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4 Topical Seminar Summary: CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL AND VISCERAL PAIN
S2
European Journal of Pain 2006, Vol 10 (suppl S1)
of the central relevance of descending modulatory influences (anti- and pro-nociceptive mechanisms) in the generation and maintenance of chronic pain states has been obtained from recent human imaging studies and these will also be discussed. Relating specific neurophysiological markers to the perceptual changes induced by pharmacological agents and identifying their site of action within the human nervous system has been a major goal for drug discovery. Recently, pharmacological functional magnetic resonance imaging (phMRI) methods have been developed and applied to the field of pain research. The non-invasive nature of FMRI enables longitudinal studies on healthy subjects and patients making it ideal for use in combination with pharmacological agents that might require multiple dosing across many imaging sessions or a serial collection of imaging data across time due to the pharmacokinetics of the drug. FMRI has been used in combination with ’gold-standard’ drugs that are currently used in the treatment of chronic pain to gain a better understanding of the action of these compounds in both human models of clinical pain as well as neuropathic and inflammatory pain patients. Experiments utilising these methodologies will be described and issues relating to measuring placebo effects discussed. Novel imaging methods such as diffusion tractography, volumetric analyses and spinal cord FMRI are further highlighting not only the nociceptive pain circuitry in normals but also the extent of damage the human central nervous system sustains after years of chronic pain. My talk will hopefully illustrate how innovative methods and ways of assessing and tackling this global problem are needed but also in development.
Topical Seminar: CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL & VISCERAL PAIN 4 Topical Seminar Summary: CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL AND VISCERAL PAIN L. Arendt-Nielsen ° . Denmark Little attention has been paid to the fact that e.g. chronic musculoskeletal and visceral pain disorders involve central hyperexcitability. In as well experimental as clinical studies it is mandatory to have techniques available to assess quantitatively the mechanisms involved in deep tissue hyperalgesia. Clinical conditions involving hyperexcitability are confounded by many factors and experimental models to induce hyperexcitability from muscles and viscera are important as surrogate models of such clinical pain condition. Such models provide the possibilities to assess quantitatively the mechanisms involved. The models can be used to obtain new knowledge and e.g. screen the potency of new drugs. Induction of deep tissue hyperalgesia is less investigated and recently we have performed series of experiments inducing and assessing hyperalgesia (injection/application of algogenic substances) from deep structures in healthy volunteers. Although large variations are seen several chronic musculoskeletal and visceral pain conditions are associated with increased pain sensitivity to specific quantitative sensory tests. Patients suffering from e.g. CLPB, whiplash, fibromyalgia, osteoarthritis have shown reduced pain thresholds and enlarged referred pain areas to experimental muscle pain stimulation. Chronic visceral pain conditions such as e.g. endometriosis, pelvic pain, irritable bowel disease, chronic pancreatitis, non-ulcer dyspepsia all show indications of central senstisation. The sensory manifestations of experimentally and clinically related musculoskeletal and visceral hyperalgesia are similar: (1) larger referred pain areas to standardised muscle/viscera stimulation as compared to control conditions, (2) increased referred pain areas for increased intensity of the nociceptive input, (3) increased referred pain areas for increased stimulus duration; (4) modality specific somatosensory changes in the referred pain areas. These manifestations seen for referred pain areas are very similar to those seen for secondary hyperalgesia related to the skin. Further insight into deep tissue hyperalgesia is needed to develop new therapies and improve the efficacy of the old therapies.
Abstracts, 5th EFIC Congress, Invited Presentations 5 CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL AND VISCERAL PAIN L. Arendt-Nielsen ° . Aalborg University, Center For Sensory-Motor Interaction, Aalborg, Denmark Many painful conditions, others than neurogenic pain, may involve neuroplastic changes within the central nervous system. Little attention has been paid to the fact that e.g. musculoskeletal or visceral chronic pain disorders may also generate neuroplastic changes. It seems evident this may happens as conventional pain management regimes do not sufficiently modulate neurogenic pain syndromes as well as many painful disorders involving deep structures. It is important to characterise the various mechanisms involved in pain syndromes with neuroplastic manifestations as a mechanism-based classification will help targeting the treatment. In as well experimental as clinical studies it is therefore mandatory to have techniques available to tease out which mechanisms are involved. Multi-modal, multi-tissue sensory testing regimes are needed for this purpose. A comprehensive investigation should involve e.g. assessment of hyperalgesia to various stimuli, reaction to repeated stimuli (temporal summation), cutaneous, muscular and visceral stimulation. On basis of such an investigation it should be possible to suggest which mechanisms are involved. On basis of such tests and results from pharmacological studies where many drugs have been screened it is possible to suggest which classes of drugs (normally in combination) would be the first choice for treating a specific pain condition. Central neuroplastic manifestations can be induced experimentally from skin, muscle and viscera. It has been known for many years how to cause sensitisation related to the skin (e.g. capsaicin application/injection) but experimentally induction of sensitisation of muscles and viscera is a new area. We have performed a long series of experiments characterising sensitisation evoked from deep structures. Further insight into the peripheral and central mechanisms of muscle and viscera pain and related phenomena (sensitisation and referred pain) is necessary to improve as well physical as pharmacological therapy. The study of referred muscle/visceral pain and muscle/visceral hyperalgesia may help to uncover such mechanisms as referred is a central mechanism. Referred muscle/visceral pain (and the possible related hyperalgesia) is manifested in somatic structures (skin, muscles, joints, tendons). These manifestations are of significant clinical importance for the diagnosis of deep-tissue pain pathologies. Sensory manifestations of hyperexcitability is found in chronic musculoskeletal (e.g. CLPB, whip-lash, fibromyalgia, osteoarthritis) and visceral pains (e.g. endometriosis, irritable bowel disease, chronic pancreatitis). Recently we have found that patients suffering from chronic musculoskeletal and visceral pains have significantly larger referred pain areas to experimentally induced pain and at the same time they show manifestations of muscle/visceral sensitisation. 6 CENTRAL SENSITIZATION – WIDESPREAD PAIN A.H. Dickenson ° . Pharmacology, University College London, UK Many pain states are driven from changes in the periphery where tissue and/or nerve damage change inputs that arrive within the spinal cord. Understanding this plasticity may lead to improved therapies for the two major types of pain, neuropathic and inflammatory pain, since the peripheral nerve and tissue damage leads to alterations not only at the source of the pain but importantly, also at central levels. Within the spinal cord, these changes underlie central sensitization whereby the response to a given input is increased by central spinal mechanisms. One first stage in this process seems to involve calcium channels that are essential for transmitter release onto spinal neurones – gabapentin and pregabalin may act on these changed channels. This increase in transmitter release leads to greater levels of activation of spinal receptors and increased neuronal excitability. In the spinal cord, the release of peptides and glutamate causes activation of the N-methyl-D-aspartate (NMDA) receptor for glutamate in persistent
European Journal of Pain 2006, Vol 10 (suppl S1)
of the central relevance of descending modulatory influences (anti- and pro-nociceptive mechanisms) in the generation and maintenance of chronic pain states has been obtained from recent human imaging studies and these will also be discussed. Relating specific neurophysiological markers to the perceptual changes induced by pharmacological agents and identifying their site of action within the human nervous system has been a major goal for drug discovery. Recently, pharmacological functional magnetic resonance imaging (phMRI) methods have been developed and applied to the field of pain research. The non-invasive nature of FMRI enables longitudinal studies on healthy subjects and patients making it ideal for use in combination with pharmacological agents that might require multiple dosing across many imaging sessions or a serial collection of imaging data across time due to the pharmacokinetics of the drug. FMRI has been used in combination with ’gold-standard’ drugs that are currently used in the treatment of chronic pain to gain a better understanding of the action of these compounds in both human models of clinical pain as well as neuropathic and inflammatory pain patients. Experiments utilising these methodologies will be described and issues relating to measuring placebo effects discussed. Novel imaging methods such as diffusion tractography, volumetric analyses and spinal cord FMRI are further highlighting not only the nociceptive pain circuitry in normals but also the extent of damage the human central nervous system sustains after years of chronic pain. My talk will hopefully illustrate how innovative methods and ways of assessing and tackling this global problem are needed but also in development.
Topical Seminar: CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL & VISCERAL PAIN 4 Topical Seminar Summary: CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL AND VISCERAL PAIN L. Arendt-Nielsen ° . Denmark Little attention has been paid to the fact that e.g. chronic musculoskeletal and visceral pain disorders involve central hyperexcitability. In as well experimental as clinical studies it is mandatory to have techniques available to assess quantitatively the mechanisms involved in deep tissue hyperalgesia. Clinical conditions involving hyperexcitability are confounded by many factors and experimental models to induce hyperexcitability from muscles and viscera are important as surrogate models of such clinical pain condition. Such models provide the possibilities to assess quantitatively the mechanisms involved. The models can be used to obtain new knowledge and e.g. screen the potency of new drugs. Induction of deep tissue hyperalgesia is less investigated and recently we have performed series of experiments inducing and assessing hyperalgesia (injection/application of algogenic substances) from deep structures in healthy volunteers. Although large variations are seen several chronic musculoskeletal and visceral pain conditions are associated with increased pain sensitivity to specific quantitative sensory tests. Patients suffering from e.g. CLPB, whiplash, fibromyalgia, osteoarthritis have shown reduced pain thresholds and enlarged referred pain areas to experimental muscle pain stimulation. Chronic visceral pain conditions such as e.g. endometriosis, pelvic pain, irritable bowel disease, chronic pancreatitis, non-ulcer dyspepsia all show indications of central senstisation. The sensory manifestations of experimentally and clinically related musculoskeletal and visceral hyperalgesia are similar: (1) larger referred pain areas to standardised muscle/viscera stimulation as compared to control conditions, (2) increased referred pain areas for increased intensity of the nociceptive input, (3) increased referred pain areas for increased stimulus duration; (4) modality specific somatosensory changes in the referred pain areas. These manifestations seen for referred pain areas are very similar to those seen for secondary hyperalgesia related to the skin. Further insight into deep tissue hyperalgesia is needed to develop new therapies and improve the efficacy of the old therapies.
Abstracts, 5th EFIC Congress, Invited Presentations 5 CENTRAL HYPERSENSITIVITY IN CHRONIC MUSCULOSKELETAL AND VISCERAL PAIN L. Arendt-Nielsen ° . Aalborg University, Center For Sensory-Motor Interaction, Aalborg, Denmark Many painful conditions, others than neurogenic pain, may involve neuroplastic changes within the central nervous system. Little attention has been paid to the fact that e.g. musculoskeletal or visceral chronic pain disorders may also generate neuroplastic changes. It seems evident this may happens as conventional pain management regimes do not sufficiently modulate neurogenic pain syndromes as well as many painful disorders involving deep structures. It is important to characterise the various mechanisms involved in pain syndromes with neuroplastic manifestations as a mechanism-based classification will help targeting the treatment. In as well experimental as clinical studies it is therefore mandatory to have techniques available to tease out which mechanisms are involved. Multi-modal, multi-tissue sensory testing regimes are needed for this purpose. A comprehensive investigation should involve e.g. assessment of hyperalgesia to various stimuli, reaction to repeated stimuli (temporal summation), cutaneous, muscular and visceral stimulation. On basis of such an investigation it should be possible to suggest which mechanisms are involved. On basis of such tests and results from pharmacological studies where many drugs have been screened it is possible to suggest which classes of drugs (normally in combination) would be the first choice for treating a specific pain condition. Central neuroplastic manifestations can be induced experimentally from skin, muscle and viscera. It has been known for many years how to cause sensitisation related to the skin (e.g. capsaicin application/injection) but experimentally induction of sensitisation of muscles and viscera is a new area. We have performed a long series of experiments characterising sensitisation evoked from deep structures. Further insight into the peripheral and central mechanisms of muscle and viscera pain and related phenomena (sensitisation and referred pain) is necessary to improve as well physical as pharmacological therapy. The study of referred muscle/visceral pain and muscle/visceral hyperalgesia may help to uncover such mechanisms as referred is a central mechanism. Referred muscle/visceral pain (and the possible related hyperalgesia) is manifested in somatic structures (skin, muscles, joints, tendons). These manifestations are of significant clinical importance for the diagnosis of deep-tissue pain pathologies. Sensory manifestations of hyperexcitability is found in chronic musculoskeletal (e.g. CLPB, whip-lash, fibromyalgia, osteoarthritis) and visceral pains (e.g. endometriosis, irritable bowel disease, chronic pancreatitis). Recently we have found that patients suffering from chronic musculoskeletal and visceral pains have significantly larger referred pain areas to experimentally induced pain and at the same time they show manifestations of muscle/visceral sensitisation. 6 CENTRAL SENSITIZATION – WIDESPREAD PAIN A.H. Dickenson ° . Pharmacology, University College London, UK Many pain states are driven from changes in the periphery where tissue and/or nerve damage change inputs that arrive within the spinal cord. Understanding this plasticity may lead to improved therapies for the two major types of pain, neuropathic and inflammatory pain, since the peripheral nerve and tissue damage leads to alterations not only at the source of the pain but importantly, also at central levels. Within the spinal cord, these changes underlie central sensitization whereby the response to a given input is increased by central spinal mechanisms. One first stage in this process seems to involve calcium channels that are essential for transmitter release onto spinal neurones – gabapentin and pregabalin may act on these changed channels. This increase in transmitter release leads to greater levels of activation of spinal receptors and increased neuronal excitability. In the spinal cord, the release of peptides and glutamate causes activation of the N-methyl-D-aspartate (NMDA) receptor for glutamate in persistent