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Rani Othman, Abdulrahman Mohammed Bajaber, Anas Mohammed Alhabshi, Majed Albadi, Rawan Aldhabi, Muataz Almaddah, Abdullah Alqarni Physical Therapy Department, King Abdulaziz University, Jeddah, Saudi ArabiaCorrespondence: Rani Othman, Email rhothman@kau.edu.saBackground: Central sensitization (CS) has been proposed as a possible contributor to persistent shoulder pain. Measures of sensitivity, such as quantitative sensory tests (QSTs) and sensitivity to movements evoked pain (SMEP), have been increasingly used to investigate CS in a wide range of painful conditions. However, there is a lack of data on whether QST and SMEP are reliable among individuals with shoulder pain. Therefore, the present study aimed to investigate the intra-rater test–retest reliability of QST and SMEP in individuals with chronic shoulder pain.Materials and Methods: Forty-seven individuals with chronic shoulder pain were enrolled in the study. The QST measures, including pressure pain threshold (PPT) and mechanical temporal summation (MTS), were tested, and SMEP was measured with a lifting task. Relative and absolute reliability were analyzed using intraclass correlation coefficients (ICC 3,1) and standard error of the measurement (SEM), respectively.Results: The results showed that the ICC coefficients for all sensitivity measures were moderate to good, ranging from 0.63 to 0.86. The SEM% for the QST measures at all sites ranged from 21.4% to 36%, with TS at the forearm demonstrating a high SEM% (greater than 30%). The SMEP measure also showed a high SEM% (46%).Conclusion: The results showed that the sensitivity measures had moderate to good reliability among individuals with shoulder pain. Acceptable limits of accuracy of measurements were demonstrated for TS and PPT measures, while SMEP demonstrated high error, highlighting the need for further refinement of this measure among these populations.Keywords: shoulder pain, quantitative sensory testing, sensitive to movement evoked pain, central sensitization, reliability

Zhiyun Zhang, Hao Zheng, Qingquan Yu, Xianghong Jing Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xianghong Jing, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Email jxhtjb@263.netAbstract: The spinal dorsal horn (SDH) transmits sensory information from the periphery to the brain. Wide dynamic range (WDR) neurons within this relay site play a critical role in modulating and integrating peripheral sensory inputs, as well as the process of central sensitization during pathological pain. This group of spinal multi-receptive neurons has attracted considerable attention in pain research due to their capabilities for encoding the location and intensity of nociception. Meanwhile, transmission, processing, and modulation of incoming afferent information in WDR neurons also establish the underlying basis for investigating the integration of acupuncture and pain signals. This review aims to provide a comprehensive examination of the distinctive features of WDR neurons and their involvement in pain. Specifically, we will examine the regulation of diverse supraspinal nuclei on these neurons and analyze their potential in elucidating the mechanisms of acupuncture analgesia.Keywords: WDR neurons, spinal dorsal horn, pain, central sensitization, receptive fields, DNIC, acupuncture analgesia

Beibei Feng,1– 4,* Chen Gong,1,3,4,* Longfei You,1,3,4,* Yangyang Lin,1,3,4 Yafei Wang,1,3,4 Wing Yuk Ip,2 Yuling Wang1,3,4 1Department of Rehabilitation Medicine, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Orthopaedics & Traumatology, the University of Hong Kong, Hong Kong, Special Administrative Regions, People’s Republic of China; 3Guangdong Provincial Clinical Research Center for Rehabilitation Medicine, Guangzhou, People’s Republic of China; 4Biomedical Innovation Center, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuling Wang, Department of Rehabilitation Medicine, the Sixth Affiliated Hospital, Sun Yat-sen University, No. 26, Yuancun 2nd Cross Road, Guangzhou, 510655, People’s Republic of China, Tel + 86-20-38476737, Fax +86-20-38254221, Email wangyul@mail.sysu.edu.cn Wing Yuk Ip, Department of Orthopaedics & Traumatology, the University of Hong Kong, Hong Kong, Special Administrative Regions, People’s Republic of China, Tel +852-22554581, Fax +852-28174392, Email wyip@hku.hkPurpose: Central sensitization (CS) is commonly seen in chronic pain disorders, including neuropathic pain. However, there exist inconsistencies concerning the presence of CS in chronic pain secondary to carpal tunnel syndrome (CTS). CS and neuropathic pain manifestations in CTS remain not well established. Therefore, this study aims to investigate the CS and pain profiles in patients with CTS and to explore the potential determinants associated with CS.Patients and Methods: Patients with suspected CTS symptoms lasting 3 months or above and healthy controls were enrolled. History, physical examinations, and nerve conduction studies were employed to confirm the diagnosis and severity of median nerve dysfunction. The central sensitization inventory (CSI) was used to screen CS. Other outcomes included neuropathic pain, CTS-specific symptom severity and functions, emotion, and health-related quality of life. Between-group comparisons were conducted in terms of the CS presence. Logistic regression analysis was performed to identify determinants associated with CS.Results: Over 60% of participants with CTS were found with clinical CS, significantly higher than that in the control group. More than 70% of the CTS participants were identified to have possible or very likely neuropathic pain components. In addition, one-fourth of CTS cases had depression or anxiety. Anxiety was associated with an increased risk of developing CS in CTS (adjusted OR=1.31, 95% CI 1.08– 1.59), whereas higher self-perceived general health rating was negatively associated with the presence of CS (adjusted OR=0.92, 95% CI 0.88– 0.97) in the multivariate adjusted regression model.Conclusion: CS is prevalent in patients with CTS. Predominant neuropathic pain characteristics were uncovered in CTS patients as well as comorbid psychological distress. Significant association was found between anxiety and CS presence. Self-perceived general health was inversely related to CS. Further research is warranted to explore the mechanisms of anxiety and central pain processing in painful entrapment neuropathy.Keywords: central sensitization, chronic pain, carpal tunnel syndrome, determinants

Soichiro Matsuda,1 Yuki Igawa,1,2 Hidekazu Uchisawa,1,2 Shinya Iki,3 Michihiro Osumi1,4 1Graduate School of Health Sciences, Kio University, Nara, Japan; 2Department of Rehabilitation, Nishiyamato Rehabilitation Hospital, Nara, Japan; 3Department of Rehabilitation, Kawaguchi Neurosurgery Rehabilitation Clinic, Osaka, Japan; 4Neurorehabilitation Research Center, Kio University, Nara, JapanCorrespondence: Soichiro Matsuda, Graduate School of Health Sciences, Kio University, 4-2-2 Umaminaka, Kitakatsuragigun, Nara, 635-0832, Japan, Tel +745-54-1601, Fax +745-54-1600, Email f1996957@kio.ac.jpPurpose: In the thermal grill illusion, participants experience a feeling similar to burning pain. The illusion is induced by simultaneously touching warm and cool stimuli in alternating positions. In post-stroke pain, central sensitization is caused by a variety of factors, including damage to the spinothalamic tract and shoulder pain. Because the thermal grill illusion depends on central mechanisms, it has recently been suggested that it may be a useful indicator of central sensitization. Therefore, we hypothesized that post-stroke patients who are more likely to experience central sensitization may also be more likely to experience a thermal grill sensation of pain and discomfort than the likelihood among those who are less likely to experience central sensitization. However, the effects of the thermal grill illusion in post-stroke patients have not yet been reported. In this pilot study, we conducted the thermal grill illusion procedure in post-stroke patients and analyzed the relationship between clinical somatosensory functions and thermal grill sensations. We also conducted brain imaging analysis to identify brain lesion areas that were associated with thermal grill sensations.Patients and Methods: Twenty patients (65.7 ± 11.9 years old) with post-stroke patients participated in this study. The thermal grill illusion procedure was performed as follows: patients simultaneously touched eight water-filled copper bars, with the water temperature adjusted to provide alternate warm (40°C) and cold (20°C) stimuli.Results: Thermal grill sensation of pain and discomfort tended to be associated with the wind-up phenomenon in bedside quantitative sensory testing and thermal grill sensation of discomfort was also related to damage to the thalamic lateral nucleus.Conclusion: These findings suggest that the thermal grill illusion might measure central sensitization, and that secondary brain hyperactivity might lead to increased thermal grill sensations.Keywords: thermal grill illusion, post stroke pain, central sensitization, thalamus, insula

Abigail T Wilson,1,2 Charlotte Razzell,2 William J Hanney1,2 1University of Central Florida, School of Kinesiology and Rehabilitation Sciences, College of Health Professions and Sciences, Orlando, FL, USA; 2Musculoskeletal Research Lab, Institute of Exercise Physiology and Rehabilitation Science, University of Central Florida, Orlando, FL, USACorrespondence: William J Hanney, University of Central Florida, College of Health Professions and Sciences, Division of Physical Therapy, Health Sciences Building I, 12805 Pegasus Drive, Orlando, FL, 32816, USA, Tel +1 407-823-0217, Fax +1 407-823-3464, Email william.j.hanney@ucf.eduPurpose: The Patient Self-Report Survey for the Assessment of Fibromyalgia may potentially be a method for subgrouping patients with musculoskeletal pain who have a nociplastic pain presentation. Limited research has explored the convergent validity of this questionnaire against psychophysical measures of pain sensitivity and psychological factors in individuals with musculoskeletal pain. Therefore, the purpose of this study is to examine the strength of the association between total scores on the Patient Self-Report Survey for the Assessment of Fibromyalgia with clinical, pain sensitivity, and psychological factors.Patients and Methods: As a secondary analysis of a cross-sectional study, participants with shoulder (n = 20) or low back pain (n = 20) completed Quantitative Sensory Testing (QST), pain-related psychological questionnaires, and the Patient Self-Report Survey for the Assessment of Fibromyalgia. A Spearman correlation determined the association between total scores on the Patient Self Report Survey for the Assessment of Fibromyalgia with psychological factors and pain sensitivity behaviorally assessed with QST.Results: Negative psychological factors demonstrate moderate to strong positive associations with the Patient Self-Report Survey for the Assessment of Fibromyalgia (rho range = 0.36– 0.80), suggesting greater negative psychological factors were observed in patients with higher severity of fibromyalgia symptoms. Pain sensitivity factors demonstrated weak to moderate negative associations with The Patient Self-Report Survey for the Assessment of Fibromyalgia (PPT rho range=− 0.36- − 0.41), suggesting that elevated pain sensitivity was observed in individuals with higher severity of nociplastic pain symptoms.Conclusion: Collectively, this supports the convergent validity of the Patient Self-Report Survey for the Assessment of Fibromyalgia with psychological and pain sensitivity factors in patients with musculoskeletal pain.Keywords: pain measurement, pain threshold, nociplastic pain, central sensitization

Morten Rune Blichfeldt-Eckhardt,1– 3 Dorte Aalund Olsen,4 Rikke Fredslund Andersen,4 Palle Toft,3,5 Laila Bendix2 1Department of Anesthesiology, Vejle Hospital, Vejle, Denmark; 2Multidiciplinary Pain Center of Southern Denmark, Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Department of Biochemistry and Immunology, Vejle Hospital, Vejle, Denmark; 5Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, DenmarkCorrespondence: Morten Rune Blichfeldt-Eckhardt, Multidisciplinary Pain Center of Southern Denmark, Department of Anesthesiology and Intensive Care, Odense University Hospital, Heden 9, Indgang 200, Odense, DK-5000, Denmark, Tel +4565414721, Fax +45 6541 3026, Email mr.be@rsyd.dkPurpose: Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization.Patients and Methods: In phase 1 of the study, 83 subjects were included for DNA analysis, eight of these subjects with post cholecystectomy syndrome. We examined the SNPs rs5275, rs16944 and rs1800795 from the Cox-2, IL-1β and IL-6 genes respectively. In phase 2 of the study, we examined concentrations of PGE2-metabolite (PGEM), IL-1β and IL-6 in CSF and plasma from 6 patients with post cholecystectomy syndrome and visceral hyperalgesia and 11 pain free volunteers.Results: We found a significant difference in distribution of the rs5275 SNP of the Cox-2 enzyme (CT-genotype=88% in pain group, 45% in pain free group, TT-genotype=0 in pain group, 41% in pain free group, p=0.05) but not in the other SNPs. PGEM, but not IL-6, was significantly elevated in CSF of the pain group (3.6 pg/mL, sd=1.9 vs 2.1 pg/mL, p=0.03), IL-1β was undetectable.Conclusion: We found elevated PGEM levels in CSF of patients with post cholecystectomy syndrome and visceral hyperalgesia, suggesting a central, possibly inflammatory component to the pain, and overrepresentation of the CT-genotype in the rs5275 SNP in the Cox2 gene, suggesting overexpression of Cox2 as a possible cause for elevated PGEM levels.Keywords: T8473, visceral pain, post cholecystectomy syndrome, hyperalgesia, central sensitization

Vivian Santiago,1 Malvin N Janal,2 Dane B Cook,3,4 Karen G Raphael1 1Department of Oral & Maxillofacial Pathology, Radiology & Medicine, New York University College of Dentistry, New York, NY, USA; 2Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY, USA; 3Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; 4Department of Kinesiology, University of Wisconsin-Madison School of Education, Madison, WI, USACorrespondence: Vivian Santiago, Department of Oral & Maxillofacial Pathology, Radiology & Medicine, New York University College of Dentistry, 137th East 25th Street, Rm 731, New York, NY, 10010, USA, Tel +1 212 998-9419, Email vs1555@nyu.eduPurpose: Mechanisms underlying myofascial temporomandibular disorder (mTMD) are poorly understood. One theory is dysfunction in the central mediation of pain, specifically in enhanced facilitatory pain modulation. Because mechanisms leading to central sensitization may differ for joint and muscle pain, this study of mTMD addressed phenotypic heterogeneity by temporomandibular (TM) joint pain in the examination of quantitative sensory testing (QST).Patients and Methods: The stimulus dependent increase in second pain (temporal summation (TS)) and associated aftersensations (AS) were examined across groups of women with mTMD with TM joint pain and without, and a demographically matched control group.Results: TS was slightly more evident in mTMD without joint pain vs with (p = 0.035), but AS were most robustly persistent in the group with joint pain vs without (p < 0.002).Conclusion: While both subgroups demonstrated evidence of central sensitization relative to controls on one of two measures, differences in QST results, if replicated, may point to possible differences in the mechanisms that yield central sensitization. Alternatively, it may represent methodological artifacts that need to be addressed. Therefore, greater consideration should be given to symptom-based phenotypes in studies examining TS and AS.Keywords: endogenous pain modulation, facilitatory pain modulation, central sensitization, muscle pain, wind-up

Dana M Tilley,1 Ricardo Vallejo,1,2 Francesco Vetri,3 David C Platt,1,2 David L Cedeno1,2 1Research and Development, SGX Medical, Bloomington, IL, USA; 2Neuroscience, Illinois Wesleyan University, Bloomington, IL, USA; 3Research Department, National Spine and Pain Centers, Bloomington, IL, USACorrespondence: David L Cedeno, SGX Medical, 2406 E. Empire St, Bloomington, IL, 61704, USA, Tel +1 309 826 6974, Email dclumbrera@gmail.comIntroduction: Spinal cord stimulation (SCS) has been used for decades to treat neuropathic pain conditions with limited understanding of its mechanisms of action. The mTOR pathway is a well-known co-factor in chronic pain and has not been previously linked to SCS therapy. Proteomic and phosphorylation analyses allow capturing a broad view of tissue response to an injury model and subsequent therapies such as SCS. Here, we evaluated the effect of differential target multiplexed SCS programming (DTMP) and traditional low-rate spinal cord stimulation (LR-SCS) on the mTOR pathway using proteomic and phosphoproteomic analyses.Methods: The spared nerve injury (SNI) model of neuropathic pain in animals was established followed by continuous treatment with either DTMP or LR-SCS for 48 hours. Control groups included sham-stimulated (No-SCS) and uninjured animals (No-SNI). Proteins were extracted from spinal cord tissue removed post-stimulation and subjected to liquid chromatography/tandem mass spectrometry to assess changes in protein expression and states of phosphorylation. Bioinformatics tools and literature were used to identify mTOR-related proteins in the various groups.Results: Over 7000 proteins were identified and filtered to find 1451 and 705 proteins significantly affected by DTMP and LR-SCS (p < 0.05), respectively, relative to No-SCS. Literature and bioinformatic tools yielded 192 mTOR-related proteins that were cross-referenced to the list of DTMP and LR-SCS affected proteins. Of these proteins, 49 were found in the proteomic dataset. Eight of these proteins showed a significant response to the pain model, 25 were significantly modulated by DTMP, and 8 by LR-SCS. Phosphoproteomic analyses yielded 119 mTOR-related phosphoproteins affected by the injury model with a 66% reversal following DTMP versus a 58% reversal by LR-SCS.Conclusion: Proteomic and phosphoproteomic analyses support the hypothesis that DTMP, and to a lesser extent LR-SCS, reverse injury induced changes of the mTOR pathway while treating neuropathic pain.Keywords: proteomic analysis, phosphoproteomic analysis, nerve injury, central sensitization, inflammation

Keisuke Suzuki, Shiho Suzuki, Tomohiko Shiina, Saro Kobayashi, Koichi Hirata Department of Neurology, Dokkyo Medical University, Mibu, JapanCorrespondence: Keisuke Suzuki, Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga, Mibu, Tochigi, 321-0293, Japan, Tel +81-282-86-1111, Fax +81-282-86-5884, Email keisuke@dokkyomed.ac.jpAbstract: Central sensitization (CS) is an increase in the responsiveness of nociceptive neurons in the central nervous system to their normal afferent input. As a result, even minor irritation can induce severe pain, leading to the chronicity and severity of various diseases, such as neurological disorders. CS is associated with migraine, which is a major neurological disorder that inflicts a high disability in daily life. Specifically, CS is thought to be involved in the pathogenesis of cutaneous allodynia as well as chronification of migraine. In this article, we reviewed the association between CS and migraine, including pathophysiological aspects and evidence from clinical studies. We suggest that appropriate screening and management of CS in migraine could further improve the quality of life of migraine patients.Keywords: migraine, central sensitization, cutaneous allodynia, restless legs syndrome

Makoto Terumitsu,1,2 Yuhei Takado,3 Ken-Ichi Fukuda,2 Eisuke Kato,2 Sei Tanaka4 1Division of Dental Anesthesiology, Department of Human Biology and Pathophysiology, Health Sciences University of Hokkaido, Hokkaido, Japan; 2Division of Special Needs Dentistry and Orofacial Pain, Department of Oral Health and Clinical Science, Tokyo Dental College, Tokyo, Japan; 3Department of Functional Brain Imaging, Institute of Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba, Japan; 4Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Tokyo, JapanCorrespondence: Makoto Terumitsu, Division of Dental Anesthesiology, Department of Human Biology and Pathophysiology, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu-cho, Ishikari-gun, Hokkaido, 061-0293, Japan, Tel/Fax +81 133 23 1445, Email terumitsu@hoku-iryo-u.ac.jpBackground: Refractory chronic pain in the orofacial region involves central sensitization (CS). However, not all chronic pain patients exhibit CS. An objective assessment of CS may be useful for pain management. Changes in the balance of excitatory and inhibitory neural activity or excessive activity of nerves and glial cells may cause CS and contribute to pain chronification.Patients and Methods: 1H-magnetic resonance spectra were acquired from the anterior cingulate cortex (ACC) and thalamus in 20 patients with chronic orofacial pain and suspected CS, and 21 healthy volunteers, using a single-voxel point-resolved spectroscopy sequence. The patients were assessed using the Central Sensitization Inventory.Results: Aspartate/total creatine (tCr) and glutathione in the ACC were significantly higher in the patient group. However, no significant difference was observed between groups in the neurometabolites measured in the thalamus. Patients also exhibited a tendency for increased gamma-aminobutyric acid (GABA)/tCr in the ACC. There were positive relationships between Central Sensitization Inventory scores and glutamate + glutamine (Glx) in the thalamus, a positive trend for Glx in the ACC and a negative relationship for GABA/tCr in the ACC.Conclusion: The high levels of aspartate/tCr and glutathione in the patient group suggest excitatory neuronal activity and hyperactivity of neurons and glial cells. The correlation analysis results suggest that excitatory and inhibitory neurometabolites are involved in the chronification of orofacial pain, including CS.Keywords: orofacial pain, central sensitization, magnetic resonance spectroscopy, Central Sensitization Inventory, anterior cingulate cortex, thalamus

Beibei Feng,1,2 Xiaoqian Hu,3 William Weijia Lu,2 Yuling Wang,1 Wing Yuk Ip2 1Rehabilitation Medicine Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, People’s Republic of China; 2Department of Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong SAR, People’s Republic of China; 3School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, People’s Republic of ChinaCorrespondence: Yuling Wang, Rehabilitation Medicine Center, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26, Yuancun 2nd Cross Road, Guangzhou, 510655, People’s Republic of China, Tel +86 20-38476737, Fax +86 20-38254221, Email wangyul@mail.sysu.edu.cn Wing Yuk Ip, Department of Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong SAR, People’s Republic of China, Tel +852 22554581, Fax +852 28174392, Email wyip@hku.hkBackground: Central sensitization (CS) is frequently reported in chronic pain, and the central sensitization inventory (CSI) is popularly used to assess CS. However, a validated Chinese CSI is lacking and its predictive ability for the comorbidity of central sensitivity syndromes (CSSs) remains unclear. Hence, this study aimed to generate the Chinese CSI (CSI-C) with cultural adaptation and examine its psychometric properties.Methods: The CSI-C was formulated through forward and backward translation, panel review and piloting and then validated among patients with chronic pain (n = 235). Its internal consistency, test–retest reliability, and concurrent validity were measured. An exploratory factor analysis (EFA) was performed for the construct validity. Receiver operating characteristic (ROC) analysis was employed to determine the discriminative ability in the presence of comorbidity of CSSs.Results: About 70% of the participants in the study experienced at least mild CS symptoms. CSI-C demonstrates a high internal consistency (Cronbach’s alpha = 0.896) and excellent test–retest reliability (ICC = 0.932). CSI-C scoring was significantly correlated with pain intensity (r = 0.188), EQ-5D index (r = − 0.375), anxiety (r=0.525), and depression (r = 0.467). The EFA generated a 5-factor model, including physical symptoms, emotional distress, hypersensitivity syndromes and so on. An CSI cutoff of 42 had a sensitivity of 71.4% and a specificity of 70% for identifying chronic pain patients with ≥ 2 CSSs.Conclusion: The CS manifestations are prevalent in those with persistent pain. CSI-C is a reliable and valid instrument for measuring CS. A CSI score ≥ 42 may predict the comorbidity of 2 or above CSSs in patients with chronic pain.Keywords: central sensitization, chronic pain, central sensitization inventory, Chinese, central sensitivity syndrome

Zhuo Li,1,2,&ast; Chi Xu,2,&ast; Jun Fu,2 Maimaiti Zulipikaer,2 Tao Deng,2 Jiying Chen2 1School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiying Chen, Department of Orthopedic Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Tel +86 10 66938104, Fax +86 10 68216336, Email jiyingchen_301@163.comBackground: Central sensitization refers to a state of hypersensitivity in the central nervous system and is associated with the development and maintenance of chronic pain. Central sensitization plays an essential role in various diseases. Nevertheless, there has been no bibliometric analysis before in this field. The purpose of this study was to provide critical themes and trends in the area of central sensitization, to build a network of knowledge, and to facilitate the future development of relevant basic and clinical research.Methods: Publications on central sensitization were extracted from the Science Citation Index-Expanded. We used R software to systematically analyze the countries, institutions, authors, journals, references, and keywords of the publications. Besides, conceptual structure, intellectual structure, and social structure were constructed.Results: A total of 4466 publications were included. Research in the field of central sensitization generally showed a steady upward trend. The three structural networks showed that the United States is the leading country in this field. Arendt-Nielsen L and Woolf CJ were the most productive and influential authors, respectively. “Pain” was the journal with the most studies. Most journals that published and cited articles about central sensitization were academically influential. Cluster analysis revealed that research in central sensitization contains three main conceptual clusters, and the themes of research evolve frequently. Current research focuses on the pathogenesis of central sensitization in neuropathic pain, the role of central sensitization in different diseases, and related clinical double-blind trials.Conclusion: Central sensitization received widespread attention. The United States led the way in academic activity. In this field, the current situation of cooperation and communication between different countries and institutions is positive. The present research hotspots were the pathogenesis of central sensitization in neuropathic pain, the role of central sensitization in different diseases, and related clinical double-blind trials.Keywords: central sensitization, bibliometric analysis, pain, co-word, co-citation, collaboration network

Yoshihisa Ohashi,1 Kensuke Fukushima,1 Kentaro Uchida,1 Tomohisa Koyama,1 Maho Tsuchiya,1 Hiroki Saito,1 Katsufumi Uchiyama,2 Naonobu Takahira,3 Gen Inoue,1 Masashi Takaso1 1Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, 252-0374, Japan; 2Department of Patient Safety and Healthcare Administration, Kitasato University School of Medicine, Sagamihara City, Kanagawa, 252-0374, Japan; 3Department of Rehabilitation, Kitasato University School of Allied Health Sciences, Sagamihara City, Kanagawa, 252-0374, JapanCorrespondence: Kensuke FukushimaDepartment of Orthopaedic Surgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara City, Kanagawa, 252-0374, JapanTel +81-42-778-9343Fax +81-42-778-5850Email kenfu@r4.dion.ne.jpBackground: In patients with hip osteoarthritis (OA), pain at rest, unlike pain on activity, is due to pain mechanisms that cannot be explained by nociceptive pain. However, it remains unclear whether central sensitization (CS) is one of the causes of exacerbated pain at rest in patients with hip OA. Therefore, we investigated the differences in causative factors and postoperative course of total hip arthroplasty (THA) between preoperative pain at rest and on activity in patients with hip OA.Methods: In total, 120 patients (125 hips, 22 men and 98 women, aged 64.5± 1.0 years) with hip OA were included. Preoperative pain at rest and on activity and CS were assessed using the visual analog scale (VAS) and CS Inventory (CSI), respectively. Postoperative assessments were evaluated using the Japanese Orthopedic Association Hip Disease Evaluation Questionnaire (JHEQ); pain, satisfaction, function, and mental scores were evaluated 6 and 12 months after THA.Results: Multivariate regression analysis indicated the CSI score as affecting VAS for pain at rest (β=0.067, P=0.002) but not VAS for pain on activity (β=0.036, P=0.073). VAS for pain at rest had a weak negative correlation with satisfaction and pain scores at both 6 and 12 months after THA (satisfaction, r=− 0.309, − 0.278; pain, r=− 0.202, − 0.22). VAS for pain on activity was not correlated with JHEQ. The CSI score had a weak or moderate negative correlation with three scores other than the function score at both 6 and 12 months after THA (satisfaction, r=− 0.266, − 0.213; pain, r=− 0.332, − 0.203, mental, r=− 0.427, − 0.370). The function score was weakly correlated with the CSI score only 6 months after THA (function, r=− 0.231, − 0.190).Conclusion: A higher level of preoperative pain at rest, a CS-related symptom, may affect postoperative pain persistence and dissatisfaction in patients with hip OA.Keywords: central sensitization, pain at rest, postoperative pain, hip osteoarthritis, total hip arthroplasty

Eiji Sasaki,1 Seiya Ota,1,2 Daisuke Chiba,1 Yuka Kimura,1 Shizuka Sasaki,1 Masataka Ando,2 Yuji Yamamoto,1 Eiichi Tsuda,3 Yasuyuki Ishibashi1 1Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; 2Department of Social Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; 3Department of Rehabilitation Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, JapanCorrespondence: Eiji SasakiDepartment of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, JapanTel +81-172-39-5083Fax +81-172-36-3826Email e_sasaki@hirosaki-u.ac.jpPurpose: Knee pain is associated with osteoarthritis (OA) and increases during this condition; however, its correlation with central sensitization (CS) in arthritis patients requires greater understanding. The present cross-sectional cohort study to explore the prevalence of knee OA, nocturnal knee pain and disability in general population and to examine the association of CS with sleep quality in Japanese general population.Patients and Methods: From among 1056 community-dowelling volunteers, 942 were enrolled as participants in this study. Bilateral weight-bearing anterior-posterior knee radiographs were classified by the Kellgren–Lawrence grade. Nocturnal knee pain and disability were assessed with self-reported questionnaires. Using the CS inventory with nine items (CSI-9), CS was defined as 10 points or higher. Sleep quality was scored using the Pittsburgh Sleep Quality Index (PSQI). Linear regression analysis, adjusted by age, sex, body mass index, Kellgren-Lawrence grade, nocturnal knee pain, and lifestyle habits, was performed to investigate the association of CS with PSQI.Results: The prevalence of OA, nocturnal knee pain, and disability was 37.9%, 7.6%, and 6.2%, respectively. The mean CSI-9 score was 4.9 ± 4.4, with a CS prevalence of 14.0%. The mean PSQI score was 3.9 ± 2.4, which was correlated with the CSI-9 value. CS was not correlated with OA severity; however, nocturnal knee pain prevalence increased from 13.3% to 25.5% in knee OA patients with CS. The CSI-9 value correlated with PSQI total score and subscales.Conclusion: Knee OA severity correlated with nocturnal pain and disability; however, its association with CS was unproven. The combined effect of knee OA and CS elevated nocturnal pain and disability, resulting in diminished sleep quality.Keywords: central sensitization, epidemiology, knee osteoarthritis, nocturnal knee pain, sleep quality

Koji Akeda, Norihiko Takegami, Junichi Yamada, Tatsuhiko Fujiwara, Akinobu Nishimura, Akihiro Sudo Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, JapanCorrespondence: Koji AkedaDepartment of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, JapanTel +81-59-231-5022Fax +81-59-231-5211Email k_akeda@clin.medic.mie-u.ac.jpPurpose: Central sensitization (CS) is defined as the increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS has been proposed as an underlying mechanism of chronic pain in musculoskeletal disorders including low back pain (LBP). A Central Sensitization Inventory (CSI) has recently been developed for screening participants with CS. However, the association of CS with chronic LBP (cLBP) in the general population remains unknown. The purpose of this study was to investigate the association of CS with cLBP using the CSI in a population-based cohort of a Japanese mountain village.Participants and Methods: Participants aged more than 50 years were recruited from the inhabitants of a mountain village in Japan. Participants completed the following patient-reported outcome measures. Severity of CS was assessed by the CSI. LBP intensity was measured on a numerical rating scale (NRS). Health-related quality of life (QOL) was measured using the EuroQol 5-dimension (EQ-5D), EuroQol-visual analogue scales (EQ-VAS), and the Oswestry Disability Index (ODI). The association of CS and each parameter was statistically evaluated.Results: A total of 272 participants (average age: 72.1 years-old) were analyzed in this study, and 28.3% had cLBP. Average NRS, ODI and CSI scores were significantly higher in the cLBP group than in the without LBP (LBP−) group. There was a significant correlation between CSI and NRS scores (r=0.34, P< 0.0001), ODI (r=0.60, P< 0.0001), EQ5D (r=− 0.55, P< 0.0001) and EQ-VAS (r=− 0.52, P< 0.0001). A multiple regression analysis identified that ODI, EQ-VAS and age were factors significantly associated with CSI.Conclusion: The results of this study suggest that CS is involved in the pathological condition of cLBP in the local residents of a Japanese mountain village.Keywords: central sensitization, low back pain, Central Sensitization Inventory, general population

Wei Li,1 Yinan Gong,1 Jingyi Liu,1 Yongming Guo,1– 3 Huiling Tang,1 Siru Qin,1 Yadan Zhao,1 Songtao Wang,1 Zhifang Xu,1– 3 Bo Chen1– 3 1Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China; 3National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of ChinaCorrespondence: Zhifang XuSchool of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, No. 10 Poyang Lake Road, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel +86-22-5959-6290Fax +86-22-2748-5189Email xuzhifangmsn@hotmail.comBo ChenSchool of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, No. 10 Poyang Lake Road, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel +86-22-5959-6290Fax +86-22-2748-5189Email tjutcmchenbo@163.comAbstract: Chronic low back pain (CLBP), lasting > 3 months, is the end result of multiple pathogenic factors. Unfortunately, little is known about CLBP pathogenesis, which limits its advancements in clinical therapy and disease management. This paper summarizes the known pathological axes of CLBP, involving both peripheral and central systems. In particular, this paper details injurious nerve stimulation, inflammation-induced peripheral pathway, and central sensitization. Lumbar components, such as intervertebral disc (IVD), facet joints, muscles, fascia, ligaments, and joint capsules, contain pain receptors called nociceptors. Degeneration of the aforementioned lumbar components activates inflammatory pathways, which can directly damage nerves, lower nociceptor threshold to fire action potentials (AP), and cause pain. Additionally, damaged lumbar IVDs and endplates can also lead to the pathologic invasion of nerve growth and innervation, followed by the compression of herniated IVDs on nerve roots, thereby causing traumatic neuropathic pain. The central mechanism of CLBP involves alteration of the sensory processing of the brain and malfunction of the descending pain modulatory system, which facilitates pain amplification in the center nervous system (CNS). Lastly, abnormalities in the brain biochemical metabolism, activation of glial cells, and subsequent inflammation also play important roles in CLBP development. Taken together, inflammation plays an important role in both peripheral and central sensitization of CLBP. Due to the heterogeneity of CLBP, its pathological mechanism remains complex and difficult to understand. Therefore, it is a worthy field for future research into the subcomponents of CLBP pathogenesis, in order to distinguish the specific form of the disease, identify its origins, and develop corresponding highly effective comprehensive therapy against CLBP.Keywords: chronic low back pain, inflammation, degeneration, nerve innervation, central sensitization

Juliane Sachau,1 Dilara Kersebaum,1 Ralf Baron,1 Anthony H Dickenson2 1Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, 24105, Germany; 2Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, UKCorrespondence: Juliane SachauDivision of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, Haus D, Kiel, 24105, GermanyTel +49 431 500 23911Fax +49 431 500 23914Email juliane.sachau@uksh.deAbstract: Pain is common in many different disorders and leads to a significant reduction in quality of life in the affected patients. Current treatment options are limited and often result in insufficient pain relief, partly due to the incomplete understanding of the underlying pathophysiological mechanisms. The identification of these pathomechanisms is therefore a central object of current research. There are also a number of rare pain diseases, that are generally little known and often undiagnosed, but whose correct diagnosis and examination can help to improve the management of pain disorders in general. In some of these unusual pain disorders like sodium-channelopathies or sensory modulation disorder the underlying pathophysiological mechanisms have only recently been unravelled. These mechanisms might serve as pharmacological targets that may also play a role in subgroups of other, more common pain diseases. In other unusual pain disorders, the identification of pathomechanisms has already led to the development of new drugs. A completely new therapeutic approach, the gene silencing, can even stop progression in hereditary transthyretin amyloidosis and porphyria, ie in pain diseases that would otherwise be rapidly fatal if left untreated. Thus, pain therapists and researchers should be aware of these rare and unusual pain disorders as they offer the unique opportunity to study mechanisms, identify new druggable targets and finally because early diagnosis might save many patient lives.Keywords: pain mechanisms, sodium channelopathies, hereditary pain diseases, sensory modulation disorder, central sensitization, gene silencing

Elzbieta Skorupska,1 Marta Jokiel,1,2 Michał Rychlik,3 Rafał Łochowski,4 Małgorzata Kotwicka5 1Department of Physiotherapy, Poznan University of Medical Sciences, Poznan, Poland; 2Department of Orthopedics, Traumatology and Hand Surgery Poznan University of Medical Sciences, Poznan, Poland; 3Department of Virtual Engineering, Poznan University of Technology, Poznan, Poland; 4Department of Mathematics and Mathematical Economics, Warsaw School of Economics, Warsaw, Poland; 5Department of Cell Biology, Poznan University of Medical Sciences, Poznan, PolandCorrespondence: Elzbieta SkorupskaDepartment of Physiotherapy, Poznan University of Medical Sciences, Smoluchowskiego 11, Poznan 60-179, PolandTel/Fax +48 61 831-02-17Email skorupska@ump.edu.plBackground: The newly proposed low back pain treatment requires case classification according to the pain mechanism (nociceptive, neuropathic or nociplastic) to determine the most effective therapeutic approach. However, there is a lack of objective tools for distinguishing these pain mechanisms. The aim of the study was to identify which symptoms, signs, and standard diagnostic parameters would allow predicting the nociplastic pain (NP) subtype among low back leg pain (LBLP) patients.Methods: A retrospective analysis of an LBLP case–control study database was carried out. The presence of NP was assumed if the patient presented with myofascial pain syndrome (MPS) and developed a short-term intensive vasodilatation reaction in the perceived lower leg pain area after provocation by a minimally invasive procedure. Clinical data and standard LBLP diagnostic parameters were analyzed to classify patients as NP (+) vs NP (-). Next, to predict NP probability, logistic regression analysis and a diagnostic classification tree were constructed.Results: NP was confirmed in 43.75% of LBLP patients. Women represented 95.24% of all NP (+) patients. The diagnostic classification tree indicated that NP was highly probable if the LBLP subject was female and the result of a positive straight leg raise (SLR) test was lower than 45 degrees. If the SLR test result was greater than or equal to 45 degrees, a negative result on the Bragard test would have diagnostic value. This classification tree was approved to a certain extent in the logistic regression model (deviance residuals, min: − 1.8519; 1Q: − 0.5551; median: − 0.1907; 3Q: 0.6565 and max: 2.1058) but should be verified in a larger group of subjects.Conclusion: Female sex, but not clinical data or standard diagnostic parameters, is indicative of nociplastic pain in LBLP patients. More sophisticated statistical methods, based on directly measurable parameters, should be proposed to distinguish NP involvement in LBLP.Keywords: central sensitization, low back pain, nociplastic pain, myofascial pain syndrome, thermovision

Laura C Seidman,1 Catherine R Temme,1 Lonnie K Zeltzer,2 Andrea J Rapkin,3 Bruce D Naliboff,4 Laura A Payne1,5 1Division of Women’s Mental Health, McLean Hospital, Belmont, MA, USA; 2Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 4Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 5Department of Psychiatry, Harvard Medical School, Boston, MA, USACorrespondence: Laura C SeidmanMcLean Hospital, Mail Stop 306, 115 Mill Street, Belmont, MA 02478, USATel +1 617 855 2746Email LCSeidman@mclean.harvard.eduPurpose: Primary dysmenorrhea (PD; menstrual pain without an identified organic cause) has been proposed as a possible risk factor for the development of chronic pelvic pain, but the mechanism through which this process occurs is unknown. One possible mechanism is central sensitization – alterations in the central nervous system that increase responsiveness to pain leading to hypersensitivity. Repeated episodes of pain, such as those experienced over time with PD, may alter how the brain processes pain. Ecological momentary assessment (EMA; collection of data in real time in participants’ natural environments) is a novel data collection method that may help elucidate pain occurring during non-menstrual cycle phases.Patients and Methods: The current observational study assessed the feasibility and acceptability of using EMA via text messages to collect pelvic pain data during menstrual and non-menstrual cycle phases in a community sample of adolescents and young adults (AYA) aged 16– 24 years with and without PD and explored occurrence rates and intensity of non-menstrual pelvic pain (NMPP) in each of these groups.Results: Thirty-nine AYA with PD and 53 healthy controls reported pelvic pain level via nightly text message. Global response rate was 98.5%, and all participants reported that the EMA protocol was acceptable. AYA with PD reported higher intensity (2.0 vs 1.6 on 0– 10 numeric rating scale; p=0.003) and frequency (8.7% vs 3.1% of days; p=0.004) of NMPP compared to healthy controls.Conclusion: The EMA protocol was feasible and acceptable. Though both the intensity and frequency of NMPP were low and at levels that would not typically warrant clinical assessment or intervention, these repeated nociceptive events may represent a potential mechanism contributing to the transition from cyclical to chronic pelvic pain in some individuals.Keywords: ecological momentary assessment, primary dysmenorrhea, menstrual pain, adolescents and young adults, central sensitization

Ping Zheng, 1 Shuangzheng Jia, 1 Dalong Guo, 2 Sikai Chen, 1 Wen Zhang, 1 Aoshuang Cheng, 1 Weijie Xie, 3 Guibo Sun, 3 Jinhua Leng, 1 Jinghe Lang 1 1Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 2Air Force Medical Center, PLA, Beijing, People’s Republic of China; 3Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, People’s Republic of ChinaCorrespondence: Jinghe Lang Email langjh@hotmail.comJinhua Leng Email lengjenny@vip.sina.comBackground: Pain sensitization processing in the central nervous system may be related to endometriosis-associated pain in patients. The purpose of this study was to understand the alterations in the abnormal pain response in central brain areas and explore the central sensitization mechanism of endometriosis-associated pain.Methods: An endometriosis model was established in 40 Sprague-Dawley rats, and the rats underwent pain model assessment through behavioral tests. Twenty Sprague-Dawley rats underwent a sham operation as the control group. Thirteen pain rats and 8 control rats received Rs-fMRI examination to explore the brain functional activity areas, and the regional homogeneity (ReHo) method was used to analyze relevant functional signals among the whole brain. The states of neurons and expression of TRPV1 and NMDRA located in the abnormal ReHo signal brain regions were observed using Nissl staining, qRT-PCR and immunohistochemistry.Results: The rats were divided into a pain group and a control group based on the different syndromes and behavioral assessments. We detected significant enhancement of ReHo signals in the anterior cingulate cortex, hippocampus, and thalamus and a reduction in the ReHo values in the basomedial amygdaloid nucleus (BM) and primary motor cortex (M1) in the pain rat group via Rs-fMRI examination. The number of Nissl bodies and apoptotic neurons was increased; moreover, the volume of neurons increased compensatorily in the cingulate cortex, thalamus and hippocampus in the pain group. TRPV1 and NMDRA were overexpressed in apoptotic neurons in the higher ReHo value brain regions in the endometriosis pain group.Conclusion: These findings suggest that in rats with endometriosis-associated pain, ReHo signal enhancement was observed in the cingulate cortex, thalamus and hippocampus, which may be due to the increase in the number of apoptotic neurons or the compensatory increase in the volume of overactive neurons.Keywords: endometriosis-associated pain, rat model, behavioral assessment, central sensitization, Rs-fMRI, regional homogeneity, TRPV1, NMDRA

Ping Zheng*, Wen Zhang*, Jinhua Leng, Jinghe LangDepartment of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workAbstract: Endometriosis-associated pain afflicts an enormous number of women who suffer from endometriosis. There is an urgent need to explore the pathogenesis of endometriosis-associated pain to identify targets for treatment of hyperalgesia. A search was conducted in PubMed, Web of Science, Embase, and the Cochrane Library using the search terms “endometriosis” AND (“pain” OR “hyperalgesia” OR “nociception” OR “allodynia”) AND “central sensitization”. The search was limited to articles published in English from 01/01/2008 to the present. Among the search results, 15 articles were eligible for systematic review, including 6 reviews, 6 human studies (one in the form of a conference abstract only), and 3 animal studies. The articles were classified into 4 lists to describe the mechanism of endometriosis-associated pain and synthesize different aspects of research on it. In conclusion, there is a need to explore the mechanism of endometriosis-associated pain in terms of innervation, vascularization, local inflammation, cross-correlated visceral sensitization, and central sensitization to identify the target molecules and signaling pathways of key genes and relevant biomarkers through new techniques, all with the goal of developing a more comprehensive treatment strategy for endometriosis than is currently available.Keywords: endometriosis-associated pain, neurogenic inflammation, mechanism, central sensitization

Akira Mibu,1 Tomohiko Nishigami,1 Katsuyoshi Tanaka,2 Masahiro Manfuku,3 Satoko Yono21Department of Nursing and Physical Therapy, Konan Women’s University, Kobe, Hyogo, Japan; 2Department of Rehabilitation, Tanabe Orthopaedics, Osaka, Japan; 3Department of Rehabilitation, Breast Care Sensyu Clinic, Kishiwada, Osaka, JapanPurpose: The aims of the present study were to investigate whether the association between the Central Sensitization Inventory (CSI) score, pain-related symptoms, pain-related disability, and health-related quality of life differed by disease (chronic low back pain [CLBP] vs knee osteoarthritis [KOA]), and to determine optimal cutoff scores for the CSI reflecting disease-specific characteristics.Patients and methods: A total of 104 patients with CLBP and 50 patients with KOA were recruited. Central sensitization-related symptoms (CSI), EuroQol 5-dimension (EQ-5D), Brief Pain Inventory, widespread pain (Widespread Pain Index [WPI]), pressure pain threshold (PPT), and temporal summation (TS) were assessed and compared between the CLBP and KOA groups. Univariate correlation analysis was performed in each group. The receiver operating characteristic (ROC) curve analysis was performed to identify 1) presence/absence of central sensitization (CS), 2) presence/absence of central sensitivity syndromes (CSSs), and 3) pain intensity and pain interference in each group.Results: The CSI and WPI scores were significantly higher in the CLBP group than in the KOA group. EQ-5D and pain interference scores significantly correlated with the CSI score in both the CLBP and KOA groups. The WPI score, PPT, and TS did not correlate with the CSI score in either the CLBP or KOA group. The suggested cutoff scores were 28 in the CLBP group and 17 in the KOA group to identify presence or absence of CSSs, and 34 in the CLBP group and 18–19 in the KOA group to identify pain severity.Conclusion: The impact of CS on pain could differ between CLBP and KOA and that cutoff scores differ by each parameter we attempted to identify. Therefore, we should use the appropriate cutoff scores for the purposes and consider the difference in the impact of CS on pain by the patient group.Keywords: central sensitization, chronic low back pain, knee osteoarthritis, cutoff score

Kanta Kido,1 Shinichi Toda,1 Yuki Shindo,1 Hitoshi Miyashita,2 Shigekazu Sugino,3 Eiji Masaki1 1Department of Dental Anesthesiology and Pain Management, Tohoku University Hospital, Sendai, Miyagi, Japan; 2Department of Oral Medicine and Surgery, Division of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan; 3Department of Anesthesiology and Perioperative Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan Purpose: Remifentanil is associated with acute opioid tolerance that can lead to increased postoperative consumption of opioid analgesics. The purpose of this study was to determine whether a low dose of ketamine prevents remifentanil-induced acute opioid tolerance and affects the neutrophil–lymphocyte ratio (NLR), a newly recognized biomarker of inflammation. Materials and methods: Forty patients undergoing orthognathic surgery were enrolled in this prospective, randomized, double-blind study and randomly assigned to intraoperative administration of one of the following anesthetic regimens: high-dose remifentanil (0.6 µg/kg/minute); low-dose remifentanil (0.2 µg/kg/minute); or high-dose remifentanil with ketamine (remifentanil 0.6 µg/kg/minute with 0.5 mg/kg ketamine just after induction followed by an intraoperative infusion of ketamine 5 µg/kg/minute until wound closure). Fentanyl by intravenous patient-controlled analgesia was used for postoperative pain control. Visual Analog Scale pain scores and fentanyl consumption were recorded in the first 24 hours postoperatively. Perioperative serum C-reactive protein level and NLR were also determined. Results: Baseline characteristics were similar in the three study groups. There were no between-group differences in Visual Analog Scale pain scores during the study period. The high-dose remifentanil group had a significantly higher requirement for fentanyl than the other two groups. Addition of ketamine did not affect the C-reactive protein level but increased the NLR; this increase was associated with decreased fentanyl consumption. Conclusion: High-dose intraoperative remifentanil induced postoperative acute opioid tolerance that was prevented by infusion of low-dose ketamine. Ketamine increased the postoperative NLR associated with decreased fentanyl requirement for postoperative pain control. Keywords: acute tolerance, central sensitization, NMDA receptor, neutrophil–lymphocyte ratio, remifentanil

Peter F van Bemmel,1 Martijn AH Oude Voshaar,2 Peter M ten Klooster,2 Harald E Vonkeman,1,2 Mart AFJ van de Laar1,2 1Department of Rheumatology, Medisch Spectrum Twente, Enschede, Netherlands; 2Department of Psychology, Health, and Technology, University of Twente, Enschede, Netherlands Purpose: Generalized pain hypersensitivity is frequently observed in chronic pain conditions. Currently, identification is based on expert clinical opinion, and in very few cases combined with quantitative sensory testing. The objectives of this study were to develop and evaluate a short self-report measure of generalized pain hypersensitivity: a generalized pain questionnaire (GPQ). Methods: Items for the GPQ were developed based on a literature review, followed by an interview study with ten rheumatic patients with suspected pain hypersensitivity. We examined the psychometric properties of the preliminary items in a sample of 212 outpatients suffering from either fibromyalgia (FM; n=98) or rheumatoid arthritis (n=114). Additionally, self-reported data were gathered on sociodemographics, fibromyalgia-survey criteria, health status, and neuropathic-like pain features. Results: Mokken-scale analyses demonstrated a unidimensional seven-item scale with strong homogeneity (H=0.65) and high reliability (ρ=0.90). Correlations between total GPQ scores and relevant external measures, such as the FM-survey criteria and neuropathic-like pain features, were consistent with a priori expectations, supporting its external construct validity. Furthermore, the GPQ had good accuracy in distinguishing between patients with FM (generally assumed to be the result of central nervous system hypersensitization) and patients with RA (assumed to result mostly in local nociceptive or inflammatory pain), with an area under the receiver-operating characteristic curve of 0.89. A cutoff value >10 had the highest combination of sensitivity (82.7%) and specificity (77.2%). Conclusion: The GPQ is psychometrically sound and appears promising for measuring the presence and severity of generalized pain hypersensitivity in chronic pain patients. Keywords: central sensitization, chronic pain, nociceptive pain, questionnaires

Jinseok Yeo,1 Sungsik Park2 1Department of Anesthesiology and Pain Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea; 2Department of Anesthesiology and Pain Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea Purpose: Complex regional pain syndrome type 1 (CRPS I) is an intractable neuropathic pain syndrome. Chronic post-ischemia pain (CPIP) model is an animal model of CRPS I which is produced by ischemia-reperfusion (IR) injury of the hind limb. Dexmedetomidine (DEX) is a selective and potent α2 adrenergic receptor agonist with analgesic and protective effects following an IR injury. We hypothesized that DEX protects the development of mechanical allodynia and central sensitization in CRPS I. Therefore, we evaluated the dose-related protective effect of DEX in a CPIP model.Methods: We divided 45 rats into five groups: sham, CPIP, CPIP + DEX 10 µg/kg, CPIP + DEX 50 µg/kg, and CPIP + DEX 100 µg/kg. Rats in the sham group underwent sham surgery, and the other rats received CPIP injury. One hour before reperfusion or end of sham surgery, normal saline was injected into the rats in the sham and CPIP groups, and DEX (designated dose) was injected into the rats in the other groups. All rats were evaluated for the withdrawal threshold of both hind paws before surgery and 1, 3, and 7 days after surgery. Phosphorylation of N-methyl-d-aspartate receptor subunits (pGluN1) and phosphorylation of extracellular signal-regulated kinases (pERK) in the spinal cord were measured 3 days after surgery.Results: Administration of DEX before reperfusion showed a significant increase in the withdrawal threshold in both hind paws and a significant decrease of the expressions of pGluN1 and pERK in CPIP rats dose dependently (P

Na Zhang,1 Chun-Fu Chen2 1Department of Emergency Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China; 2Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China Objective: The clinical characteristics of migraine with and without allodynia were compared to evaluate the risk factors of cutaneous allodynia in migraine. The effects of prophylactic therapy on allodynia in patients with migraine were assessed based on the change in pain threshold after therapy. Patients and methods: A total of 71 patients with migraine admitted to the Department of Neurology of Shandong Provincial Hospital were recruited in this study. The included patients were aged 18–70 years and did not present positive symptoms according to the nervous system examination. The variation in cutaneous allodynia was assessed for the role of classic prophylactic therapy in migraine-related allodynia, also termed as central sensitization (CS). Patients with migraine were randomized into two groups (topiramate and flunarizine groups), and the effect of drugs was evaluated by the change in cutaneous pain threshold between the two groups. Fifty-five patients were tested for pain threshold due to instrument failure. Pressure allodynia was measured with a force gage, and pricking was measured with Electronic von Frey Anesthesiometer. The pain threshold was measured every 3 months for 6 months. The variations in pain threshold after treatment were compared using t-test and X2 test. Results: Allodynia was seen in 70.4% of the patients; of these, 76.3% were females. Female gender, duration of illness, and frequency of migraine attacks per month were significantly associated with allodynia. The rate of allodynia and frequency of headache declined significantly, the number of patients with allodynia was reduced, and the pain threshold improved dramatically after treatment. The composite adverse events were low after treatment with topiramate and flunarizine. Conclusion: Allodynia was observed, especially in females who experienced frequent migraine attacks for a prolonged period. Gender, duration of illness, and number of migraine attacks per month were the major predictors of allodynia. Topiramate and flunarizine administered orally for a short duration can effectively improve the pain threshold and CS of patients with migraine, and efficiently relieve allodynia. Keywords: migraine, prophylaxis, topiramate, flunarizine, allodynia, central sensitization

Wolnei Caumo,1–4 Luciana C Antunes,1 Jéssica Lorenzzi Elkfury,1 Evelyn G Herbstrith,5 Raquel Busanello Sipmann,6 Andressa Souza,7 Iraci LS Torres,1,8 Vinicius Souza dos Santos,1 Randy Neblett9 1Postgraduate Program in Medical Sciences, School of Medicine, 2Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre, 3Laboratory of Pain and Neuromodulation, 4Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, 5School of Psychology, Pontifícia Universidade Católica do Rio Grande do Sul, 6School of Medicine, Universidade Federal do Rio Grande do Sul, 7Postgraduate Program in Health and Human Development, La Salle University Center, Canoas, 8Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 9PRIDE Research Foundation, Dallas, TX, USA Objectives: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, reproducibility, and factor structure) of the Central Sensitization Inventory (CSI), adapted and validated for a Brazilian population (CSI-BP). Additionally, we evaluated the relationship between the CSI-BP and the serum brain-derived neurotrophic factor (BDNF) and determined if the symptoms elicited by the CSI-BP discriminate between subjects who do/do not respond to the conditioned pain modulation (CPM) task, as assessed by change in numeric pain scale (0–10) score. Patients and methods: A cross-sectional study was conducted in a pain clinic in a tertiary teaching hospital. A total of 222 adults with chronic musculoskeletal pain and 63 healthy control subjects completed the CSI-BP and the Brazilian Portuguese pain-catastrophizing scale (BP-PCS). A team of experts translated the CSI according to the international guidelines. Test–retest, item analysis, convergent validity, and factor analysis were performed. Later, a random subsample (n=77) was used to correlate the CSI-BP adjusted index with change in numeric pain-scale score during the CPM task and a BDNF blood sample. Results: The CSI-BP presented strong psychometric properties (test–retest reliability 0.91, Cronbach’s a=0.91). Confirmatory factor analysis yielded a four-factor structure, supporting the original English version. The CSI-BP adjusted index showed moderate positive correlation with the BP-PCS, and classified more than 80% of patients correctly vs healthy controls. Serum BDNF levels explained 27% of the variation in the CSI-BP adjusted index. Subjects with impairment in the descending modulatory system had higher CSI-BP adjusted index scores than subjects who responded normally to the CPM task: 49.35 (12.1) vs 39.5 (12.33), respectively (P

Kai-Uwe Kern, Myriam Schwickert Institute of Pain Medicine/Pain Practice, Wiesbaden, Germany Abstract: Fibromyalgia appears to present in subgroups with regard to biological pain induction, with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative, or muscular factors and/or central sensitization. Recent research has also discussed glial activation or interrupted dopaminergic neurotransmission, as well as increased skin mast cells and mitochondrial dysfunction. Therapy is difficult, and the treatment options used so far mostly just have the potential to address only one of these aspects. As ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments, the present paper outlines the scientific argument for this approach by looking at each of the aforementioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation. Keywords: Nav 1.8, Nav 1.7, bromhexine, hyperalgesia, sympathetically maintained pain, central sensitization, interleukins, neuropathic pain, sodium channels

Chronic pain of uncertain etiology often presents a challenge to both patients and their health care providers. It is a complex condition influenced by structural and physiological changes in the peripheral and central nervous systems, and it directly influences, and is modulated by, psychological well-being and personality style, mood, sleep, activity level and social circumstances. Consequently, in order to effectively treat the pain, all of these need to be evaluated and addressed. An effective management strategy takes a multidisciplinary biopsychosocial approach, with review of all current medications and identification and careful withdrawal of those that may actually be contributing to ongoing pain. The management approach is primarily nonpharmacological, with carefully considered addition of medication, beginning with pain-modulating treatments, if necessary. In this article, we present a primary care approach to the assessment and management of a patient with chronic pain where the cause cannot be identified. [ABSTRACT FROM AUTHOR]

Malvin N Janal,1 Karen G Raphael,2 Dane B Cook,3 David A Sirois,2 Lena Nemelivsky,2 Roland Staud4 1Epidemiology and Health Promotion, 2Oral and Maxillofacial Pathology, Radiology, and Medicine, NYU College of Dentistry, New York, NY, 3Department of Kinesiology, University of Wisconsin, Madison, WI, 4Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA Introduction: Chronic myofascial temporomandibular disorders (TMD) may have multiple etiological and maintenance factors. One potential factor, central pain sensitization, was quantified here as the response to the temporal summation (TS) paradigm, and that response was compared between case and control groups. Objectives: As previous research has shown that fibromyalgia (FM) is diagnosed in ~20% of TMD patients, Aim 1 determined whether central sensitization is found preferentially in myofascial TMD cases that have orofacial pain as a regional manifestation of FM. Aim 2 determined if the report of after-sensations (AS) following TS varied depending on whether repeated stimuli were rated as increasingly painful. Methods: One hundred sixty-eight women, 43 controls, 100 myofascial TMD-only cases, and 25 myofascial TMD + FM cases, were compared on thermal warmth and pain thresholds, thermal TS, and decay of thermal AS. All cases met Research Diagnostic Criteria for TMD; comorbid cases also met the 1990 American College of Rheumatology criteria for FM. Results: Pain thresholds and TS were similar in all groups. When TS was achieved (~60%), significantly higher levels of AS were reported in the first poststimulus interval, and AS decayed more slowly over time, in myofascial TMD cases than controls. By contrast, groups showed similar AS decay patterns following steady state or decreasing responses to repetitive stimulation. Conclusion: In this case–control study, all myofascial TMD cases were characterized by a similar delay in the decay of AS. Thus, this indicator of central sensitization failed to suggest different pain maintenance factors in myofascial TMD cases with and without FM. Keywords: temporomandibular joint dysfunction syndrome, temporal summation of pain, women, central sensitization, QST

Objectives: The effects of pre-emptive infusion of ketamine–lidocaine with tramadol on the suppression of central sensitization were investigated in a dog ovariohysterectomy model. Patients and methods: Twelve dogs were randomly assigned to two groups: ketamine–lidocaine– tramadol (KLT) and tramadol (T) groups. Both groups received intravenous tramadol 4 mg/kg body weight as premedication. Immediately after induction, the KLT group received ketamine and lidocaine at 0.5 and 2 mg/kg loading dose, followed by continuous rate infusion of 50 and 100 μg/kg/min, respectively, for 2 hours. Dogs in T group received saline bolus and continuous rate infusion at equi-volume. Intraoperatively, hemodynamic responses to surgical stimulation were recorded, whereas postoperative pain was evaluated using an algometer and short form of the Glasgow composite measure pain scale. Results: Intraoperatively, hemodynamic responses to surgical stimulation were obtunded to a greater degree in KLT compared to T group. Postoperatively, the pain scores increased only for the first hour in KLT group, compared to 12 hours in T group. Mechanical thresholds at the abdomen decreased postoperatively between 12 and 60 hours in KLT group versus the entire 72 hours in T group. Thresholds at tibia and radius in both groups increased in the immediate 1 hour postoperatively, but decreased thereafter. Significant decrement of thresholds from baseline were detected in the tibia at 24, 42, and 60 hours in KLT group compared to 24–72 hours in T group, and in the radius between 36 and 48 hours in T group, but none in KLT group. Conclusion: Addition of pre-emptive ketamine–lidocaine infusion to single intravenous dose of tramadol enhanced attenuation of central sensitization and improved intra- and postoperative analgesia. [ABSTRACT FROM AUTHOR]

Chronic pain has major adverse effects on health-related quality of life and contributes to significant socioeconomic burden. Hysterectomy is a very common gynecological surgery, resulting in chronic post-hysterectomy pain (CPHP), an important pain syndrome. We conducted a prospective cohort study in 216 Asian women who underwent abdominal or laparoscopic hysterectomy for benign conditions. Demographic, psychological, and perioperative data were recorded. Postoperative 4- and 6-month phone surveys were conducted to assess the presence of CPHP and functional impairment. The incidence rates of CPHP at 4 and 6 months were 32% (56/175) and 15.7% (25/159), respectively. Women with CPHP at 4 and 6 months had pain that interfered with their activities of daily living. Independent association factors for CPHP at 4 months were higher mechanical temporal summation score, higher intraoperative morphine consumption, higher pain score in the recovery room, higher pain score during coughing and itching at 24 hours postoperatively, and preoperative pain in the lower abdominal region. Independent association factors for CPHP at 6 months were preoperative pain during sexual intercourse, higher mechanical temporal summation score, and higher morphine consumption during postoperative 24 and 48 hours. In a majority of cases, CPHP resolved with time, but may have significant impact on activities of daily living. [ABSTRACT FROM AUTHOR]

Background: Endoplasmic reticulum (ER) stress is involved in many neurological and inflammatory responses. Peripheral inflammatory responses can induce central sensitization and trigger inflammatory pain. However, there is little research on the relationship between ER stress and inflammatory pain. In this study, we examined whether the ER stress response is involved in peripheral inflammatory pain using a formalin-induced rat pain model. Methods: Rats were divided into the following five groups: control, formalin, formalin + vehicle, formalin + 4-phenylbutyric acid (4-PBA) (40 mg/kg) and formalin + 4-PBA (100 mg/ kg). Formalin-induced pain was assessed behaviorally by recording licking activity. The expression levels of immunoglobulin-binding protein (BIP), activating transcription factor-6 (ATF6), phosphorylated inositol-requiring enzyme-1 (p-IRE1), phosphorylated protein kinase RNA-like ER kinase (p-PERK) and c-fos were quantitatively assessed by Western blot, and the distribution of BIP, ATF6 and c-fos in the lumbar enlargement of spinal cord were identified by immunohistochemistry in spinal dorsal horn slices. In addition, the concentrations of nitric oxide (NO) and prostaglandin E2 (PGE2) in the spinal cord were tested by biochemical measurement and enzyme-linked immunosorbent assay (ELISA), respectively. Results: Intraperitoneal injection of 4-PBA at the dose of 100 mg/kg before formalin injection significantly decreased nociceptive behavior in the second phase compared with control, formalin, formalin + vehicle and formalin + 4-PBA (40 mg/kg) (P<0.05). Western blot showed that formalin injection significantly upregulated the expression of BIP, ATF6, p-PERK and c-fos in the spinal cord. This upregulation was reduced by peritoneal injection of 4-PBA (P<0.05), while expression of p-IRE1 was not altered by formalin treatment. Immunohistochemistry revealed markedly increased staining density for BIP, ATF6 and c-fos in the superficial spinal dorsal horn after formalin injection. This was significantly decreased by administration of 4-PBA (P<0.05). Compared with the formalin + vehicle group, 4-PBA inhibited the release of NO and PGE2 in the spinal cord (P<0.05). Conclusion: These results suggest that ER stress is involved in formalin-induced inflammatory pain and that inhibition of ER stress may attenuate central sensitization induced by peripheral inflammatory stimulation. [ABSTRACT FROM AUTHOR]

Introduction: The area of secondary hyperalgesia following brief thermal sensitization (BTS) of the skin and heat pain detection thresholds (HPDT) may both have predictive abilities in regards to pain sensitivity and clinical pain states. The association between HPDT and secondary hyperalgesia, however, remains unsettled, and the dissimilarities in physiologic properties suggest that they may represent 2 distinctively different pain entities. The aim of this study was to investigate the association between HPDT and BTS-induced secondary hyperalgesia. Methods: A sample of 121 healthy male participants was included and tested on 2 separate study days with BTS (45°C, 3 minutes), HPDT, and pain during thermal stimulation (45°C, 1 minute). Areas of secondary hyperalgesia were quantified after monofilament pinprick stimulation. The pain catastrophizing scale (PCS) and hospital anxiety and depression scale (HADS) were also applied. Results: A significant association between HPDT and the size of the area of secondary hyperalgesia (p<0.0001) was found. The expected change in area of secondary hyperalgesia due to a 1-degree increase in HPDT was estimated to be -27.38 cm2, 95% confidence interval (CI) of -37.77 to -16.98 cm2, with an R2 of 0.19. Likewise, a significant association between HADSdepression subscore and area of secondary hyperalgesia (p=0.046) was found, with an estimated expected change in secondary hyperalgesia to a 1-point increase in HADS-depression subscore of 11 cm2, 95% CI (0.19-21.82), and with R2 of 0.03. We found no significant associations between secondary hyperalgesia area and PCS score or pain during thermal stimulation. Conclusion: HPDT and the area of secondary hyperalgesia after BTS are significantly associated; however, with an R2 of only 19%, HPDT only offers a modest explanation of the interparticipant variation in the size of the secondary hyperalgesia area elicited by BTS. [ABSTRACT FROM AUTHOR]

Background: Cutaneous allodynia (CA) is a common feature of migraine, which has a complex underlying pathophysiology that is not well understood. In addition to pain, photophobia, phonophobia, osmophobia, nausea, and vomiting, CA can contribute to the overall disability caused by migraine. The presence of CA can be established via a validated questionnaire. Validated questionnaires and other tests are rarely performed in clinical practice. As such, current prevalence estimates for CA may be an underestimation. Methods: Utilizing a validated questionnaire, we assessed the presence of CA in consecutive patients (n=44) presenting with chronic migraine at a tertiary headache center. Results: CA appears to be quite prevalent, at 90%, among female patients with chronic migraine. Conclusion: CA prevalence in chronic migraine may be underestimated in the literature, and larger studies may better demonstrate a more accurate estimate of its prevalence. [ABSTRACT FROM AUTHOR]

Background: Pain control in chronic pancreatitis is a major challenge; the mechanisms behind analgesic treatment are poorly understood. This study aims to investigate the differences in pain sensitivity and modulation in chronic pancreatitis patients, based on their clinical response (responders vs nonresponders) to placebo or pregabalin treatment. Methods: This study was part of a randomized, double-blind, placebo-controlled trial evaluating the analgesic effects of pregabalin and placebo in chronic pancreatitis. Post hoc, patients were assigned to one of four groups, ie, responders and nonresponders to pregabalin (n=16; n=15) or placebo (n=12; n=17) treatment. Responders were defined as patients with .30% pain reduction after 3 weeks of treatment. We measured change in pain sensitivity before and after the treatment using electric pain detection thresholds (ePDT) in dermatomes C5 (generalized effects) and Ventral T10 (segmental effects). Descending endogenous pain modulation was quantified via conditioned pain modulation (CPM) paradigm. Results: Sixty patients were analyzed in a per-protocol analysis. ePDT change in C5 was significant vs baseline and greater in pregabalin (1.3 mA) vs placebo responders (-0.1 mA; P=0.015). This was not so for ePDT in Ventral T10. CPM increased more in pregabalin (9%) vs placebo responders (-17%; P,0.001). CPM changed significantly vs baseline only for pregabalin responders (P=0.006). Conclusion: This hypothesis-generating study provides the first evidence that pain relief with pregabalin is associated with anti-hyperalgesic effects and increased endogenous inhibitory modulation. No such effects were observed in patients experiencing pain relief with the placebo treatment. The mechanisms underlying analgesic response to placebo vs drug treatments are different and, together with their interactions, deserve further study. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether there is central sensitization in patients with phantom limb pain (PLP) after traumatic limb amputation. Methods: Seventeen patients after unilateral lower limb amputation secondary to trauma were enrolled. Ten patients had chronic PLP, while the other seven patients had no PLP. Tactile-sensation threshold, cold- and warm-sensation thresholds, cold- and heat-pain thresholds, electrical-sensation threshold (EST), and electrical-pain threshold on the distal residual limb and the symmetrical site on the sound limb were measured in all tested patients. Their thresholds were compared within the PLP and non-PLP group, and between the groups. Results: The novel findings included: 1) electrical-pain threshold was only decreased in the sound limb in the PLP group and there was no difference between two limbs in the non-PLP group, suggesting central sensitization in patients with PLP; and 2) EST was increased on the affected limb as compared to the sound limb within the PLP group, but there were no significant differences in EST between the PLP and non-PLP group. There were in general no significant differences in other tested thresholds within the groups and between groups. Conclusion: Our results demonstrate central sensitization in the patients with PLP after traumatic limb amputation. [ABSTRACT FROM AUTHOR]

Introduction: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm2 versus 12.5-15.7 cm2). Study design and methods: After Institutional Review Board approval, 15 adult healthy volunteers participated in two study sessions, scheduled 1 week apart (Part A). In both sessions, subjects were exposed to the heat/capsaicin cutaneous sensitization model. Areas of hypersensitivity to brush stroke and von Frey (VF) filament stimulation were measured at baseline and after rekindling of skin sensitization. Another group of 15 volunteers was exposed to an identical schedule and set of sensitization procedures, but, in each session, received either gabapentin or placebo (Part B). Results: Unlike previous reports, a similar reduction of areas of hyperalgesia was observed in all groups/sessions. Fading of areas of hyperalgesia over time was observed in Part A. In Part B, there was no difference in area reduction after gabapentin compared to placebo. Conclusion: When using smaller thermal probes than originally proposed, modifications of other parameters of sensitization and/or rekindling process may be needed to allow the heat/capsaicin sensitization protocol to be used as initially intended. Standardization and validation of experimental pain models is critical to the advancement of translational pain research. [ABSTRACT FROM AUTHOR]