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Chronic pain affects almost 38% of the Portuguese adult population, with high costs for both patients and society. Those who suffer with chronic pain frequently complain of feeling misunderstood and of lack of support. These complaints are the main reason why support telephone lines for chronic pain were created in some countries. However, there is no scientific data supporting their creation or evaluating their performance. This paper presents a qualitative study protocol to assess patients and healthcare professionals’ perspectives on the creation of a telephone support line for chronic pain. It constitutes the first step to attain the main goal of developing and implementing a functioning support line for chronic pain in Portugal. The methodology to assess patients and healthcare professionals’ perspectives and needs is presented. In order to gather information as close to reality as possible, focus groups interviews were chosen as data sources. Given the present context of the COVID-19 pandemic, meetings will take place online, using a digital platform. All interviews will be transcribed verbatim, coded and synthesised into categories and main themes. Thematic analysis will be conducted using NVivo® V12 software, employing an iterative and reflexive approach. Finally, comparative and relational analysis will be performed in order to identify topics where patients and professionals converge or greatly diverge. The findings will be useful for grounding the creation of a telephone support line for chronic pain patients. Results dissemination will be important for policy-makers to develop a new perspective towards chronic pain services available.

Introduction Sleep disturbances and pain are common non-motor symptoms in Parkinson's disease (PD). This study aimed to explore the association between these two symptoms in a cohort of patients with PD. Materials and methods The Parkinson's Disease Sleep Scale (PDSS-2) was used to identify sleep disturbances in a series of 229 PD patients. The identification and characterization of pain was performed by a semi-structured interview and by the application of the Ford classification and the Brief Pain Inventory (BPI). The Unified Parkinson's Disease Rating Scale-III, Hoehn & Yahr (H&Y), and Schwab and England Independence Scale were used to assess motor symptoms and functional independence in off and on conditions. The Hospital Anxiety and Depression Scale (HADS) and SF-36 were applied to screen for anxiety and depression and to evaluate the quality of life. Non-parametric tests were used for group comparisons and logistic regressions were applied to explore predictors of sleep disturbances. Results Seventy-five (33%) patients had clinically relevant sleep disturbances (PDSS-2≥18) and 162 patients (71%) reported pain. Of those with pain, 38 (24%) had central parkinsonian pain. PD patients with sleep disturbances experienced more pain and had more severe motor symptoms, lower functional independence, more anxiety and depression symptoms, and worst quality of life. Among patients with pain, central parkinsonian pain was the subtype of pain with the highest odds of sleep disturbances, even when taking into account motor symptoms (H&Y off), motor fluctuations, intensity of pain (BPI), and symptoms of anxiety and depression (HADS). Conclusions The association between pain and sleep disturbances in PD appears to be dependent on subtype of pain. The close relationship between central parkinsonian pain and sleep disturbances in PD raises the possibility of common pathophysiological mechanisms. A better understanding of the relationship between sleep disturbances and central parkinsonian pain may contribute to the development of new care strategies in PD patients.

Introduction. Pain is a major nonmotor symptom of Parkinson’s disease (PD), and central parkinsonian pain is the core feature of the putative Park pain subtype of PD. This study aimed to explore the cognitive and behavioral profile of PD patients with central parkinsonian pain. Material and Methods. A structured interview was used to identify and characterize pain in a cohort of 260 consecutive PD patients. The Ford classification of pain was applied. The Dementia Rating Scale-2 (DRS-2) and the Impulse Control Disorders in Parkinson’s Disease Short Form (QUIP-S) were administered, and patients’ smoking habits were recorded. The Unified Parkinson’s Disease Rating Scale (UPDRS) was used to assess motor and nonmotor symptoms in off and on conditions. Results. One hundred and eighty-eight patients (68%) reported pain; and in 41 (22%) of them, the pain was classified as central parkinsonian pain. PD patients with central parkinsonian pain had better cognitive performance in DRS-2 Initiation/Perseveration and Conceptualization subscales but reported more other compulsive behaviors (e.g., hobbyism, punding, and walkabout) and had more current smoking habits than those without pain or with non-central parkinsonian pain. Multiple logistic regression analyses revealed that the DRS-2 Conceptualization subscale, other compulsive behaviors, and smoking habits remained statistically associated with central parkinsonian pain even when other significant covariates were considered. Only patients with pain, regardless of type, had a gambling disorder. Discussion. The study results provide further evidence that pain revealed that patients with central parkinsonian pain are more likely to present compulsive or addictive behaviors, despite having more preserved cognitive performance. Patients with central parkinsonian pain appear to have a distinct phenotype of PD.

Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the detection of pathogen-associated molecular patterns (PAMPs), but also a “danger-sensing” receptor that recognizes host-derived endogenous molecules called damage-associated mole-cular patterns (DAMPs). The involvement of TLR4 in rheumatic diseases is becoming evident, as well as its potential role as a target for therapeutic intervention. Moreover, increasing evidence also suggests that TLR4 is implicated in chronic pain states. Thus, in this study, we evaluated whether a systemic administration of a synthetic antagonist of TLR4 (TLR4-A1) could decrease nociception and cartilage degradation in experimental osteoar-thritis (OA). Furthermore, as the activation transcription factor (ATF)-3 serves as a negative regulator for TLR4-stimulated inflammatory response, we also evaluated the effect of TLR4 inhibition on ATF-3 expression in primary afferent neurons at the dorsal root ganglia (DRG)., Granted by FEDER funds through COMPETE – Programa Operacional Factores de Competitividade (FCOMP-01– 0124-FEDER-021359) and by National Funds through FCT – Fundação para a Ciência e a Tecnologia (PTDC/ SAU-NSC/119986/2010); and by Ministerio de Economia y Competitividad (SAF2012–40075-C02–02).

ObjectivesOpioid use in chronic pain has increased worldwide in recent years. The aims of this study were to describe the trends and patterns of opioid therapy over two years of follow-up in a cohort of chronic noncancer pain (CNCP) patients and to assess predictors of long-term opioid use and clinical outcomes.MethodsA prospective cohort study with two years of follow-up was undertaken in four multidisciplinary chronic pain clinics. Demographic data, pain characteristics, and opioid prescriptions were recorded at baseline, three, six, 12, and 24 months.ResultsSix hundred seventy-four CNCP patients were recruited. The prevalence of opioid prescriptions at baseline was 59.6% (N = 402), and 13% (N = 86) were strong opioid prescriptions. At 24 months, opioid prescription prevalence was as high as 74.3% (N = 501), and strong opioid prescription was 31% (N = 207). Most opioid users (71%, N = 479) maintained their prescription during the two years of follow-up. Our opioid discontinuation was very low (1%, N = 5). Opioid users reported higher severity and interference pain scores, both at baseline and after two years of follow-up. Opioid use was independently associated with continuous pain, pain location in the lower limbs, and higher pain interference scores.ConclusionsThis study describes a pattern of increasing opioid prescription in chronic pain patients. Despite the limited improvement of clinical outcomes, most patients keep their long-term opioid prescriptions. Our results underscore the need for changes in clinical practice and further research into the effectiveness and safety of chronic opioid therapy for CNPC.

Background and aimsThe recent economic crisis started in the USA in 2008 but quickly had worldwide impact. Ireland, Greece, and Portugal were in economic distress in 2009 and received rescue monetary packages from the European Union (EU) and the International Monetary Fund (IMF) in the following years. Meanwhile, the economic recovery has begun for those countries, but at different paces. The aim of the present study was to evaluate if the economic crisis influenced pain research outcomes, by performing a bibliometric analysis based on the ISI Web of Science to evaluate the evolution of the scientific production and performance in the field of pain research between 1997 and 2017.MethodsArticles search was conducted using the ISI Web of Science, search keywords “pain or nocicep*”, between 1997 and 2017, and one author affiliated in an Irish, Greek or Portuguese institution. The total number of published articles per country, total citations, h-index, document types and authors’ institution were tabulated to determine the quantity and quality of the publications in this field.ResultsThe search retrieved 2,368 publications over the 20 years’ period, increasing from 26 in 1997 to 230 in 2017. The number of Irish publications per year increased steadily along the studied period, while the number of Greek publications stabilized from 2008 onward and Portuguese publications started to increase only in 2007 but declined slightly after 2014. In total, Irish authors published 1,143 articles, Greek authors 624 and Portuguese authors 618. There were nine articles with more than 100 citations, and Irish publications had a higher h-index (52) than Greek’s (45) or Portuguese’s (36) publications. Ireland had the highest number of pain publications per capita, but in 2016 Portugal had the lowest cost per publication, as measured by the GDP per capita per publication (in 1997 Portugal had the highest cost). The three major research fields of the publications were neurosciences/neurology (19%), general internal medicine (16%) and anaesthesiology (13%), and the affiliation institutions were mostly universities or universities hospitals.ConclusionsThe number of Irish, Greek, and Portuguese pain publications increased between 1997 and 2017, but at different paces. It appears that the economic crisis had no impact on the rate of pain publications in Ireland, had a delayed impact in Portugal, and affected mostly Greek pain scientific research. This may be related to the fact that Greece was the country that received more rescue packages and where the economic crisis was deepest and lasted longer.ImplicationsEconomics and scientific production have a mutual influence: usually research investment decreases in recession times (reducing grants and scientific employment), but health scientific production can improve health and quality of life and also benefit the economy. So in crisis periods, governments should create means to protect and foster scientific work.

OBJECTIVE The psychological health of patients with chronic low back pain (CLBP) influences their response to a number of conservative and invasive pain treatments. However, evidence is still scarce regarding the impact of anxiety and depression in the clinical outcomes of multidisciplinary pain management over time. This study, based on longitudinal data from a clinical practice setting, aimed to assess the effectiveness of the usual multidisciplinary approach provided to CLBP patients and to explore the impact of anxiety and depression symptoms and their interaction on clinical outcomes. METHODS In this study, participants included were adult patients in their first consultation in a multidisciplinary chronic pain clinic. Anxiety and depression symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS). The Brief Pain Inventory (BPI) and the Shortened Treatment Outcomes in Pain Survey (S-TOPS) were used to assess outcomes. Linear mixed effects models were used to assess the impact of anxiety, depression, and their interaction on treatment outcomes. RESULTS A total of 284 patients (age 60.4 ± 13.7 years, 74.6% female) with CLBP were included at baseline. The majority of patients had both anxiety and depression and experienced higher pain severity (P

Persistent postoperative pain (PPP) has been described as a complication of cardiac surgery (CS). We aimed to study PPP after CS (PPPCS) by conducting a systematic review of the literature regarding its incidence, intensity, location, and the presence of neuropathic pain, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The review comprised 3 phases: a methodological assessment of 6 different databases identifying potential articles and screening for inclusion criteria by 2 independent reviewers; data extraction; and study quality assessment. Meta-analysis was used to estimate the pooled incidence rates using a random effects model. We have identified 442 potentially relevant studies through database searching. A total of 23 studies (involving 11,057 patients) met our inclusion criteria. Persistent postoperative pain affects 37% patients in the first 6 months after CS, and it remains present more than 2 years after CS in 17%. The reported incidence of PPP during the first 6 months after CS increased in recent years. Globally, approximately half of the patients with PPPCS reported moderate to severe pain. Chest is the main location of PPPCS followed by the leg; neuropathic pain is present in the majority of the patients. This is the first systematic review and meta-analysis to provide estimates regarding incidence and intensity of PPPCS, which elucidates its relevance. There is an urgent need for adequate treatment and follow-up in patients with PPPCS.

Objectives To quantify the prevalence of neurological complications among breast cancer patients at one and three years after diagnosis, and to identify factors associated with neuropathic pain (NP) and chemotherapy-induced peripheral neuropathy (CIPN). Material and methods Prospective cohort study including 475 patients with newly diagnosed breast cancer, recruited among those proposed for surgical treatment (Portuguese Institute of Oncology, Porto). Patients underwent a neurological evaluation and had their cognitive function assesses with the Montreal Cognitive Assessment, before treatment and at one and three years after enrollment. We estimated the prevalence of each neurological complication, and odds ratios (OR), adjusted for socio-demographic and clinical characteristics, to identify factors associated with NP and CIPN. Results More than half of the patients [54.7%, 95% confidence interval (95%CI): 50.2–59.2] presented at least one neurological complication, at one or at three years after cancer diagnosis. Between the first and the third year of follow-up, there was an increase in the prevalence of NP (from 21.1% to 23.6%), cognitive impairment (from 7.2% to 8.2%), cerebrovascular disease (from 0.6% to 1.5%) and brain metastasis (from 0.0% to 0.6%). The prevalence of CIPN decreased from 14.1% to 12.6%. Axillary lymph node dissection was associated with NP at one year (OR = 2.75, 95%CI: 1.34–5.63) and chemotherapy with NP at three years (OR = 2.10, 95%CI: 1.20–3.67). Taxane-based chemotherapy was strongly associated with prevalence of CIPN at one and three years. Conclusion Neurological complications are frequent even three years after cancer diagnosis and NP remained the major contributor to the burden of these conditions among survivors.

Animal studies performed in orofacial pain have been relatively few, mainly because of the difficulties in testing freely moving animals1. A rat model where neuropathy was produced by chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-TN) has been developed for studying orofacial neuropathic pain2. This model induces significant inflammatory response and the optimum degree of nerve constriction is difficult to achieve3. In addition, the surgical approach for CCI-TN is more complex than for other peripheral nerves such as the sciatic4. As an alternative, some investigators proposed the transection of the inferior alveolar nerve (IAN)5,6 that causes an afferent hyperexcitability of the injured IAN leading to orofacial allodynia6. On the other hand, the spared nerve injury (SNI) approach for modelling clinical neuropathic pain has been widely used since it is technically easy to perform and subject to minimal variability. The sensitive maxillary nerve is the major branch of the trigeminal nerve (infraorbital nerve or ION) and does not contain any autonomic or motor fibers7,8. Different tests are used to access behaviour in animal pain models. The formalin test, that is one of the most frequently used in the orofacial region, evaluates the behavioural responses to a prolonged noxious chemical stimulus and can be used for the assessment of pain and analgesia in rats1. Formalin solution injected into the rat's ION territory (orofacial formalin test) evokes two distinct periods of intensive grooming activity and it has been validated by analgesic treatments9,10. Face grooming and brisk head withdrawals are both considered pain-like behaviours and represent nocifensive responses to the formalin test2,11. In this study we adapted the spared nerve injury (SNI) model of the sciatic nerve12 to the infraorbital nerve to develop a SNI-face model of trigeminal pain in rats, and evaluated hyperalgesia by using the orofacial formalin test.

Background Pain in Parkinson's disease (PD) is a common and heterogeneous non-motor symptom. Although the characteristics and predictors of pain in general and of central pain in particular are still largely unknown. Methods A semi-structured interview, the Brief Pain Inventory and the Pain Disability Index were used to identify and characterize pain in a consecutive series of 292 PD patients. Unified PD Rating Scale-III, Hoehn & Yahr, Schwab and England Independence Scale and Freezing of Gait Questionnaire were applied to assess motor symptoms and functional independence in off and on conditions. Hospital Anxiety and Depression Scale and Questionnaire of Impulsive-Compulsive Control Disorders were used to screen for anxiety, depression and impulse control disorders. Results Two hundred and twelve patients (73%) reported pain, which was classified as: musculoskeletal (63%), dystonia-related (27%), central parkinsonian (22%) and/or radicular or neuropathic (9%). Patients with pain had more comorbidities and more severe motor symptoms. Patients with central parkinsonian pain were significantly younger, had earlier disease onset, fewer comorbidities, greater non-axial motor symptom severity in on, more pain-related disability and more relief of pain with antiparkinsonian medication than patients with non-central parkinsonian pain. Conclusions PD patients with central parkinsonian pain have some distinctive demographic and clinical features, including lower levodopa responsiveness of motor appendicular/limb symptoms to levodopa, associated with greater responsiveness of pain symptoms to these same medications. These findings suggest the need for a more integrated approach to motor and non-motor symptoms in these patients' clinical care. Significance In a consecutive series of 292 patients with PD, almost three quarters of patients with PD reported pain. The study results revealed that pain was related to more severe motor symptoms, anxiety symptoms and comorbidities. Among patients with pain, those with central parkinsonian subtype had distinct demographic and clinical features, including lower levodopa responsiveness for non-axial motor symptoms and greater responsiveness of pain to antiparkinsonian treatment.

Background Amylin is a calcitonin gene-related peptide family member expressed by nociceptors. Amylin's expression is down-regulated following nerve damage, and studies suggested it affects nociception. We aimed at clarifying amylin's effects on chronic neuropathic pain and investigating its site of action. Methods Chronic neuropathic pain was induced in rats by spared nerve injury (SNI) surgery. Mechanical allodynia/hyperalgesia and cold allodynia/hyperalgesia were assessed by the von Frey, pinprick, acetone and cold plate behavioural tests, respectively. Amylin, amylin-receptor antagonist (AC187) or vehicle solutions were delivered chronically, by a subcutaneous (SC) mini-osmotic pump, or acutely, by SC or intrathecal (IT) injections. Cellular and fibre markers were used to detect spinal cord alterations in SNI rats after chronic amylin administration. Results Continuous subcutaneous amylin administration aggravated cold allodynia in SNI animals, possibly via amylin-receptors (AmyR) in supraspinal areas. Acute intrathecal administration of amylin attenuated mechanical hyperalgesia, whereas AC187 reduced mechanical allodynia, suggesting distinct roles of endogenous amylin and of pharmacological amylin doses when targeting spinal cord amylin receptors. Chronic amylin administration promoted c-Fos activation only in the dorsal horn neurons of SHAM animals, suggesting a distinctive role of amylin in the activation of the spinal neuronal circuitry under neuropathic and physiological conditions. ERK1/2 phosphorylation increased in the dorsal horn neurons of SNI rats chronically treated with amylin. This ERK1/2 cascade activation may be related to amylin's effect on the aggravation of cold allodynia in SNI rats. Conclusions Amylin's nociceptive effects seem to depend on the treatment duration and route of administration by acting at different levels of the nervous system. Significance Amylin modulated neuropathic pain by acting at different levels of the nervous system. Whereas supraspinal areas may be involved in amylin's induced pronociception, modulation of spinal cord amylin receptors by endogenous or pharmacological amylin doses triggers both pro- and antinociceptive effects.

The global burden of lung cancer has been increasing over the past years, and is still a major threat to public health worldwide, leading to disabilities and premature mortality. Despite multifactorial cause, smoking remains as the major etiological factor, followed by occupational exposure to carcinogens, genetic predisposition and other concomitant diseases. In order to reduce the individual and social burden due to the direct and indirect costs related to the lung cancer treatment, accurate methods of screening are needed. Among those, x-ray with cytological analysis of sputum was first proposed. Nowadays, more sensitive methods such as low-dose computed tomography are being used to improve the early detection. In the future, molecular biomarkers may complement low-dose computed tomography and improve the robustness of early lung cancer detection.

Summary Objective Pain exacerbated by movement and loading on the joint is the major symptom of osteoarthritis (OA), but the mechanisms of chronic pain in this pathology are still poorly understood. Using the intra-articular (i.a.) injection of collagenase in the knee of rats as a model of OA, we aimed at evaluating whether injury of sensory neurons may contribute to the development of OA-associated nociception. Design OA was induced by i.a. injection of collagenase into the left knee joint of adult male Wistar rats. Histopathological changes and movement and loading-induced nociception were assessed for 6 weeks. A time-course analysis of the expression of the neuronal injury markers activating transcription factor-3 (ATF-3) and neuropeptide Y (NPY) and of the neuropeptide SP in the dorsal root ganglion (DRG) was performed. Gabapentin's effect on nociception was evaluated, as well as the expression of the α2δ-1 voltage-gated calcium channel subunit. Results Collagenase induced the development of OA-like histopathological changes and of movement-induced nociception. Altered expression of ATF-3, NPY and SP was observed in the DRG, correlating with the degree of articular degeneration after 6 weeks of disease progression. Repeated administration of gabapentin reversed the nociceptive responses 6 weeks after the induction of OA. α2δ-1was upregulated in the DRG. Conclusion By inducing nociceptive behaviours associated with relevant joint structural changes, the i.a. injection of collagenase presents itself as a pertinent model for the study of OA pain. The findings in this study support the hypothesis that injury of sensory neurons innervating OA joints may be a significant element in the mechanisms of OA-associated pain.

Background Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the initiation of inflammatory responses to control pathogen infections, but is also a “danger-sensing” receptor that recognizes host-derived endogenous molecules called damage-associated molecular patterns (DAMPs). The role of TLR4 in rheumatic diseases is becoming evident, as well as its potential role as a therapeutic option. Objectives The aim of this study was to evaluate the effect, both on articular histopathology and pain behaviour, of a TLR4 antagonist (TLR4-A1) on an experimental model of OA. The effect of the TLR4-A1 on the activating transcription factor-3 (ATF-3) signalling pathway was also assessed. Methods OA was induced in adult Wistar rats through an intra-articular injection of 2mg of sodium mono-iodoacetate (MIA) into the left knee. Control animals received a similar injection with saline. TLR4-A1 (10 mg/kg), synthesized by Dr. Quesada from a compound previously described by the Peri Laboratory (Piazza et al., 2009), was intraperitoneally administered, daily, from days 14 to 28 after OA induction. Under the same procedure a control group of animals received the vehicle. Movement- and loading- induced nociception was evaluated in all animals, by the Knee-Bend and CatWalk tests, before and after TLR4-A1 or vehicle administration, at several time-points. Animals were sacrificed 28 days after OA induction. L3-L5 Dorsal Root Ganglia (DRG) were used for immunohistochemistry for TLR4 and ATF-3, spinal cords were immunoreacted for TLR4 and knee joints were processed for histopathological evaluation. Results Antagonism by TLR4-A1 significantly reduced the nociceptive behavior of OA animals both in the Knee-Bend and Catwalk tests. The effect was immediately observed 1 day after TLR4-A1 administration, but became more evident 4 days later, maintaining thereafter. No improvement in the cartilage histology was observed. The increased ATF-3 expression observed in DRG of OA animals was significantly reduced by TLR4-A1. On the contrary, TLR4 expression slightly increased after antagonist administration both at DRG and superficial dorsal horn levels. Conclusions Chronic treatment with TLR4-A1 showed an antinociceptive effect on OA animals, not related to articular histopathological improvement, possibly through an ATF-3 dependent mechanism. References Piazza M, Rossini C, Fiorentina SD, Pozzi C, Cornelli F, Bettoni I, Fusi P, Costa B and Peri F. Glycolipids and Benzylammonium Lipids as Novel Antisepsis Agents: Synthesis and Biological Characterization. J Med Chem 2009, 52, 1209–1213. Acknowledgements Granted by FEDER funds through COMPETE – Programa Operacional Factores de Competitividade (FCOMP-01–0124-FEDER-021359) and by National Funds through FCT – Fundacao para a Ciencia e a Tecnologia (PTDC/SAU-NSC/119986/2010); and by Ministerio de Economia y Competitividad (SAF2012–40075-C02–02). Disclosure of Interest None declared

Purinergic receptors (P2XRs) have been widely associated with pain states mostly due to their involvement in neuron-glia communication. Interestingly, we have previously shown that satellite glial cells (SGC), surrounding dorsal root ganglia (DRG) neurons, become activated and proliferate during monoarthritis (MA) in the rat. Here, we demonstrate that P2X7R expression increases in ipsilateral DRG after 1 week of disease, while P2X3R immunoreactivity decreases. We have also reported a significant induction of the activating transcriptional factor 3 (ATF3) in MA. In this study, we show that ATF3 knocked down in DRG cell cultures does not affect the expression of P2X7R, P2X3R, or glial fibrillary acidic protein (GFAP). We suggest that P2X7R negatively regulates P2X3R, which, however, is unlikely mediated by ATF3. Interestingly, we found that ATF3 knockdown in vitro induced significant decreases in the heat shock protein 90 (HSP90) expression. Thus, we evaluated in vivo the involvement of HSP90 in MA and demonstrated that the HSP90 messenger RNA levels increase in ipsilateral DRG of inflamed animals. We also show that HSP90 is mostly found in a cleaved form in this condition. Moreover, administration of a HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), attenuated MA-induced mechanical allodynia in the first hours. The drug also reversed the HSP90 upregulation and cleavage. 17-DMAG seemed to attenuate glial activation and neuronal sensitization (as inferred by downregulation of GFAP and P2X3R in ipsilateral DRG) which might correlate with the observed pain alleviation. Our data indicate a role of HSP90 in MA pathophysiology, but further investigation is necessary to clarify the underlying mechanisms.

Background. Interventional Pain Management (IPM) is performed in multidisciplinary chronic pain clinics (MCPC), including a range of invasive techniques to diagnose and treat chronic pain (CP) conditions. Current patterns of use of those techniques in MCPC have not yet been reported. Objective. We aimed to describe quantitatively and qualitatively the use of IPM and other therapeutic procedures performed on-site at four Portuguese MCPC. Methods. A prospective cohort study with one-year follow-up was performed in adult patients. A structured case report form was systematically completed at baseline and six and 12 months. Results. Among 808 patients referred to the MCPC, 17.2% had been prescribed IPM. Patients with IPM were on average younger and had longer CP duration and lower levels of maximum pain and pain interference/disability. The three main diagnoses were low back pain (n=28), postoperative CP, and knee pain (n=16 each). From 195 IPM prescribed, nerve blocks (n=108), radiofrequency (n=31), and viscosupplementation (n=22) were the most prevalent. Some IPM techniques were only available in few MCPC. One MCPC did not provide IPM. Conclusions. IPM are seldom prescribed in Portuguese MCPC. Further studies on IPM safety and effectiveness are necessary for clear understanding the role of these techniques in CP management.

Background: We aimed to perform the translation, cultural adaptation, and validation of the Pain Beliefs and Perceptions Inventory (PBPI) for the European Portuguese language and chronic pain population. Methods: This is a longitudinal multicenter validation study. A Portuguese version of the PBPI (PBPI-P) was created through a process of translation, back translation, and expert panel evaluation. The PBPI-P was administered to a total of 122 patients from 13 chronic pain clinics in Portugal, at baseline and after 7 days. Internal consistency and test-retest reliability were assessed by Cronbach's alpha (α) and intraclass correlation coefficient (ICC). Construct (convergent and discriminant) validity was assessed based on a set of previously developed theoretical hypotheses about interrelations between the PBPI-P and other measures. Exploratory and confirmatory factor analyses were performed to test the theoretical structure of the PBPI-P. Results: The internal consistency and test-retest reliability coefficients for each respective subscale were α = 0.620 and ICC = 0.801 for mystery; α = 0.744 and ICC = 0.841 for permanence; α = 0.778 and ICC = 0.791 for constancy; and α = 0.764 and ICC = 0.881 for self-blame. Exploratory and confirmatory factor analysis revealed a four-factor structure (performance, constancy, self-blame, and mystery) that explained 63% of the variance. The construct validity of the PBPI-P was shown to be adequate, with more than 90% of the previously defined hypotheses regarding interrelations with other measures confirmed. Conclusion: The PBPI-P has been shown to be adequate and to have excellent reliability, internal consistency, and validity. It may contribute to a better pain assessment and is suitable for research and clinical use. info:eu-repo/semantics/publishedVersion

In addition to its high frequency and relevant individual and social impact, chronic pain (CP) has been shown to be a major contributor to increased healthcare utilisation, reduced labour productivity, and consequently large direct and indirect costs. In the context of a larger nationwide study, we aimed to assess the total annual direct and indirect costs associated with CP in Portugal. A population-based study was conducted in a representative sample of the Portuguese adult population. The 5,094 participants were selected using random digit dialling and contacted by computer-assisted telephone interviews. Questionnaires included the brief pain inventory and pain disability index. Estimates were adequately weighted for the population. From all CP subjects identified, a subsample (n = 562) accepted to participate in this economic study. Mean total annualised costs per CP subject of €1,883.30 were observed, amounting to €4,611.69 million nationally, with 42.7 % direct and 57.3 % indirect costs, and corresponding to 2.71 % of the Portuguese annual GDP in 2010. Only socio-demographic variables were significantly and independently associated with CP costs, and not CP severity, raising the possibility of existing inequalities in the distribution of healthcare in Portugal. The high economic impact of CP in Portugal was comprehensively demonstrated. Given the high indirect costs observed, restricting healthcare services is not a rational response to these high societal costs; instead improving the quality of CP prevention and management is recommended.

The Bowel Function Index (BFI) is a simple and sound bowel function and opioid-induced constipation (OIC) screening tool. We aimed to develop the translation and cultural adaptation of this measure (BFI-P) and to assess its reliability and validity for the Portuguese language and a chronic pain population.The BFI-P was created after a process including translation, back translation and cultural adaptation. Participants (n = 226) were recruited in a chronic pain clinic and were assessed at baseline and after one week. Internal consistency, test-retest reliability, responsiveness, construct (convergent and known groups) and factorial validity were assessed.Test-retest reliability had an intra-class correlation of 0.605 for BFI mean score. Internal consistency of BFI had Cronbach's alpha of 0.865. The construct validity of BFI-P was shown to be excellent and the exploratory factor analysis confirmed its unidimensional structure. The responsiveness of BFI-P was excellent, with a suggested 17-19 point and 8-12 point change in score constituting a clinically relevant change in constipation for patients with and without previous constipation, respectively.This study had some limitations, namely, the criterion validity of BFI-P was not directly assessed; and the absence of a direct criterion for OIC precluded the assessment of the criterion based responsiveness of BFI-P. Nevertheless, BFI may importantly contribute to better OIC screening and its Portuguese version (BFI-P) has been shown to have excellent reliability, internal consistency, validity and responsiveness. Further suggestions regarding statistically and clinically important change cut-offs for this instrument are presented.

Background Cardiac surgery (CS) ranks among the most frequently performed interventions worldwide and persistent postoperative pain (PPP) has been recognized as a relevant clinical outcome in this context. We aimed to evaluate its incidence, characteristics, associated factors and patient's quality of life (QoL). Methods Observational prospective study conducted in patients undergoing CS in a tertiary university hospital. PPP was defined as persistent pain after surgery with higher than 3 months’ duration, after excluding other causes of pain. We used a set of questionnaires for data collection: Pain Catastrophizing Scale, Duke Health Profile, Brief Pain Inventory Short Form, McGill Pain Questionnaire Short Form, Douleur Neuropathique en 4 Questions and standardized questions regarding pain periodicity. Results: A total of 288 patients have completed the study and 43% presented PPP assessed at 3 months (PPP3M); out of which 84% were not under any treatment. PPP patients reported significantly lower QoL, and a neuropathic pain (NP) component was present in 50% of them. Younger age, female gender, higher body mass index, catastrophizing, coronary artery bypass graft, osteoarthritis, history of previous surgery (excluding sternotomy) and moderate to severe acute postoperative pain were independent predictors of PPP3M. Conclusion This is the first study comprehensively describing PPP after CS and identifying NP in half of them. Our results support the important role that PPP plays after CS in considering its interference in patients’ daily life and their lower QoL, which deserves the attention of health care professionals in order to improve prevention, assessment and treatment of these patients. What does this study add? This study comprehensively describes persistent postoperative pain (PPP) after cardiac surgery (CS) and identifies neuropathic pain (NP) in half of them. Our results support the important role that PPP plays after CS in considering its interference in patients’ daily life and their lower quality of life.

PURPOSE:The purposes of this study were to estimate the incidence of chemotherapy-induced peripheral neuropathy (CIPN) and to identify its main determinants and impact in patient-reported outcomes. METHODS:We performed a prospective cohort study including 296 patients with incident breast cancer submitted to chemotherapy, followed for 1 year. Patients with incident CIPN were reevaluated 6 months after this diagnosis. Relative risks (RR) with 95 % confidence intervals (95 % CI) were computed to quantify the relation between different clinical characteristics and the occurrence of CIPN, using Poisson regression. The variation of patient-reported outcomes between baseline and 1-year follow-up assessments was compared between patients with and without CIPN. RESULTS:The cumulative incidence of CIPN in the first year after diagnosis was 28.7 % (95 % CI 23.8-34.1), and more than 80 % of the patients were still symptomatic after 6 months. Among the latter, there was a significant decrease in the median total neuropathy score, clinical version (7 versus 4) between the two periods. In multivariable analysis, the risk of CIPN was higher for treatment with docetaxel (cumulative doses ≤300 mg/m(2), RR = 6.96, 95 % CI 2.53-19.10; >300 mg/m(2), RR = 13.32; 95 % CI 4.11-43.14). Alcohol consumption and diabetes were not significantly associated with CIPN. There were no significant differences in the variation of patient-reported outcomes between the baseline and 1-year follow-up evaluations. CONCLUSIONS:CIPN was frequent in this contemporary cohort of early-stage breast cancer patients and was strongly associated with docetaxel-based regimens. Symptoms persisted for at least 6 months in most patients, but severity was low and CIPN had no impact on patient-reported outcomes.

Activating transcription factor 3 (ATF-3) expression has been associated with several signaling pathways implicated in cellular stress response in many cell types and is usually regarded as a neuronal damage marker in dorsal root ganglia (DRG). We investigated ATF-3 expression in primary afferents in the monoarthritic (MA) model of chronic inflammatory joint pain. Immunohistochemistry revealed that ATF-3 is highly induced mainly in small and medium neurons, especially at 2 and 4 days of MA in L(5) DRGs. Colocalization with calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) demonstrated that ATF-3-immunoreactive cells are mainly peptidergic. The lack of significant differences in ATF-3 and pAkt colocalization indicated that ATF-3 is probably not involved in a pAkt-mediated survival pathway. Anti-inflammatory (ketoprofen) administration failed to reverse ATF-3 induction in MA rats, but significantly increased CGRP expression. These data suggest that ATF-3 expression is definitely involved in MA, actually marking injured neurons. Some degree of neuronal damage seems to occur right from the first days of disease, mainly affecting small-to-medium peptidergic neurons. The intra-articular injection of complete Freund's adjuvant and the generation of a neuroinflammatory environment seem to be the plausible explanation for the local nerve damage.

Objective Pain is a prominent feature of osteoarthritis (OA). To further understand the primary mechanisms of nociception in OA, we studied the expression of the phenotype markers calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), and neurofilament 200 (NF200) in sensory neurons innervating the OA knee joint in rats. Methods OA was induced in rats by intraarticular injection of 2 mg of mono-iodoacetate (MIA) into the knee. Neurons innervating the joint were identified by retrograde labeling with fluorogold in dorsal root ganglia (DRG) and colocalized with neurochemical markers by immunofluorescence. The total number of DRG cells was determined by stereologic methods in Nissl-stained sections. Results A 37% decrease in the number of fluorogold-backlabeled cells was observed in rats with OA when compared with control rats, even though no decrease in the total number of cells was observed. However, an increase in the number of medium/large cell bodies and a decrease in the number of the smallest cells were observed, suggesting the occurrence of perikarya hypertrophy. The percentage of CGRP-positive cells increased significantly, predominantly in medium/large cells, suggesting the occurrence of a phenotypic switch. Colocalization of CGRP and NF200 revealed no significant changes in the percentage of double-labeled cells, but an increase in the number of medium/large double-labeled cells was observed. No differences in the expression of either IB4 or NF200 were observed in fluorogold-backlabeled cells. Conclusion These results indicate that MIA-induced OA causes an up-regulation of CGRP in different subpopulations of primary afferent neurons in DRG due to a phenotypic switch and/or cell hypertrophy which may be functionally relevant in terms of the onset of pain in this pathologic condition.

The role of mu-opioid receptors (MORs) in the inflammatory pain processing mechanisms within the ventrobasal complex of the thalamus (VB) is not well understood. This study investigated the effect of modulating MOR activity upon nociception, by stereotaxically injecting specific ligands in the VB. Nociceptive behaviour was evaluated in two established animal models of inflammatory pain, by using the formalin (acute and tonic pain) and the ankle-bend (chronic monoarthritic pain) tests. Control (saline intra-VB injection) formalin-injected rats showed acute and tonic pain-related behaviours. In contrast, intrathalamic administration of [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO), a MOR-specific agonist, induced a statistically significant decrease of all tonic phase pain-related behaviours assessed until 30–35 min after formalin hind paw injection. In the acute phase only the number of paw-jerks was affected. In monoarthritic rats, there was a noticeable antinociceptive effect with approximately 40 min of duration, as denoted by the reduced ankle-bend scores observed after DAMGO injection. Intra-VB injection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a specific MOR antagonist, or of CTOP followed, 10 min after, by DAMGO had no effects in either formalin or ankle-bend tests. Data show that DAMGO-induced MOR activation in the VB has an antinociceptive effect in the formalin test as well as in chronic pain observed in MA rats, suggesting an important and specific role for MORs in the VB processing of inflammatory pain.

Although there are several reports on pain behavioral tests in rat models of knee osteoarthritis (OA), most of them focus on the paw. The aim of this study was to investigate pain-related behaviors on the affected knee joint, the primary source of nociception, in animals with mono-iodoacetate-induced OA, using the knee-bend (which provides information on movement pain) and pin-prick tests, and to evaluate nociception elicited by walking using the CatWalk test. The von Frey and Randall-Selitto tests applied to the paw allowed us to compare our study results with previous studies. A further aim was to compare the behavioral nociceptive responses of the most used doses of mono-iodoacetate, 2 and 3 mg. Knee-bend score of OA animals was higher than those of control animals throughout the study (P.05). At every time point, the ipsilateral hind-paw load of OA rats, as measured by the CatWalk test, was lower than that of control rats (P.05), and paw withdraw threshold to von Frey filaments was also decreased (P.01). No changes were observed in pin-prick and Randall-Selitto tests. Results obtained with the 2 doses of mono-iodoacetate were similar. The knee-bend and CatWalk tests are effective for evaluating movement-related nociception, a hallmark of clinical OA, which was present throughout the experimental period.Behavioral characterization of models of OA pain is important and useful for use in future studies to test pharmacological treatments. Furthermore, it is important to find methods that correlate better with the human symptoms of OA.

Context: Neuropathic pain (NP) may be an important contributor to the morbidity burden of breast cancer. Objectives: We aimed to quantify the incidence of NP in the first year after diagnosis of breast cancer and to identify its main determinants. Methods: We performed a prospective cohort study including 506 patients with incident breast cancer, recruited at the Portuguese Institute of Oncology of Porto, and followed for one year; patients with incident NP were additionally evaluated when this condition was diagnosed and after six months, to identify chronic NP. Results: During the first year, 156 patients were diagnosed with NP (30.8%, 95% CI 27.0–35.0). Anxiety (relative risk [RR] 1.50; 95% CI 1.06–2.13), arm symptoms (RR 1.44; 95% CI 1.02–2.05), cancer Stage III/IV (RR 2.47; 95% CI 1.66–3.66), breast-conserving surgery with axillary lymph node dissection (RR 3.13; 95% CI 1.51–6.48), mastectomy with axillary lymph node dissection (RR 2.52; 95% CI 1.25–5.11), and damaging of the intercostobrachial nerve (RR 2.05; 95% CI 1.25–3.37) were predictors of a higher risk of NP. A total of 97 patients (62.2%, 95% CI 54.4–69.4) diagnosed with NP remained symptomatic after six months. Conclusion: NP and chronic NP were frequent in this population, being associated with anxiety and arm symptoms before breast cancer treatments and type of surgical management. These results highlight the need for monitoring the occurrence of this neurologic side effect of treatments and to develop strategies for reducing the morbidity burden of breast cancer. The work of F. F. was co-funded by “Fundação para a Ciência e a Tecnologia” (grant number SFRH/BD/92630/2013) and by the “Programa Operacional Capital Humano” (POCH/FSE). Data management activities were supported by the Chair on Pain Medicine of the Faculty of Medicine, University of Porto and by the Grünenthal Foundation—Portugal. The authors declare no conflicts of interests.

Objectives Neurological complications secondary to breast cancer treatment may be an important contributor to these patients morbidity. We aimed to quantify the incidence of neurological complications of breast cancer treatment during the first year after diagnosis. Materials and methods We performed a prospective cohort study with 506 patients recruited at the Portuguese Institute of Oncology of Porto, among those newly diagnosed. Participants underwent a neurological examination before treatment, after surgery, after chemotherapy (whenever applicable) and at one year after enrollment. The Montreal Cognitive Assessment was used to assess cognitive function, at baseline and at one year. We computed one-year cumulative incidence estimates and the corresponding 95% confidence intervals (95%CI) for each of the neurological complications. Results Just over half of women had breast cancer stage 0 or I. A total of 6.9% were submitted to neoadjuvant chemotherapy but most of them completed adjuvant treatment – endocrine therapy, radiotherapy or chemotherapy (83.9%, 73.0% and 52.5%, respectively). The cumulative incidence of at least one oncological-related neurological complication during the first year after diagnosis was 48.4% (95%CI: 44.1–52.8); the most frequent were neuropathic pain (30.8%, 95%CI: 27.0–35.0), chemotherapy-induced peripheral neuropathy (16.8%, 95%CI: 13.8–20.3), phantom breast pain/syndrome (16.6%, 95%CI: 13.6–20.1) and cognitive decline (8.1%, 95%CI: 5.8–11.1). Conclusions Neurological complications were a frequent side-effect of breast cancer management in the first year after diagnosis, especially neuropathic pain and chemotherapy-induced peripheral neuropathy. Accurate diagnosis and treatment of these complications are important to minimize the burden associated with breast cancer treatment in breast cancer survivors.

Many studies have implicated GABA B receptors in pain transmission mechanisms, especially in the spinal cord. In the thalamus, mRNA expression of the GABA B(1b) isoform was shown to be regulated in relay nuclei in response to chronic noxious input arising from experimental monoarthritis. GABA B(1a) and GABA B2 mRNA expression was here determined by in situ hybridisation in the brain of control, 2, 4, 7 and 14 days monoarthritic rats, to evaluate whether this expression was regulated by chronic noxious input in thalamic nuclei. mRNA labelling was analysed quantitatively in the ventrobasal complex, posterior, central medial/central lateral and reticular thalamic nuclei; the thalamic visual relay and dentate gyrus were examined for control. No mRNA expression was detected for GABA B(1a) in control and monoarthritic animals. Similarly, GABA B2 mRNA was not found in the reticular nucleus. However, GABA B2 mRNA expression was observed in the ventrobasal complex, posterior and central medial/central lateral nuclei of control animals. A significant decrease of 42% at 2 days and 27% at 4 days of monoarthritis was observed in the ventrobasal complex contralaterally, when compared with controls, returning to basal levels at 7 days of monoarthritis. In the ipsilateral posterior nucleus, there was a significant decrease of 38% at 2 days of monoarthritis. No significant changes were observed in central medial/central lateral nuclei. The data suggest that GABA B2 mRNA expression in the ventrobasal complex and posterior nucleus is regulated by noxious input and that GABA B receptors might play a role in the plasticity of these relay nuclei during chronic inflammatory pain.

The ventrobasal complex of the thalamus (VB) participates in the transmission and modulation of noxious information. Recent data suggested that GABA(B) receptors in the VB might be involved in the modulation of neuronal activity in response to chronic noxious input. However, in acute inflammatory pain, the role of GABA(B) receptors in the VB remains unknown. The formalin test of nociception was performed in rats stereotaxically injected in the VB contralateral to the formalin-injected paw, with saline (controls), baclofen (0.5 and 0.875 microg), a specific GABA(B) receptor agonist or CGP35348 (25 microg), a GABA(B) receptor antagonist. Control animals exhibited phase 1 (acute pain) and phase 2 (tonic pain) nociception-related activities as previously described. The higher dose of baclofen induced a significant decrease of all pain-related behaviors in both phases of the test and had no observable effects on the animals' motor function, while the lower dose could not reduce the total pain-related activities. Injection of CGP35348 prior to baclofen reduced the antinociceptive effect caused by baclofen during phase 2 in the paw-jerks and in total pain-related activities. CGP35348 alone had antinociceptive effects in both phases, though less pronounced than baclofen 0.875 microg in the total pain-related activities during phase 2. Data demonstrate that both the blockade and the activation of GABA(B) receptors in the VB of rats induce antinociception in acute and tonic pain. An important role for GABA(B) receptors on the thalamic processing of nociceptive input in the VB is suggested.

GABA(B) receptors have been implicated in the plastic changes occurring in the spinal cord during the development of chronic inflammatory pain. In this study, we evaluated whether the expression of GABA(B(1b)) receptor mRNA is regulated supraspinally, namely in the thalamus, as part of the response to chronically enhanced noxious input arising from experimental monoarthritis (MA). In situ hybridization with [(35)S]-labelled oligonucleotide probes was performed in sections of control, 2, 4, 7 and 14 days MA rats' brains (n = 6/group). The distribution of GABA(B(1b)) mRNA was determined bilaterally in the ventrobasal complex (VB), posterior (Po), centromedial/centrolateral (CM/CL) and reticular (Rt) thalamic nuclei. The amount of GABA(B(1b)) mRNA was expressed as times fold of background values. In normal animals, values of mRNA expression were very similar in VB, Po and CM/CL, ranging from 2.2 +/- 0.2 to 2.7 +/- 0.4 (mean +/- S.E.M.) times higher than background levels. No expression of GABA(B(1b)) mRNA was found in the Rt of control or MA animals. A significant decrease of 26% at 4 days, and 37% at 7 days of MA, was observed in the VB contralateral to the affected joint. On the contrary, in the Po there was a significant bilateral increase at 2 days (38% contralaterally, 25% ipsilaterally), returning to basal levels at 4 days MA. No significant changes were observed in CM/CL. These results suggest that the expression of GABA(B(1b)) in the VB and Po is regulated by noxious input, and might contribute to the functional changes that occur in the thalamus during chronic inflammatory pain.

Modulation of nociceptive transmission at the brainstem involves several neurochemical systems. The precise location and specific characteristics of nociceptive neurons activated in each system was never reported. In thisstudy, the presence of GABA B , μ-opioid, and neurokinin-1 (NK-1) receptors in brainstem nociceptive neurons was investigated by double-immunocytochemical detection of each receptor and noxious-evoked induction of the c-fos proto-oncogene. Noxious cutaneous mechanical stimulation significantly increased the proportions of neurons double-labelled for Fos and GABA B receptors in several brainstem regions, namely, the reticular formation of the caudal ventrolateral medulla (VLMlat and VLMrf), lateral reticular nucleus, spinal trigeminal nucleus, pars caudalis (Sp 5 C), nucleus of the solitary tract, dorsal reticular nucleus, ventral reticular nucleus, raphe obscurus nucleus and dorsal parabrachial nucleus (DPB). For μ-opioid receptors, the proportions of double-labelled neurons in noxious-stimulated animals were higher than in controls only in the VLMlat, VLMrf, Sp 5 C, DPB and A 5 noradrenergic cell group. As for the NK-1 receptor, no significant differences were found between control and stimulated animals. According to these results, neurons expressing GABA B , μ-opioid and NK-1 receptors at several pain control centres of the brainstem are differentially involved in processing nociceptive mechanical input. The data provide the definition of new supraspinal targets for selective modulation of nociceptive neurons in order to define better strategies of pain control.

Background Experimental osteoarthritis entails neuropathic-like changes in dorsal root ganglia (DRG) neurons. Since glial activation has emerged as a key player in nociception, being reported in numerous models of neuropathic pain, we aimed at evaluating if glial cell activation may also occur in the DRG and spinal cord of rats with osteoarthritis induced by intra-articular injection of collagenase. Methods Osteoarthritis was induced by two injections, separated by three days, of 500 U of type II collagenase into the knee joint of rats. Movement-induced nociception was evaluated by the Knee-Bend and CatWalk tests during the following six weeks. Glial fibrillary acidic protein (GFAP) expression in satellite glial cells of the DRG was assessed by immunofluorescence and Western Blot analysis; the pattern of GFAP and activating transcription factor-3 (ATF-3) expression was also compared through double immunofluorescence analysis. GFAP expression in astrocytes and IBA-1 expression in microglia of the L3-L5 spinal cord segments was assessed by immunohistochemistry and Western Blot analysis. The effect of the intrathecal administration of fluorocitrate, an inhibitor of glial activation, on movement-induced nociception was evaluated six weeks after the first collagenase injection. Results GFAP expression in satellite glial cells of collagenase-injected animals was significantly increased six weeks after osteoarthritis induction. Double immunofluorescence showed GFAP upregulation in satellite glial cells surrounding ATF-3-positive neurons. In the spinal cord of collagenase-injected animals, an ipsilateral upregulation of GFAP and IBA-1 was also observed. The inhibition of glial activation with fluorocitrate decreased movement- and loading-induced nociception. Conclusion Collagenase-induced knee osteoarthritis leads to the development of nociception associated with movement of the affected joint and to the activation of glial cells in both the DRG and the spinal cord. Inhibition of glial cell activation by fluorocitrate decreases these osteoarthritis-associated nociceptive behaviours. These results suggest that glial cell activation may play a role in the development of chronic pain in this experimental model of osteoarthritis.

IntroductionThe improvement in breast cancer survival rates, along with the expected overdiagnosis and overtreatment associated with breast cancer screening, requires a comprehensive assessment of its burden. Neurological complications can have a devastating impact on these patients; neuropathic pain and chemotherapy-induced peripheral neuropathy are among the most frequently reported. This project aims to understand the burden of neurological complications of breast cancer treatment in Northern Portugal, and their role as mediator of the impact of the treatment in different dimensions of the patients’ quality of life.Methods and analysisA prospective cohort study was designed to include 500 patients with breast cancer, to be followed for 3 years. The patients were recruited at the Portuguese Oncology Institute of Porto and evaluations were planned at different stages: pretreatment, after surgery, after chemotherapy (whenever applicable) and at 1 and 3 years after enrolment. Patients diagnosed with neuropathic pain or chemotherapy-induced peripheral neuropathy (subcohorts), were also evaluated at the moment of confirmation of clinical diagnosis of the neurological complication and 6 months later. In each of the follow-up periods, a neurological examination has been performed by a neurologist. Data were collected on sociodemographic and clinical characteristics, quality of life, sleep quality, and anxiety and depression. Between January and December 2012, we recruited and conducted the baseline evaluation of 506 participants. The end of the follow-up period is scheduled for December 2015.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the Portuguese Oncology Institute of Porto and all patients provided written informed consent. All study procedures were developed in order to assure data protection and confidentiality. Results from this project will be disseminated in international peer-reviewed journals and presented in relevant conferences.

Joint inflammatory diseases are debilitating and very painful conditions that still lack effective treatments. Recently, glial cells were shown to be crucial for the development and maintenance of chronic pain, constituting novel targets for therapeutic approaches. At the periphery, the satellite glial cells (SGCs) that surround the cell bodies of primary afferents neurons in the dorsal root ganglia (DRG) display hypertrophy, proliferation, and activation following injury and/or inflammation. It has been suggested that the expression of neuronal injury factors might initially trigger these SGCs-related events. We then aimed at evaluating if SGCs are involved in the establishment/maintenance of articular inflammatory pain, by using the monoarthritis (MA) model, and if the neuronal injury marker activating transcriptional factor 3 (ATF3) is associated with these SGCs' reactive changes. Western Blot (WB) analysis of the glial fibrillary acidic protein (GFAP) expression was performed in L4-L5 DRGs from control non-inflamed rats and MA animals at different time-points of disease (4, 7, and 14d, induced by complete Freund's adjuvant injection into the left hind paw ankle joint). Data indicate that SGCs activation is occurring in MA animals, particularly after day 7 of disease evolution. Additionally, double-immunostaining for ATF3 and GFAP in L5 DRG sections shows that SGCs's activation significantly increases around stressed neurons at 7d of disease, when compared with control animals. The specific labelling of GFAP in SGCs rather than in other cell types was also confirmed by immunohistochemical labeling. Finally, BrdU incorporation indicates that proliferation of SGCs is also significantly increased after 7 days of MA. Data indicate that SGCs play an important role in the mechanisms of articular inflammation, with 7 days of disease being a critical time-point in the MA model, and suggest that ATF3 might be involved in SGCs' reactive changes such as activation.

Objective To evaluate the results of lumbar epiduroscopic adhesiolysis using mechanical methods and a radiofrequency catheter followed by epidural steroid and local anesthetic administration in patients with postoperative fibrosis and persistent or recurrent symptoms. Study Design Prospective study. Methods Patients with persistent or recurrent low back and/or lower limb pain after lumbar spine surgery, in whom no relevant findings were present on MR images besides epidural scar tissue, were submitted to epiduroscopic adhesiolysis. Patient-reported outcomes including pain and disability were assessed in predefined time intervals and compared to baseline. Results Twenty-four patients were enrolled. It was possible to elicit the patient's usual pain by probing the epidural scar tissue in all patients. Statistically significant improvement in low back and lower limb pain was observed in all assessment periods up to 12 months. A pain relief over 50% was achieved in 71% of the patients at 1 month, 63% at 3 and 6 months, and 38% at 12 months. Disability scores significantly improved for around 6 months. Mean patient satisfaction rates were 80% at 1 month, 75% at 3 months, 70% at 6 months, and 67% 1 year after intervention. Only 1 transient postprocedural complication was detected. Conclusion Endoscopic adhesiolysis is a potentially useful treatment for the relief of chronic intractable low back and lower limb pain in patients with previous lumbar spine surgery and epidural fibrosis. The use of larger volumes of saline during endoscopy and the employment of radiofrequency for the lysis of epidural adhesions are safe procedures, which may provide an additional benefit to the intervention.

Introduction: Animal models currently used in osteoarthritis-associated pain research inadequately reproduce the initiating events and structural pathology of human osteoarthritis. Conversely, intra-articular injection of collagenase is a structurally relevant model, as it induces articular degeneration both by digesting collagen from cartilage and by causing articular instability, thereby reproducing some of the main events associated with osteoarthritis onset and development. Here, we evaluated if the intra-articular injection of collagenase can be an alternative model to study nociception associated with osteoarthritis. Methods: Osteoarthritis was induced by two intra-articular injections of either 250 U or 500 U of collagenase into the left knee joint of adult male Wistar rats. A six weeks time-course assessment of movement- and loadinginduced nociception was performed by the Knee-Bend and CatWalk tests. The effect of morphine, lidocaine and diclofenac on nociceptive behaviour was evaluated in animals injected with 500 U of collagenase. Joint histopathology was scored for both doses throughout time. The expression of transient receptor potential vanilloid 1 (TRPV1) in ipsilateral dorsal root ganglia (DRG) was evaluated. Results: An increase in nociceptive behaviour associated with movement and loading of affected joints was observed after intra-articular collagenase injection. With the 500 U dose of collagenase, there was a significant correlation between the behavioural and the histopathological osteoarthritis-like structural changes developed after six weeks. One week after injection of 500 U collagenase, swelling of the injected knee and inflammation of the synovial membrane were also observed, indicating the occurrence of an early inflammatory reaction. Behavioural changes induced by the 500 U dose of collagenase were overall effectively reversed by morphine and lidocaine. Diclofenac was effective one week after injection. TRPV1 expression increased six weeks after 500 U collagenase injection. Conclusion: We conclude that the intra-articular injection of 500 U collagenase in the knee of rats can be an alternative model for the study of nociception associated with osteoarthritis, since it induces significant nociceptive alterations associated with relevant osteoarthritis-like joint structural changes.

Metabotropic glutamate receptors (mGluR) have been shown to play a role in the modulation of acute and inflammatory pain. Additionally, we have recently detected time-dependent changes in the mRNA expression of several mGluR subtypes in thalamic nuclei of monoarthritic (MA) rats. In the present study, mGluR1, -3, -4, and -7 subtype mRNA expression was analyzed by in situ hybridization with radioactively labelled oligonucleotide probes in cerebral cortical regions of normal and MA rats at 2, 4, and 14 days of the disease. The mGluR1, -4, and -7 mRNAs were at background level in normal rats and did not change in MA animals. In contrast, mGluR3 mRNA expression was abundant in normal rats and was significantly increased in cortical areas of MA rats at all time points. Higher changes were detected bilaterally at 4 days, predominantly in layers IV/V, in the motor, primary, and secondary somatosensory cortices (average increases of 50-75%), but maximum rises occurred in the contralateral cingulate cortex (+138%). No changes were detected in the auditory cortex. The present data show an up-regulation of mGluR3 mRNA expression in the motor, somatosensory, and limbic cortices of MA rats. This possibly reflects the occurrence of central mechanisms counteracting the increased transmission of nociceptive input arising from the inflamed paw and the impaired motor behavior of these rats. Changes in the cingulate cortex may be related to the motivational-affective component of nociception.

Adult rats were rendered monoarthritic (MA) by injection of 50 microl of complete Freund's adjuvant (CFA) into the tibiotarsal joint. The ankle-bend (AB) test of nociception was performed in those animals before and during 60 min after the stereotaxic injection of 2 microl of either saline (controls) or (2S)-alpha-ethylglutamic acid (EGLU, 80 nmol in 2 microl), a group II metabotropic glutamate receptors (mGluR) antagonist, in the reticular thalamic nucleus (Rt) contralateral to the arthritic joint. AB scores reached near maximum values before the stereotaxic injections (18.7+/-0.8), and remained constant throughout the entire experimental period in the control group, denoting marked allodynia. In the EGLU-treated group, AB scores gradually decreased after EGLU injection, with minimum values at 10 min (7.7+/-1.6), recovering to scores near maximum at 60 min (19.7+/-0.3). The data point to an activation of group II mGluR by noxious inputs in the Rt of MA rats, suggesting their participation in inhibiting local gamma-aminobutyric acid (GABA)ergic inhibitory neurones.

In order to further clarify the role of gamma-aminobutyric acid (GABA) receptors in spinal sensory processing we have studied the effects of baclofen, a GABA(B) agonist, and midazolam, a benzodiazepine agonist, on the activation of spinal neurones by peripheral innocuous or noxious stimulation, in normal or monoarthritic rats, as signalled by the induction of the proto-oncogene c-fos. Baclofen (10 mg/kg, i.v.) caused a significant reduction in the number of Fos-positive neurones following noxious stimulation of both normal and monoarthritic animals, which was prevented by the GABA(B) antagonist CGP 35348 (200 mg/kg, i.v.). The latter caused an increase of c-fos expression in normal animals subject to noxious stimulation, suggesting an endogenous tonic activation of GABA(B) receptors. This effect was not observed in monoarthritic animals. Baclofen also reduced the number of Fos-positive neurones in monoarthritic animals subject to innocuous stimulation. Midazolam (5 mg/kg, i.v.) had no effect in normal animals, but caused an increase in c-fos expression induced by noxious stimulation in monoarthritic animals. Flumazenil (1 mg/kg, i.v.), a benzodiazepine antagonist, prevented the effect of midazolam, and if given alone evoked a decrease in Fos-positive neurones. It can be concluded that although GABA(B) receptors modulate sensory input at the spinal level, high doses of systemic baclofen are required to inhibit nociceptive-induced c-fos expression. The paradoxical facilitation of c-fos expression by midazolam in monoarthritic animals, may be due to the reported increase in spinal GABA levels found in those animals.

Previous data have shown that noxious thermal stimulation of the hind leg in the anesthetized rat causes c-fos activation in the paraventricular nucleus of the hypothalamus (PVN); in other brain nuclei, including the cathecholaminergic cell groups of the caudal medulla; and in the adenohypophysis. Stimulation was followed by adrenocorticotropic hormone plasma release but did not provoke cardiovascular changes. In the current study, the afferent central pathways conveying the nociceptive input to the PVN were studied throughout the brain by using double labeling for the Fos-protein and the retrograde tracer cholera toxin subunit B (CTb) injected into the PVN. Although double labeling occurred in several hypothalamic nuclei, the periaqueductal gray, the lateral parabrachial area, and the catecholaminergic medullary groups, high rates of double labeling occurred only in the cells of the A1 region of the ventrolateral medulla (≈83% of CTb-labeled cells expressing c-fos). Further triple labeling with tyrosine hydroxylase (TH) revealed that > 80% of the double-labeled cells were TH-immunoreactive. The spinal cord had the usual strong c-fos expression but showed no retrograde labeling from the PVN. Noxious stimulation caused corticosterone plasma release. To ascertain a possible link of spinofugal neurons with the A1 cells, biotinylated dextran amine was injected into the spinal dorsal horn. Numerous anterogradely labeled fibers with bouton-like structures were observed, with the latter apposed to double- and triple-labeled cells in the A1 region. It is suggested that a dysynaptic route relayed in the A1 region conveys the nociceptive somatic input from the spinal cord to the PVN. Noxious stimulation may act as a systemic stressor, activating the hypothalamic-pituitary-adrenal axis. J. Comp. Neurol. 413:129–145, 1999. © 1999 Wiley-Liss, Inc.

The development of chronic pain is associated with activity-dependent plastic changes in neuronal structures in the peripheral and central nervous system. In order to investigate the time-dependent processing of afferent noxious stimuli in the spinal cord we employed the quantitative autoradiographic 2-deoxyglucose technique in a model of chronic monoarthritic pain in the rat. Spinal metabolic activity was determined at various time-points (two, four and 14 days) after the injection of complete Freund's adjuvant into the left tibiotarsal joint. In addition, the effect of acute noxious mechanical stimulation of the arthritic joint was investigated at 14 days of monoarthritis. Local glucose utilization was determined in lumbar segments L2-L5, ipsi- and contralateral to the inflamed hindpaw, and compared with saline-injected controls. In general, monoarthritic animals had bilaterally increased metabolic activity in all laminae of the spinal cord. Detailing the time-course showed that in rats with two days of monoarthritis metabolic activity was significantly increased to a similar extent on both sides of all spinal laminae. In contrast, at four days, glucose utilization in deep laminae of the dorsal horn (laminae V-VI), the central gray area (laminae X) and the ventral horn (laminae VII-IX) tended to return to control levels. At 14 days of monoarthritis, however, metabolic activity showed a further increase in all laminae of the spinal cord. This increase was more pronounced on the side ipsilateral to inflammation, reaching 65% above corresponding control levels in laminae V, VI. Animals with 14 days of monoarthritis which were subjected to mechanical noxious stimulation of the arthritic joint displayed clear behavioral signs of acute pain. Although in this group metabolic activity was above control levels, it was lower than in animals with 14 days of monoarthritis that were not additionally stimulated. The data show not only a general increase of spinal cord metabolic activity during the time-course of the development of a chronic pain state, but also show a region-specific non-linear time profile. This may reflect the complexity of transducing and suppressive transmitter systems involved in the central processing of ongoing pain.

Peripheral noxious stimulation evokes functional and biochemical changes in the spinal cord which results in central sensitization and hyperalgesia, but at the same time also induces the activation of inhibitory control systems. The purpose of the present study was to investigate whether the adaptive changes induced by ongoing peripheral inflammation influence the spinal cord expression of c-Fos (a commonly used marker of neuronal activity) following an additional acute noxious stimulus. Therefore, the spinal expression of c-Fos was immunohistochemically investigated following noxious thermal stimulation of a rat monoarthritic hindpaw at various time points (1, 4, 8, 21 days) after induction of monoarthritis. Compared to normal rats, c-Fos expression following ipsilateral noxious thermal stimulation of monoarthritic rats was strongly modified in the deep laminae of the dorsal horn depending on the time course of inflammation. At 1 day of monoarthritis, an enhanced ipsilateral expression (135% and 208% of normal rats in laminae III-VI and VII, respectively) and at 3 weeks a reduced expression (38% and 23% of normal rats in laminae III-VI and VII, respectively) was detected. The amount of c-Fos-positive neurons in the ipsilateral superficial laminae I and II was unchanged at all time points investigated. To assess excitability changes on the contralateral side at an early stage of inflammation, a group of monoarthritic rats received a contralateral noxious stimulus at day 1 of monoarthritis. This resulted in a potentiated expression of c-Fos ipsilateral to the acute noxious stimulus (i.e., contralateral to the monoarthritic hindpaw) restricted to lamina II (137% of normal rats) of the dorsal horn. The data showed that changes in c-Fos expression depended on the time point of noxious heat stimulation (NHS) of monoarthritic rats, and differed in the ipsi- and contralateral side of the spinal cord. In addition to a possible habituation of c-Fos expression, it may be speculated that the time course-dependent changes reflect laminae-specific modulations of excitatory and inhibitory mechanisms during monoarthritis. Further studies are necessary in order to provide more insights into the contribution of these mechanisms on noxious stimulus-evoked c-Fos expression.

We have shown in previous c-fos studies that noxious stimulation or electroacupuncture in deeply anaesthetized rats activate the hypothalamic–pituitary corticotrope axis in a specific way. C-fos expression was more pronounced in the arcuate than the paraventricular hypothalamic nuclei, and none occurred in the pituitary intermediate lobe. The absence of the usual autonomic responses to psychological stress, such as tachycardia or blood pressure elevation, suggested a specific action of the somatosensory input on the hypothalamic–pituitary axis. To prove this hypothesis, c-fos expression was examined in the paraventricular, arcuate and other hypothalamic nuclei, the pituitary gland, and the A1 and A2 medullary catecholaminergic cell groups of animals deprived of nociceptive primary afferent input by neonatal capsaicin. After noxious stimulation or electroacupuncture, no c-fos enhancement occurred in any of those sites in capsaicin-treated animals, and there was no increased plasma release of adrenocorticotropic hormone. In contrast, the hypothalamic–pituitary c-fos activation provoked by immobilization stress though markedly decreased, was not abolished by capsaicin, whereas plasma release of adrenocorticotropic hormone remained undiminished. These findings suggest that noxious stimulation or electroacupuncture act on the hypothalamic–pituitary corticotrope axis through an exclusively physical effect depending on the noxious signal elicited in the somatosensory pathway. They also demonstrate the occurrence of a minor somatosensory physical component after forced immobilization, acting on the hypothalamic–pituitary axis probably together with the prevalent component of emotional arousal elicited by this form of stress.

Chronic peripheral inflammation or peripheral neurectomy cause changes in GABA levels and GABA immunoreactivity in the spinal cord dorsal horn. The present study aimed to investigate if such changes are accompanied by alterations in GABA receptor binding. Neurectomy of the sciatic nerve caused an ipsilateral down-regulation of GABAB receptor binding in lamina II of the spinal cord 2-4 weeks after the nerve injury. Since approximately 50% of GABAB receptor binding in that region is located on primary afferent endings, degenerative changes of such endings caused by the nerve lesion can explain the observed reduction. In contrast, GABAA binding was substantially enhanced following neurectomy, which may be due to an up-regulation of the receptors issued by the concomitant decrease of endogenous GABA. In rats bearing unilateral chronic peripheral inflammation induced by intraarticular injection of complete Freund's adjuvant we found a reduction of GABAB binding in the superficial dorsal horn. This effect, which was maximal at 3-4 weeks after adjuvant injection, was attributed to an enhanced release of GABA by spinal interneurons. GABAA receptor binding was not changed in this experimental model. Together, these results suggest that the two receptor types may be located at different loci and are differently affected by variations in sensory input.

Background: It was recently reported that the mono-iodoacetate (MIA) experimental model of osteoarthritis (OA) courses with changes of neurons innervating the affected joints that are commonly interpreted as a neuronal response to axonal injury. To better characterize these changes, we evaluated the expression of two markers of neuronal damage, ATF-3 and NPY, and the growth associated protein GAP-43, in primary afferent neurons of OA animals injected with three different doses of MIA (0.3, 1 or 2 mg). Measurements were performed at days 3, 7, 14, 21 and 31 post-MIA injection. Results: OA animals showed the characteristic histopathological changes of the joints and the accompanying nociceptive behaviour, evaluated by the Knee-Bed and CatWalk tests. An increase of ATF-3 expression was detected in the DRG of OA animals as early as 3 days after the injection of 1 or 2 mg of MIA and 7 days after the injection of 0.3 mg. NPY expression was increased in animals injected with 1 or 2 mg of MIA, at day 3 or in all time-points, respectively. From day 7 onwards there was a massive increase of GAP-43 expression in ATF-3 cells. Conclusions: The expression of the neuronal injury markers ATF-3 and NPY as well as an up-regulation of GAP-43 expression, indicative of peripheral fibre regeneration, suggests that axonal injury and a regeneration response may be happening in this model of OA. This opens new perspectives in the unravelling of the physiopathology of the human disease.