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ABSTRACT Background Objectives Methods Results Conclusion Temporomandibular disorders (TMDs) are conditions that involve the temporomandibular joints, masticatory muscles, and associated tissues, causing orofacial pain. Central sensitisation (CS) is a relevant part of the TMD pathophysiology. Migraine, psychological aspects, parafunctional oral habits and widespread pain are commonly associated with both TMD and CS and could confound the association between them.To investigate the association between painful TMD and the Central Sensitisation Inventory (CSI) score, and to assess the presence of confounders in this association.Cross‐sectional study that assessed women with and without orofacial pain complaints using telehealth. The TMD Pain Screener and an online physical examination determined the presence of painful TMD. The following questionnaires were applied: CSI, Headache Screening Questionnaire, Generalized Anxiety Disorder‐7, Patient Health Questionnaire‐9, Oral Behavior Checklist, Jaw Functional Limitation Scale and the Nordic musculoskeletal questionnaire. A single regression investigated the association between the CSI score and TMD, and a multiple regression investigated the effect of the other outcomes as possible confounders. Confounding was considered present when the association between TMD and the CSI score changed more than 10% after adding a possible confounder to the regression model.Forty‐two women with painful TMD and 53 without TMD were included. There was a significant association between the CSI score and the presence of painful TMD (R2 = 0.639; p < 0.001). This association changed when the following outcomes were added to the model: presence of migraine, symptoms of depression, widespread pain and parafunctional oral habits.The positive association between TMD and the CSI score was confounded by migraine, symptoms of depression, widespread pain and parafunctional oral habits. [ABSTRACT FROM AUTHOR]

Introduction: The mechanism underlying endometriosis‐related pain remains poorly understood. Previous studies have indicated that γ‐aminobutyric acid (GABA) type A (GABAA) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABAA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABAA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relation between GABAA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABAA receptor, in the participating women. Material and methods: 15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom‐free, control women, aged 18–40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection. Results: Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABAA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels. Conclusions: Women with painful endometriosis show altered GABAA receptor function, depicted as a muted response to an exogenous GABAA receptor agonist. [ABSTRACT FROM AUTHOR]

Background: Rotator cuff‐related shoulder pain (RCRSP) was proposed to have a complex pain mechanism, but the exact aetiology is still unclear. A recent review summarised the updated research to analyse the traditional concept of shoulder impingement which may not be accurate. Current studies have demonstrated that mechanical factors including a reduction in subacromial space, scapular dyskinesia and different acromial shapes are unlikely directly contributing to RCRSP. Aims: Since the precise RCRSP pain mechanism remains unclear, the aim of this narrative review is to discuss possible sources of pain contributing to RCRSP according to the mechanisms‐based pain classifications. Results and Discussion: Research findings on potential mechanical nociceptive factors of RCRSP are conflicting; investigations of neuropathic and central pain mechanisms of RCRSP are limited and inconclusive. Overall, available evidence has indicated moderate to strong correlations between RCRSP and chemical nociceptive sources of pain. Conclusion: Results from current research may provide new directions for future studies on the aetiology of RCRSP and its clinical management towards a biochemical view instead of the traditional mechanical hypothesis. [ABSTRACT FROM AUTHOR]

Summary: Identifying factors associated with persistent pain after breast cancer surgery may facilitate risk stratification and individualised management. Single‐population studies have limited generalisability as socio‐economic and genetic factors contribute to persistent pain development. Therefore, this prospective multicentre cohort study aimed to develop a predictive model from a sample of Asian and American women. We enrolled women undergoing elective breast cancer surgery at KK Women's and Children's Hospital and Duke University Medical Center. Pre‐operative patient and clinical characteristics and EQ‐5D‐3L health status were recorded. Pain catastrophising scale; central sensitisation inventory; coping strategies questionnaire‐revised; brief symptom inventory‐18; perceived stress scale; mechanical temporal summation; and pressure‐pain threshold assessments were performed. Persistent pain was defined as pain score ≥ 3 or pain affecting activities of daily living 4 months after surgery. Univariate associations were generated using generalised estimating equations. Enrolment site was forced into the multivariable model, and risk factors with p < 0.2 in univariate analyses were considered for backwards selection. Of 210 patients, 135 (64.3%) developed persistent pain. The multivariable model attained AUC = 0.807, with five independent associations: age (OR 0.85 95%CI 0.74–0.98 per 5 years); diabetes (OR 4.68, 95%CI 1.03–21.22); pre‐operative pain score at sites other than the breast (OR 1.48, 95%CI 1.11–1.96); previous mastitis (OR 4.90, 95%CI 1.31–18.34); and perceived stress scale (OR 1.35, 95%CI 1.01–1.80 per 5 points), after adjusting for: enrolment site; pre‐operative pain score at the breast; pre‐operative overall pain score at rest; postoperative non‐steroidal anti‐inflammatory drug use; and pain catastrophising scale. Future research should validate this model and evaluate pre‐emptive interventions to reduce persistent pain risk. [ABSTRACT FROM AUTHOR]

Aims: Diabetic peripheral neuropathy (DPN) occurs in about half of people with diabetes, of whom a quarter may develop chronic pain. Pain may remain for years yet be difficult to treat because the underlying mechanisms remain unclear. There is consensus that processing excessive glucose leads to oxidative stress, interfering with normal metabolism. In this narrative review, we argue that oxidative stress may also contribute to pain. Methods: We reviewed literature in PubMed published between January 2005 and August 2021. Results and conclusions: In diabetes, hyperglycaemia and associated production of reactive species can directly increase pain signalling and activate sensory neurons; or the effects can be indirect, mediated by mitochondrial damage and enhanced inflammation. Furthermore, pain processing in the central nervous system is compromised in painful DPN. This is implicated in central sensitisation and dysfunctional pain modulation. However, central pain modulatory function is understudied in diabetes. Future research is required to clarify whether central sensitisation and/or disturbances in central pain modulation contribute to painful DPN. Positive results would facilitate early detection and future treatment. [ABSTRACT FROM AUTHOR]

Persistence of low back pain is thought to be associated with different underlying pain mechanisms, including ongoing nociceptive input and central sensitisation. We hypothesised that primary motor cortex (M1) representations of back muscles (a measure of motor system adaptation) would differ between pain mechanisms, with more consistent observations in individuals presumed to have an ongoing contribution of nociceptive input consistently related to movement/posture. We tested 28 participants with low back pain sub‐grouped by the presumed underlying pain mechanisms: nociceptive pain, nociplastic pain and a mixed group with features consistent with both. Transcranial magnetic stimulation was used to study M1 organisation of back muscles. M1 maps of multifidus (deep and superficial) and longissimus erector spinae were recorded with fine‐wire electromyography and thoracic erector spinae with surface electromyography. The nociplastic pain group had greater variability in M1 map location (centre of gravity) than other groups (p <.01), which may suggest less consistency, and perhaps relevance, of motor cortex adaptation for that group. The mixed group had greater overlap of M1 representations between deep/superficial muscles than nociceptive pain (deep multifidus/longissimus: p =.001, deep multifidus/thoracic erector spinae: p =.008) and nociplastic pain (deep multifidus/longissimus: p =.02, deep multifidus/thoracic erector spinae: p =.02) groups. This study provides preliminary evidence of differences in M1 organisation in subgroups of low back pain classified by likely underlying pain mechanisms. Despite the sample size, differences in cortical re‐organisation between subgroups were detected. Differences in M1 organisation in subgroups of low back pain supports tailoring of treatment based on pain mechanism and motor adaptation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Temporomandibular disorders (TMD) and migraine can be co‐morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine‐like symptoms. However, the underlying mechanisms involved are unknown. Our objective was to investigate these neural mechanisms and the role of CGRP as a key modulator in this co‐morbidity. Experimental Approach We combined experimental approaches using CGRP, which triggers a migraine‐like response in patients, with that of masseteric muscle injection of complete Freund's adjuvant (CFA), to model myofascial TMD‐like inflammation. Using validated electrophysiological methods to assess each of the above approaches independently or in combination, we examined their effects on the response properties of migraine‐like dural‐trigeminocervical neurons. Key Results: Independently, in ~2/3 of animals (rats) each approach caused delayed migraine‐like activation and sensitisation of dural‐trigeminocervical neurons. The response to masseteric‐CFA was attenuated by a selective CGRP receptor antagonist. The combination approach caused a migraine‐like neuronal response in all animals tested, with somatosensory‐evoked cranial hypersensitivity significantly exacerbated. Conclusion and Implications: The data demonstrate a neuronal phenotype that translates to the exacerbated clinical co‐morbid phenotype, supporting this combination approach as a relevant model to study the mechanisms involved. It provides a pathophysiological rationale for this exacerbated phenotype, strongly implicating the involvement of CGRP. The results provide support for targeting the CGRP pathway as a novel monotherapy approach for treating this co‐morbid condition. This has key implications into our understanding of this co‐morbid condition, as well as potentially addressing the major unmet need for novel and effective therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Changes in quantitative sensory testing (QST) parameters following topical anaesthesia could contribute to better elucidate underlying mechanisms of somatosensory alterations in temporomandibular disorder (TMD) pain patients. This placebo‐controlled crossover investigation compared the somatosensory profile following topical anaesthesia between TMD patients (n = 20) and healthy participants (n = 20). Methods: Cold detection threshold, warm detection threshold, cold pain threshold, heat pain threshold, mechanical detection threshold, mechanical pain threshold, wind‐up ratio and pressure pain threshold were assessed on the skin overlying the masseter at three consecutive days (baseline and immediately after lidocaine 4%/placebo cream). Mixed ANOVA and a coding system that accounts for the diversity of types of peripheral axons associated with the somatosensory parameters were applied for data analysis. Results: The lidocaine application caused no changes in the somatosensory sensitivity in the masseter region in TMD patients (P >.050), but sensitivity to cold, cold pain, touch and pinprick stimuli were reduced after topical anaesthesia in healthy participants (P <.050). Also, the degree of topical anaesthesia was greater in healthy participants (P =.008). The coding system suggested that TMD patients presented only Aδ‐fibre block, whereas a combination of either Aβ‐ and/or C‐fibre block was observed in 35% of healthy participants in addition to Aδ‐fibre block following lidocaine application. Conclusion: Quantitative sensory testing can be successfully applied to identify meaningful differences in the degree of hypoalgesia and hypoesthesia following short‐time topical anaesthesia. [ABSTRACT FROM AUTHOR]

Introduction: Central sensitisation (CS) can't be demonstrated and thus only be assumed to be present in humans: Human Assumed Central Sensitization (HACS)1. The Central Sensitisation Inventory (CSI)2 is a screening instrument for HACS with a cut-off score of 40 (range 0-100) 3. This study aims to re-establish the optimal cut-off value for the CSI and to study associated factors. Methods: Via ROC-analyses we compared patients with chronic pain with healthy controls. Regression analysis was performed on factors (descriptives; pain-related characteristics) possibly associated with CSI-score. Results: Based on patients (n = 1730) and controls (n = 250), CSI cut-off values for the presence of HACS were established at =30 (women: = 33; men: = 25(table)). Regression analyses showed that the CSI-score was associated with all factors (adjusted R2 = 54-58%). A low association between the CSI-score and pain severity was shown in women and men separately. Discussion: In contrast with previous studies, a lower cut-off score is established for patients with chronic pain, being higher for women than for men. Process evaluation: The question rises whether CSI should be used with a dichotomous, categorical or continuous scale. More insight is needed in the presence of HACS and, the influence of sex, other characteristics and specific sub-populations of patients. [ABSTRACT FROM AUTHOR]

Background In most individuals, injury results in activation of peripheral nociceptors (pain-sensing neurons of the peripheral nervous system) and amplification of central nervous system (CNS) pain pathways that serve as a disincentive to continue harmful behaviour; however, this may not be the case in some developmental disorders that cause intellectual disability (ID). Moreover, individuals affected by ID disorders may initiate self-injurious behaviour to address irritating or painful sensations. In normal individuals, a negative feedback loop decreases sensation of pain, which involves descending inhibitory neurons in the CNS that attenuate spinal nociceptive processing. If spinal nociceptive signalling is impaired in these developmental disorders, an exaggerated painful stimulus may be required in order to engage descending anti-nociceptive signals. Methods Using electronic databases, we conducted a review of publications regarding the incidence of chronic pain or altered pain sensation in ID patients or corresponding preclinical models. Results There is a body of evidence indicating that individuals with fragile X mental retardation and/or Rett syndrome have altered pain sensation. These findings in humans are supported by mechanistic studies using genetically modified mice harbouring mutations consistent with the human disease. Thus, once self-injurious behaviour is initiated, the signal to stop may be missing. Several developmental disorders that cause ID are associated with increased incidence of gastroesophageal reflux disease (GERD), which can cause severe visceral pain. Individuals affected by these disorders who also have GERD may self-injure as a mechanism to engage descending inhibitory circuits to quell visceral pain. In keeping with this hypothesis, pharmacological treatment of GERD has been shown to be effective for reducing self-injurious behaviour in some patients. Hence, multiple lines of evidence suggest aberrant nociceptive processing in developmental disorders that cause ID. Conclusions There is evidence that pain pathways and pain amplification mechanisms are altered in several preclinical models of developmental disorders that cause ID. We present hypotheses regarding how impaired pain pathways or chronic pain might contribute to self-injurious behaviour. Studies evaluating the relationship between pain and self-injurious behaviour will provide better understanding of the mechanisms underlying self-injurious behaviour in the ID population and may lead to more effective treatments. [ABSTRACT FROM AUTHOR]

Abstract: In anaesthetised rats, systematic electrophysiological recordings from dorsal horn neurones in spinal segments Th13–L5 were made to obtain information about the spinal nociceptive processing from the lumbar thoracolumbar fascia. Six to fourteen percent of the neurones in the spinal segments Th13–L2 had nociceptive input from the thoracolumbar fascia in naïve animals, no neurones responsive to input from the lumbar fascia were found in segments L3–L5. The segmental location of the receptive fields in the fascia was shifted 2–4 segments caudally relative to the spinal segment recorded from. Most neurones were convergent in that they received additional input from other deep somatic tissues in the low back (87%) and from the skin in the abdominal wall or the proximal leg (50%). The proportion of neurones responsive to input from the thoracolumbar fascia rose significantly from 4% to 15% (P <0.05) in animals with an experimentally-induced inflammation of a low back muscle (multifidus). Moreover, neurones in spinal segment L3 – that did not receive input from the fascia in normal animals – responded to fascia input in animals with inflamed muscle. The data suggest that the nociceptive input from the thoracolumbar fascia contributes to the pain in low back pain patients. [Copyright &y& Elsevier]

Abstract: There is increasing evidence that spinal glial cells play an important role in chronic pain states. However, so far no data on the role of microglia in muscle pain are available. The aim of the present study was to investigate the involvement of spinal microglial cells in chronic muscle pain. In a rat model of chronic muscle inflammation (injection of complete Freund´s adjuvant into the gastrocnemius-soleus muscle) alterations of microglia were visualized with quantitative OX-42 immunohistochemistry in the dorsal horn of the segments L4 and L5 12 days after induction of inflammation. In behavioural experiments the influence of chronic intrathecally applied minocycline – a specific microglia inhibitor - or an antibody against tumour necrosis factor-α (TNF-α; a cytokine released from microglia) on pain-related behaviour was investigated after 1, 3, 6, and 12 days. The immunhistochemical data show that in the deep laminae of the spinal dorsal horn microglial cells reacted with morphological changes to the muscle inflammation. Following inflammation, the mean boundary length surrounding the OX-42 immunostained area was significantly shorter. This indicates that microglial cells were activated by the myositis and withdrew their processes. Chronic intrathecal administration of minocycline or anti TNF-α with an osmotic mini-pump largely normalised the inflammation-induced changes in spontaneous exploratory behaviour and attenuated the hypersensitivity to mechanical stimulation. Both the immunohistochemical and behavioural data show that spinal microglial cells are involved in nociceptive processes in the cause of a chronic muscle inflammation. [Copyright &y& Elsevier]

Abstract: Thoracotomy is often responsible for chronic pain, possibly of neuropathic origin. To confirm preclinical studies, the preventive effects of perioperative ketamine were tested in a randomized, double-blind, placebo-controlled clinical trial on persistent neuropathic pain after thoracotomy. Eighty-six patients scheduled for thoracotomy under standardised general anaesthesia were randomised to receive either ketamine (1mgkg−1 at the induction, 1mgkg−1 h−1 during surgery, then 1 mgkg−1 during 24h; n =42) or normal saline (n =44). Postoperative analgesia included a single dose of intrapleural ropivacaine, intravenous paracetamol and nefopam, and patient-controlled intravenous morphine. Vital parameters and analgesia were recorded during the 48 first postoperative hours. Seventy-three patients were followed up. The patient’s chest was examined 1–2 weeks, 6 weeks and 4 months after surgery. At the last two observations, spontaneous pain score over a one-week period (visual analogue scale), neuropathic pain score (NPSI), and intake of analgesics, were assessed. No drug affecting neuropathic pain (except opiates) was given during the follow-up. Two patients in each group were lost to follow-up after the 6 week visit. Ketamine improved immediate postoperative pain, but the groups were similar in terms of neuropathic pain and intake of analgesics, 6 weeks (NPSI score: ketamine: 1.25 [0–4.125]; placebo: 1 [0–4]) and 4 months after surgery. Thus, ketamine given in 24-h infusion failed to prevent chronic neuropathic pain after thoracotomy. Other perioperative preventive long-lasting treatments or techniques could be tested in this context. [Copyright &y& Elsevier]

Abstract: The aim was to investigate the mechanisms of pain referral in patients with whiplash associated disorder. Pain was induced in 12 controls and 12 patients with whiplash associated disorder by intramuscular electrical stimulation in the infraspinatus muscle and the ipsilateral upper arm, i.e., the area where all subjects perceived referred pain during conditioning stimulation in the infraspinatus muscle. Conditioning stimulation amounted to a pain intensity rated as 2/10 and 4/10. During conditioning stimulation in the infraspinatus muscle, sensitivity to test stimuli was assessed in the referred pain area (i.e., upper arm) and vice versa. Test stimuli consisted of intramuscular electrical stimulation corresponding to innocuous perception threshold, electrical pain threshold, and pain intensities rated as 2/10, 4/10 and 6/10, respectively. Compared to controls, patients with whiplash associated disorder had increased pain sensitivity (p ⩽0.01) and indicated larger areas of referred pain ((p ⩽0.003) during stimulation at the infraspinatus muscle; p ⩽0.03 during stimulation at the upper arm), including proximal referral of pain which was never reported by controls (p ⩽0.05). During conditioning stimulation in the infraspinatus muscle (4/10) all subjects reported referred pain in the upper arm (corresponding to the test site) and innocuous perception thresholds (p <0.05)(patients) and electrical pain thresholds (p <0.001) (controls) decreased. Conditioning stimulation in the upper arm did not affect sensitivity to test stimuli in the infraspinatus muscle. In conclusion, patients with whiplash associated disorder had increased sensitivity to painful stimulation, reported larger areas of referred pain during the same subjectively painful conditioning stimulation (i.e., lower absolute stimulus intensities), including proximal pain referral which was never seen in controls, indicating aberrant processing of nociceptive input. The perceptual integration of nociceptive stimuli during simultaneous stimulation did not differ between groups suggesting that divergence of nociceptive input from the focal pain area leading to excitation of neurones with projected fields in the referred pain area most likely explains referred pain in both groups alike. [Copyright &y& Elsevier]

Abstract: Objective: Psychosocial stress is a risk factor for musculoskeletal pain, but how stress affects musculoskeletal pain is poorly understood. We wanted to examine the relationship between low-grade autonomic activation and stress-related pain in patients with fibromyalgia and localised chronic shoulder/neck pain. Methods: Twenty-three female patients with fibromyalgia, 29 female patients with chronic shoulder–neck pain, and 35 healthy women performed a stressful task lasting 60min. With a blinded study design, we recorded continuous blood pressure, heart rate, finger skin blood flow and respiration frequency before (10min), during (60min) and after (30min) the stressful task. The physiological responses were compared with subjective reports of pain. Results: The increase in diastolic blood pressure and heart rate in response to the stressful task were smaller in fibromyalgia patients compared with the healthy controls. Furthermore, fibromyalgia patients had reduced finger skin blood flow at the end of the stressful task compared to healthy controls. We also found an inverse relationship between the heart rate response and development and recovery of the stress-related pain in fibromyalgia patients. Conclusion: We found abnormal cardiovascular responses to a 60min long stressful task in fibromyalgia patients. Furthermore, we found a negative association between the heart rate response and the pain which developed during the stressful task in the fibromyalgia group, possibly a result of reduced stress-induced analgesia for fibromyalgia patients. [Copyright &y& Elsevier]

Abstract: Background: The pain of chronic pancreatitis remains challenging to manage, with treatment all too often being unsuccessful. A main reason for this is lacking understanding of underlying mechanisms of chronic pain in these patients. Aim: To document, using somatic quantitative sensory testing, changes in central nervous system processing (neuroplasticity) associated with chronic pancreatitis pain and thus gain insight into underlying pain mechanisms. Patients and methods: We studied 10 chronic pancreatitis patients on stable opioid analgesic medication. Ten matched surgical patients without pain served as controls. Pain verbal numeric rating scores (NRS) and thresholds to electric skin stimulation and pressure pain were measured in dermatomes T10 (pancreatic area), C5, T4, L1 and L4. Results: The pancreatitis patients had a median NRS pain score of 5 (range 3–8). Electric sensation and pain thresholds were significantly increased in the pancreatic region, tending to be more so in female pancreatitis patients. Pressure pain thresholds were significantly lower in pancreatitis patients than in controls, with men tending towards greater generalised relative hyperalgesia than women. Conclusions: Chronic pancreatitis patients show pronounced generalised deep hyperalgesia that is present despite opioid therapy. These signs, consistent with central sensitisation, appear relatively more prominent in men than women. There is also evidence suggesting that women may have a better segmental inhibitory response than men, possibly explaining their relatively less prominent generalised deep tissue hyperalgesia compared to men. [Copyright &y& Elsevier]

Abstract: Many neuropathic pain conditions are characterized by abnormal responses to noxious or innocuous mechanical stimulation, including wind-up pain. Whereas previous brain imaging studies have explored the cerebral correlates of hyperalgesia and allodynia, no studies are available on mechanical-induced wind-up pain in neuropathic pain patients. We therefore used positron emission tomography (PET) to investigate the cerebral response pattern of mechanical wind-up pain in a homogenous group of 10 neuropathic pain patients with long-standing postherniotomy pain in the groin area. Patients were scanned in the following conditions: (1) rest; (2) wind-up pain, induced by 2Hz von Frey stimulation in the painful area; (3) non-painful 2Hz von Frey stimulation in the homologous contralateral area and (4) tonic pressure pain in the homologous contralateral area. A direct comparison between wind-up pain and non-painful von Frey stimulation revealed that the former more strongly activated contralateral secondary somatosensory cortex, insula, anterior cingulate cortex, right dorsolateral prefrontal cortex, thalamus and cerebellum. In addition, wind-up pain also activated the sublenticular extended amygdala (SLEA) and the brain stem. A direct comparison between wind-up pain and pressure pain revealed that both activated a largely overlapping network. Since no de novo brain areas were activated by wind-up pain, our data suggest that the processes specific to wind-up pain do not occur at the cerebral level. [Copyright &y& Elsevier]