Structural imaging has revealed changes in cortical thickness in migraine patients compared to healthy controls is reported, but presence of dynamic cortical and subcortical changes during migraine attack versus inter-ictal phase is unknown. The aim of the present study was to investigate possible changes in cortical thickness during spontaneous migraine attacks. We hypothesized that pain-related cortical area would be affected during the attack compared to an inter-ictal phase.p = 0.025.Twenty-five patients with migraine without aura underwent three-dimensional T1-weighted imaging on a 3-Tesla MRI scanner during spontaneous and untreated migraine attacks. Subsequently, 20 patients were scanned in the inter-ictal phase, while 5 patients did not show up for the inter-ictal scan. Four patients were excluded from the analysis because of bilateral migraine pain and another one patient was excluded due to technical error in the imaging. Longitudinal image processing was done using FreeSurfer. Repeated measures ANOVA was used for statistical analysis and to control for multiple comparison the level of significance was set at p = 0.023), pericalcarine (p = 0.024), and temporal pole (p = 0.017) cortices during the attack compared to the inter-ictal phase. Cortical volume was reduced in prefrontal (p = 0.018) and pericalcarine (p = 0.017) cortices. Hippocampus volume was increased during attack (p = 0.007). We found no correlations between the pain side or any other clinical parameters and the reduced cortical size.In a total of 15 patients, we found reduced cortical thickness of the precentral .The study was registered at  Structural neuroimaging studies in migraine had focus on unveiling underlying pathophysiological mechanisms and radiological biomarkers of the disease. Several data supported the presence of cortical and sub-cortical morphological alterations in the migraine brain, although conflicting evidences were published . When coThe aim of this study is to investigate the morphological changes of cortical and sub-cortical brain structures during spontaneous migraine attacks of migraine without aura compared to outside of the attack. We hypothesized that migraine attacks would be accompanied by morphological changes in pain-related areas in the brain.http://www.forsoegsperson.dk). Inclusion criteria were: age 18 to 65 years; diagnosis of episodic migraine without aura according to the ICHD criteria [Patients were recruited from 2013 to 2014 among those attending the outpatient clinic of the Danish Headache Center  and through web a page (criteria . ExclusiThe patients underwent two MRI scans during two separate sessions: session 1 (S1) was performed during a spontaneous migraine attack, while session 2 (S2) was performed in the inter-ictal period.During S1, patients were asked to call an investigator of the study (FMA) as soon as possible after the onset of a migraine attack. All patients were previously instructed about the International Headache Society’s migraine without aura criteria . After tWe obtained the MRI recordings from a Philips Achieva 3 T MRI scanner  using a 32-channel SENSE head coil. To minimize motion artefacts due to head movement, we placed foam pads in both temple regions in the head coil. The three-dimensional high-resolution T1-weighted MP-RAGE (magnetization-prepared rapid gradient-echo) images of the brain were acquired with the following parameters: repetition time 6.9 ms, echo time 2.78 ms, field-of-view 263 mm × 281 mm × 150 mm, matrix size 256 mm × 256 mm, 137 sagittal slices, and voxel size 1.1 mm × 1.1. mm × 1.1 mm. FreeSurfer version 5.3.0 was used to process the acquired T1-weighted images using the longitudinal processing pipeline described in detail elsewhere , 13, 14.The statistical analysis was performed with SPSS version 21.0 for Windows. All clinical and demographic variables and cortical thickness values, including volume of cortical and subcortical structures showed a normal distribution using the Kolmogorov-Smirnov test. The analysis was performed with a two factors ANOVA for repeated measures: factor SESSION (2 levels: S1 scan vs. S2 scan) and factor SIDE (pain side vs. non-pain side), followed by a post-hoc correction for multiple comparison according to Bonferroni. Association between clinical and demographic variables and MRI data were performed by mean of specifically designed linear regression models. The experimental conditions before S1 and S2 scans were compared with a Student t-test for paired samples. Continuous variables are presented as “mean +/- standard deviation”, while categorical variables are presented as “absolute numbers with percentages”. Finally, considering that every ROI was tested twice , to further control for multiple comparison we set the level of significance at alpha = 0.025.Twenty-five patients were enrolled in the study and completed the S1 session . Of these, 10 patients were excluded for the following reasons: 5 patients were lost to follow-up and did not complete the S2 session; 4 patients had a bilateral migraine attack during the S1 scan; 1 patient was excluded because it was impossible to analyze the S1 MRI scan for the presence of movement artefacts.A complete dataset was available for 15 patients . The study population had an average disease duration of 19.7 ± 10.1 years, and a migraine frequency of 3.3 ± 1.9 days per month. Four patients (26.7%) were on a stable preventive drug therapy during the overall study period (data are summarized in Table p = 0.954) and the days elapsed since the last menses (p = 0.145) were comparable between S1 and S2 MRI sessions. In contrast, the days elapsed since last migraine attacks were higher before S1 scan (p = 0.015) . Regarding subcortical structures, we found an increase of hippocampus volume during S1 (p = 0.007).When compared to S2 , during S1 (migraine attack scan) we found a significant reduction of thickness and volume of precentral cortex (p = 0.009), but the post-hoc analysis was not statistically significant. Descriptively, it showed a trend toward a reduction of its thickness ipsilaterally to the migraine attack pain side (p = 0.080), and toward an increase of thickness contralaterally to the pain side (p = 0.056). Exploratively, a linear regression model analysis showed a positive correlation between the number of days elapsed since the last migraine attack and the rostral anterior cingulate cortex thickness ipsilateral to the migraine pain side recorded during S1 (R2 = 0.727). When corrected for age, sex, disease duration, and migraine frequency, the thickness of rostral anterior cingulate cortex showed an increase of 0.014 mm for every day elapsed since last migraine attack (p = 0.014)  Table .Table 3This is the first study specifically designed to evaluate whether cortical and sub-cortical brain structures show morphological changes during a spontaneous migraine attack when compared to the inter-ictal period. The main findings of our study are that thickness and volume of precentral and pericalcarine cortices, and thickness of the temporal pole cortex were reduced during a spontaneous migraine attack. At subcortical level, the hippocampus volume was increased during migraine attack. All these structures are involved in pain modulation and perception as part of the pain matrix , 20.Cortical thickness and volume are measures of the size of brain cortex, which is progressively reduced with the age. However, cortical thickness can also be modified by various stimuli, including for instance transcranial magnetic stimulation (TMS)  and elecThe role of hippocampus and its morphological alterations were also evaluated in migraine patients . It is nThe biological significance of the structural changes observed in the present study is yet to be elucidated but could be a consequence of hypoperfusion rather than shrinking of the neurons and glial cells. In this view, it is worth noting that even if these brain areas showed a significant modulation during a spontaneous migraine attack in our cohort of patients, we were not able to find an association with the migraine pain side as well as significant correlations with other clinical features of the disease. For these reasons, our results must be interpreted with caution, because they could represent a fast plastic adaptation to a non-specific stimulus, more than a specific reaction of the brain to the migraine attack. Reduced cortical thickness of the visual cortex and the prefrontal cortex may most likely reflect trigeminovascular and general pain respectively , 43. In Another interesting, but explorative finding was that the cortical thickness recorded during the spontaneous migraine attack of rostral anterior cingulate cortex ipsilateral to the migraine pain side, positively correlated with number of days elapsed since the previous migraine attack. This result was consistent after correction for age, sex, disease duration, and migraine frequency. The plastic adaptation of the cingulate cortex is not specific to migraine as it was reported in several pain and non-pain conditions . In our The low sample size of the present cohort limits further analyses in subgroups of patients (e.g. those with nausea versus without nausea etc.). Moreover, this study was designed to investigate the pain phase, why we waited at least 4 h from onset to scan. Thus, we cannot examined the early phase of the attack which is a limitation of this study.We have presented the first study on morphological MRI changes during spontaneous migraine attacks compared to the inter-ictal phase. Acute attacks are accompanied by reduced cortical thickness and volume in pain and previously migraine-related areas. Although, we do not ascribe present findings as being migraine specific, these findings constitute a fingerprint of acute pain in migraine patients. In future studies, this fingerprint can be used as a biomarker in order to evaluate antimigraine treatment effect.


The lockdown period due to the COVID−19 pandemic has drastically decreased levels of physical activity in the population. Hemophilia is characterized by hemarthrosis that leads to chronic, progressive and degenerative joint deterioration. (2) Methods. This observational study recruited 27 patients with hemophilia and arthropathy. Knee, ankle and elbow joints were assessed. The frequency of clinical hemarthrosis, pain intensity, pressure pain threshold, and joint ROM were evaluated. (3) Results. Following lockdown, a significant deterioration of joint condition, perceived joint pain and range of motion was noted in all joints. There were no changes in the frequency of knee hemarthrosis, while the frequency of ankle hemarthrosis significantly reduced. However, the frequency of elbow hemarthrosis increased. Depending on the degree of hemophilia severity, there were changes in pressure pain threshold in the elbow and in pain intensity and range of motion of the ankle joint. According to the type of treatment, i.e., prophylaxis vs. on-demand treatment, there were differences in the joint condition in elbows and the plantar flexion movement of the ankle. There were no differences in the knee joint based on the severity of the disease, the type of treatment or the development of inhibitors (4). Conclusions. Because of the COVID−19 lockdown, the musculoskeletal status of patients with hemophilia deteriorated. Joint condition, perceived pain, and range of motion were significantly affected. The frequency of clinical hemarthrosis did not increase during this period. A more active therapeutic model could prevent rapid deterioration in patients with hemophilic arthropathy during prolonged sedentary periods. Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV−2) emerged in the last quarter of 2019, leading to COVID−19 disease . COVID−1The World Health Organization declared the global pandemic due to COVID−19 in mid-March 2020. The Spanish Government declared a state of alarm, confining the entire population from March 14 to June 21, 2020. As a result of this lockdown, physical activity reduced significantly in the population .Hemophilia is characterized by the absence or deficiency of blood clotting factors. Depending on the missing factor, there are two types of hemophilia: hemophilia A (deficiency of clotting factor VIII) and hemophilia B (deficiency of clotting factor IX). According to the clotting factor levels in functional plasma, there are three categories of hemophilia severity: mild (5%–40%), moderate (1%–5%) and severe (<1%) .There are two types of treatment strategies: on-demand treatment and prophylactic treatment, considered the gold standard for reducing bleeding and preventing effects in the joints . InhibitHemarthroses are hemorrhagic episodes that appear in the intra-articular space due to direct or indirect trauma. Hemarthrosis is the main clinical manifestation of hemophilia, appearing mainly in knees, elbows and ankles. The recurrence of hemarthrosis in the same joint causes progressive joint deterioration, leading to cartilage, bone and synovial membrane alterations. These intraarticular alterations together with the development of new hemarthroses generate synovial hypertrophy (hemophilic synovitis) leading to a degenerative and chronic lesion (hemophilic arthropathy). The main consequences of arthropathy include chronic pain, loss of joint functionality and limitations in the range of motion. These changes cause biomechanical and gait alterations, proprioception alterations and atrophy of the periarticular muscles. Without prophylactic treatment, joint damage develops at an early age in 85% of patients with severe hemophilia [Joint health prior to onset, a low body mass index, limitation in the development of activities, the type of joint injury, the frequency of bleeding events and the development of synovitis are factors that are associated with the degree of joint deterioration . HoweverThe objective was to evaluate the frequency of clinical hemarthrosis, joint condition, perceived joint pain and range of motion in patients with hemophilic arthropathy following the COVID−19 lockdown period.This was a prospective observational study in patients with hemophilic arthropathy. This study was conducted between February and July 2020. The Research Ethics Committee of the Virgen de la Arrixaca University Hospital approved the project subject (id. 2020−2−9-HCUVA). The study was likewise registered with an international register (NCT04491318).Patients were recruited from the physiotherapy clinic of the Spanish Federation of Hemophilia (CEE Fishemo). The study included patients diagnosed with hemophilia A and B; over 18 years of age; able to walk ; and able to perform daily life activities without the help of others. Exclusion criteria were patients with neurological or cognitive disorders; patients who had been infected with COVID−19; and patients enrolled in a clinical trial with FVIII/FIX concentrates.Evaluation at baseline (T0) was carried out in February 2020 and the post-treatment evaluation (T1) was carried out in July 2020. Four dependent variables were evaluated: frequency of clinical hemarthrosis, joint condition, perceived joint pain and range of motion. The same physiotherapist, blinded to study objectives, following the same protocol and the same measuring instructions, performed all assessments. Prior to the study, an interobserver reliability analysis was performed between the rater and one of the study researchers.The frequency of bleeding was controlled by an online self-reporting system made available to patients at baseline. This report included a monthly schedule where patients recorded the date, the main symptoms  and the joint affected by hemarthrosis . AdherenHemophilia Joint Health Score (HJHS), version 2.1., was used to assess joint status . This in2. The pressure pain threshold was measured on the lateral epicondyle [Perceived pain was measured with two measuring instruments: the visual analog scale and a pressure algometer . The visual analog scale scores perceived pain ranging from 0 to 10 points . The pressure algometer bilaterally measures the pressure pain threshold at which the patient perceives pain at pressure at a given location when increasing this pressure at a speed of approximately 50 kPa/s. The unit of measurement is Newton/cmicondyle , 3 cm fricondyle , and froicondyle .The ranges of motion of the joints were measured with a goniometer. This measuring instrument has demonstrated good intra-and inter-observer reliability in the evaluated joints. Mobility in the elbow , knee ant-Test. The student’s t-test for independent samples was used to obtain the changes based on the type of treatment (prophylaxis or on demand) and the presence of antibodies (inhibitors). With a one-factor ANOVA test, changes were calculated depending on the degree of severity of hemophilia patients. The significance level of the study was α < 0.05.The statistical analysis was performed using SPSS software, version 19.0, for Windows . The main descriptive statistics (median and interquartile range) were calculated. Sample distribution was analyzed using the Shapiro-Wilk test. The difference in means between the two assessments were calculated using the Paired Samples 2. There were changes in body weight between the two evaluations (T0 = 80.50 (16.00); T1 = 82.50 (14.25); p < 0.001). A total of 82.5% of patients were diagnosed with hemophilia A, the severe phenotype being the most common (70.4%). Only 25.9% of patients had inhibitors, while 70.4% of subjects received prophylactic treatment. The median age of the 27 patients included in the study was 42 (IQR: 15) years, with a median body mass index of 26.42 (IQR: 4.59) kg/mp < 0.001), knees (p = 0.001) and ankles (p = 0.03). Range of motion decreased (p < 0.001) in all joints evaluated. Likewise, we noted a deterioration of the joint health in elbows (p < 0.01), knees (p < 0.01), and ankles (p = 0.03). In terms of pain, pain intensity increased (p < 0.001) in all joints and the pressure pain threshold dropped in elbows (p = 0.001), knees (p = 0.03) and ankles (p = 0.002). An increase in the frequency of clinical hemarthrosis was observed in the elbows (p = 0.04). However, the incidence of bleeding in the ankle joint decreased (p = 0.01). No changes were reported in the knee joint (p = 1.00). Following the confinement period, changes were observed in the joint state of elbows (p < 0.05) in pain intensity in the elbow (p = 0.001) and ankle (p = 0.009), and in dorsal (p = 0.02) and plantar (p < 0.001) flexion movements of the ankle. When the analysis was performed according to the type of treatment (on demand vs prophylactic), we found differences in the joint state of the elbow  and ankle plantar flexion . With regard to the analysis based on the development of inhibitors, there were differences in the frequency of ankle hemarthrosis . When analyzing changes according to the degree of severity of hemophilia, differences were noted  due to the drastic reduction of activity during the stay-at-home order . StephenJoint health of patients with hemophilic arthropathy deteriorated during lockdown in all three joints. Under normal conditions, changes in the joint health of patients with hemophilic arthropathy do not take place in such a short period of time. A number of studies with follow-up periods of 5 to 10 years reported minimal changes in joint health in young adults with hemophilia, measured on the HJHS9, the Orthopedic joint score of the World Federation of Hemophilia  and the Recent studies have reported no changes in the joint condition of elbows , knees  or anklePatients have experienced a worsening in pain-related variables. Pain is described as a sensitive and emotional experience that patients perceive as slightly or very unpleasant, associated with real or potential tissue damage, or described in terms of the injury in itself . This seThis lockdown situation has drastically reduced social relationships and activities, preventing any positive effect on patients . AlleviaInactivity promotes decreased range of motion in the especially affected diarthrodial joints in patients with hemophilia. Likewise, the involvement of periarticular structures such as capsule, tendons, and ligaments, can induce movement alterations . At the The various inactivity-related factors  can cause changes in the movement pattern of these patients , modifyiThe main limitation of this study is the failure to measure psychosocial variables such as perceived quality of life, catastrophism, anxiety or depression. Their evaluation could widen our understanding of the situation of these patients in a context of confinement. Another limitation is the failure to assess joint functionality, something that would allow us to evaluate joint deterioration in these patients. Finally, only patients from Spain have been included, which may make it difficult to extrapolate the results to other countries subjected to varying degrees of confinement.Public health services should promote research to establish the relationship between the clinical situation of patients with hemophilia and confinement to homes during the quarantine periods taking place worldwide. Similarly, factors which may mitigate these adverse effects must be identified. Thus, it is important to develop aspects such as: (i) the optimal way to carry out physical activity during lockdown; (ii) the best tools to improve the quality of life of patients after confinement; and (iii) preventive measures against a new wave of COVID−19 or other potential pandemics .The total interruption of everyday activities in this population of patients adversely affects pain and mobility. The prolonged period of home confinement due to the COVID−19 pandemic made face-to-face intervention models impossible. This should prompt us to address the importance of introducing remote physiotherapy measures in order to maintain a minimum control on the physical activity of our patients and the course of their degenerative joint processes. Access to work models that allow us to offer feedback on their implementation would strengthen the model for the involvement of patients as active subjects taking part in their treatment process, educating them and promoting their commitment.Lockdown due to the COVID−19 pandemic deteriorated joint health, increased pain intensity, and reduced pressure pain threshold and range of motion in adult patients with hemophilic arthropathy. The frequency of hemarthrosis reduced in cases of ankle arthropathy, while increasing in the elbow joint after the three-month lockdown period.The treatment model for these patients needs to be changed, reinforcing their early and active treatment. The promotion of educational programs and access to non-face-to-face interventions in situations in which on-site assistance is not possible could help to prevent the rapid deterioration of joint health in patients with hemophilic arthropathy.


The World Health Organization regards chronic pain to be a public health concern. In clinical medicine, fibromyalgia (FM) is the most prevalent chronic widespread pain disease. In terms of impairment, consumption of health and social resources, and impact on primary and speciality care systems, it has reached worrisome proportions. This disease is frequently managed by primary care providers. Because of its intricacy, fibromyalgia diagnosis and treatment can be difficult.Fibromyalgia is a controversial condition. It might appear ill-defined in comparison to other pain conditions, with no clear knowledge of pathophysiology and hence no particular targeted therapy. This invariably sparks debates and challenges. There is no obvious cut-off point that distinguishes FM from non-FM. The diagnosis of fibromyalgia has been complicated by several factors, including patients' health-seeking behaviour, symptom identification, and physician labelling of the disease.Fibromyalgia is currently considered a centralized pain condition, according to research that has improved our understanding of its etiopathology. A multidisciplinary strategy combining pharmacological and non-pharmacological therapies based on a biopsychosocial paradigm can result in effective therapy. Cultural and psychosocial variables appear to be a recent development in fibromyalgia, and they appear to have a larger influence on physician diagnosis than severe symptom levels in FM patients. Although physicians rely on FM criteria as the only way to classify FM patients in research and clinical settings, some crucial elements of the diagnostic challenge of fibromyalgia remain unsolved - invalidation, psychosocial variables, and diverse illness manifestation are some examples.Beyond the existing constructional scores, physicians' judgment gained in real communicative contexts with patients, appears to be the only dependable route for a more accurate diagnosis for fibromyalgia. We have performed an exhaustive review of the literature using the keywords "Fibromyalgia", "challenges" and "diagnosis" in PubMed and Google Scholar indexes up to September 2021. This article aims to examine the causes, diagnosis, and current treatment protocols of FM, as well as discuss some continuing debates and diagnostic challenges which physicians face in accurately diagnosing fibromyalgia. Fibromyalgia (FM) is among the most impairing causes of chronic widespread musculoskeletal pain. Insomnia, fatigue, cognitive problems, anxiety, and depression are the other characteristic manifestations -3. The wFM has been known for several decades; however, the diagnosis remains a challenge owing to the lack of a specific pathophysiological explanation ,10. The The biggest diagnostic challenge for FM has been the absence of a reliable objective measure of disease activity . WithoutAt present, there is a lack of strong evidence-based guidelines for the treatment of fibromyalgia. The general approach is a mix of patient education, cognitive behavioural therapy, exercise, and pharmacological therapy -26.We have comprehensively reviewed available literature about the pathogenesis, current diagnostic methods, factors associated with delayed diagnosis, diagnostic challenges, possible future of diagnosis, and treatment options of FM in this article.Pathogenesis of fibromyalgiaDespite extensive efforts to define the origin and progress of FM over the past three decades, the complete etiopathogenesis remains uncertain. Several factors like genetic predisposition, environmental exposure, hormonal factors, and neural factors have been implicated in triggering FM; however, there is no conclusive evidence yet ,28. Our A. Central SensitizationAt present, the concept of FM being a “centralized sensitivity syndrome,” originally put forward by Yunus et al., is the most accepted one . AccordiMany studies have substantiated the concept of central sensitization by revealing a lack of balance between the nociceptive and the anti-nociceptive systems in FM patients . FunctioFM patients are also believed to have a cognitive-emotional sensitization to pain, which explains the impaired responses  to painful or other adverse stimuli. According to this concept, the working of the pain network in the central nervous system is influenced by cognitive factors -40. The The role of chronic sensitization in decreasing the threshold for pain has already been described extensively in disorders like myofascial pain syndrome, irritable bowel syndrome, and interstitial cystitis. However, it has not thoroughly explained the other characteristic features of FM like fatigue and sleep disturbances .B. Dysautonomia-Related Neuropathic Pain SyndromeFM is viewed as stress-related dysautonomia by some researchers. They propose that psychological stress, physical trauma, different types of infections, or other stressors lead to uninhibited sympathetic hyperactivity in susceptible individuals with the maladaptive autonomic nervous system. This concept is verified by sympathetic hypo-reactivity (low heart rate variability) to orthostatic stress on diverse heart rate studies in FM patients -45. MoreAccording to this hypothesis, changes in the dorsal root ganglia are responsible for sympathetically triggered pain. Typically, dorsal root ganglia have few sympathetic fibres, but in FM, stressors-mediated nerve growth factor overexpression induces sympathetic nerve proliferation. Consequently, there is excessive sensory neuron firing. Mutation in the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene produces a defective Nav 1.7 sodium channel in the dorsal root ganglia leading to the severe neuropathic pain seen in FM. These sodium channels situated in the dorsal root ganglia are the gatekeepers of pain transmission from peripheral receptors. In total, nine such sodium channel subunits (Nav 1.1-Nav 1.9) have been found distributed throughout the peripheral and central nervous systems -50. ThusThe concept of FM as a dysautonomia-associated neuropathic pain syndrome has been reinforced by the recent reporting of small fibre neuropathy (SFN) in a large population of fibromyalgia patients . It is aC. Inflammatory SyndromeAccording to this hypothesis, immune system activation plays a crucial role in the increased excitability of the pain pathways . There iThe results of various studies are contradicting, with some demonstrating no difference in inflammatory markers level among FM patients and healthy controls . In addiThe proponents of the inflammatory theory suggest elevated cytokine levels, distinct cytokine/chemokine profile, elevated neutrophil-lymphocyte ratio (NLR), and elevated platelet counts can be helpful diagnostic markers of FM. Anti-inflammatory drugs are also candidates for FM treatment .Diagnostic protocols2). In addition, a three-month history of generalized pain in the axial skeleton and at least three-quarters of the body quadrants was needed. After the 1990s a connection arose between fibromyalgia and neurobiological findings. With more interest in the ACR criteria, it led to numerous studies revealing many co-diagnoses such as irritable bowel syndrome and chronic fatigue syndrome [Over the years the diagnosis of fibromyalgia has undergone several changes. The term fibromyalgia syndrome came into use in the 1990s by the American College of Rheumatology (ACR) disposing of the previously used term fibrositis. At the time, to attain a diagnosis, it was necessary to elicit pain on palpation, seen in 18 body points bilaterally, by applying pressure of up to 4 kilograms/square centimetre  which was unrealistic it still played a prominent role in setting the base criteria for diagnosing fibromyalgia . Up untiSince 2010, new ACR criteria have been presented and are based on two new components: the score on the Symptom Severity Scale (SSS) score (range 0-12) and the Widespread Pain Index (WPI) (range 0-19) .After the publication of the 2010/2011 criteria, the criteria progressed from a chiefly chronic pain disorder to a multi-symptom disorder while also removing the tender point exam as a prerequisite for diagnosis. In 2016, the preceding precedent was revisited to attain a more accurate diagnostic criterion of fibromyalgia. To achieve the 2016 amended criteria, the patient must meet the following, generalized pain characterized in at least four of five regions and present for at least three months and a WPI >7/19 and SSS score >5/12, or also acceptable is a WPI of 4-6/19 and SSS score ≥9/12. In approaching the WPI the patient demonstrates the number of painful regions that they have experienced in the past seven days ranging from 0-19 including right/left lower and upper leg, buttocks/hip, lower and upper arm, shoulder, and jaw. It also includes the abdomen, lower and upper back, and neck.The SSS plays a role in that it's based on the average of how drastic a patient experiences cognitive impairment (concentration and memory), unrefreshing sleep and fatigue in the past seven days, the scoring ranges from (0-3) with 0 being "no problem" and 3 being "severe problem." The SSS also considers symptoms that the patient has been experiencing in the past six months. Symptoms include depression, pain in the lower abdomen, and headaches, and this scoring is based on whether it is present or not (0-1) . OverallDiagnostic challenges of fibromyalgiaFibromyalgia diagnosis has been one of the challenges because many patients are unable to describe their presenting complaints and sometimes doctors do not identify the patient's chronic pain as fibromyalgia pain. Some physicians consider a diagnosis of fibromyalgia will affect the impact on patient health so physicians must counsel the patient in such a way that improves patient compliance. According to a US national health interview survey, 75% of patients reported that they are not satisfied with a physician diagnosis of fibromyalgia . AccuratACR Criteria for DiagnosisThe American College of Rheumatology formulated the diagnostic criteria for fibromyalgia that is tenderness. According to a study, many people have tenderness in the full body while others don't feel symptoms of pain. A survey was also conducted to investigate fibromyalgia diagnostic complications, patients presenting complaints were recorded and no need for tender examination. If the patient tender points were 11/18 then the patient is suffering from severe FM .Multifocal PainIn patients, fibromyalgia could be suspected if they have multifocal pain but no experience of injury and dominant features of musculoskeletal pain. Major commonly observed symptoms are headache, pelvic pain, sore throat, abdominal pain, and chest pain. So these multifocal pain affects the diagnosis process and further complicates this process .Non-applicable Results of Laboratory TestingLaboratory testing has not been very applicable in the diagnosis measurement of fibromyalgia but mainly tests include C-reactive protein, thyrotropin, complete blood count, vitamin-D, serum chemistries, and erythrocyte sedimentation. Fibromyalgia can be easily confused with many other diseases, leading to difficulty in diagnosis. Lack of specific investigation has been one of the most critical factors that contribute towards the delayed diagnosis of fibromyalgia . Mostly,Comorbidities and Stigmatization of the DisorderChallenges in diagnosis include multiple comorbidities, symptoms, and stigmatization of disorder that may interfere with a fibromyalgia diagnosis. Other challenges include patient non-compliance and lack of treatment adherence. Another reason is the sceptical role of society to delay diagnosis. According to the National Fibromyalgia Association (NFA) survey report, accurate diagnosis of fibromyalgia takes optimum five years and disease progression takes place due to inadequate management. Other complications include emotional distress, maladaptive behaviour, poor and psychiatric ailments that lead towards negative consequences .Heterogenous Condition and Phenotypical ChangesFibromyalgia is a heterogeneous condition; phenotypes change with time and symptoms appear include physical exhaustion, sleep issues, weight fluctuations, and cognitive difficulties, weakness, swelling in extremities, and heat cold intolerance ,73. Its Functional DisordersMany functional disorders are also associated with fibromyalgia such as heartburn, chest pain, palpitations, and pelvic complaints. Such functional disorders further complicate the diagnosis of fibromyalgia, leading to misinterpretation. In females, comorbid diagnosis includes endometriosis, dysmenorrhea, vulvar vestibulitis, interstitial cystitis, and vulvodynia. In males, non-bacterial prostatitis could be observed so these overlapping of diseases make it difficult to diagnose fibromyalgia .Dermatological AssociationsIn fibromyalgia, some skin problems have similarities with systemic lupus erythematosus (SLE) as it involves Raynaud-like, malar flushing, livedo reticularis, and reddening of hands so these are misdiagnosed as SLE . This caConsidering It as a Diagnosis of ExclusionFibromyalgia is mostly considered as a diagnosis of exclusion. Doctors rule out all other causes of pain, fatigue, mood disturbances, and sleep-related disorders before considering fibromyalgia as a potential cause of the patient's symptoms. It accounts for a significant delay until the clinician reaches a point where fibromyalgia is considered a possible cause of the patient's symptoms. Proper education of the clinicians can significantly reduce the time taken to diagnose this condition .Invalidation of Patient’s SymptomsIt has also been observed that invalidation of the patient's symptoms by their medical provider has also been one of the reasons for delayed diagnosis. Patients have to face this issue of invalidation with their medical providers, families, and relatives. This impacts a patient's quality of life and becomes a hurdle in the early diagnosis of a patient .Lack of Knowledge Among CliniciansLack of proper awareness and knowledge also contribute toward a delayed diagnosis of fibromyalgia. According to the study by Choy et al. (2010), 45% of physicians had no idea about ACR fibromyalgia classification criteria. Educating doctors about the diagnosis and management of patients with fibromyalgia can go a long way in improving the time taken to diagnose this condition .Recent studies have found an association between delayed diagnosis of fibromyalgia and worse response to different treatment options. It implies that quicker diagnosis and treatment may result in better health outcomes and quality of life for fibromyalgia patients .Treatment optionsFibromyalgia syndrome (FMS) management requires an adequate diagnosis and a symptom-based approach to treatment. With fibromyalgia being under the radar due to limited knowledge regarding the disease and its pathogenesis, the development of disease-modifying therapy is a challenge many physicians encounter. Managing fibromyalgia based on evidence-based treatment plans is another one of the challenges faced by many physicians. The treatment of fibromyalgia patients requires an interdisciplinary approach instead of a focussed pharmacological treatment. It includes education of the patient, along with pharmacological therapy and alternative medicine techniques . PatientStrategies to Manage FibromyalgiaFor the accurate diagnosis of the disorder and to formulate a treatment plan, patient education, physician education, and appropriate goal setting are vital. Physicians need to be provided with the required tools and training to recognize the symptoms. Being on par with ongoing clinical trials and updates regarding the latest treatment options available and educating the patient regarding their availability, and assisting them in making a decision should be the goal of physician education.There is improved diagnostic accuracy and a delay in the initiation of treatment with the development, validation, and implementation of tools to simplify symptom assessment . Supporting patients in understanding and accepting the disease and educating them regarding self-management can increase adherence to treatment in the long run. Knowledge regarding the current limitations in the availability of treatment options and engaging the patients in formulating a treatment plan increases the likelihood of positive outcomes.PharmacotherapyAPS and EULAR put forward many evidence-based treatment guidelines for fibromyalgia . All theAccording to an internet survey, the most commonly used medications for treating fibromyalgia were acetaminophen, ibuprofen, naproxen, and amitriptyline. Some of the top 10 drugs that were rated as most helpful were hydrocodone, alprazolam, oxycodone, diazepam, and zolpidem. There is a discrepancy between the most commonly used and the most effective medications according to the survey. This may be associated with the heavy use of over-the-counter drugs, as they are generally cheaper than prescription drugs .Neuromodulatory DrugsTricyclic anti-depressants (TCAs): The prototype of this class, amitriptyline is a well-studied and evaluated drug. It aids in improving pain, sleep disturbance, fatigue and improves the daily quality of life. The typical dose is 10-50 milligram (mg) daily. A meta-analysis was done using amitriptyline, milnacipran, and duloxetine for the treatment of fibromyalgia, which indicated that amitriptyline could improve fatigue, pain, and quality of life in fibromyalgia patients and was found superior to duloxetine and milnacipran . Common Serotonin and norepinephrine reuptake inhibitors (SNRIs): The FDA approved duloxetine and milnacipran for the treatment of fibromyalgia. They improve pain and aid patients with depressive symptoms. A recent review of milnacipran for adult fibromyalgia stated that it is effective only in about 40% of patients, providing moderate pain relief. Effective dosages were 100-200 mg . AdverseAnti-epileptic drugs (AED): Pregabalin and gabapentin are anti-epileptic drugs used in the treatment of fibromyalgia. Pregabalin is one of the first drugs to be approved by the FDA in 2007 for fibromyalgia . AlthougAnalgesicsThe use of opioids in fibromyalgia is controversial, and the guidelines vary in their recommendations.Opioids have relatively high abuse potential, and it is essential to avoid such medications. There is no evidence-based data support for the use of opiates in fibromyalgia. And the recent evidence of opiate-induced hyperalgesia also suggests their limited usefulness ,86. In aMost or almost none of the currently available drugs are fully effective against the entire spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances, and depression .Newer DrugsTransdermal testosterone is a novel agent for the treatment of fibromyalgia and appears to reduce pain response in animal models. The rationale behind this is the presence of aromatase-positive cells in the primary pain processing site in the spinal cord, that is dorsal root ganglion, where transmission of pain information to the thalamus and cerebral cortex originates . In fibrA co-agonist of glutamate at the N-methyl-D-aspartate receptors (NMDA), "NYX-2925", was studied and found to be safe and well-tolerated in healthy volunteers, the results are in favour of its continued clinical development for the treatment of chronic pain conditions .Other anti-depressants like mirtazapine, a pre-synaptic alpha-2 antagonist, esreboxetine (norepinephrine reuptake inhibitor), and desvenlafaxine (serotonin-norepinephrine reuptake inhibitor) are currently being explored in clinical trials.Probiotics are also among the proposed treatments for fibromyalgia. They were thought to act via the gut-microbiota-brain axis but they did not exhibit any promising results apart from improved decision-making capabilities with no effect on cognition, quality of life, pain, depressive, and anxiety symptoms .Non-pharmacological ModalitiesThe guidelines for encompassing non-pharmacological modalities in the treatment of fibromyalgia vary, and a multidisciplinary approach that combines pharmacotherapy, cognitive therapy, physical therapy, and natural remedies is favoured. The non-pharmacological management of fibromyalgia has a significant impact on the clinical manifestations, symptoms, and quality of life in comparison to pharmacologic treatment. The various forms of non-pharmacological modalities include exercise regimens, diet, behavioural therapies, complementary and alternative medicinal practices that play a role in the overall management of the symptoms of a fibromyalgia patient. A holistic model of treatment is required in individuals with more severe disease and for those who fail to respond to initial treatment . LimitedDiet and ExerciseSome studies have reported that dietary changes can be efficacious and have positive effects on pain. Nutrients that reduce neuronal inflammation and improve muscle strength are deficient in some patients with fibromyalgia. Pain and functional symptoms in FMS patients improved with the incorporation of various diets like the low-calorie diet, a vegetarian diet, or a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) diet. Diet impacted some patient-reported outcomes, such as quality of life, quality of sleep, anxiety, depression, and inflammatory biomarkers also showed an improvement with these interventions .Exercise is an effective component of treatment that improves pain and quality of life and decreases the burden of the disease. Aerobic exercises, strength training, and flexibility training have been shown to provide benefits in fibromyalgia . ExercisDancing is a type of aerobic exercise that can be used in fibromyalgia as an alternative therapy. Belly dancing is another form of physical activity found to be efficacious in improving functional capacity, pain, quality of life, and improving the body image of women with fibromyalgia syndrome . AccordiAlternative TherapiesAcupuncture: It is a traditional Chinese medicine practice where thin needles are inserted at different points on the body. It is generally in use to relieve pain. In fibromyalgia, the effect of acupuncture correlates with a change in serum serotonin levels . Pain anElectrical therapy: Fibromyalgia, apart from pain, can present with anxiety, depression, fatigue, decreased working memory, and attention referred to as "fibro fog". Transcranial electric and magnetic stimulation is a non-invasive brain stimulation method effective in the modulation of brain areas and their perception of pain. Therapeutic electrical stimulation via transcutaneous electric nerve stimulation appears to have a potential role in the treatment of pain in FMS .Thermal therapy: Body warming and cryotherapy have a minor role in the management of fibromyalgia. Modulation of nociception can be accomplished through the application of both hot and cold temperatures. They act on the opioid pain inhibitory system and alternation of rhythm in temperature . It has Mind and body therapy, vibroacoustic and rhythm therapy, and massage therapy are other alternative ways that are in use for the management of fibromyalgia ,107.Due to the complex nature of fibromyalgia, many patients are prescribed multiple medications to manage the various symptoms and accompanying comorbid medical and psychiatric disorders. Although polypharmacy can be an effective clinical strategy for patients with complex medical conditions, several potential problems and adverse effects are to be considered. The use of multiple medications can exacerbate adverse events or an increased risk of unwanted drug-drug interactions. Effective communication between patients and treatment providers may be the most effective way to manage the potential risks of multiple medication use .Due to the chronicity of the disease, one of the main concerns in the treatment of fibromyalgia patients is poor compliance with long-term treatment. Physicians should be able to tailor the therapy to the most prevalent manifestations in a patient. Internet-based platforms and group educational programs can aid in providing additional social support. Increasing treatment adherence and improving the quality of life is an added benefit.Biomarkers: possible future of fibromyalgia diagnosisFibromyalgia is a disease that does not have universal criteria for a diagnosis due to a wide range of possible clinical examinations. Several findings suggest the validity of genetics, environmental factors such as trauma, illness, stress-response, sleep patterns, in FM progression . The proGenetic OutlookIn an investigation of the genome, the first-degree relatives of individuals with fibromyalgia displayed a 13.6-fold greater risk of developing the disease . The assEpigenetic OutlookPrior research has shown the effects of early life experience and environmental factors on genome function and the phenotype without changing the DNA sequence through the mechanism of epigenetics . The lonDeoxyribonucleic Acid (DNA) MethylationThe first study investigating epigenetic changes in FM women focused on a genome-wide methylation pattern. The study highlighted 69 differentially methylated sites in cases against controls and 91% of these sites were accountable for an increased micronuclei frequency in FM women . The stuMicro Ribonucleic Acids (miRNAs)MiRNAs are small non-coding ribonucleic acid molecules that regulate the expression of genes. They were found to play a vital role in chronic pain diseases  Table 22. In a pGene ExpressionJones et al. conducted a genome-wide expression profiling in the peripheral blood of 70 patients with fibromyalgia and 70 healthy controls, 421 differentially expressed genes were identified, several were related to pain processing pathways. The test captured a subset of 10 probe sets with a sensitivity of 95% and a specificity of 96% for FM, but it needs to be validated in larger cohorts of patients . DolcinoMu-Opioid Receptor on B LymphocytesThe role of Mu opioid receptor on B lymphocytes in chronic pain disease was studied on three groups of females  patients, and healthy individuals) and the results showed that the percentage of Mu-positive B cells was statistically lower in FM and OA patients compared to pain-free subjects . ApproacSerological markersThe idea of having a simple blood test to diagnose FM seems appealing. But even after many years of research on markers such as inflammatory cytokines, neurotransmitters, and autoantibodies, we do not have any confirmed tests available.Inflammatory CytokinesDuring exercise, muscles release IL-6, which in turn causes secretion of IL-10 and IL-1β (anti-inflammatory cytokines) . IL-10 mNeurotransmittersThe levels of neuropeptides Y were frequently higher in FM patients when compared to healthy subjects ,139. SubAutoantibodiesExtensive studies have been done by many researchers displaying a major correlation between thyroid autoimmunity and FM ,142. ImmFibromyalgia is undeniably a difficult diagnostic and treatment issue. Although the American College of Rheumatology (ACR) has established diagnostic criteria for FM, they are not frequently used in clinical practice. Some health care providers, particularly in basic care are unaware of the condition. In addition to diagnostic challenges, there is a lack of prescription consistency among clinicians. Many patients may not get the right treatment, and those who do are likely to have frequent therapeutic switching or abrupt cessation of therapy. Some patients may have excessive treatment expectations and difficulties coping with their symptoms, which can make treating their illness more challenging.The varied presentations of FM and ambiguity in understanding its etiopathogenesis and genetic correlations also add to the difficulty in diagnosis. The rapid development of knowledge about the aetiology of pain, inflammation, and behavioural processes, as well as breakthroughs in the field of functional assessment of the brain, should make FM detection and therapy more successful. We encourage further studies and research into improving the currently existing diagnostic protocol for fibromyalgia and we also recommend continued medical education of primary care providers about the diagnosis and treatment of this condition.


Subcutaneous infusion (SC) or hypodermoclysis is an old perfusion technique that is often used off-label although it has been shown to be effective. Acetaminophen (paracetamol) subcutaneous injection is performed in some centers despite the lack of conclusive evidence on its effectiveness. This study aims to evaluate the efficacy of subcutaneous infusion of Acetaminophen in the treatment of pain and fever in geriatrics and in palliative care and to determine its safety profile and possible side effects.This experimental study was conducted between 2018 and 2019 on adult patients in palliative care or in geriatrics in several hospitals and nursing homes in Lebanon. Primary outcomes were change in temperature; change in pain score on the numerical rating scale (NS) or on the Algoplus scale after 60 min from the start of the infusion; and the appearance of local side effects at the infusion site. Changes in the various parameters at 30 min and 180 min were also evaluated as secondary outcomes.Thirty-one patients were included in the study, with a total of 120 doses of acetaminophen. At 60 min, the mean decrease in pain on the NS was 5.35 points, while the mean decrease in temperature was 0.79 degrees Celsius. At 60 min, 75%, CI = [47.62-92.73] of the patients who received acetaminophen for pain and 66.67%, CI = [38.38-88.17] of those who received it for fever had clinically significant improvement. The overall effect of subcutaneous acetaminophen, defined as any clinically significant effect on pain or fever, was 70.97%, CI = [51.96-85.78]. The overall effect at 30 min and at 180 min was 23.33%, CI = [9.93-42.28] and 87.10%, CI = [70.17-96.37], respectively. The side effects reported 30 min after the injection and observed after at least one of the doses were: local edema in 16 patients (51.61%), induration in one patient (3.23%), local pain in one patient (3.23%) and local heat in one patient (3.23%). At 180 min, only 2 patients (6.45%) still had edema at the infusion site.Subcutaneous administration of acetaminophen is effective and well tolerated in geriatric and palliative care patients. It is appropriate when no other route is available, especially for home-based care. Comparative studies are needed to allow the expansion of this practice. Subcutaneous infusion (SC) or hypodermoclysis is an old technique that is often used off-label, although it has been shown to be effective. It is mainly used in palliative care and in geriatrics for its ease of use or when a venous line is no longer available , 2. It iSince many palliative care patients prefer to be cared for and die at home –8, hypodWhile a good level of scientific evidence for the use of the subcutaneous route is available for a number of molecules from different therapeutic classes, evidence still lacks for some widely used drugs, such as acetaminophen . Although the efficacy of acetaminophen as an intravenous (IV) analgesic and antipyretic is well known, its use remains controversial through the subcutaneous route. Some teams, especially in France, have nevertheless integrated its use in their daily practice , 15; howGiven the lack of established scientific evidence for the use of acetaminophen by this route, our study aims to (1) assess the efficacy of an acetaminophen subcutaneous infusion in the treatment of pain and fever in geriatrics and palliative care patients; (2) determine its safety profile and possible adverse reactions; (3) determine certain characteristics related to this route of administration .This experimental study was carried out between 2018 and 2019 on geriatrics and palliative care patients who were hospitalized in several hospitals, nursing homes and geriatric centers in Lebanon.ClinicalTrials.gov under registration number NCT03635684, first registered on 17/08/2018.The study was approved by the Institutional Review Board of Hôtel-Dieu de France Hospital (CEHDF 1065) and registered on To be included in the study, hospitals and nursing homes staff had to be already routinely using the subcutaneous route for drug or fluid infusions. All nurses involved received adequate training to standardize the preparation of the subcutaneous hypodermoclysis infusion and to report the results.Adult patients seen by the palliative care consultation team or admitted to the palliative care unit of a university hospital, and geriatric (aged 65 and above) residents of participating nursing homes were included, provided they experienced pain or fever requiring the administration of acetaminophen in the absence of an IV line.Each patient was informed of the course of the study and signed an informed consent form for their inclusion and use of their data. When the patient was unable to communicate, a legal representative was informed about the study and signed the consent.A specific subcutaneous route was set up for the exclusive infusion of paracetamol. All other drugs or subcutaneous fluids, if prescribed, were administered via an alternate infusion site to limit drug mixing and subsequent bias.The subcutaneous route was installed at least 6 hours before administration of the first dose of acetaminophen in order to avoid attributing to acetaminophen some signs or symptoms of discomfort that could be related to the puncturing procedure itself. If a dose had to be given urgently or before the 6-h delay, it was given on a separate injection site and was not taken into consideration in the study. Acetaminophen, available in vials containing 1 g in 100 mL of solution, was infused at a rate of 5 mL/minute . To limit bias that could be due to a personal sensitivity (or resistance) to acetaminophen, we estimated that if a patient was receiving 3 doses per day, we would include him/her for a maximum of 1 week, which corresponds to 21 doses. Once this limit was reached, the patients were excluded from the study.If the patient could receive several analgesics of different classes, the choice between acetaminophen and other analgesics was made according to the usual local protocol in the center where the patient was admitted. Collected data was recorded on daily collection sheets that were dated and signed by the nurse in charge. If an IV route was subsequently installed in a patient, the acetaminophen-specific subcutaneous route could be maintained, and data could continue to be collected following the approval of the treating physician and the consent of the patient.The onset of local side effects was managed according to the same protocol applied in the department for an IV route.The main endpoints were a change in temperature or pain scores and the onset of local side effects.Regarding pain scores, for conscious and cooperative patients, the primary outcome was defined as a change of the pain score on the numerical evaluation scale (NS), 60 min after the start of the infusion. This measure evaluates the decrease in pain scores between t0 (right before acetaminophen administration) and t60 using the NS, where 10/10 is the worst imaginable pain and 0/10 equals no pain. A minimal clinically important difference (MCID) of 2/10 was used following a review of the literature , 17.For patients with verbal communication difficulties, the Algoplus Pain Scale was used to evaluate the decrease in pain scores between t0 (right before paracetamol administration) and t60. The Algoplus scale is a behavioral rating scale for acute pain in patients with verbal communication difficulties, where a score of at least 2 over 5 can diagnose pain with a sensitivity of 87% and a specificity of 80%. The score assesses facial expressions, appearance, complaints, body position and atypical behaviors of patients with verbal communication difficulties. Each item marked “yes” is given one point. For the purpose of this study, effectiveness was defined as a decrease in score from ≥2/5 to less than 2/5 , 19.For patients presenting with fever, a decrease in temperature 60 min after the start of the infusion with an MCID of 0.5° Celsius was defined as the primary outcome.A composite result for the overall effect on pain at 60 min, combining the results collected using the NS and the Algoplus scale, as well as a composite result for the overall effect on pain and fever, were computed.Local adverse effects at the infusion site were reported, including: edema, induration, erythema, tenderness, heat, abscess, necrosis. Any other local side effects were noted by the nurses. Side effects were assessed before the first injection as well as 30 min, 1 h and 3 h after each injection. They were also evaluated 24 h after removal of each of the sites of subcutaneous administration of acetaminophen.Changes in pain scores and temperature at t30 and t180 were evaluated as secondary outcomes and a composite result for an overall effect on pain at 30 min, as well as a result for the overall effect at 180 min, were created.Several factors likely to influence the occurrence of local side effects or the effectiveness of the drug were gathered: age, sex, weight, use of other analgesic drugs, total number of paracetamol injections, injection site, pain etiology (cancer or non-cancer pain), cause of fever , acetaminophen manufacturer, and inclusion center.Statistical analysis was carried out using STATA version 10 software, the quantitative variables being represented by their means and standard deviations, the qualitative variables by their numbers and percentages.Sample size was calculated based on an expected efficacy on pain of 36% , with a To determine the effectiveness of the treatment, the following calculations were performed:For patients in the NS group, the mean change per patient at 30 min, 60 min, and 180 min was calculated to determine whether the infusion was overall effective for that patient. For example, if the mean change at 60 min on the NS, all doses combined, for a patient was greater than or equal to 2, paracetamol was deemed effective for that patient after a period of 60 min. If the mean change at 60 min was less than 2/10, the infusion was considered ineffective in this patient.For patients in the Temperature group, the mean change in fever per patient at 30 min, 60 min, and 180 min was calculated to determine whether the infusion was overall effective for that patient. For example, if the mean change at 60 min, all doses combined, for a patient was greater than or equal to 0.5 degrees Celsius, paracetamol was judged effective for that patient after a period of 60 min. If the mean change at 60 min was less than 0.5 degrees Celsius, the infusion was considered ineffective in this patient.For patients assessed using the Algoplus scale, at least half of the doses received by the patient had to be effective (thus causing a decrease in the Algoplus score to less than 2/5) in order to consider paracetamol effective for this patient, at 30 min, 60 min and 180 min.Thirty-one patients were included in the study, with a total of 120 doses of acetaminophen administered.The main characteristics of the patients are summarized in Table For all patients included and all doses combined, at 60 min, the mean decrease in pain on the NS was 5.35 points, and the average decrease in temperature was 0.79 degrees Celsius. At 180 min, the mean decrease was 6.23 points and 1.35 degrees Celsius, respectively.On the Algoplus scale, for all patients and all doses combined, 2.86% of doses were effective at 30 min (reduction in the score to less than 2/5), 80% at 60 min, and 88% at 180 min.  of 16 patients who received acetaminophen for pain had clinically significant improvement in their symptom, 10  of 15 patients who received acetaminophen for fever had clinically significant improvement of their fever. The overall effect of subcutaneous acetaminophen, defined as any clinically significant effect on pain or fever, was 70.97%, CI = [51.96-85.78].Among the patients who received acetaminophen for pain relief, only 3  had a clinically significant improvement after 30 min and 14  had a prolonged effect after 180 min.Among the 15 patients who received acetaminophen for fever, 4  showed a clinically significant improvement after 30 min and 13  had a prolonged effect after 180 min.The overall effect of subcutaneous paracetamol at 30 min and 180 min was 23.33% (CI = [9.93-42.28]) and 87.10% (CI = [70.17-96.37]), respectively. , induration in one patient (3.23%), pain in one patient (3.23%) and local heat in one patient (3.23%).At 180 min, only 2 patients (6.45%) still had edema at the infusion site and no other side effects were reported at this time. In all cases, edema was described as minimal by the nurses.No adverse events were reported the day after SC line removal. Table .Table 4PThe main reason for stopping the infusion was resolution of symptoms (38.71%), followed by death (19.35%) due to baseline illness. In one patient, the maximum number of doses allowed by the study protocol was reached (21 doses) and data collection was therefore stopped, although the infusion was continued at the request of the patient who was satisfied with the effectiveness of the treatment.This study is the first to our knowledge to have evaluated and demonstrated the efficacy of acetaminophen subcutaneously. Our results showed overall efficacy in nearly 71% of cases as well as, all doses and all patients combined, an average pain reduction of 4 to 6 points on the numerical scale (at 60 min and 180 min), and an average fever decrease of 1.3 degrees Celsius sustained at 180 min.The efficacy of acetaminophen as an analgesic and IV antipyretic has long been demonstrated –27, and Our results show a higher efficacy of subcutaneous acetaminophen compared to a 2016 Cochrane review  .Our results also show a higher average decrease on the NS than other published studies. Although we do not have a definitive explanation to this finding, we understand that the pain experience and rating can vary widely across cultures. Even within the United States, it was noted that African Americans and Hispanics tend to report higher pain scores when compared to Whites and Asians . As our n = 33) with that of propacetamol at 30 mg/kg (n = 32) in the treatment of pediatric patients with acute fever due to infection [The effect of IV acetaminophen on fever was evaluated in a double-blind non-inferiority study comparing the efficacy of a single dose of intravenous acetaminophen at 15 mg/kg n =  with thaUsually, the maximum efficacy of drugs with first-order pharmacokinetics, when injected subcutaneously, is reached 30 min after the time of injection . Many anThe action of subcutaneous acetaminophen is sustained in our study for at least 3 h after injection. These results agree with the data on oral and IV  acetaminophen in the literature .Given the small number of patients included, this study does not have the necessary power to assess patients’ subclasses and correlate efficacy and/or side effects with different demographics or symptoms etiologies leading to the prescription of acetaminophen.We note, however, that the only patient who had no improvement in her temperature had paraneoplastic fever. In addition, it appears that the presence of edema of the lower extremities in another patient limited the effectiveness of the infusion, as the results seemed to be better following resolution of the edema.A good level of scientific evidence for the use of the subcutaneous route is available for a number of molecules from different therapeutic classes, which allows their frequent use in geriatrics and palliative care , 37–41. Regarding tolerability, this study demonstrated the safety of the subcutaneous injection of acetaminophen. Throughout the study, no patient experienced a serious side effect, whether ulceration, necrosis, or abscess. Edema was the main adverse effect observed, which is in agreement with the perception of prescribers of this practice and with the results found by a team of French researchers led by Dr. Leheup during a prospective observational study published in July 2018 , 15. OneLocal edema as a side effect of subcutaneous infusions is often found in the literature, and no serious consequences related to this phenomenon have been reported , 14, 41.These results are promising, given the multiple benefits of the parenteral formulation of acetaminophen compared to the oral one. It has a faster onset of action and a higher maximum serum concentration . For an Nowadays, when patients fail to tolerate the oral route and in the absence of an IV route, many clinicians would adopt the rectal administration of acetaminophen suppositories before thinking of the subcutaneous route. Rectal route can be limited by cultural acceptance  as well as medical conditions like hemorrhoids and anorectal diseases like anal ulcers and abscesses. Our results are encouraging as they may help spare patients the disagreements of a rectal administration, in terms of physical discomfort  and psychological distress.This study has limitations. First, the small number of included patients and doses which could have led to an overestimation of the effectiveness or the incidence of side effects of the treatment, as well as the inability to conduct subgroup analyses. We faced two major difficulties, one being the low cooperation and engagement from the local prescribing physicians in some centers, who despite our repetitive visits and reminders, did not consistently propose inclusion into our study to their patients; the second being the presence of an IV line or a port-a-cath in most hospitalized patients, which was an exclusion criterion in our study following the requirement of the ethics committee. In Lebanon, the hospital system is heavily dependent on private insurers, who refuse to keep paying for a hospital stay if there is no need for IV treatments – Thus the systematic insertion of an IV line to virtually all patients as soon as they are admitted. This constituted a major difficulty in finding patients for our study. However, and although we could not hit our target of 255 doses, our results are encouraging and could help predict the sample size of a bigger study in the future.Although no serious side effects were observed, our study may not have the power to detect rare events and it is therefore possible that they went unnoticed, knowing that our results are similar to those of bigger, multicentric studies . FinallyOur study shows that the subcutaneous administration of acetaminophen is effective and well tolerated in geriatric and palliative care patients. It would therefore appear to be appropriate when no other route is available, reliable, or acceptable to the patient, when patient’s comfort is among their goals of care, or when the patient is receiving care at home. However, comparative experimental studies are necessary to allow the expansion of this practice.


Objective: Despite the effectiveness of pain medicines, nonadherence to prescribed medication remains a major problem faced by healthcare systems. The aim of present study was to perform the translation, cultural adaptation, and validation of the Intentional Non-Adherence Scale (INAS) for the European Portuguese language in a sample of chronic pain patients.Methods: A Portuguese version of the INAS scale was constructed through a process of translation, back translation, and expert’s panel evaluation. A total of 133 chronic pain patients were selected from two chronic pain clinics from tertiary hospitals in Porto, Portugal. The protocol interview included the assessment of pain beliefs (PBPI), beliefs about medicine (BMQ), medication adherence (MARS-P9), and two direct questions about adherence previously validated.Results: The internal consistency in all subscales was α = 0.902 for testing treatment; α = 0.930 for mistrust treatment; α = 0.917 for resisting treatment; and α = 0.889 for resisting illness. Exploratory and confirmatory factor analysis revealed a four-factor structure that explained 74% of the variance. The construct validity of the INAS was shown to be adequate, with the majority of the previously defined hypotheses regarding intercorrelations with other measures confirmed.Conclusion: The Portuguese version of INAS could be a valuable and available instrument for Portuguese researchers and clinicians to assess the intentional nonadherence determinants during the management of chronic pain. Chronic pain (CP) is the main cause of suffering and disability in the world , affectiAn extremely important factor for the success of chronic pain treatment is the patient’s adherence to pharmacological treatment . HoweverGiven the great complexity and heterogeneity of human behavior, it is extremely difficult to reliably predict patients’ medication adherence . MoreoveIn recent years, several adherence self-reporting tools have emerged; despite this, there is still no consensus on what the gold standard is and, to adequately evaluate adherence, one must apply diverse strategies . HoweverThe Intentional Non-Adherence Scale (INAS) is a tool developed by The aim of this study was to provide a translated and culturally adapted Portuguese version of the INAS for evaluating treatment adherence as well as assessing its applicability, reliability, and validity in a population of chronic pain patients. Nonadherence ubiquity across all therapeutic fields and the importance of treatment adherence in chronic pain make it appropriate to validate the questionnaire in the chosen population.The guidelines for translation and adaptation of self-report instruments defined by the ISPOR Task Force for Translation and Cultural Adaptation  were folA total of 133 CP outpatients were selected from two chronic pain clinics from tertiary hospitals in Porto, Portugal. The inclusion criteria were: at least 18 years old, confirmed CP for more than 3 months, able to communicate in Portuguese language, the absence of psychiatric and cognitive disorders precluding the interviews, and willingness to participate in the study. The patient selection was performed using a consecutive sampling scheme, and the sample size calculation was performed aiming to estimate reliability and validity coefficients with a maximum margin of error of ±0.1 and a confidence level of 95% .The study protocol was approved by the hospital review boards and ethics committee of the two hospitals involved.1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, 5 = strongly agree ((RI)—the decision not to take treatment with not wanting to be reminded of one’s illness, the association of medication with illness, and the desire to feel “normal”; and Testing Treatment (TT)—the reasons for not taking treatment based on the person’s attempts to see if they can get away with taking less or no treatment . The third factor is associated with the mysterious or enigmatic nature of pain and its causes, and includes statements about the poorly understood nature of pain (Mystery). The fourth factor is associated with beliefs and perceptions of self-blame in relation with pain (Self-blame). The total score is obtained by dividing the total sum by the number of items. Higher scores indicate greater endorsement of the beliefs and perceptions.The Pain Beliefs and Perception Inventory (PBPI-P) assesses the degree of agreement with a statement referring to pain-related beliefs or perceptions . The PBPThe BMQ has proven to be useful to assess patients’ beliefs associated with nonadherence to treatments and providing information about patients’ actual medication taking behavior . The Porα = 0.84) superior than that to a sample of asthma patients (α = 0.83) (α = 0.77)   and with = 0.77) . Concern = 0.77) . Uninten = 0.77) . Respons = 0.77)  is inverFrom March 2019 to January 2020, 133 CP patients were enrolled after their consultation with the attending physician. Patients followed a standardized protocol that included a first face-to-face interview performed by one of the two trained interviewers, and with the attending physician and nurse collaboration to access the clinical file of the patient. The same protocol was repeated after one month by telephone interviewing performed by the same interviewer that was with patient at the first assessment moment. The protocol interview included sociodemographic questions, the Portuguese versions of the questionnaires previously described , and two direct questions about adherence previously validated  , and 95% confidence intervals (CI). Summary statistics were presented for each item and subscale, including the proportion of scores in the extremes of the scales, to assess the ceiling and floor effects . The assAnalysis of internal consistency was performed by assessing the Cronbach’s alpha statistic, the Cronbach’s alpha coefficient when the items were deleted, and the item-total correlation. The test-retest reliability was assessed by the estimation of agreement between the baseline and the 1 month assessments, using appropriate statistics (intraclass correlation coefficient). Assessments of the construct (convergent and discriminant) validity was performed by calculating and evaluating the correlations, defined by a set of previously developed theoretical hypotheses, between the subscales of INAS and MARS-9P, BMQ, and PBPI [measures of the same constructs used in the original study (22)]. The existence of significant correlations was assumed, namely, the beliefs and perceptions about pain, and its treatment could be associated to the intentional constructs of nonadherence to the pain treatment.As general practical rules, interpretation of the reliability and correlation coefficients was based, respectively, on the quantitative criteria and qualitative descriptors defined by Models of exploratory factor analysis were defined using principal components analysis for factor extraction . OrthogoConfirmatory factor analysis was performed using structural equation models (SEMs), with parameter estimation based on maximum likelihood methods using jamovi software program (version 1.1.3). A multiple index was computed to assess the model fit: 1) the comparative fit index (CFI) with a good fit for values above 0.9; 2) the Tucker–Lewis index (TLI) with a good fit for values above 0.95; and 3) root-mean-square error of approximation (RMSEA) and its respective 90% confidence interval with a good fit for values between 0.05 and 0.08.For all hypothesis tests, a significance level of 0.05 was defined. Statistical analysis was performed using the software Statistical Package for the Social Sciences (SPSS) v. 24.0; and jamovi software program (version 1.1.3) for SEMs.A panel of six experts performed the assessment and reconciliation of translations and cultural adaptation of the INAS, considering the minutiae of Portuguese language and the particular characteristics of CP patients. Consensus among all panel members was reached for all items. A preliminary version of INAS was tested on a sample of 10 CP patients to confirm the applicability of the questionnaire and the quality of the translation and cultural adaptation. The back translation was approved by the author of INAS, Professor John Weinman. Only one question was raised concerning the translation of item 19, namely, a misinterpretation of the back-translation, and it was agreed to add “…to take it” to finish the item: “Because it is good not have to remember to take it.”n = 133) were 95 females and 38 males, between 27 and 84 years old, with a mean age of 57 years (SD = 12.7). The majority had completed four or fewer years of education (33%), 29% attended basic second and third cycles, 20% attended high school, and 18% have a higher education degree. Almost 34% of patients were retired, 34% had a full-time job, and 13% were on sick leave. According to the Chronic Pain Syndromes Classification of the International Association for the Study of Pain—IASP  for all subscales.The analysis of internal and test-retest reliability of INAS is presented in p < 0.001). Four factors with eigenvalues greater than 1.0 were extracted accounting for 74% of total variance. It yielded eighteen items with component loadings greater than 0.50. Factor loadings are shown in Construct validity was assessed by performing factor analysis with principal components and varimax rotation methods . The suiConfirmatory factor analysis, testing the four-factor model, was also performed using SEM techniques and the results are presented in Materials and Methods), presented in Taking into account the theoretical model on which the INAS is based, we defined a set of previously described hypotheses regarding the interrelations between the INAS and other instruments (see p = 0.001), mistrust (p = 0.002), resisting treatment (<0.001), and also resisting illness (p = 0.001). After one-month treatment, those who changed the adherence pattern tend to test the treatment more (0.02) and nonadherents continue to resist treatment.Considering the adherence behavior pattern at the two assessment moments, 39% of patients change their adherence behavior (from adherent to nonadherent or from nonadherent to adherent), 31% were adherent during one month, and 30% reveal a nonadherence behavior. At the baseline, there is a propensity to nonadherents testing (α = 0.902) for the total scale. Concerning the Resisting Illness subscale, the result for consistency was slightly below the original, α = 0.889 compared to α = 0.950, and equally excellent for Testing Treatment subscale α = 0.930) (α = 0.930) and the Resisting Treatment subscale (α = 0.917). These subscales must be interpreted within the patient’s view about their adherence behavior to CP treatment  . Two add= 0.930) , which, reatment , which treatment . Moreovereatment  and thatreatment , which mThe present study used the same criteria to assess the validity of the Portuguese version of the scale as the original INAS validation . UnsurprWe believe that assessing different aspects of intentional nonadherence to pain medicines, using INAS as a self-report measure in clinical practice, is simple and can inform the patient’s own perspective, precluding some previously clinical judgment . The conThis study must be interpreted taking into account its main limitations. Two additional factors emerged to explain different aspects of intentional nonadherence in CP, which need further evaluation; also, the educational level in our sample, that is, the real reflection of the educational level of the elderly population in Portugal. Following this, the questionnaires were filled in by the interviewer which could influence some of the responses. The final model shows a good adjustment using RMSE metric, but the remaining metrics, namely, CFI and TLI, did not reach the ideal adjustment value but are very close. This is a limitation which could be related to the small sample size. Models with small to modest sample sizes and maximum likelihood (ML) estimation of confirmatory factor analysis (CFA) models can show serious estimation problems, such as nonconvergence or parameter estimates, that are outside the admissible parameter space . DespiteIn conclusion, INAS has demonstrated to be adequate and to have some excellent psychometric characteristics. Although the newly emergent INAS subscales do not fit exactly with original factor structure, the Portuguese version of INAS could be a valuable and available instrument for Portuguese researchers and clinicians to assess the intentional nonadherence determinants during the management of chronic pain. There is an urgent need to characterize different “phenotypes” of nonadherence which could create a strong basis for future patient tailored interventions.