RESUMEN
INTRODUCTION: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation. METHODS: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM). RESULTS: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not. CONCLUSION: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.
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Síndrome de Fatiga Crónica , Fibromialgia , Estudios de Casos y Controles , Sensibilización del Sistema Nervioso Central , Síndrome de Fatiga Crónica/epidemiología , Fibromialgia/epidemiología , Humanos , Umbral del DolorRESUMEN
Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.
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Neoplasias Óseas/complicaciones , Neoplasias Óseas/tratamiento farmacológico , Difosfonatos/administración & dosificación , Imidazoles/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/etiología , Animales , Densidad Ósea/efectos de los fármacos , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/patología , Ácido Clodrónico/administración & dosificación , Femenino , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Hiperestesia/tratamiento farmacológico , Hiperestesia/etiología , Modelos Animales , Trasplante de Neoplasias , Variaciones Dependientes del Observador , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Pamidronato , Radiografía , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tibia/efectos de los fármacos , Tibia/patología , Tibia/cirugía , Tacto/efectos de los fármacos , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
Pain is the most common complaint of individuals with osteoarthritis but the cause of symptoms in this disorder remains unclear. Quantitative sensory testing reveals that in patients with chronic joint disease there is diffuse and persistent alteration of nociceptive (pain) pathways, irrespective of the level of activity of the underlying disease. Inflammatory mediators contribute to this plasticity either by directly activating high threshold receptors or more commonly by sensitizing nociceptive neurons to subsequent everyday stimuli. This involves early post-translational modification of receptors/ion channels and later, longer-lasting transcription-dependent mechanisms involving changes to the chemical phenotype of the neuron. Included amongst these changes are the increased production and release of various pro- and anti-inflammatory neuropeptides which have diverse actions on both circulating and resident cell populations. These neurally derived mediators act synergistically with cytokines and growth factors to contribute to ongoing tissue injury. It is becoming apparent that the interaction between a damaged joint and the sensory nervous system is far from straightforward and that activity arising from such interactions may produce not only pain but may also influence the subsequent course of the underlying disease.
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Artralgia/fisiopatología , Mediadores de Inflamación/fisiología , Nociceptores/fisiopatología , Osteoartritis/fisiopatología , Artralgia/etiología , Humanos , Osteoartritis/complicaciones , Sistema Nervioso Periférico/fisiopatología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/fisiopatologíaRESUMEN
We sought to characterise the contribution of the neuropeptide substance P to the outcome of two models of footpad inflammation of differing severity. In an intense inflammatory model produced by intra-plantar Mycobacterium tuberculosus (10 mg/ml) substantial reductions in footpad swelling, histological outcome and mechanical hyperalgesia were observed from early time points in mice lacking the neurokin-1 receptor for substance P compared with wild-type controls. Conversely, in a less intense model (M. tuberculosus 1 mg/ml) no differences were observed other than for a reduction in mechanical hyperalgesia at later time points (day 9 onwards). The results point to a previously unrecognised influence of substance P on peripheral tissue injury and the maintenance of hyperalgesia during more severe or more chronic phases of inflammatory disease.
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Artritis Experimental/genética , Hiperalgesia/genética , Inflamación/genética , Receptores de Neuroquinina-1/deficiencia , Receptores de Neuroquinina-1/genética , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/prevención & control , Femenino , Hiperalgesia/prevención & control , Inflamación/prevención & control , Masculino , Ratones , Ratones NoqueadosRESUMEN
A complex relationship exists between back pain and the presence of spinal disease. Particularly in chronic situations, back pain and its behavioural and emotional consequences are as likely to reflect the influence of psychosocial factors as any underlying spinal pathology. Nevertheless, physical factors are clearly important and it is significant that whereas in normal discs only the outer third of the annulus fibrosus is innervated, a much more extensive innervation develops in the presence of degeneration. Inflammation, as evidenced by leukocyte infiltration and expression of inflammatory mediators, is associated with disc degeneration and serves to alter the neural responses resulting in local and referred pain. It is probable that similar inflammatory processes, as well as direct root compression, contribute to radicular symptoms following disc herniation. An appreciation of these mechanisms encourages the search for novel treatments and permits a more rational and effective use of existing strategies for relieving pain.
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Dolor de Espalda/diagnóstico , Dolor de Espalda/fisiopatología , Enfermedades de la Columna Vertebral/diagnóstico , Enfermedades de la Columna Vertebral/fisiopatología , Columna Vertebral/inervación , Columna Vertebral/fisiopatología , Dolor de Espalda/etiología , Humanos , Enfermedades de la Columna Vertebral/complicacionesRESUMEN
Current evidence suggests that although persistent arthritic pain is initiated and maintained by articular pathology, it is also heavily influenced by a range of other factors. Strategies for treating arthritic pain are therefore different from those adopted for acute pain. Although published guidelines offer general assistance, the complexity of underlying mechanisms requires that measures designed to relieve pain must take into account individual biological, psychological and societal factors. It follows that a combination of both pharmacological and non-pharmacological approaches offers the best opportunity for therapeutic success, although determining the effectiveness of such complex interventions remains difficult. Pharmacological therapy is often prolonged, and safety and tolerability issues become as important as efficacy over time.
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Artritis/complicaciones , Artritis/fisiopatología , Manejo del Dolor , Dolor/etiología , Dolor/fisiopatología , Guías como Asunto , HumanosRESUMEN
OBJECTIVE: To model pain intensity and consequent disability by independent physical, psychological, and social variables in a group of patients with chronic upper limb pain. METHODS: We studied a group of 73 hospital outpatients with either chronic work related diffuse upper limb pain or carpal tunnel syndrome. We assessed pain intensity, disability, and personality by self-rated questionnaires; and psychiatric morbidity by a standardized interview. We measured illness behavior by assessing coping strategies, illness beliefs, financial benefits, and movements of the most affected limb. RESULTS: In both pain conditions, disability was positively correlated with present pain intensity, depression, helpless coping style, and receipt of state financial benefits; and was negatively correlated with age. This explained 43% of the variance and correctly classified 85% of all patients. Present pain intensity was positively correlated with both depression and the number of arm movements at night. This model explained 15% of the variance and correctly classified 75% of all patients. Inclusion of diagnostic group has no effect on these models. CONCLUSION: The correlations between disability and pain intensity with both psychosocial and physical factors support the biopsychosocial model of disability in particular, and pain to a lesser extent, irrespective of the diagnosis.
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Evaluación de la Discapacidad , Modelos Biológicos , Modelos Psicológicos , Dolor/fisiopatología , Extremidad Superior/fisiopatología , Adolescente , Adulto , Anciano , Síndrome del Túnel Carpiano/fisiopatología , Enfermedad Crónica , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Dimensión del Dolor , Encuestas y CuestionariosRESUMEN
Therapies directed against tumour necrosis factor (TNF) are effective for the treatment of rheumatoid arthritis and reduce pain scores in this condition. In this study, we sought to explore mechanisms by which TNF contributes to inflammatory pain in an experimental model of arthritis. The effects of an anti-TNF agent, etanercept, on behavioural pain responses arising from rat monoarthritis induced by complete Freund's adjuvant were assessed and compared with expression of TNF receptors (TNFRs) by dorsal root ganglion (DRG) cells at corresponding time points. Etanercept had no effect on evoked pain responses in normal animals but exerted a differential effect on the thermal and mechanical hyperalgesia associated with rat arthritis induced by complete Freund's adjuvant (CFA). Joint inflammation was associated with increased TNFR1 and TNFR2 expression on DRG cells, which was maintained throughout the time course of the model. TNFR1 expression was increased in neuronal cells of the DRG bilaterally after arthritis induction. In contrast, TNFR2 expression occurred exclusively on non-neuronal cells of the macrophage-monocyte lineage, with cell numbers increasing in a TNF-dependent fashion during CFA-induced arthritis. A strong correlation was observed between numbers of macrophages and the development of mechanical hyperalgesia in CFA-induced arthritis. These results highlight the potential for TNF to play a vital role in inflammatory hyperalgesia, both by a direct action on neurons via TNFR1 and by facilitating the accumulation of macrophages in the DRG via a TNFR2-mediated pathway.
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Artritis/metabolismo , Hiperalgesia/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Artritis/patología , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Calor/efectos adversos , Hiperalgesia/patología , Inflamación/metabolismo , Inflamación/patología , Masculino , Estimulación Física/efectos adversos , Ratas , Ratas Wistar , Receptores Tipo I de Factores de Necrosis Tumoral/biosíntesis , Receptores Tipo II del Factor de Necrosis Tumoral/biosíntesisRESUMEN
OBJECTIVE: To compare behavioral and other psychosocial factors in patients with diffuse upper limb pain disorder (ULPD) and patients with carpal tunnel syndrome (CTS). METHODS: We compared 37 hospital outpatients with diffuse ULPD with 36 hospital outpatients with CTS, matched by sex, pain intensity, and duration of illness. We assessed psychiatric morbidity by a standardized interview, and both symptoms and personality by self-rated questionnaires. We measured illness behavior by assessing financial benefits and compensation, coping strategies, illness beliefs, treatments received, and 24 hours of monitoring movements of the most affected arm and the body as a whole. RESULTS: There were no significant differences in the prevalence of either current or premorbid psychiatric disorders, personality scores, symptom amplification, disability, or treatments received. Subjects with ULPD had significantly lower self-rated scores for depression, somatic distress, sleep disturbance, and physical fatigue than subjects with CTS, although there were more than normal levels of anxiety, fatigue, and sleep disturbance in both groups. There were no significant differences in the numbers of arm or body movements by day and night. Significantly more ULPD subjects had been involved in litigation, but litigating patients were a minority. CONCLUSION: The primary etiology of endemic diffuse ULPD, presenting in secondary care, is no more psychiatric, psychological, behavioral, or related to personality than is the case with a similarly chronic and painful condition of known pathology. We cannot exclude either a specific role for psychosocial factors at work, or a more general role for psychosocial factors in maintaining disability in patients with chronic pain.
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Enfermedades Musculoesqueléticas/epidemiología , Enfermedades Musculoesqueléticas/psicología , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/psicología , Rol del Enfermo , Adaptación Psicológica , Adulto , Afecto , Brazo , Síndrome del Túnel Carpiano/diagnóstico , Síndrome del Túnel Carpiano/epidemiología , Síndrome del Túnel Carpiano/psicología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morbilidad , Movimiento , Enfermedades Musculoesqueléticas/diagnóstico , Enfermedades Profesionales/diagnóstico , Dolor/diagnóstico , Dolor/epidemiología , Dolor/psicología , Personalidad , Prevalencia , Psicología , Clase SocialRESUMEN
Early angiogenesis is a key step in the transition from acute to persistent inflammation. The nervous system has long been known to play a role in inflammation, in part through the release of substance P from peripheral nerve terminals (neurogenic inflammation). Application of substance P can stimulate vessel growth in a variety of angiogenesis assays, although it was previously not known whether endogenous substance P released from sensory nerves could modulate angiogenesis. We hypothesized that endogenous substance P can initiate angiogenesis during acute neurogenic inflammation. Here we show that 10 nmol of substance P can stimulate angiogenesis within the rat knee synovium, as shown by increased endothelial cell proliferation index [PCNA index, 19% (95% confidence interval (CI), 17 to 20%)] compared with saline injected knees [6% (95% CI, 4% to 8%), p < 0.05]. Moreover, this was prevented by coadministration of an antagonist of the neurokinin-1 (NK1) subtype of neurokinin receptor SR140333 (nolpitantium), 1 micro mol [8% (95% CI, 5% to 11%)]. Capsaicin 0.5%, which stimulates release of endogenous substance P from sensory nerves, was also found to enhance synovial angiogenesis, [PCNA index 17% (95% CI, 14% to 19%)] compared with saline injected control knees [2% (95% CI, 1% to 3%), p < 0.05], and this also was inhibited by 1 micro mol of SR140333 [11% (95% CI, 8 to 16%)]. Inhibition of capsaicin-enhanced angiogenesis was incomplete, and this may indicate a contribution of other neuropeptides, in addition to substance P-NK1 receptor interactions, in capsaicin-enhanced angiogenesis. NK1 receptor antagonists could have therapeutic potential in conditions where neurogenic angiogenesis contributes to disease.