Reply to Jensen, O.K. On the Use of Quantitative Sensory Testing to Estimate Central Sensitization in Humans. Comment on "Schuttert et al. The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review. J. Clin. Med. 2021, 10, 5931".

We thank Dr. Jensen for his interest [...].

The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review.

Central sensitisation is assumed to be one of the underlying mechanisms for chronic low back pain. Because central sensitisation is not directly assessable in humans, the term 'human assumed central sensitisation' (HACS) is suggested. The objectives were to investigate what definitions for HACS have been used, to evaluate the methods to assess HACS, to assess the validity of those methods, and to estimate the prevalence of HACS. Database search resulted in 34 included studies. Forty different definition references were used to define HACS. This review uncovered twenty quantitative methods to assess HACS, including four questionnaires and sixteen quantitative sensory testing measures. The prevalence of HACS in patients with chronic low back pain was estimated in three studies. The current systematic review highlights that multiple definitions, assessment methods, and prevalence estimates are stated in the literature regarding HACS in patients with chronic low back pain. Most of the assessment methods of HACS are not validated but have been tested for reliability and repeatability. Given the lack of a gold standard to assess HACS, an initial grading system is proposed to standardize clinical and research assessments of HACS in patients with a chronic low back.

Strength training in addition to neuromuscular exercise and education in individuals with knee osteoarthritis-the effects on pain and sensitization.

BACKGROUND: There is a lack of evidence of the relative effects of different exercise modes on pain sensitization and pain intensity in individuals with knee osteoarthritis (KOA). METHODS: Ninety individuals with radiographic and symptomatic KOA, ineligible for knee replacement surgery, were randomized to 12 weeks of twice-weekly strength training in addition to neuromuscular exercise and education (ST+NEMEX-EDU) or neuromuscular exercise and education alone (NEMEX-EDU). Outcomes were bilateral, lower-leg, cuff pressure pain- and tolerance thresholds (PPT, PTT), temporal summation (TS), conditioned pain modulation (CPM), self-reported knee pain intensity and number of painful body sites. RESULTS: After 12 weeks of exercise, we found significant differences in increases in PPT (-5.01 kPa (-8.29 to -1.73, p = .0028)) and PTT (-8.02 kPa (-12.22 to -3.82, p = .0002)) in the KOA leg in favour of ST+NEMEX-EDU. We found no difference in effects between groups on TS, CPM or number of painful body sites. In contrast, there were significantly greater pain-relieving effects on VAS mean knee pain during the last week (-8.4 mm (-16.2 to -0.5, p = .0364) and during function (-16.0 mm (-24.8 to -7.3, p = .0004)) in favour of NEMEX-EDU after 12 weeks of exercise. CONCLUSION: Additional strength training reduced pain sensitization compared to neuromuscular exercise and education alone, but also attenuated the reduction in pain intensity compared to neuromuscular exercise and education alone. The study provides the first dose- and type-specific insight into the effects of a sustained exercise period on pain sensitization in KOA. Future studies are needed to elucidate the role of different exercise modes. SIGNIFICANCE: This study is an important step towards better understanding the effects of exercise in pain management of chronic musculoskeletal conditions. We found that strength training in addition to neuromuscular exercise and education compared with neuromuscular exercise and education only had a differential impact on pain sensitization and pain intensity, but also that regardless of the exercise mode, the positive effects on pain sensitization and pain intensity were comparable to the effects of other therapeutic interventions for individuals with knee osteoarthritis.

Impaired exercise-induced hypoalgesia in individuals reporting an increase in low back pain during acute exercise.

OBJECTIVES: Exercise therapy is recommended for low back pain (LBP) although the immediate effects on pain are highly variable. In 96 individuals with LBP this cross-sectional study explored (a) the magnitude of exercise-induced hypoalgesia (EIH) and (b) measures of pain sensitivity and clinical pain manifestations in individuals reporting a clinical relevant increase in back pain during physical activity compared with individuals reporting low or no increase in back pain during physical activity. METHODS: Cuff algometry was performed at baseline on the leg to assess pressure pain threshold (cPPT), tolerance (cPTT) and temporal summation of pain (cTSP). Manual PPTs were assessed on the back and leg before and after a 6-min walk test (6MWT). Back pain was scored on a numerical rating scale (NRS) after each minute of walking. The EIH-effect was estimated as the increase in PPTs after the walk exercise. RESULTS: Twenty-seven individuals reported an increase of ≥2/10 in pain NRS scores during walking and compared with the individuals with <2/10 NRS scores: cPPT and EIH-effects were lower whereas cTSP, pain intensity and disability were increased (p < 0.03). Baseline NRS scores, EIH and pain thresholds were associated with the likelihood of an increase of ≥2/10 in back pain intensity during walking (p < 0.05). CONCLUSIONS: Pain flares in response to physical activity in individuals with LBP seem to be linked with baseline pain sensitivity and pain intensity, and impair the beneficial EIH. Such information may better inform when individuals with LBP will have a beneficial effect of physical activity. SIGNIFICANCE: Pain flares in response to physical activity in individuals with LBP seem to be linked with baseline pain sensitivity and pain intensity, and impair the beneficial exercise-induced hypoalgesia. Such information may better inform when individuals with LBP will have a beneficial effect of physical activity.

Patients With High Chronic Postoperative Knee Pain 5 Years After Total Knee Replacement Demonstrate Low-grad Inflammation, Impairment of Function, and High Levels of Pain Catastrophizing.

OBJECTIVES: Total knee replacement (TKR) normally provides improvements of physical function and reduces pain. However, ∼20% of the patients report chronic postoperative knee pain. The aims of the present study were to assess the pain, physical function, and physiological characteristics 5 years after TKR surgery. MATERIALS AND METHODS: Eighty patients were recruited 5 years after TKR and divided into 2 groups based on their average 24-hour knee pain intensity assessed on a visual analog scale (VAS 0 to 10) ("high pain group": VAS≥3; "low pain group": VAS<3). The patients completed the PainDETECT Questionnaire (PDQ), Oxford Knee Score (OKS), Pain Catastrophizing Scale, and Forgotten Joint Score-12. Furthermore, the patients underwent a clinical examination of the knees and high-sensitivity serum C-reactive protein was measured as an inflammatory marker. RESULTS: A total of 53% of the patients in the high pain group were not satisfied with the outcome, while only 11% of the patients in the low pain group was not satisfied, and the pain intensities in the 2 groups were 5.1 (4.6 to 5 to 6) and 1.1 (0.6 to 1.5) (P<0.001), respectively. Furthermore, the high pain group demonstrates worse scores in: Forgotten Joint Score-12 (P=0.001), OKS function (P<0.001), OKS pain (P<0.001), and Pain Catastrophizing Scale (P<0.001).The high pain group demonstrated increased level of high-sensitivity serum C-reactive protein (4.3 mg/L [3.2 to 5.5] vs. 1.7 mg/L [1.2 to 2.2], P<0.001), and decreased range of motion in the knee (110 vs. 119-degree range of motion, P=0.013). DISCUSSION: Patients with high chronic postoperative knee pain 5 years after TKR demonstrate decreased physical function, higher levels of catastrophizing thoughts, and increased levels of inflammation.

Pain Catastrophizing, Self-reported Disability, and Temporal Summation of Pain Predict Self-reported Pain in Low Back Pain Patients 12 Weeks After General Practitioner Consultation: A Prospective Cohort Study.

OBJECTIVES: Patients with low back pain (LBP) often demonstrate pain sensitization, high degree of pain catastrophizing, and psychological distress. This study investigated whether pain sensitization mechanisms, the Pain Catastrophizing Scale (PCS), and Start Back Screening Tool were associated with pain in recurrent LBP patients 12 weeks after consulting their general practitioner (GP). MATERIALS AND METHODS: In 45 LBP patients, pressure pain thresholds, temporal summation of pain (TSP), conditioned pain modulation (CPM), the Roland Morris Disability Questionnaire (RMDQ), and the PCS were assessed before consultation. Patients were classified into low to medium or high risk of poor prognosis on the basis of the Start Back Screening Tool. Worst pain within the last 24 hours was assessed on a visual analogue scale (VAS) at inclusion and 12 weeks after GP consultation. RESULTS: VAS scores were reduced after 12 weeks in the low-to-medium (N=30, P<0.05), but not the high-risk group (N=15, P=0.40). RMDQ was reduced after 12 weeks (P<0.001), but with no difference between the groups. PCS was reduced in the low-to-medium and the high-risk group (P<0.05). TSP was significantly higher at follow-up in the high-risk group compared with the low-to-medium-risk group (P<0.05). A linear regression model explained 54.9% of the variance in VAS scores at follow-up utilizing baseline assessments of TSP, RMDQ, and PCS. DISCUSSION: This study indicate that patients with LBP and high self-reported disability, high pain catastrophizing, and facilitated TSP assessed when consulting the GP might predictive poor pain progression 12 weeks after the consultation.

Chronic Postoperative Pain After Hysterectomy for Endometrial Cancer: A Metabolic Profiling Study.

INTRODUCTION: One out of seven women will develop a state of chronic postoperative pain following robot-assisted hysterectomy for endometrial cancer. Recently, metabolic studies have indicated that circulating lipids and lipoproteins could act as nociceptive modulators and thereby influence the induction and perpetuation of pain. The objectives of this explorative study were (1) to examine the preoperative serologic variations in concentrations of lipids, lipoproteins, and various low-molecular metabolites in patients with and without chronic postoperative pain after robot-assisted hysterectomy and (2) to explore if any of these serological biomarkers were predictive for development of chronic postoperative pain. MATERIALS AND METHODS: The study was designed as a nested case-control study within a cohort of women treated for endometrial cancer with robot-assisted laparoscopic hysterectomy. Twenty-six women with chronic postoperative pain were matched on age and body mass index with fifty-two controls without chronic postoperative pain, and metabolic profiling of preoperatively drawn blood samples from a biobank was performed by means of nuclear magnetic resonance spectroscopy. RESULTS: Nineteen metabolites, including cholesterol, cholesteryl ester, linoleic acid, phospholipids, lipids, and triglycerides had statistically significant higher concentrations in a subgroup of patients who would develop chronic postoperative pain on a later stage compared to the group of patients who would not develop chronic postoperative pain (p < 0.05). A sparse Partial Least Squares-Discriminant Analysis model explained 38.1% of the variance and had a predictive accuracy of 73.1%. CONCLUSIONS: This explorative study substantiates the hypothesis that certain lipids, lipoproteins, and fatty acids are associated with chronic postoperative pain.

Brain perfusion patterns are altered in chronic knee pain: a spatial covariance analysis of arterial spin labelling MRI.

Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity, for example, in postoperative pain after knee replacement. Other factors such as low mood, anxiety, and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain and 29 pain-free participants, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal component analysis of CBF identified 5 components that significantly discriminated chronic pain participants from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default mode, thalamus, and sensory regions. One component correlated positively with the pain sensitization score (r = 0.43, P = 0.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitization.

Investigating the Effect of Perioperative Chlorzoxazone on Acute Postoperative Pain After Total Hip and Knee Replacement Surgery.

BACKGROUND AND AIMS: Severe preoperative and acute postoperative pain have been associated with the development of chronic postoperative pain. Chlorzoxazone (a muscle relaxant) has been suggested to enhance acute postoperative pain recovery, but the lack of larger randomized controlled trials has, however, questioned the continued use. Despite this, chlorzoxazone is still used for acute postoperative pain management following total knee replacement (TKR) or total hip replacement (THR). The current randomized, double-blinded, placebo-controlled, parallel-group, clinical trial aimed to assess the effect of chlorzoxazone for postoperative pain management following TKR or THR. METHODS: A total of 393 patients scheduled for TKR or THR were included in the trial. Patients were assigned to 250 mg chlorzoxazone 3 times daily for the first 7 days postoperatively or to placebo. The primary outcome was pain after 5 m walk assessed 24 hours postoperatively. Secondary outcomes included changes in preoperative pain at rest, worst pain in the last 24 hours, and Oxford Knee or Hip Score compared with 12 months' follow-up. In addition, adverse events were assessed in the perioperative period. RESULTS: No significant differences were found for any of the outcome parameters after TKR or THR. As regards TKR or THR, no effects were demonstrated for pain after 5 m walk 24 hours after surgery (P>0.313), or for any of the secondary outcomes (P>0.288) or adverse events (P>0.112) in the group receiving chlorzoxazone compared with placebo. CONCLUSION: The current study demonstrated no analgesic effects of postoperative chlorzoxazone administration compared with placebo on acute or chronic postoperative pain 12 months following TKR and THR.

Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.

OBJECTIVES: Osteoarthritis (OA) is known to be a slowly progressive disease that alters all tissue compartments of the joint involved with a characteristic degradation of the cartilage, bone remodeling, and inflammation. One of the prominent symptoms in OA patients is pain, but a few radiologic, inflammatory, or structurally related biomarkers have shown few if any associations with pain. This study aimed to assess serum levels of 92 markers involved in inflammatory pathways in patients with knee osteoarthritis (KOA) and evaluate their possible associations with the clinical pain intensity. MATERIALS AND METHODS: Serum samples were collected from 127 KOA patients and 39 healthy participants with no knee pain. Each serum sample was analyzed for 92 inflammatory markers using the Proximity Extension Array (PEA) technology. Clinical pain intensity was assessed using a Visual Analog Scale, and patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. RESULTS: Fifteen markers were significantly different when comparing KOA patients and healthy participants. Two markers, fibroblast growth factor-21 and Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), correlated positively with pain intensity (R=0.235, P=0.008; R=0.233, P=0.008). Moreover, a linear regression model showed interleukin-6, macrophage colony-stimulating factor 1, fibroblast growth factor-21, and tumor necrosis factor superfamily member 12 (TWEAK) as significant independent parameters for pain intensity. DISCUSSION: The associations between specific cytokines and KOA pain intensities provide new insights into the understanding of the underlying factors driving the pain in OA.

Pretreatment Exercise-induced Hypoalgesia is Associated With Change in Pain and Function After Standardized Exercise Therapy in Painful Knee Osteoarthritis.

OBJECTIVES: Exercise-induced hypoalgesia (EIH), a measure of descending pain inhibitory control, has been found hyperalgesic in subgroups of painful knee osteoarthritis (KOA) patients. The effect of standardized exercise therapy (ET) on clinical pain intensity in KOA has been demonstrated. However, the prognostic value of EIH in KOA patients completing an ET program has not been investigated. This study investigated the prognostic value of EIH on pain relief following ET in KOA patients. MATERIALS AND METHODS: In 24 painful KOA patients (Numerical Rating Scale, 0 to 10 ≥3), EIH was assessed as change in pressure pain threshold after 2-minute "lateral raises" before and after ET in this observational study. In addition, temporal summation of pain, clinical pain scores (Numerical Rating Scale, Knee injury and Osteoarthritis Outcome Score [KOOS], and PainDETECT Questionnaire) were assessed before and after ET. The KOOS-4 is defined by the KOOS subscale scores for Pain, Symptoms, Activities of Daily Living, and Quality of Life and was used as the primary outcome. RESULTS: Following ET, all clinical pain scores improved (P<0.01) but no changes in pressure pain threshold, temporal summation of pain, or EIH were found (P>0.05). Linear regression models identified pretreatment EIH (ß=0.59, P<0.005) and PainDETECT Questionnaire (ß=0.57, P<0.005) as independent factors for relative change in KOOS-4 after ET (adjusted R=46.8%). DISCUSSION: These preliminary and exploratory results suggest that patients with a high EIH response before a standardized ET program may be associated with a large improvement in pain after treatment. This measure may potentially help clinicians as a prognostic tool for outcome prediction following ET in KOA patients.

Less Severe Preoperative Synovitis is Associated With Higher Self-reported Pain Intensity 12 Months After Total Knee Arthroplasty-An Exploratory Prospective Observational Study.

OBJECTIVES: Synovitis is one of the possible pain generators in osteoarthritis (OA) and is associated with upregulation of proinflammatory cytokines, which can lead to worsening of the postoperative pain. This exploratory study aimed to investigate the association between perioperative synovitis and self-reported pain 12 months after total knee arthroplasty (TKA) in patients with OA. MATERIALS AND METHODS: Twenty-six knee OA patients were included in this analysis. The perioperative volume of synovitis in predefined locations was assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Perioperative synovitis was assessed histologically from biopsies of the synovium. Highest pain intensity within the last 24 hours (Visual Analog Scale, VAS, 0 to 100) was assessed before and 12 months after TKA. Patients were divided into a low-pain intensity (VAS≤30) and a high-pain intensity (VAS>30) group on the basis of 12 months postoperative VAS. RESULTS: The high-pain intensity group had significantly lower perioperative contrast-enhanced-synovitis (P=0.025), DCE-synovitis (P<0.04), and a trend toward lower histologically assessed synovitis (P=0.077) compared with the low-pain intensity group. Perioperative synovitis scores were inversely correlated with pain intensity 12 months after TKA (P<0.05), indicating that more severe perioperative synovitis is associated with less severe pain intensity at 12 months. DISCUSSION: Higher degrees of perioperative synovitis scores are found to be associated with less postoperative pain 12 months after TKA. Further, correlation analysis revealed that less severe perioperative CE-MRI and DCE-MRI synovitis was associated with higher pain intensity 12 months after TKA, suggesting that CE-MRI and DCE-MRI synovitis grades could be used as imaging markers for prediction of chronic postoperative pain after TKA.

Temporal aspects of endogenous pain modulation during a noxious stimulus prolonged for 1 day.

BACKGROUND: This study investigated (a) if a prolonged noxious stimulus (24-hr topical capsaicin) in healthy adults would impair central pain inhibitory and facilitatory systems measured as a reduction in conditioned pain modulation (CPM) and enhancement of temporal summation of pain (TSP) and (b) if acute pain relief or exacerbation (cooling and heating the capsaicin patch) during the prolonged noxious stimulus would affect central pain modulation. METHODS: Twenty-eight participants (26.2 ± 1.0 years; 12 women) wore a transdermal 8% capsaicin patch on the forearm for 24 hr. Data were collected at baseline (Day 0), 1 hr, 3 hr, Day 1 (post-capsaicin application) and Day 3/4 (post-capsaicin removal) that included capsaicin-evoked pain intensity, heat pain thresholds (HPTs), TSP (10 painful cuff pressure stimuli on leg) and CPM (cuff pressure pain threshold on the leg prior vs. during painful cuff pressure conditioning on contralateral leg). After 3 hr, cold (12°C) and heat (42°C) stimuli were applied to the capsaicin patch to transiently increase and decrease pain intensity. RESULTS: Participants reported moderate pain scores at 1 hr (2.5 ± 2.0), 3 hr (3.7 ± 2.4), and Day 1 (2.4 ± 1.8). CPM decreased 3-hr post-capsaicin (p = .001) compared to Day 0 and remained diminished while the capsaicin pain score was reduced (0.4 ± 0.7, p < .001) and increased (6.6 ± 2.2, p < .001) by patch cooling and heating. No significant differences occurred for CPM during patch cooling or heating compared to initial 3HR; however, CPM during patch heating was reduced compared with patch cooling (p = .01). TSP and HPT did not change. CONCLUSIONS: This prolonged experimental pain model is useful to provide insight into subacute pain conditions and may provide insight into the transition from acute to chronic pain. SIGNIFICANCE: During the early hours of a prolonged noxious stimulus in healthy adults, CPM efficacy was reduced and did not recover by temporarily removing the ongoing pain indicating a less dynamic neuroplastic process.

Exercise-induced hypoalgesia in young adult females with long-standing patellofemoral pain - A randomized crossover study.

BACKGROUND: Patellofemoral pain (PFP) is a common knee pain condition where hip and knee exercises help improve treatment outcomes. This study compared the acute effect of hip versus knee exercises on anti-nociceptive and pro-nociceptive mechanisms in young females with long-standing PFP. METHODS: In this randomized cross-over study, 29 females with PFP performed hip and knee exercises in randomized order during a single day. Pressure pain thresholds (PPTs) were assessed by handheld pressure algometry at the patella, the tibialis anterior muscle, and the contralateral elbow. Cuff pressure algometry at the lower legs was used to assess pain detection threshold (cPDT) and tolerance (cPTT) as well as conditioned pain modulation (CPM: change in cPDT during contralateral cuff pain conditioning) and temporal summation of pain (TSP: ten painful cuff stimulations assessed on a visual analogue scale [VAS]). RESULTS: PPTs at the tibialis anterior muscle but not at the patella increased compared with baseline following both exercises (p < .002). Compared with baseline, the cPDTs and cPTTs increased after both types of exercises (p < .001). The cPTTs increased more after knee compared to hip exercises (p < .007). VAS scores for TSP were increased following hip exercises (p < .001) although the rate of VAS increase over repeated stimulations was not significantly affected by exercises. The CPM-effect was reduced after both types of exercises (p < .001). CONCLUSION: A general hypoalgesic response to slowly increasing pressure stimuli was observed following both hip and knee exercises as well as decreased conditioned pain modulation, potentially indicating an attenuated ability from exercise to inhibit pain.

Presurgical Comorbidities as Risk Factors For Chronic Postsurgical Pain Following Total Knee Replacement.

OBJECTIVES: Chronic postsurgical knee pain (CPSP) is a burden for ∼20% of the patients following total knee replacement (TKR). Presurgical pain intensities have consistently been found associated with CPSP, and it is suggested that comorbidities are likewise important for the development of CPSP. This study aimed to identify presurgical risk factors for the development of CPSP 5 years after TKR on the basis of medical records containing information with regard to comorbidities. MATERIALS AND METHODS: Patients undergoing primary TKR surgery were contacted 5 years after TKR. Presurgical Knee Society Score and comorbidities were evaluated. Postsurgical knee pain at 5 years of follow-up was assessed on a Numeric Rating Scale (NRS, 0 to 10). Logistic regression models were utilized to identify patients with moderate-to-severe (NRS≥3) and mild-to-no (NRS<3) CPSP at 5-year follow-up. Odds ratio (OR) for significant factors was calculated. RESULTS: A total of 604 patients were contacted, 493 patients responded, 352 patients provided a completed questionnaire. A total of 107 patients reported NRS≥3 at follow-up. Significant presurgical factors associated with CPSP were fibromyalgia (OR=20.66; P=0.024), chronic pain in body parts other than the knee (OR=6.70; P=0.033), previous diagnosis of cancer (OR=3.06; P=0.001), knee instability (OR=2.16; P=0.021), younger age (OR=2.15; P=0.007), and presurgical knee pain (OR=1.61; P=0.044). Regression analysis identified 36 of 107 (33.6%) patients with CPSP on the basis of presurgical factors, and 231 patients (94.3%) without CPSP were classified correctly. DISCUSSION: The current study found that a variety of presurgical clinical factors can correctly classify 33.6% of patients at risk for developing CPSP 5 years following TKR.

Assessment of conditioned pain modulation in healthy participants and patients with chronic pain: manifestations and implications for pain progression.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent findings on conditioned pain modulation (CPM) in humans with a focus on methodology, factors modulating CPM, and the potential for CPM as a clinical marker for pain progression. RECENT FINDINGS: CPM can be evoked by combining different stimulus modalities with good reliability; sequential CPM effects are stable over time with limited carryover effects. Optimism and pain catastrophizing might influence pain inhibition. Further, studies suggest that the CPM effect can be improved by gabapentinoids, transcranial direct current stimulation to cortical structures, and exercise and that long-term opioid use might impair CPM in patients with chronic pain. Clinical evidence suggests that preoperative impaired CPM may predict more severe chronic postoperative pain. The effect of pain duration on CPM impairment has been challenged by recent studies. SUMMARY: As CPM methodology is optimized, studies are revealing factors that can modulate descending pain inhibitory pathways. Understanding underlying mechanisms of CPM will improve the utility of CPM in a clinical setting and potentially lead to personalized treatments for chronic pain patients.

Clinical Outcomes and Central Pain Mechanisms are Improved After Upper Trapezius Eccentric Training in Female Computer Users With Chronic Neck/Shoulder Pain.

OBJECTIVES: The effects of eccentric exercises on clinical outcomes and central pain mechanisms are unclear in neck/shoulder pain (NSP). The aims were to: (1) evaluate the clinical impact of unilateral eccentric training in female computer users with chronic NSP; (2) compare pressure pain sensitivity, temporal summation of pain (TSP); and conditioned pain modulation (CPM) in female office workers with and without NSP; and (3) assess sensitization and central pain responses after training. METHODS: In part A, 20 females with NSP were compared with 20 controls. In part B, the NSP group underwent a 5-week upper trapezius eccentric training program. Participants reported their pain intensity and completed the Neck Disability Index, and the Disabilities of the Arm, Shoulder and Hand questionnaire. Pressure pain thresholds (PPTs) were assessed over the neck and forearm. Cuff algometry identified pain detection threshold (PDT) and pain tolerance thresholds (PTT). TSP was evaluated by visual analog scale pain scores during 10 repetitive cuff stimulations. CPM was calculated as the difference in PDT with and without a conditioning painful stimulus. Outcomes were measured at baseline and after intervention. Pain intensities were collected at 3- and 6-month follow-up. RESULTS: Pain and disability decreased after intervention (P<0.05) and at follow-ups (P=0.002). The NSP group showed reduced PTT (P≤0.02), but no differences in TSP (P=0.947) or CPM (P=0.059) compared with controls. After training, participants with NSP had improved CPM, PPTs, and PTT at the nontreated side (P<0.05). DISCUSSION: Eccentric training improved pain and disability, reduced sensitization, and enhanced CPM efficiency in female computer users with NSP.

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 Role of Preoperative Radiologic Severity, Sensory Testing, and Temporal Summation on Chronic Postoperative Pain Following Total Knee Arthroplasty.

OBJECTIVES: Knee osteoarthritis (KOA) can be associated with local and central sensitization. As an indicator of the central gain, facilitated temporal summation of pain (TSP) has been found in KOA patients. This facilitation is predictive of the development of chronic postoperative pain after total knee arthroplasty (TKA). Other studies have suggested hypoesthesia/hypoalgesia to thermal stimuli as a feature in KOA. This study investigated associations between preoperative TSP, thermal sensitivity, and radiologic severity for the development of chronic postoperative pain after TKA. METHODS: Radiologic KOA (Kellgren and Lawrence), TSP, and thermal stimuli were collected, preoperatively. Clinical knee pain intensity (VAS 0-10) was assessed before and 12 months following TKA. Patients were categorized into a chronic postoperative pain group if they experienced <30% pain reduction of the initial pain after 12 months. RESULTS: In total, 19% of the patients were categorized as chronic pain patients and presented facilitated preoperative TSP (P<0.05) and a trend towards increased heat pain threshold (P=0.077) compared with patients with normal recovery. Pearson correlations found that preoperative TSP (R=0.193; P=0.013), Kellgren and Lawrence (R=-0.168; P=0.027), warm detection threshold (R=0.195; P=0.012), and heat pain threshold (R=0.196; P=0.012) were associated with pain intensity 12 months after TKA where TSP was identified as an independent factor. DISCUSSION: This study showed that preoperatively facilitated TSP in KOA patients was predictive of the development of chronic postoperative pain following TKA. Furthermore, this study is the first to find an association between preoperative hypoalgesia to heat and the development of chronic postoperative pain following TKA.

Age Interactions on Pain Sensitization in Patients With Severe Knee Osteoarthritis and Controls.

OBJECTIVES: Widespread pressure hyperalgesia, facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM) have been found in knee osteoarthritis (KOA) patients compared with controls and these parameters have further been suggested to be altered in the elderly. This study investigated the influence of age on pressure hyperalgesia, TSP, and CPM in patients with KOA and controls. MATERIALS AND METHODS: One hundred thirty-three severe KOA patients and 50 age-matched and sex-matched asymptomatic controls were assessed by cuff algometry and handheld pressure algometry. Pain sensitivity was assessed around the head of the gastrocnemius muscle to identify mild pain detection threshold (MPDT) and pressure tolerance threshold (PTT). TSP was assessed by visual analogue scale scores of the pain evoked by 10 repetitive cuff stimulations. CPM was assessed as the difference in PTT before and during cuff-induced tonic arm pain. Pressure pain thresholds (PPTs) were assessed by handheld algometry at the tibialis anterior muscle. Two subgroups were analyzed in the age range below and above 65 years. Pearson correlations between age and pain parameters were applied. RESULTS: Patients demonstrated reduced MPDT, PTT, and PPT (P<0.01), facilitated TSP (P<0.02), and a trend toward impaired CPM (P=0.06) compared with controls. A negative correlation was found between MPDT, PTT, and PPT and age (P<0.05) but no age-related association was found for TSP and CPM. DISCUSSION: Pressure hyperalgesia was affected by age whereas dynamic pain mechanisms such as TSP and CPM were unaffected suggesting that these parameters are robust for a larger age range and reliable for long-term follow-up studies.