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Fluctuation-related pain (FRP) affects more than one third of people with Parkinson’s disease (PwP, PD) and has a harmful effect on health-related quality of life (HRQoL), but often remains under-reported by patients and neglected by clinicians. The National Institute for Health and Care Excellence (NICE) recommends The Parkinson KinetiGraph TM (the PKG TM ) for remote monitoring of motor symptoms. We investigated potential links between the PKG TM -obtained parameters and clinical rating scores for FRP in PwP in an exploratory, cross-sectional analysis of two prospective studies: “ The Non-motor International Longitudinal , Real-Life Study in PD—NILS ” and “ An observational-based registry of baseline PKG™ in PD—PKGReg ”. 63 PwP (41.3% female; age: 64.24±9.88 years; disease duration, DD: 6.83±5.63 years; Hoehn and Yahr Stage, H&Y: 2 (1–4); Levodopa Equivalent Daily Dose 535 (0–3230) mg) were included. PwP with FRP (n = 23) had longer DD (8.88 (1.29–19.05) vs. 3.16 (0.34–28.92), p = 0.001), higher severity of motor symptoms (H&Y 3 (1–4) vs. 2 (1–4), p = 0.015; SCOPA Motor total score 21.35±10.19 vs. 13.65±8.99, p = 0.003), more dyskinesia (SCOPA Motor Item 18 ≥1 60.9% vs. 7.5%, p <0.001), and worse HRQoL (PDQ-8 Total Score 10.74±5.98 vs. 6.78±5.13, p = 0.007) then PwP without FRP (n = 40). In the multivariate logistic regression, after the adjustment for DD, H&Y and SCOPA-Motor total score, the presence of FRP was significantly associated with the PKG TM -derived Fluctuation-dyskinesia score (Exp (B) = 1.305, 95% CI for Exp (B) 1.012–1.683, p = 0.040) and the Bradykinesia score (Exp (B) = 0.917, 95% CI for Exp (B) 0.842–0.999, p = 0.048). The PKG TM system may potentially advance the way we screen for, assess, and treat FRP in clinical practice.

Background Neck pain, with or without radiculopathy, can have significant negative effects on physical and mental wellbeing. Mental health symptoms are known to worsen prognosis across a range of musculoskeletal conditions. Understanding the association between mental health symptoms and health outcomes in this population has not been established. Our aim was to systematically review the association between psychosocial factors and/or mental health symptoms on health outcomes in adults with neck pain, with or without radiculopathy. Methods A systematic review of published and unpublished literature databases was completed. Studies reporting mental health symptoms and health outcomes in adults with neck pain with or without radiculopathy were included. Due to significant clinical heterogeneity, a narrative synthesis was completed. Each outcome was assessed using GRADE. Results Twenty-three studies were included (N = 21,968 participants). Sixteen studies assessed neck pain only (N = 17,604 participants); seven studies assessed neck pain with radiculopathy (N = 4,364 participants). Depressive symptoms were associated with poorer health outcomes in people with neck pain and neck pain with radiculopathy. These findings were from seven low-quality studies, and an additional six studies reported no association. Low-quality evidence reported that distress and anxiety symptoms were associated with poorer health outcomes in people with neck pain and radiculopathy and very low-quality evidence showed this in people with neck pain only. Stress and higher job strain were negatively associated with poorer health outcomes measured by the presence of pain in two studies of very low quality. Conclusions Across a small number of highly heterogenous, low quality studies mental health symptoms are negatively associated with health outcomes in people with neck pain with radiculopathy and neck pain without radiculopathy. Clinicians should continue to utilise robust clinical reasoning when assessing the complex factors impacting a person’s presentation with neck pain with or without radiculopathy. PROSPERO registration number CRD42020169497.

The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent α2-adrenoceptor-mediated inhibitory system and 5-HT3 (and likely also 5-HT2) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control.

Background The identification of pain originating from distinct biological processes may lead to individualised pain treatment. In this study, we aimed to explore the pain experiences of patients with rheumatoid arthritis (RA), differentiating between those predominantly exhibiting features of peripheral inflammatory versus centrally mediated pain. Methods Through a multimethods approach we (i) quantitatively analysed the differences in pain descriptors between patients diagnosed with RA experiencing peripheral inflammatory and centrally mediated pain, utilising the Short Form‐McGill Pain Questionnaire which includes the pain visual analogue scale (VAS) and (ii) qualitatively explored their subjective pain experiences grounded in the biopsychosocial model, commonly applied in chronic pain. Results Participants with centrally mediated pain reported higher pain scores on the VAS, used a wider range of pain descriptors, and a higher proportion selected each descriptor compared to those with inflammatory pain (p < .001). The qualitative analysis revealed the centrally mediated pain group's experiences were overwhelming and relentless, struggling to precisely articulate the nature of their pain. In contrast, individuals with inflammatory pain expressed their pain in more tangible terms and shared their adaptive and coping strategies. Importantly, both groups revealed the substantial psychological, functional and social impacts of their pain, highlighting the often ‘invisible’ and misunderstood nature of their symptoms. Conclusion This study has gained a deeper insight into the pain experiences of patients living with RA, particularly in differentiating between centrally mediated and inflammatory types of pain, potentially facilitating a more individualised approach to pain treatment. Patient Contribution Patients actively participated in the study conception and design. This engagement includes collaboration with key stakeholders, such as members of the National Rheumatoid Arthritis Society and Patient Research Partners (PRPs), who provided continuous feedback and guidance throughout the research process. Specifically, the qualitative element was coproduced with two PRPs, who were involved in co‐leading the focus groups and data analysis.

Background Descending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the α2δ-1 and 5-HT3A subunit mRNA levels in L3–6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA. Results Osteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10–100 μg/50 μl) or systemic pregabalin (0.3 – 10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of α2δ-1 and 5-HT3A subunit mRNA levels in L3–6 DRG revealed a significant increase in α2δ-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged. Conclusion These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in α2δ-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.

Background Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson’s disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi). Methods OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King’s Parkinson’s disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson’s Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient’s Global Impressions of Change, and change in functional status via Hauser’s diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022. Discussion The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain. Trial registration EudraCT number 2020–001175-32 ; registered on 2020-08-07.

People with Parkinson’s disease (PD) may live for multiple decades after diagnosis. Ensuring that effective healthcare provision is received across the range of symptoms experienced is vital to the individual’s wellbeing and quality of life. As well as the hallmark motor symptoms, PD patients may also suffer from non-motor symptoms including persistent pain. This type of pain (lasting more than 3 months) is inconsistently described and poorly understood, resulting in limited treatment options. Evidence-based pain remedies are coming to the fore but therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Since the ability to establish a link between the neurodegenerative changes that underlie PD and those that underlie maladaptive pain processing leading to persistent pain could illuminate mechanisms or risk factors of disease initiation, progression and maintenance, we evaluated the latest research literature seeking to identify causal factors underlying persistent pain in PD through experimental quantification. The majority of previous studies aimed to identify neurobiological alterations that could provide a biomarker for pain/pain phenotype, in PD cohorts. However heterogeneity of patient cohorts, result outcomes and methodology between human psychophysics studies overwhelmingly leads to inconclusive and equivocal evidence. Here we discuss refinement of pain-PD paradigms in order that future studies may enhance confidence in the validity of observed effect sizes while also aiding comparability through standardisation. Encouragingly, as the field moves towards cross-study comparison of data in order to more reliably reveal mechanisms underlying dysfunctional pain processing, the potential for better-targeted treatment and management is high.

Many advances in understanding the pathophysiology of Parkinson disease (PD) have been based on research addressing its motor symptoms and phenotypes. Various data-driven clinical phenotyping studies supported by neuropathological and in vivo neuroimaging data suggest the existence of distinct non-motor endophenotypes of PD even at diagnosis, a concept further strengthened by the predominantly non-motor spectrum of symptoms in prodromal PD. Preclinical and clinical studies support early dysfunction of noradrenergic transmission in both the CNS and peripheral nervous system circuits in patients with PD that results in a specific cluster of non-motor symptoms, including rapid eye movement sleep behaviour disorder, pain, anxiety and dysautonomia (particularly orthostatic hypotension and urinary dysfunction). Cluster analyses of large independent cohorts of patients with PD and phenotype-focused studies have confirmed the existence of a noradrenergic subtype of PD, which had been previously postulated but not fully characterized. This Review discusses the translational work that unravelled the clinical and neuropathological processes underpinning the noradrenergic PD subtype. Although some overlap with other PD subtypes is inevitable as the disease progresses, recognition of noradrenergic PD as a distinct early disease subtype represents an important advance towards the delivery of personalized medicine for patients with PD.Some patients with Parkinson disease (PD) present with mostly non-motor symptoms. Here, Chaudhuri et al. discuss the evidence for CNS abnormalities in noradrenergic function in these individuals. Recognition of this noradrenergic subtype of PD might ultimately lead to subtype-specific treatments and personalized medicine.

With over 10 million people affected worldwide, Parkinson's disease is the fastest-growing neurological disorder. More than two-thirds of people with Parkinson's disease live with chronic pain, which can manifest in various stages of the disease, substantially affecting daily activities and quality of life. The Parkinson's disease Pain Classification System overcomes the limitations of previous classification systems by distinguishing between pain related to Parkinson's disease and unrelated pain, while also incorporating clinical and pathophysiological (mechanistic) descriptors such as nociceptive, neuropathic, and nociplastic pain. This system provides a framework for accurate diagnosis and mechanism-based therapy. Alongside the appropriate classification of pain, consideration of treatment approaches that include non-invasive (pharmacological and non-pharmacological) and invasive strategies tailored to specific types of pain will refine and inform research trials and clinical practice when it comes to treating pain in Parkinson's disease.

Pain is one of the most debilitating symptoms of rheumatoid arthritis (RA), and yet remains poorly understood, especially when pain occurs in the absence of synovitis. Without active inflammation, experts most often attribute joint pain to central nervous system dysfunction. However, advances in the past 5 years in both immunology and neuroscience research suggest that chronic pain in RA is also driven by a variety of abnormal interactions between peripheral neurons and mediators produced by resident cells in the local joint environment. In this Review, we discuss these novel insights from an interdisciplinary neuro-immune perspective. We outline a potential working model for the peripheral drivers of pain in RA, which includes autoantibodies, resident immune and mesenchymal cells and their interactions with different subtypes of peripheral sensory neurons. We also offer suggestions for how future collaborative research could be designed to accelerate analgesic drug development.Emerging data suggest that resident cells and locally produced mediators interact with nerves in the joint to promote pain in rheumatoid arthritis. This Review discusses the potential neuro–immune–stromal interactions promoting joint pain and highlights the need for an interdisciplinary approach to therapeutic development.