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Elisabeth Kjær Jensen,1,* Thomas K Ringsted,1,* Joakim M Bischoff,1 Morten A Petersen,2 Kirsten Møller,3,4 Henrik Kehlet,5 Mads U Werner1,6 1Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 2Statistical Research Unit, Department of Palliative Care, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Neuroanaesthesiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Section for Surgical Pathophysiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Sciences, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Elisabeth Kjær Jensen, Multidisciplinary Pain Center 7612, Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, Ole Maaløes Vej 26, Copenhagen N, 2200, Denmark, Tel +45 3545 7612, Email elisabeth.kjaer@live.dkPurpose: After groin hernia repair (globally more than 20 million/year) 2– 4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy.Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8– 11.5) months before and 4.0 (3.5– 4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed.Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of − 2.0, − 2.5, and − 2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001).Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.Keywords: groin, hernia repair, chronic post-surgical pain, reoperation, sensory thresholds

Introduction:Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, ca

Dried blood spot (DBS) testing allows fast, easy and minimally invasive collection of microvolumes of blood. In an anti-doping context, DBS testing has particular relevance for substances prohibited in-competition only such as ephedrine, which is currently detected by urine analysis, because DBS can add information about the blood drug concentrations during the in-competition period. Several collection methods and devices exist for DBS collection from different anatomical sites. Thus, agreements between concentrations of target analytes in DBS samples from different sampling sites, along with between DBS and those in conventional venous plasma samples, need to be evaluated. Herein, we collected matched upper-arm DBS, fingerprick DBS and venous plasma samples from eight healthy male subjects in an 8-h period following oral administrations of 20 mg ('low dose') and 60 mg ('high dose') of ephedrine. We show that the use of alternative sampling sites and matrices is a feasible possibility for ephedrine analysis in doping control. We observed very good agreement between collection sites and that specificity and sensitivity can be upheld despite use of an alternative collection site. However, potential concentration differences between DBS and venous plasma should be considered, and distinct threshold might be necessary if implementing both blood matrices in ephedrine analysis., (© 2022 John Wiley & Sons Ltd.)

This study aimed to determine and compare the perception, painfulness, and usability of the minimally invasive dried blood spot (DBS) collections from fingertip versus upper arm from different athlete populations: males and females representing sports dependent on hand/arm, sports less dependent on hand/arm and para-athletes. To accomplish this, 108 national level athletes from Denmark were recruited (♀ = 49, ♂ = 59, 25 ± 6 years; mean ± SD) and 11 Doping Control Officers (DCOs) collected manual fingerprick DBS (HemaSpot HF) and automated upper-arm DBS (Tasso-M20) from each athlete. Athletes and DCOs responded to questionnaires regarding the perception of sample collection procedures. On a 0-10 scale, the athletes reported a low pain score and a very good general experience for both sampling sites, but following upper-arm DBS collection, the associated pain was rated lower (-0.4 ± 1.6, p < 0.05), and the general experience rated better (+0.6 ± 2.3, p ≤ 0.001) than after the fingerprick DBS collection. The DCOs rated the general experience with the upper-arm DBS collection better (+1.6 ± 1.1, p ≤ 0.01) than the fingerprick DBS collection, partly because problems occurred more frequently during the DBS collection from the fingertip (28%) than from the upper arm (6%). In conclusion, it appears that DBS sampling is affiliated with minimal sensation of pain and is preferred by both DCOs and athletes, independent of gender and discipline, over conventional sample collection methods. Collection of DBS from the upper arm was preferred over fingerprick by both athletes and DCOs., (© 2021 John Wiley & Sons, Ltd.)

Severe persistent pain after groin hernia repair impairs quality-of-life. Prospective, consecutive cohort study including patients with pain-related impairment of physical and social life. Relevant surgical records were obtained, and examinations were by standardized clinical and neurophysiological tests. Patients demonstrating pain sensitivity to pressure algometry in the operated groin underwent re-surgery, while patients with neuropathic pain received pharmacotherapy. Questionnaires at baseline (Q0) and at the 5-year time point (Q5Y) were used in outcome analyses of pain intensity (numeric rating scale [NRS] 0-10) and pain-related effect on the activity-of-daily-living (Activities Assessment Scale [AAS]). Data are mean (95% CI).Analyses were made in 172/204 (84%) eligible patients. In 54/172 (31%) patients re-surgery (meshectomy/selective neurectomy) was performed, while the remaining 118/172 (69%) patients received pharmacotherapy. In the re-surgery group, activity-related, and average NRS-scores at Q0 were 6.6 (5.6-7.9) and 5.9 (5.6-5.9), respectively. Correspondingly, NRS-scores at Q5Y was 4.1 (3.3-5.1) and 3.1 (2.3-4.0; Q0 vs. Q5Y: P < .0005), respectively. Although both groups experienced a significant improvement in AAS-scores comparing Q0 vs. Q5Y (re-surgery group: 28% (4-43%; P < .0001); pharmacotherapy group: 5% (0-11%; P = .005)) the improvement was significantly larger in the re-surgery group (P = .02).This 5-year cohort study in patients with severe persistent pain after groin hernia repair signals that selection to re-surgery or pharmacotherapy, based on examination of pain sensitivity, is associated with significant improvement in outcome. Analyzing composite endpoints, combining pain and physical function, are novel in exploring interventional effects.ClinicalTrials.gov Identifier NCT03713047.

Background: Severe, persistent inguinal postherniorrhaphy pain (PIPP) is a debilitating condition that develops in 2-5% of patients. PIPP may be neuropathic in nature, yet the lesion in the peripheral nervous system has not been located. Most PIPP-patients demonstrate a tender point (TP) in the medial aspect of the inguinal region that triggers pain upon minimal pressure. As TPs may play a role in the pathophysiology of PIPP, the aim of this trial was to investigate the analgesic effects of local anaesthetic TP-blockade., Methods: A randomized, double-blind, placebo-controlled, crossover trial was performed in 14 PIPP-patients and six healthy volunteers. All participated in two sessions, seven days apart, receiving 10 ml of 0.25% bupivacaine or normal saline via an ultrasound-guided fascial plane block at the TP. The TP-area was used for pain assessments (at rest, on movement, with 100 kPa pressure-algometry) and quantitative sensory testing (pressure pain thresholds, thermal detection/pain thresholds, supra-threshold heat perception), before and after the TP-blockade., Results: The median (95% CI) reduction in pain was 63% (44.1 to 73.6%) after bupivacaine compared with 36% (11.6 to 49.7%; P=0.003) after placebo. Significant increases in cool detection (P=0.01) and pressure pain thresholds (P=0.009) with decreases in supra-threshold heat pain perception (P=0.003) were seen after bupivacaine only. In four out of six volunteers, increased thermal and evoked-pain thresholds after bupivacaine compared with placebo, was demonstrated., Conclusions: This trial demonstrates that peripheral afferent input from the TP-area is important for maintenance of spontaneous and evoked pain in PIPP., Clinical Trial Registration: NCT02065219., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The risk of persistent postsurgical pain (PPP) and subsequent pain-related functional impairment may potentially be reduced by video-assisted thoracic surgery (VATS) compared to thoracotomy. The aim of the study was therefore to assess in detail the incidence and consequences on activities of daily living of PPP after VATS., Methods: Using a prospective observational design, 47 patients undergoing VATS completed both preoperative, early postoperative and 3 months follow-up. Preoperative pain, pain characteristics, psychological factors, pain-related functional impairment and quantitative sensory testing (QST) including nociceptive thresholds were compared with postoperative data., Results: Only five (11%) patients developed PPP with NRS > 3 originating from the surgical area. However, about 30% of patients still reported some pain-related functional impairment from the surgical area within four well-defined domains of everyday activities. Psychological and sensory thermal tests did not predict persistent postoperative pain, except preoperative pin-prick sensitivity was higher in patients with PPP. Postoperative pain 7 days after surgery was significantly higher in PPP patients. Preoperative pain originating from remote areas did not predict PPP., Conclusion: The incidence of PPP, nerve damage (based on QST) and pain-related functional impairment following VATS was lower than reported following thoracotomy. No psychological or other factors predicted PPP. These findings call for further large-scale studies to support VATS to decrease PPP., (© 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Secondary hyperalgesia is increased sensitivity in normal tissue near an injury, and it is a measure of central sensitization reflecting injury-related effects on the CNS. Secondary hyperalgesia areas (SHAs), usually assessed by polyamide monofilaments, are important outcomes in studies of analgesic drug effects in humans. However, since the methods applied in demarcating the secondary hyperalgesia zone seem inconsistent across studies, we examined the effect of a standardized approach upon the measurement of SHA following a first degree burn injury (BI)., New Method: The study was a two-observer, test-retest study with the two sessions separated by 6wk. An observer-blinded design adjusted to examine day-to-day and observer-to-observer variability in SHA was used. In 23 healthy volunteers (12 females/11 males) a BI was induced by a contact thermode (47.0°C, 420s, 2.5×5.0cm(2)). The SHA, demarcated by polyamide monofilaments (bending force: 0.2, 69 and 2569mN) and a "weighted-pin" stimulator (512mN), were assessed 45 to 75min after each BI., Results: A random effect, linear mixed model demonstrated a logarithmic correlation between elicited skin pressures (mN/mm(2)) and the SHAs (P<0.0001). No day-to-day or observer-to-observer differences in SHAs were observed. Intraclass correlation coefficients, in the range of 0.51 to 0.84, indicated a moderate to almost perfect reliability between observers., Comparison With Existing Methods: No standardized approach in SHA-assessment has hitherto been presented., Conclusions: This is the first study to demonstrate that demarcation of secondary hyperalgesia zones depends on the developed pressure of the punctate stimulator used., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Persistent pain after inguinal herniorrhaphy is a disabling condition with a lack of evidence-based pharmacological treatment options. This randomized placebo-controlled trial investigated the efficacy of a capsaicin 8% cutaneous patch in the treatment of severe persistent inguinal postherniorrhaphy pain., Methods: Forty-six patients with persistent inguinal postherniorrhaphy pain were randomized to receive either a capsaicin 8% patch or a placebo patch. Pain intensity (Numerical Rating Scale [NRS 0-10]) was evaluated under standardized conditions (at rest, during movement, and during pressure) at baseline and at 1, 2 and 3 months after patch application. Skin punch biopsies for intraepidermal nerve fiber density (IENFD) measurements were taken at baseline and 1 month after patch application. Quantitative sensory testing was performed at baseline and at 1, 2, and 3 months after patch application. The primary outcome was comparisons of summed pain intensity differences (SPIDs) between capsaicin and placebo treatments at 1, 2 and 3 months after patch application (significance level P < 0.01)., Results: The maximum difference in SPID, between capsaicin and placebo treatments, was observed at 1 month after patch application, but the pain reduction was not significant (NRS, mean difference [95% CI]: 5.0 [0.09 to 9.9]; P = 0.046). No differences in SPID between treatments were observed at 2 and 3 months after patch application. Changes in IENFD on the pain side, from baseline to 1 month after patch application, did not differ between capsaicin and placebo treatment: 1.9 [-0.1 to 3.9] and 0.6 [-1.2 to 2.5] fibers/mm, respectively (P = 0.32). No significant changes in sensory function, sleep quality or psychological factors were associated with capsaicin patch treatment., Conclusions: The study did not demonstrate significant differences in pain relief between capsaicin and placebo treatment, although a trend toward pain improvement in capsaicin treated patients was observed 1 month after patch application., Trial Registration: Clinicaltrialsregister.eu 2012-001540-22 ClinicalTrials.gov NCT01699854.

Objectives: Quantitative sensory testing is a reference method for characterization of postsurgical neuropathic components. Correct interpretation of data requires detailed information concerning the validity of the testing methods. The objective of the study was to assess the test-retest variability of thermal thresholds in patients (n = 14) with the postthoracotomy pain syndrome., Methods: Sensory mapping with a metal roller (25°C) on the surgical side delineated an area with cool sensory dysfunction. In this area and in a contralateral area, 4 prespecified sites (2.6 cm) were outlined, in addition to the maximum pain site on the surgical side. In these total 9 sites, warmth detection threshold, cool detection threshold, and heat pain threshold were assessed., Results: Comparisons of thermal test-retest assessments did not demonstrate any significant intraside differences. The SDs of the thermal assessments in nonpain sites and in the maximum pain site ranged from 1.9 to 2.5°C and 3.5 to 6.9°C, respectively. The estimated within-patient and between-patient variances were 5% to 28% and 72% to 95%, respectively, of the total variances. Although a generally poor test-retest agreement was demonstrated, the much lower within-patient than between-patient variances facilitated estimations of highly statistical significant, within-patient differences in thermal thresholds., Discussion: In patients with postthoracotomy pain syndrome, several statistical methods indicated an excessively high variability in thermal thresholds, questioning the use of single quantitative sensory testing in assessments to characterize patients with chronic pain states.

Objectives: Mirror-image sensory dysfunction (MISD) has not been systematically characterized in persistent postoperative pain., Methods: The presence of MISD was evaluated with standardized stimuli, in preoperative patients scheduled for a thoracotomy (n = 14) and in patients with postthoracotomy pain syndrome [PTPS (n = 14)]. The primary outcome was investigation of the areas of sensory dysfunction, evaluated twice by dynamic sensory mapping with metal rollers and a brush., Results: In PTPS patients, sensory dysfunction was present on the surgical side, and in 12 of 14 patients MISD was demonstrated. The total areas of sensory dysfunction [median (interquartile range)] were: day 1, 500 (289 to 636) cm and 60 (0 to 379) cm on the surgical and nonsurgical side (P < 0.005), respectively; and day 2, 355 (266 to 697) cm and 81 (0 to 202) cm on the surgical and nonsurgical side (P < 0.0002), respectively. Magnitudes of areas on the surgical side, respective of the nonsurgical side, did not significantly differ between the 2 days of investigation (P > 0.5). The agreement between test-retest assessments was fair to excellent on the surgical side but poor on the nonsurgical side. None of the PTPS patients experienced mirror pain., Discussion: MISD is a common finding in PTPS patients and deserves further study involving mechanism and clinical implications.

Objective: Persistent postoperative pain is an acknowledged entity that reduces daily activities. Evaluation of the post-thoracotomy pain syndrome (PTPS) is often measured using traditional pain scales without in-depth questions on pain impairment. Thus, the purpose was to create a procedure-specific questionnaire for assessment of functional impairment due to PTPS., Methods: Activities were obtained from the literature supplemented by interviews with patients and surgeons. The questionnaire was validated using the Rasch model in order to describe an underlying pain impairment scale., Results: Four of 17 questions were redundant. The remaining 13 questions from low to intensive activity described functional impairment following persistent pain from thoracotomy and video-assisted thoracic surgery (VATS). No evidence for differential item functioning for gender, age or differences between open or VATS, were found. A generalized log-linear Rasch model including local dependence was constructed. Though local dependence influenced reliability, the test-retest reliability estimated under the log-linear Rasch model was high (0.88-0.96). Correlation with items from the Disability of the Arm, Shoulder and Hand (quick) questionnaire supported validity (γ = 0.46, P < 0.0001), and procedure specificity. The analysis also procured evidence that the pain impairment questionnaire measured 2 qualitatively different pain dimensions although highly correlated (γ = 0.76)., Conclusions: This study presents method, results and validation of a new unidimensional scale measuring procedure specific functional impairment due to PTPS following open surgery and VATS. Procedure specific tools such as this could provide important outcomes measures for future trials on persistent postsurgical pain states allowing better assessment of interventions (250).

Background: It is well known that chest drains are associated with severe movement-related acute pain. These noxious stimuli could play a significant role in development and maintenance of persistent post-operative pain. Therefore we studied chest drain sites in post-thoracotomy pain syndrome (PTPS) patients, in regard to pain and sensory dysfunction., Methods: We quantified thermal and pressure thresholds on both the chest drain side and the contralateral side in 11 PTPS patients and 10 pain-free post-thoracotomy patients 33 months after the thoracotomy. On average, each patient had two chest drains inserted during surgery., Results: At follow up, two patients experienced pain at the chest drain sites, but had maximal pain near or at the thoracotomy scar. Comparison between chest drain side and control side for all 21 patients demonstrated significantly elevated thresholds for warmth detection and heat pain on the chest drain side (P < 0.01), but not for cool detection or pressure. No significant differences between chest drain side and control side were observed within PTPS or pain-free patients. Comparing PTPS and pain-free patients (chest drain-to-control side), no significant differences in thresholds were found. Although all 11 PTPS patients suffered from incisional pain, only two patients had pain from chest drains., Conclusion: Increased thresholds for thermal detection suggest that chest drain insertion is associated with late nerve injury. Because no significant differences in sensory thresholds between PTPS and pain-free patients were found, the pathophysiological role of small fibre nerve injury from chest drains in relation to PTPS remains unclear., (© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Introduction: Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury., Methods: Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds., Results: Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects., Conclusion: Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

Objectives: No golden standard for analgesia in video-assisted thoracic surgery (VATS) lobectomy exists. A simple multimodal approach using an intercostal catheter (ICC) may be of benefit since acute post-operative pain following VATS lobectomy primarily originates from the chest drain area., Methods: Prospective observational cohort. Forty-eight consecutive patients received a standardized regimen consisting of paracetamol, non-steroidal anti-inflammatory drug and gabapentin. Further, surgeons performed a single-shot paravertebral block (PVB) at five levels (15 ml of 0.5% bupivacaine) and inserted an ICC at the drain site level for continuous delivery of 6 ml of 0.25% bupivacaine h(-1). Pain scores at rest, mobilization and with the extended arms were followed until discharge or for 4 days., Results: Forty-eight patients, mean age 64 years (CI: 61-68), were included. The mean time for the PVB and ICC placement was 5 min (CI: 4.7-5.9). The mean pain score at rest using a numerical rating scale (NRS, 0-10) was <3 for 1-16 h and decreased from 4.7 to 1.7 (NRS day 1-4, getting out of bed). The ICC was removed with the drain in 48/73/92% on day 1/2/3 after surgery. The median day of discharge was 3 (interquartile range 2-4) with >85% of patients reporting satisfactory or very satisfactory pain treatment all days., Conclusions: Acute pain after VATS lobectomy may be adequately controlled using a multimodal non-opioid regime including PVB and an ICC. The low pain scores and reduced time used inserting the ICC may present an alternative to continuous epidural analgesia or conventional PVB.

Background: Video-assisted thoracic surgery (VATS) lobectomy may potentially reduce the risk of post-thoracotomy pain syndrome (PTPS). However, it may still carry a risk of intraoperative nerve damage and thereby development of PTPS. Thus, our aim was to present a detailed long-term neurophysiological characterization of PTPS after VATS., Methods: Quantitative sensory testing, using thermal and mechanical stimuli, was performed in 13 PTPS patients and 35 pain-free patients recruited 33 months after VATS lobectomy., Results: When comparing the operated side with the control side in PTPS patients, increased thresholds of tactile and warmth detection were observed, while in pain-free patients, increased thresholds of warmth detection, cool detection, and heat pain were demonstrated. At the anterior porthole, pain-free patients displayed increased threshold to thermal detection when compared with the control side. Only side-to-side difference for tactile detection threshold was increased in PTPS patients compared with pain-free patients. Assessment of central sensitization showed no significant differences within or between PTPS and pain-free patients nor did group comparison of area of hypo- and hyperaesthesia to cool. Anxiety and depression scores (HADS) were higher in PTPS patients, but the area of hyper- and hypoaesthesia did not differ significantly between HADS groups., Conclusions: Increased sensory thresholds suggest nerve injury to be present on the operated side in both PTPS and pain-free patients. However, no significant quantitative differences between PTPS and pain-free patients could be found, implicating the presence of factors other than intercostal nerve injury as important for development of PTPS after VATS lobectomy.