Pain Threshold Tolerance Research Articles

Preoperative Neuropathic Pain-like Symptoms and Central Pain Mechanisms in Knee Osteoarthritis Predicts Poor Outcome 6 Months After Total Knee Replacement Surgery

Preoperative pain characteristics in patients with osteoarthritis may explain persistent pain after total knee replacement. Fifty patients awaiting total knee replacement and 22 asymptomatic controls were recruited to evaluate the degree of neuropathic pain symptoms and pain sensitization. Patients with OA were pain phenotyped into 2 groups based on the PainDETECT questionnaire: high PainDETECT group (scores ≥19) indicating neuropathic pain-like symptoms and low PainDETECT group (scores <19) indicating nociceptive or mixed pain. Cuff algometry assessing pain detection thresholds and pain tolerance thresholds was conducted on the lower legs. Temporal summation of pain was assessed using 10 sequential cuff stimulations and a von Frey stimulator. Conditioning pain modulation was assessed by cuff pain conditioning on 1 leg and parallel assessment of pain detection thresholds on the contralateral leg. Pressure pain thresholds were recorded by pressure handheld algometry local and distant to the knee. Knee pain intensity (visual analogue scale) and pain assessments were collected before and 6 months after total knee replacement. Thirty percent of patients demonstrated neuropathic pain-like symptoms (high PainDETECT group). Facilitated temporal summation of pain and reduced pressure pain thresholds distant to the knee were found in the high PainDETECT group compared with the low PainDETECT group and healthy controls (P < .001). Patients with OA with high PainDETECT scores had higher postoperative visual analogue scale pain scores than the low PainDETECT patients (P < .0001) and facilitated temporal summation of pain (P = .022) compared with healthy control subjects.Perspective: This study has found that preoperative PainDETECT scores independently predict postoperative pain. Patients with knee OA with neuropathic pain-like symptoms identified using the PainDETECT questionnaire are most at risk of developing chronic postoperative pain after TKR surgery.

The effects of propranolol on heart rate variability and quantitative, mechanistic, pain profiling: a randomized placebo-controlled crossover study.

Background and aims The autonomic nervous system (ANS) is capable of modulating pain. Aberrations in heart rate variability (HRV), reflective of ANS activity, are associated with experimental pain sensitivity, chronic pain, and more recently, pain modulatory mechanisms but the underlying mechanisms are still unclear. HRV is lowered during experimental pain as well as in chronic pain conditions and HRV can be increased by propranolol, which is a non-selective β-blocker. Sensitization of central pain pathways have been observed in several chronic pain conditions and human mechanistic pain biomarkers for these central pain pathways include temporal summation of pain (TSP) and conditioned pain modulation (CPM). The current study aimed to investigate the effect of the β-blocker propranolol, and subsequently assessing the response to standardized, quantitative, mechanistic pain biomarkers. Methods In this placebo-controlled, double-blinded, randomized crossover study, 25 healthy male volunteers (mean age 25.6 years) were randomized to receive 40 mg propranolol and 40 mg placebo. Heart rate, blood pressure, and HRV were assessed before and during experimental pain tests. Cuff pressure pain stimulation was used for assessment of pain detection (cPDTs) and pain tolerance (cPTTs) thresholds, TSP, and CPM. Offset analgesia (OA) was assessed using heat stimulation. Results Propranolol significantly reduced heart rate (p<0.001), blood pressure (p<0.02) and increased HRV (p<0.01) compared with placebo. No significant differences were found comparing cPDT (p>0.70), cPTT (p>0.93), TSP (p>0.70), OA-effect (p>0.87) or CPM (p>0.65) between propranolol and placebo. Conclusions The current study demonstrated that propranolol increased HRV, but did not affect pressure pain sensitivity or any pain facilitatory or modulatory outcomes. Implications Analgesic effects of propranolol have been reported in clinical pain populations and the results from the current study could indicate that increased HRV from propranolol is not associated with peripheral and central pain pathways in healthy male subjects.

2196 Pre-treatment sleep disturbance as a risk factor for radiation therapy induced pain in 676 women with breast cancer

OBJECTIVES/SPECIFIC AIMS: The purpose of the present secondary data analysis was to examine the effect of moderate-severe disturbed sleep before the start of radiation therapy (RT) on subsequent RT-induced pain. METHODS/STUDY POPULATION: Analyses were performed on 676 RT-naïve breast cancer patients (mean age 58, 100% female) scheduled to receive RT from a previously completed nationwide, multicenter, phase II randomized controlled trial examining the efficacy of oral curcumin on radiation dermatitis severity. The trial was conducted at 21 community oncology practices throughout the US affiliated with the University of Rochester Cancer Center NCI’s Community Oncology Research Program (URCC NCORP) Research Base. Sleep disturbance was assessed using a single item question from the modified MD Anderson Symptom Inventory (SI) on a 0–10 scale, with higher scores indicating greater sleep disturbance. Total subjective pain as well as the subdomains of pain (sensory, affective, and perceived) were assessed by the short-form McGill Pain Questionnaire. Pain at treatment site (pain-Tx) was also assessed using a single item question from the SI. These assessments were included for pre-RT (baseline) and post-RT. For the present analyses, patients were dichotomized into 2 groups: those who had moderate-severe disturbed sleep at baseline (score≥4 on the SI; n=101) Versus those who had mild or no disturbed sleep (control group; score=0–3 on the SI; n=575). RESULTS/ANTICIPATED RESULTS: Prior to the start of RT, breast cancer patients with moderate-severe disturbed sleep at baseline were younger, less likely to have had lumpectomy or partial mastectomy while more likely to have had total mastectomy and chemotherapy, more likely to be on sleep, anti-anxiety/depression, and prescription pain medications, and more likely to suffer from depression or anxiety disorder than the control group (all p’s≤0.02). Spearman rank correlations showed that changes in sleep disturbance from baseline to post-RT were significantly correlated with concurrent changes in total pain (r=0.38; p&lt;0.001), sensory pain (r=0.35; p&lt;0.001), affective pain (r=0.21; p&lt;0.001), perceived pain intensity (r=0.37; p&lt;0.001), and pain-Tx (r=0.35; p&lt;0.001). In total, 92% of patients with moderate-severe disturbed sleep at baseline reported post-RT total pain compared with 79% of patients in the control group (p=0.006). Generalized linear estimating equations, after controlling for baseline pain and other covariates (baseline fatigue and distress, age, sleep medications, anti-anxiety/depression medications, prescription pain medications, and depression or anxiety disorder), showed that patients with moderate-severe disturbed sleep at baseline had significantly higher mean values of post-RT total pain (by 39%; p=0.033), post-RT sensory pain (by 41%; p=0.046), and post-RT affective pain (by 55%; p=0.035) than the control group. Perceived pain intensity (p=0.066) and pain-Tx (p=0.086) at post-RT were not significantly different between the 2 groups. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that moderate-severe disturbed sleep prior to RT is an important predictor for worsening of pain at post-RT in breast cancer patients. There could be several plausible reasons for this. Sleep disturbance, such as sleep loss and sleep continuity disturbance, could result in impaired sleep related recovery and repair of tissue damage associated with cancer and its treatment; thus, resulting in the amplification of pain. Sleep disturbance may also reduce pain tolerance threshold through increased sensitization of the central nervous system. In addition, pain and sleep disturbance may share common neuroimmunological pathways. Sleep disturbance may modulate inflammation, which in turn may contribute to increased pain. Further research is needed to confirm these findings and whether interventions targeting sleep disturbance in early phase could be potential alternate approaches to reduce pain after RT.

The application of laser electrophoresis of biologically active substances for the combined treatment of the patients presenting with dorsopathy

The article discusses the possibilities of modern pain management methods that find application in the combined treatment of back pain. The present study had the objective to demonstrate the possibility for substituting the non-steroidal anti-inflammatory drugs by biologically active substances possessed of the anti-inflammatory and antispasmodic activity in order to avoid complications encountered in the therapy with NSAIDs and to evaluate the effectiveness of the application of laser electrophoresis of these substances for the combined treatment of the patients presenting with dorsopathy. The patients included in the study were divided into two groups depending on the therapeutic modalities prescribed to individual patients. The patients of both groups were given the combined treatment, including anti-inflammatory therapy, the traction treatment, and transcranial electrical stimulation. The herbal extracts used for laser electrophoresis were drug extractions from equisetum and hypericum. The first (main) group was comprised of 24 patients presenting with dorsopathy who received the local anti-inflammatory in the form of laser electrophoresis of the herbal extracts. The second group consisted of 20 patients who were prescribed the standard course of NSAID-basedanti-inflammatory therapy. The study included the observation and monitoring of the parameters of interest during 14 days of the outpatient care as well as the two-month long post-treatment follow-up period designed to detect the possible relapses. The methods employed in the study were the visual pain scale and pressure tensoalgometry. The dynamic observations before and after the treatment revealed the indicators of pain and tensoalgometry giving evidence of a more rapid and effective relief of pain in the patients of the main group. The study has demonstrated rather high analgesic potency of the herbal extracts accounting for their biochemical effects and the anti-inflammatory action of low-intensity laser radiation. The intensity of pain in the patients of the main group decreased by 62% after treatment. In the control group, the decrease in pain intensity did not exceed 39%. In the main group, the pain threshold and the pain tolerance threshold increased by 33% in comparison with 13% in the control group. This pilot study has demonstrated the well pronounced analgesic action of laser electrophoresis of the biologically active substances applied for the combined treatment of the patients presenting with dorsopathy. The results of the study suggest the necessity of further investigations including the randomized placebo-controlled studies for the more reliable substantiation of the substitution of the non-steroidal anti-inflammatory drugs by biologically active substances contained in phytoextracts and possessed of the anti-inflammatory and antispasmodic activity to be used for the combined treatment of the patients presenting with dorsopathy.

Predictors of disability and absenteeism in workers with non-specific low back pain: A longitudinal 15-month study

The objective of this study was to identify baseline predictors of disability and absenteeism in workers with a history of non-specific low back pain (LBP). One hundred workers with a history of non-specific LBP participated in three evaluations (baseline, 7 and 15 months follow-up). Current and past history of LBP, clinical pain intensity, disability, absenteeism, fear-avoidance beliefs, pain catastrophizing, pain hypervigilance, work satisfaction and patient stratification based on "risk of poor clinical outcome assessment" (RPCO) were evaluated using questionnaires and interviews. In addition, cutaneous heat pain thresholds, cutaneous heat pain tolerance thresholds, conditioned pain modulation (CPM), trunk kinematics and muscle activity were measured during each evaluation. Logistic regression models were used to determine predictors of LBP disability and absenteeism at 15-months. Sixty-eight workers returned for the 15-month follow-up and among this sample, 49% reported disability and 16% reported absenteeism at follow-up. Baseline clinical pain intensity predicted disability (OR=1.08, 95%CI: 1.03-1.13) at 15-month while work satisfaction (OR=0.93, 95%CI: 0.87-0.99) and RPCO (OR=1.51, 95%CI: 1.05-2.16) predicted absenteeism. These results remained significant after adjustments for age, gender as well as type of work and intervention. This study highlights the importance of clinical pain and psychological factors in the prediction and potentially the prevention of future disability. Screening tools assessing these risk factors can be useful to evaluate workers with past history of low back pain.

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.

Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans. A randomized, double-blind, single-dose, placebo- and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50mg, PF-06273340 400mg, pregabalin 300mg, ibuprofen 600mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo. Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the ultraviolet (UV) B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64-1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and electrical stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints. The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.

Study of the relation between body weight and functional limitations and pain in patients with knee osteoarthritis.

ABSTRACTObjective To assess the influence of the body weight in functional capacity and pain of adult and elderly individuals with knee osteoarthritis.Methods The sample consisted of 107 adult and elderly patients with knee osteoarthritis divided into two groups (adequate weight/adiposity and excessive weight/adiposity) according to body mass index and percent of body fat mass, assessed by electric bioimpedance. Subjects were evaluated for functional mobility (Timed Up and Go Test), pain, stiffness and function (Western Ontario and MacMaster Universities Osteoarthritis Index − WOMAC), pain intensity (Visual Analogue Scale − VAS) and pressure pain tolerance threshold (algometry in vastus medialis and vastus lateralis muscles). Data were analyzed with Statistical Package of the Social Sciences, version 22 for Windows. Comparisons between groups were made through Student’s t test, with significance level set at 5%.Results There was predominance of females in the sample (81.3%), and mean age was 61.8±10.1 years. When dividing the sample by both body mass index and adiposity, 89.7% of them had weight/adiposity excess, and 59.8% were obese. There was no difference between groups regarding age, pain intensity, pressure pain tolerance threshold, functional mobility, stiffness and function. However, pain (WOMAC) was higher (p=0.05) in the group of patients with weight or adiposity excess, and pain perception according to VAS was worse in the group of obese patients (p=0.05).Conclusion Excessive weight had negative impact in patients with osteoarthritis, increasing pain assessed by WOMAC or VAS, although no differences were observed in functionality and pressure pain tolerance.

Fixed or adapted conditioning intensity for repeated conditioned pain modulation

Abstract Aims Conditioned pain modulation (CPM) is used to assess descending pain modulation through a test stimulation (TS) and a conditioning stimulation (CS). Due to potential carry-over effects, sequential CPM paradigms might alter the intensity of the CS, which potentially can alter the CPM-effect. This study aimed to investigate the difference between a fixed and adaptive CS intensity on CPM-effect. Methods On the dominant leg of 20 healthy subjects the cuff pressure detection threshold (PDT) was recorded as TS and the pain tolerance threshold (PTT) was assessed on the non-dominant leg for estimating the CS. The difference in PDT before and during CS defined the CPM-effect. The CPM-effect was assessed four times using a CS with intensities of 70% of baseline PTT (fixed) or 70% of PTT measured throughout the session (adaptive). Pain intensity of the conditioning stimulus was assessed on a numeric rating scale (NRS). Data were analyzed with repeated-measures ANOVA. Results No difference was found comparing the four PDTs assessed before CSs for the fixed and the adaptive paradigms. The CS pressure intensity for the adaptive paradigm was increasing during the four repeated assessments (P &lt; 0.01). The pain intensity was similar during the fixed (NRS: 5.8±0.5) and the adjusted paradigm (NRS: 6.0±0.4). The CPM-effect was higher using the fixed condition compared with the adaptive condition (P &lt; 0.05). Conclusions The current study found that sequential CPM paradigms using a fixed conditioning stimulus produced an increased CPM-effect compared with adaptive and increasing conditioning intensities.

Paradoxical differences in pain ratings of the same stimulus intensity

Abstract Aims Stimulus intensity used for assessing temporal summation of pain (TSP) is commonly set at the participants’ pain tolerance. Yet pain ratings during TSP rarely reach that initial pain tolerance pain rating. This study aimed to explore the differences between baseline pain tolerance assessed by cuff algometry and subsequent pain ratings of the same stimulus intensity, and the reliability of these ratings over 2 sessions. Methods In two sessions, separated by one week, 24 healthy, pain-free males had their pressure pain detection (PDT) and tolerance threshold (PTT) recorded using a staircase inflation paradigm (5 kPa increments, 1sec-ON:4sec-OFF) with a cuff algometry system. The pain intensity was assessed during cuff stimulation using an electronic visual analogue scale (VAS, 0–10 cm). Three different inflation paradigms were then performed, using the PTT level as stimulation intensity, and a 1-s duration for each stimulus: PEAKS: 3 inflations at 0.17 Hz, SLOW: 10 inflations at 0.01 Hz, FAST: 10 inflations at 0.5 Hz). Approximately 5-min was kept between the staircase assessment and the first stimulation paradigm, and between each of the 3 inflation paradigms. The PTT and first inflation VAS rating from each paradigm was extracted. Results The VAS rating of PTT pressure was higher in the staircase (VAS: 8.5±2.1 cm) than the first PPT stimulus in any other paradigm (PEAKS: 5.4±2.0; SLOW: 4.6±2.1; FAST: 4.0±2.3, P &lt; 0.05). VAS ratings were also lower in each subsequent paradigm (i.e. PEAKS &gt; SLOW &gt; FAST, P &lt; 0.05). Intra-class coefficients demonstrated excellent reliability for each paradigm (all ICC &gt; 0.79) between sessions. Conclusions PTT, as assessed with the staircase inflation paradigm, was rated more painful during baseline assessment than when the identical stimulus profile (PPT intensity for 1-s) was applied afterwards and this finding is considered reliable.

Preoperative Hypoalgesia After Cold Pressor Test and Aerobic Exercise is Associated With Pain Relief 6 Months After Total Knee Replacement.

Chronic pain after total knee replacement (TKR) is not uncommon. Preoperative impaired conditioning pain modulation (CPM) has been used to predict chronic postoperative pain. Interestingly, exercises reduce pain sensitivity in patients with knee osteoarthritis (KOA). This pilot study investigated the association between exercise-induced hypoalgesia (EIH) and CPM on post-TKR pain relief. Before and 6 months post-TKR, 14 patients with chronic KOA performed the cold pressor test on the nonaffected leg and 2 exercise conditions (bicycling and isometric knee extension), randomized and counterbalanced. Before and during the cold pressor test and after exercises test stimuli were applied to extract the pain sensitivity difference: computer-controlled cuff inflation on the affected lower leg until the participants detected the cuff pain threshold (cPPT) and subsequently the cuff pain tolerance (cPTT) and manual pressure pain thresholds (PPTs) at the legs, arm, and shoulder. Clinical pain intensity (numerical rating scale [NRS]) and psychological distress (questionnaires) were assessed. Clinical pain intensity, psychological distress, cPPT, and PPT at the affected leg improved post-TKR compared with pre-TKR (P<0.05). Preoperatively, the CPM and bicycling EIH assessed by the increase in cPTT correlated with reduction in NRS pain scores post-TKR (P<0.05). Improved CPM and EIH responses after TKR were significantly correlated with reduction in NRS pain scores post-TKR (P<0.05). In KOA patients, hypoalgesia after cold pressor stimulation and aerobic exercise assessed preoperatively by cuff algometry was associated with pain relief 6 months after TKR. EIH as a novel preoperative screening tool should be further investigated in larger studies.

Effects of a respiratory functional training program on pain and sleep quality in patients with fibromyalgia: A pilot study

ObjectiveTo evaluate the effect of 8-week respiratory functional training program on pain tolerance, sleep, and urinary antioxidant and cortisol levels in 18 patients with fibromyalgia. MethodsParticipants underwent a 12-week intervention: 4 weeks as control and 8 weeks of breathing exercises. Pain tolerance assay was done by using an algometer, whereas sleep quality was evaluated by actigraphy and by the Pittsburgh Sleep Quality Index. Cortisol and antioxidant levels were determined using commercial assay kits. ResultsIncreases in the pain tolerance threshold were detected in the occiput point after one month of intervention as well as in the low cervical and second rib points after one and two months. Actigraphy revealed a decrease in sleep latency, whereas sleep questionnaire showed improvements in sleep quality, sleep duration and sleep efficiency. No changes in cortisol and antioxidant levels were detected. ConclusionThe 8-week breathing exercise intervention reduced pain and improved sleep quality.

Pain threshold reflects psychological traits in patients with chronic pain: a cross-sectional study

BackgroundChronic pain enhances sensory sensitivity and induces the biased development of psychological traits such as depression and pain catastrophizing, leading to the formation of heterogeneous conditions. Fluctuations in the sensory-related thresholds of non-injured sites (with normal peripheral tissue) in patients with chronic pain are thought to be related to central sensitization. The objectives of this study were to analyze the association between pain tolerance thresholds (PTTs) in non-injured sites and the psychological traits of patients with chronic pain and to evaluate the usefulness of PTT measures in assessments of pathological conditions related to chronic pain.MethodsThis study included 57 patients with chronic pain. The PTTs were measured in non-injured sites with quantitative sensory testing (QST) with electrical stimulation and then classified with cluster analysis. The Short-Form McGill Pain Questionnaire was used to subjectively assess pain in the injured sites. The Minnesota Multiphasic Personality Inventory (MMPI) was used to assess the patients’ psychological traits.ResultsBased on the cluster analysis of PTTs, the patients were classified into a High-Sensitivity group and an Others group consisting of the remaining patients. The results of the MMPI profiles showed that the High-Sensitivity group included significantly more patients with the Neurotic Triad pattern and no patients with the Conversion V pattern. The scores of the hypochondriasis and hysteria scales were significantly lower in the High-Sensitivity group than in the Others group.ConclusionsThis study indicated that patients with chronic pain can be classified according to PTTs in non-injured sites and suggests that patients with High-Sensitivity have characteristic psychological traits. Assessment of PTTs in non-injured sites would be useful for evaluating the psychological condition of patients with chronic pain.

Differences in Pain Processing Between Patients with Chronic Low Back Pain, Recurrent Low Back Pain, and Fibromyalgia

Background: The impairment in musculoskeletal structures in patients with low back pain (LBP) is often disproportionate to their complaint. Therefore, the need arises for exploration of alternative mechanisms contributing to the origin and maintenance of non-specific LBP. The recent focus has been on central nervous system phenomena in LBP and the pathophysiological mechanisms underlying the various symptoms and characteristics of chronic pain. Knowledge concerning changes in pain processing in LBP remains ambiguous, partly due to the diversity in the LBP population. Objective: The purpose of this study is to compare quantitative sensory assessment in different groups of LBP patients with regard to chronicity. Recurrent low back pain (RLBP), mild chronic low back pain (CLBP), and severe CLBP are compared on the one hand with healthy controls (HC), and on the other hand with fibromyalgia (FM) patients, in which abnormal pain processing has previously been reported. Study Design: Cross-sectional study. Setting: Department of Rehabilitation Sciences, Ghent University, Belgium. Methods: Twenty-three RLBP, 15 mild CLBP, 16 severe CLBP, 26 FM, and 21 HC participated in this study. Quantitative sensory testing was conducted by manual pressure algometry and computercontrolled cuff algometry. A manual algometer was used to evaluate hyperalgesia as well as temporal summation of pain and a cuff algometer was used to evaluate deep tissue hyperalgesia, the efficacy of the conditioned pain modulation and spatial summation of pain. Results: Pressure pain thresholds by manual algometry were significantly lower in FM compared to HC, RLBP, and severe CLBP. Temporal summation of pain was significantly higher in FM compared to HC and RLBP. Pain tolerance thresholds assessed by cuff algometry were significantly lower in FM compared to HC and RLBP and also in severe CLBP compared to RLBP. No significant differences between groups were found for spatial summation or conditioned pain modulation. Limitations: No psychosocial issues were taken into account for this study. Conclusion: The present results suggest normal pain sensitivity in RLBP, but future research is needed. In mild and severe CLBP some findings of altered pain processing are evident, although to a lesser extent compared to FM patients. In conclusion, mild and severe CLBP presents within a spectrum, somewhere between completely healthy persons and FM patients, characterized by pain augmentation. Key words: Low back pain, fibromyalgia, pain assessment, quantitative sensory testing, central sensitization, hypersensitivity, temporal summation, spatial summation, conditioned pain modulation

Responses to Slowly Repeated Evoked Pain Stimuli in Fibromyalgia Patients: Evidence of Enhanced Pain Sensitization.

The pathophysiology of fibromyalgia has been related to central pain sensitization. This study tested a laboratory protocol evaluating responses to slowly repeated evoked pain stimuli (SREP) that may index central pain sensitization in fibromyalgia. A between-subjects controlled laboratory study. Twenty-four fibromyalgia patients and 24 healthy participants. A SREP protocol was administered to all subjects, consisting of a single series of nine low-intensity pressure stimuli of five-second duration and thirty-second interstimulus interval. Subjective evoked pain intensity was assessed with a visual analogical scale. Clinical fibromyalgia pain was assessed with the McGill Pain Questionnaire. Perceived pain intensity increased during the SREP protocol in fibromyalgia patients but not in healthy participants. Neither pain threshold nor pain tolerance was associated with SREP. Degree of SREP sensitization was associated with McGill Pain Questionnaire-Sensory ratings of fibromyalgia pain. The effect size for differences between the fibromyalgia and healthy control groups was greater, and the overlaps of the groups distributions lower, for SREP sensitization than for traditional evoked pain measures of pain threshold and tolerance. SREP demonstrated higher specificity in discriminating fibromyalgia and control groups relative to pain threshold or tolerance. A protocol employing a single series of nine low-suprathreshold-intensity slowly repeated pain stimuli elicits increased perceived pain in fibromyalgia patients, consistent with central sensitization despite relatively long interstimulus intervals. SREP appears to be more useful than traditional evoked pain threshold tolerance measures in terms of predicting levels of clinical pain and discriminating between fibromyalgia patients and healthy individuals.

Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

AimA high inter-individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p-glycoprotein (ABCB1), and the UDP-glucuronosyltransferase-2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and -dynamics in healthy volunteers. MethodsPharmacokinetic and pharmacodynamic data were collected from a double-blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time-concentration relationship of morphine, morphine-3-glucuronide, and morphine-6-glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0–150min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation (“the cold pressor test” where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n=22), ABCB1 (n=37), and UGT2B (n=22)) were examined. ResultsNeither AUC0–150min, ktr, CL, nor VD were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P>0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P>0.05). ConclusionsIn this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.

Comparative study of response to experimental cold pain in dysmenorrheic and nondysmenorrheic women

Background: There has been keen research interest into the gender differences in tolerance of pain sensation. Dysmenorrheic pain is common among women of reproductive age group. Assessment of pain perception will result in better management of this chronic state. In this era of personalized medicine, optimizing analgesic treatment in patients with chronic pain is essential. Aims and Objectives: To compare levels of pain threshold and pain tolerance determined using cold pressor test in dysmenorrheic and nondysmenorrheic women during a single menstrual cycle in different phases. Materials and Methods: This is a comparative study done on 31 dysmenorrheic and nondysmenorrheic women between the ages of 18 and 22 years conducted in a tertiary care institution. We performed cold pressor test on 1st, 14th, and 21st day of menstrual cycle denoting the menstrual phase, late follicular phase, and luteal phase on the participants. Results: The levels of pain tolerance and pain threshold were significantly higher in dysmenorrheic women in comparison to nondysmenorrheic women. Conclusions: Higher thresholds may be supportive of a model of pain adaptation as dysmenorrheic women tend to compare cold pressor pain with internal menstrual pain. The knowledge of varying pain perception would benefit the gynecologists in dose adjustments of analgesics.

Pain tolerance and cardiorespiratory fitness in women with dysmenorrhea

ABSTRACT BACKGROUND AND OBJECTIVES: Hormonal changes are known to affect quality of life of women and may interfere in pain tolerance and cardiorespiratory exercise performance. Thus, the aim of this study was to evaluate and compare pressure pain tolerance threshold and cardiorespiratory fitness in women in luteal and follicular phases of the menstrual cycle. METHODS: University students aged 18-30 years old with a regular menstrual cycle were evaluated for cardiorespiratory fitness (ergospirometry), pain perception through the visual analog scale and pressure pain tolerance (algometry). RESULTS: When evaluated in follicular phase, the 13 participants exhibited a significant increase (p<0.001) in pain perception. Follicular phase also resulted in a significant reduction in pressure pain tolerance in all sites evaluated (p<0.05). At rest, follicular phase resulted in a significant increase (p<0.05) in systolic and diastolic blood pressure, but no effect was observed in heart rate. At peak exercise, follicular phase caused a significant reduction (p<0.05) in heart rate and peak VO2, without significantly affecting speed, test duration and indicators of metabolism efficiency. CONCLUSION: Healthy women with dysmenorrhea show higher pain perception in follicular phase, which results in increased pain sensitivity and prejudice in hemodynamic aspects at rest and during exercise, as well as in cardiorespiratory fitness, without significant alterations in metabolism.

Assessment of pain in adolescents: Influence of gender, smoking status and tobacco abstinence

PurposeWe examined sex differences between smokers and nonsmokers in pain threshold, tolerance, and intensity and the effect of pain on cardiovascular measures, withdrawal, and craving during acute smoking abstinence. MethodsNinety-six (53 smokers, 43 nonsmokers) adolescents completed the Cold Pressor Task (CPT) to assess pain responses after minimal (1h) and 42-hour smoking deprivation. Vital signs and craving were assessed before and after CPT completion. ResultsSmokers, compared to nonsmokers, had significantly lower pain tolerance (p<0.01) and pain threshold (p<0.001). Female smokers had significantly lower pain tolerance prior to, and following, 42-hour deprivation compared to male smokers (p's<0.01), male nonsmokers (p's<0.01), and female nonsmokers (p's<0.001), while male smokers demonstrated significantly decreased pain tolerance following 42-hour deprivation (p<0.05). Additionally, during minimal deprivation, at time of hand removal, female smokers had higher pain intensity compared to female nonsmokers (p<0.05) and male smokers (p<0.01). Withdrawal was not significantly correlated with any CPT measures or subjective pain during or following minimal deprivation or acute abstinence. Craving was associated with pain 15s after hand submersion (p=0.007) at 42-hour deprivation. ConclusionsSmokers had a lower pain threshold than non-smokers, with female smokers demonstrating lower pain tolerance during minimal deprivation than all comparison groups, and, continuing to have diminished pain tolerance compared to female nonsmokers following 42h of abstinence. Male smokers demonstrated tobacco-deprivation-induced reductions in pain tolerance. Further study of pain-related factors that may contribute to relapse and maintenance of smoking behaviors, and mechanisms of these relationships among adolescent smokers is warranted.

Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties.

Xen2174 is a synthetic 13-amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects. This was a randomized, blinded, placebo-controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks). Twenty-five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration-time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post-lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5mg-placebo (95% confidence interval), 22.2% (-5.0%, 57.1%); P = 0.1131]. At the Xen2174 dose level of 2.5mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed.

Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition.

BackgroundPersistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia.Methods138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months.Results48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively.ConclusionsPerioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain.