Monika Salgueiro

Hyperexcitable C nociceptors in fibromyalgia

To test the hypothesis that peripheral C nociceptor function may be abnormal in fibromyalgia and that C nociceptor dysfunction may contribute to the symptoms reported by these patients.

Validation of a Spanish version of the Revised Fibromyalgia Impact Questionnaire (FIQR)

BackgroundThe Revised version of the Fibromyalgia Impact Questionnaire (FIQR) was published in 2009. The aim of this study was to prepare a Spanish version, and to assess its psychometric properties in a sample of patients with fibromyalgia.MethodsThe FIQR was translated into Spanish and administered, along with the FIQ, the Hospital Anxiety Depression Scale (HADS), the 36-Item Short-Form Health Survey (SF-36), and the Brief Pain Inventory (BPI), to 113 Spanish fibromyalgia patients. The administration of the Spanish FIQR was repeated a week later.ResultsThe Spanish FIQR had high internal consistency (Cronbach’s α was 0.91 and 0.95 at visits 1 and 2 respectively). The test-retest reliability was good for the FIQR total score and its function and symptoms domains (intraclass correlation coefficient (ICC > 0.70), but modest for the overall impact domain (ICC = 0.51). Statistically significant correlations (p < 0.05) were also found between the FIQR and the FIQ scores, as well as between the FIQR scores and the remaining scales’ scores.ConclusionsThe Spanish version of the FIQR has a good internal consistency and our findings support its validity for assessing fibromyalgia patients. It might be a valid instrument to apply in clinical and investigational grounds.ResumenAntecedentesEl Cuestionario de Impacto de Fibromialgia (FIQ) ha sido utilizado como medida de valoración en numerosos estudios clínicos. En 2009 se publicó en inglés su versión revisada (FIQR). El presente estudio se llevó a cabo para traducir al español y validar dicha versión.Pacientes y MétodoLa traducción fue realizada por dos de los autores. La versión traducida del FIQR se administró a 113 pacientes con fibromialgia junto con el FIQ, la Escala Hospitalaria de Ansiedad y Depresión, el Cuestionario de Salud SF-36 y la versión abreviada del Cuestionario Breve de Dolor. Una semana después se administró de nuevo el FIQR. Su consistencia interna se evaluó mediante el coeficiente α de Cronbach. Se calcularon los coeficientes de correlación intraclase (ICC) entre las puntaciones de la nueva versión y la anterior, así como las subescalas del Cuestionario SF-36, de la Escala Hospitalaria de Ansiedad y Depresión y del Inventario Breve de Dolor. La fiabilidad test-retest se evaluó igualmente mediante coeficientes de correlación intraclase.ResultadosEl coeficiente α de Cronbach de la versión en estudio fue elevado (0,91 en la primera visita y de 0,95 en la segunda). La fiabilidad test-retest fue buena para la puntuación total del FIQR y para las dimensiones de función y síntomas ( ICC ≥ 0,70) pero modesta para la dimensión de impacto global (ICC = 0,51). Asimismo se encontraron coeficientes de correlación elevados y estadísticamente significativos respecto a las restantes escalas aplicadas (p < 0,05).ConclusiónLa versión española del FIQR es un instrumento válido para su uso en la evaluación e investigación clínicas.

Selective impairment of spinal mu-opioid receptor mechanism by plasticity of serotonergic facilitation mediated by 5-HT2A and 5-HT2B receptors

Summary Plasticity of serotonergic neurotransmission mediated by 5‐HT2A and 5‐HT2B receptors impairs spinal mu‐opioid of receptor efficacy during neuropathic pain, including upregulation of receptor expression in mu‐opioid receptor containing neurons. ABSTRACT Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis‐coupled serotonin receptor 5‐HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5‐HT2A and 5‐HT2B receptors, which have been previously shown to become pro‐excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100 nM) mu‐opioid receptor (MOR)‐agonist DAMGO significantly depressed C fiber‐evoked spinal field potentials. Simultaneous administration of subclinical 5‐HT2AR antagonist 4F 4PP (100 nM) or 5‐HT2BR antagonist SB 204741 (100 nM) significantly reduced the IC50 value for DAMGO in nerve‐ligated rats (97.56 nM ± 1.51 and 1.20 nM ± 1.28 respectively, relative to 104 nM ± 1.08 at the baseline condition), but not in sham‐operated rats. Both antagonists failed to alter depression induced by delta‐opioid receptor (DOR)‐agonist D‐ala2‐deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5‐HT2AR and 5‐HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co‐localization color overlay for 5‐HT2AR/MOR, 5‐HT2BR/MOR, 5‐HT2AR/DOR, or 5‐HT2BR/DOR in sham‐operated rats. Intensity correlation‐based analyses showed significant increases in 5‐HT2AR/MOR and 5‐HT2BR/MOR co‐localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5‐HT2A and 5‐HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR.

Valoración de factores sociales y clínicos en el síndrome de fibromialgia

Resumen Introduccion La depresion y la ansiedad son estados afectivos negativos que con frecuencia se asocian con el dolor cronico. Por el contrario, factores psicosociales como el apoyo social influyen en la percepcion de dolor y contribuyen al bienestar del paciente con dolor cronico. Objetivos Valorar el tipo de terapia que recibe y el apoyo social que percibe de su entorno el paciente con sindrome de fibromialgia (SFM) y determinar su relacion con sus indices de depresion y de ansiedad. Material y metodos Se han recabado datos de 229 pacientes de SFM mediante un cuestionario autoaplicado que ha incluido los aspectos mas preocupantes de la enfermedad, el efecto de las terapias empleadas, la satisfaccion con la atencion sanitaria recibida, la percepcion de apoyo social, asi como indices de ansiedad y de depresion. Resultados y conclusiones Las personas que han valorado mas positivamente el apoyo de su entorno social y familiar demuestran mayor proteccion frente al estres psicologico en terminos de ansiedad y depresion. La intervencion sobre el apoyo del entorno inmediato del paciente con SFM podria contribuir a la reduccion del dolor reduciendo los niveles de ansiedad y de depresion.

Depression of C fibre-evoked spinal field potentials by the spinal δ opioid receptor is enhanced in the spinal nerve ligation model of neuropathic pain: Involvement of the μ-subtype

The depression rate of C fibre-evoked spinal field potentials by spinally applied morphine is increased in two states of spinal hyperexcitation, namely the spinal ligation model (SNL) of neuropathic pain and long-term potentiation (LTP) of C fibre-evoked spinal field potentials. This present work sought to determine opioid receptor subtypes involved in such increase in the SNL model. We recorded spinal field potentials during spinal superfusion with increasing, cumulative concentrations of selective subtype-specific agonists in rats subjected to SNL, as well as in non-ligated animals. The mu opioid receptor (MOR) agonist DAMGO significantly depressed field potentials evoked by C (100 nM) or Adelta fibres (1 microM) both in neuropathic and non-ligated rats, whereas the kappa receptor opioid (KOR) agonist +/-U-50488 was ineffective. The delta opioid receptor (DOR) (D-Ala2)-Deltorphin II was more effective in reducing C fibre-evoked spinal field potentials in rats subjected to SNL (100 nM) than in non-ligated rats (100 microM). Subclinical MOR activation (10 nM DAMGO) produced a leftward shift in (D-Ala2)-Deltorphin II dose-response curve in non-ligated rats (IC50 16.59 +/- 0.99 microM vs 120.3 +/- 1.0 microM in the absence of DAMGO), and isobolar analysis revealed synergistic interaction (interaction index 0.25). MOR blockade (100 microM CTOP) disinhibited C fibre-evoked potentials in neuropathic, but not in basal animals, and partially impeded DOR depression in both groups. DOR blockade (1 mM naltrindole) was ineffective in either group. We show that DOR-mediated depression of spinal responses to peripheral unmyelinated fibre-input is increased in the SNL model, an increase that is contributed to by positive interaction with the spinal MOR.

Is psychological distress intrinsic to fibromyalgia syndrome? Cross-sectional analysis in two clinical presentations

Clinical presentation of fibromyalgia syndrome (FMS) is heterogeneous and often involves psychological comorbidities. Clinical subgrouping of FMS patients has been proposed as a strategy to improve patients’ long-term outcomes by helping identify specific treatment needs. Using the 90 Symptom Checklist Revised (SCL-90-R), we have assessed emotional distress in two FMS patient subpopulations discriminated on the basis of their differences in scores on specific items of the Fibromyalgia Impact Questionnaire (FIQ). Subjects classed as type II exhibited high emotional distress on all ten dimensions studied, which included somatization, obsessive–compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism, and additional items subscales, as well as on the global severity index (GSI), positive symptom total (PST), and positive symptom distress index (PDSI). T-scores in these patients were above diagnostic cutoff level of 60 on somatization, obsessive–compulsive, and depression subscales. In contrast, the profile exhibited by type I subjects fell entirely within normal values for nonpsychiatric population. Emotional status was significantly inversely correlated with present clinical pain in type I-, but not in type II-fibromyalgia patients. Regression analysis revealed a model based on phobic anxiety, paranoid ideation, and depression subscales as best contributing to classification. The present data suggest that associated psychological distress and maladaptive emotional responses that are commonly attributed to the general FMS population may be largely a distinguishing feature of one subset of patients.

An artificial neural network approach for predicting functional outcome in fibromyalgia syndrome after multidisciplinary pain program.

OBJECTIVE The objective of this study was to evaluate the ability of artificial neural networks (ANNs) to predict, on the basis of clinical variables, the response of persons with fibromyalgia syndrome (FMS) to a standard, 4-week interdisciplinary pain program. DESIGN The design of this study is retrospective longitudinal. SETTING Fibromyalgia outpatient clinic in a tertiary-care general hospital. SUBJECTS The subjects of this study include outpatients with FMS. INTERVENTION Multidisciplinary pain program including pain pharmacotherapy, cognitive-behavioral therapy, physical therapy, and occupational therapy. OUTCOME MEASURES Reliable change (RC) of scores on the Stanford Health Assessment Questionnaire (HAQ), and accuracy of ANNs in predicting RC at discharge or at 6-month follow-up as compared to Logistic Regression. RESULTS ANN-based models using the sensory-discriminative and affective-motivational subscales of the McGill Pain Questionnaire, the HAQ disability index, and the anxiety subscale of Hospital Anxiety and Depression Scale at baseline as input variables correctly classified 81.81% of responders at discharge and 83.33% of responders at 6-month follow-up, as well as 100% of nonresponders at either evaluation time-point. Logistic regression analysis, which was used for comparison, could predict treatment outcome with accuracies of 86.11% and 61.11% at discharge and follow-up, respectively, based on baseline scores on the HAQ and the mental summary component of the Medical Outcomes Study-Short Form 36. CONCLUSIONS Properly trained ANNs can be a useful tool for optimal treatment selection at an early stage after diagnosis, thus contributing to minimize the lag until symptom amelioration and improving tertiary prevention in patients with FMS.

Efficacy of a cognitive and behavioural psychotherapy applied by primary care psychologists in patients with mixed anxiety-depressive disorder: a research protocol

BackgroundIn contrast with the recommendations of clinical practice guidelines, the most common treatment for anxiety and depressive disorders in primary care is pharmacological. The aim of this study is to assess the efficacy of a cognitive-behavioural psychological intervention, delivered by primary care psychologists in patients with mixed anxiety-depressive disorder compared to usual care.Methods/DesignThis is an open-label, multicentre, randomized, and controlled study with two parallel groups. A random sample of 246 patients will be recruited with mild-to-moderate mixed anxiety-depressive disorder, from the target population on the lists of 41 primary care doctors. Patients will be randomly assigned to the intervention group, who will receive standardised cognitive-behavioural therapy delivered by psychologists together with usual care, or to a control group, who will receive usual care alone.The cognitive-behavioural therapy intervention is composed of eight individual 60-minute face-to face sessions conducted in eight consecutive weeks. A follow-up session will be conducted over the telephone, for reinforcement or referral as appropriate, 6 months after the intervention, as required.The primary outcome variable will be the change in scores on the Short Form-36 General Health Survey. We will also measure the change in the frequency and intensity of anxiety symptoms (State-Trait Anxiety Inventory) and depression (Beck Depression Inventory) at baseline, and 3, 6 and 12 months later. Additionally, we will collect information on the use of drugs and health care services.DiscussionThe aim of this study is to assess the efficacy of a primary care-based cognitive-behavioural psychological intervention in patients with mixed anxiety-depressive disorder. The international scientific evidence has demonstrated the need for psychologists in primary care. However, given the differences between health policies and health services, it is important to test the effect of these psychological interventions in our geographical setting.Trial registrationNCT01907035 (July 22, 2013).

Reply: To PMID 24243538.

We are grateful to Professor Gemignani for his interest in our recent study on hyperexcitable nociceptors in fibromyalgia patients, as it allows us to touch on 2 important issues: that of the circularity of arguments in the definition of fibromyalgia, and that of the relevance of “central sensitization” to fibromyalgia in particular, and to chronic pain patients in general. First, regarding circularity of arguments. Several medical conditions are diagnosed solely on the basis of the clinical expression of symptoms and signs. Trigeminal neuralgia is a classic example in neurology; before the advent of neuroimaging techniques, diagnosis was based solely on the clinical presentation of symptoms and signs. Since magnetic resonance imaging was developed, it has been proposed that some trigeminal neuralgias are due to an arterial loop impinging on the trigeminal root exit zone, but some are not. Are both conditions the same disease? The answer to the above question may seem semantic, but it depends how one chooses to define what a single, welldefined disease entity is. Fibromyalgia seems to fall into this category. This has also been recognized by many of the experts in the field, to the point that there has been a move away from calling this condition fibromyalgia toward calling it fibromyalgia syndrome (FMS), which acknowledges the difficulties of defining fibromyalgia as a single disease. The dangers of being trapped in a circular argument are clearly exemplified by Gemignani himself when he asks about our cohort of patients, “Are they actually FMS patients with associated small-fiber pathology, or do they represent cases of non–length-dependent SFN [small-fiber neuropathy] mimicking FMS?” Our answer would probably be that both statements are correct, provided that one understands FMS not as an etiologically defined, single disease entity, but rather as a stereotyped collection of symptoms and signs, that is, a syndrome. Many neurologists would feel more comfortable viewing FMS as an SFN, whereas many rheumatologists would feel more comfortable with the view that a particular FMS patient has “associated small-fiber pathology.” In any case, our view is that the best approach to enable diseasemodifying strategies will be to identify FMS patients with SFN, and to conduct a thorough screening of possible causes for their SFN. Such an approach seems clearly called for in view of recent findings by us and by others. It would be a disservice to patients if potentially treatable medical conditions leading to an SFN that expresses clinically as FMS remained undiagnosed because FMS is considered the end of a diagnostic process rather than its beginning. Second, regarding central sensitization. From its inception, there has been a level of controversy about the concept of “central” sensitization in pain. For example, the initial studies describing this phenomenon were paradoxically carried out studying motor reflex responses, rather than sensory neurons, in the spinal cord. The concept has been extensively used as an explanation for many pain conditions in which there was no clear evidence of any underlying pathology; but, as far as we are aware, there is no direct electrophysiological evidence in humans that central sensitization on its own (ie, without peripheral input) can help explain the maintenance of chronic pain. Whereas peripheral nociceptor input was once regarded as just an epiphenomenon in most cases of chronic pain, it is now appreciated that maintained peripheral nociceptor input is crucial in the maintenance of chronic pain. This changing view is also reflected in Gemignani’s comments when he states, “Although recent findings point to the role of distal small fibers in FMS, this does not exclude the possibility of central pain amplification as well.” Neuroimaging and abnormal temporal summation of pain found in FMS may suggest altered excitation/inhibition processes within the pain processing network. However, that similar findings have been reported in other chronic pain states, including patients with peripheral neuropathy, probably indicates that these abnormalities are a common central nervous system response to an abnormal, continued peripheral input from altered nociceptors. Without wishing to engage in endless “chicken or egg” discussions, it is becoming clear that ongoing peripheral nociceptor input is the crucial event in the painfulness of SFN, and it may actually be the only biomarker for spontaneous pain. One of the specific C-nociceptor abnormalities found in our study, namely, a very marked slowing of conduction velocity, seems specific to FMS patients, and deserves further investigation, as it may point to the cause of FMS. In summary, we would like to stress again that our findings, together with those of other authors, strongly indicate that many patients with FMS may actually have SFN. These findings of a possible peripheral basis for the pain of FMS carry the important implication that targeting spontaneous activity in peripheral nociceptors may constitute an attractive option to treat pain in FMS.

The Affective-Motivational Domain of the McGill Pain Questionnaire Discriminates Between Two Distinct Fibromyalgia Patient Subgroups – A Preliminary Study Based on Self-Organizing Maps

For two decades, FMS was diagnosed based on the criteria established on 1990 by the American College of Rheumatology, i.e. by the identification of widespread pain of at least 3 months duration, and pain and tenderness evoked by palpation in at least 11 of 18 specific bodily sites (Wolfe et al., 1990). Recently, the ACR preliminary diagnostic recommendations for fibromyalgia abandoned the tender point examination criterion, and were established as the following 3 conditions: (i) Widespread Pain Index (WPI) equal to or greater than 7 and Symptom Severity Score (SS) equal to or greater than 5, or WPI ranging between 3 and 6 and the SS equal to or greater than 9; (ii) steady presence of symptoms for at least 3 months; and (iii) the absence of a disorder that would otherwise explain the pain. Despite being highly prevalent, the etiology and pathophysiology of FMS remains obscure. Diverse factors contributing to this condition have so far been identified, however none has been proven unequivocally responsible. Due to limited understanding of the etiology and pathophysiology of FMS, a diversity of pharmacological and nonpharmacological interventions alone and in combination have been attempted to treat the symptoms, largely on a trial-and-error basis. However, this condition remains largely refractory to treatment.