequency/small pad (5 cm × 2.5 cm) group, and (6) low frequency/small pad group. Subjective intensity at a comfortable level was standardized on a regular pad for current density. The determined TENS intensity with consistent current density on large or small pads was then applied to the same participant. Each participant experienced a 30-min TENS and a 30-min post-TENS follow-up. The blunt pressure pain threshold was measured twice every 10 min during the 60-min experimental period. The TENS intervention with a high frequency and a large pad was found to significantly reduce pain starting from the 10th minute of TENS application and provided the best effects for reducing the blunt pressure pain during TENS. Pulse frequency is more crucial than pad size on the differentiated effects of TENS outcome. The meaningful treatment effect was statistically judged using a cut-off score of 40 N of force for the experimental pain threshold. These suggested the hypoalgesic effects of pulse frequencies and pad sizes of TENS while its temporal and spatial characteristics were considered.

The effect of Apium Nodiflorum in experimental osteoporosis.

Treatment of osteoporosis remains a therapeutic challenge. The effect of Apium Nodiflorum extract on development of experimental osteoporosis, pain thresholds and carrageenan-induced inflammation has been studied in ovariectomized osteoporotic Wistar rats. After osteoporosis verification rats were randomized and received vehicle only, HPLC-standardized Apium extract (equal to 2.4 mg/kg Quercetin) or Genistein (2.5 mg/kg) for 8 weeks. To verify the effect of Apium on the development of osteoporosis, bone mineral density (BMD) and bone mineral content (BMC), bone histology and plasma levels of IL-6 and RANKL were measured 6 months after ovariectomy and 8 weeks after treatment with Apium extract or Genistein as comparator. Inflammatory hyperalgesia was induced by intraplantar injection of 1% Carrageenan. Apium extract and Genistein impeded the development of osteoporosis (significant differences were shown for BMC and BMD levels in drug vs. vehicle treated rats) and improved bone histology and histological score. Apium and Genistein decreased IL-6 level. Both treatments alleviated mechanical hyperalgesia, decreased exudative reaction and lowered inflammatory pain threshold. The results suggested that Apium extract could be an alternative therapy for post-menopausal osteoporosis.

Correlation between the levels of non-specific physical symptoms and pressure pain thresholds measured by algometry in patients with temporomandibular disorders.

Recent studies showed that patients with chronic TMD pain also feature increased sensitivity in other craniofacial regions, and even in remote peripheral areas, suggesting that nociceptive processing is centrally facilitated in this patient population. The aim of this study was to investigate the existence of a negative correlation between the levels of non-specific physical symptoms and pressure pain thresholds measured by algometry at sites distant from the chief complaint of oro-facial pain in patients with TMD. A total of 20 female patients were evaluated comprising 11 patients diagnosed with myofascial pain (Group I of RDC/TMD) and 9 patients with arthralgia (Group III of RDC/TMD), with both reporting chronic TMD pain for at least 3months. Patients were tested by the pressure algometry technique, and, in the same visit, clinical diagnosis and levels of non-specific physical symptoms, including pain-related issues or not, were obtained. The raw scores were then standardised into a T-score. The possible correlation between the dependent variable levels of non-specific physical symptoms and pressure pain thresholds measured by algometry at sites distant from the chief complaint of oro-facial pain was assessed with Spearman's correlation coefficient. Results were considered statistically significant, which stood a lower than 5% probability of occurring by chance (P<0·05). A statistically significant (P=0·02) negative correlation (-0·51) was found to exist between the levels of non-specific physical symptoms, only if including issues involving pain-related symptoms, and experimental pressure pain thresholds in patients with painful TMD.