- Email: [email protected]
21 CAN SHARED MECHANISMS AND SUBSTRATES INFORM ON TREATMENTS?
Oral presentations / European Journal of Pain Supplements 4 (2010) 1–46
21 CAN SHARED MECHANISMS AND SUBSTRATES INFORM ON TREATMENTS? A. Dickenson. Neuroscience, Physiology, Pharmacology, University College London, London, UK Organisms need to respond to the external world and then process incoming sensory information. It is not surprising then, that commonalities may occur between pain processes and other CNS functions. Many of the peripheral pain receptors arose from families of sensors that allowed organisms to sense their environment. The ability of the spinal cord to increase sensitivity is thought to have its origins in associative learning in primitive organisms. Changes in genes in the spinal cord after persistent inputs include those also associated with chemical sense of smell and memory. Many of these outputs to the brain arrive in limbic areas where affective and vegatative functions reside. Descending controls, originating in these midbrain and brainstem regions and projecting to spinal cord are key links in multiple neural networks that interact to produce the overall pain experience. The balance between descending controls, both excitatory and inhibitory, are altered in various pain states ranging from nerve injury to cancer pain. The potential for higher cognitive function through cortical controls that project to shift descending controls allows for “top-down” processing of pain pathways to alter spinal sensitization, has been shown for placebo. The major transmitter systems implicated in the descending controls are the monoamines, noradrenaline and 5-HT and opioids, also implicated in the pain induced co-morbidities of sleep problems, anxiety and depression. Indeed, increasing NA alters bitter and sour tastes whereas 5HT regulates sweet. Opioids alter taste perception. Broadly, NA and 5HT can alter CNS processes in opposite or complementary directions, with 5HT able to enhance pain whereas NA is generally inhibitory. Preclinical data can explain this on the basis that descending NA actions clearly mediate inhibitions through spinal alpha-2 adrenoceptor receptors whereas 5HT, via 5HT2 and 3 receptors, is the key transmitter in descending facilitations. A number of analgesic drugs interact with descending controls: opioids have direct supraspinal interactions with brainstem systems, pregabalin and gabapentin actions are regulated by descending NA and 5HT pathways and the TCA and SNRI alter synaptic levels of NA and 5HT. Tramadol and tapentadol have mixed mu opioid receptor and reuptake inhibition actions, the former with dual NA/5HT actions, the latter with NA only. TCA and SNRI have greater efficacy than SSRI in neuropathic pain and tapentadol is more powerful than tramadol. Thus increasing 5HT levels appears to reduce the analgesic effects of various molecules, enhance pain and favour negative functions. 22 SHARED MECHANISMS, SHARED TREATMENTS: NEUROPATHIC PAIN AND OTHER PATHOPHYSIOLOGIES J. Hathornthwaite. Center for Mind Body Research, Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA Nerve injuries can precipitate sensitisation in peripheral and central nervous systems so that pain signals are exacerbated (hyperalgesia) or are newly evoked by non-noxious stimuli (allodynia). Similarly, the experience of pain can evoke emotional, behavioral and cognitive responses that may further sensitize these systems and enhance pain. Negative emotions (e.g., anxiety or depression), pain-specific cognitions (e.g., catastrophizing), and behavioral perturbations (e.g., sleep disturbance) are examples of behavioral responses to pain that can further exacerbate pain and have been increasingly linked to alterations in pain modulation. Recent studies of these behavioral processes have direct relevance to the onset and persistence of neuropathic pain, as well as implications for treatment.
7
A2. How to Diagnose Neuropathic Pain 23 WORKSHOP SUMMARY: HOW TO DIAGNOSE NEUROPATHIC PAIN P. Hansson1,2 , M. Backonja3 , D. Bouhassira4 . 1 Department of Molecular Medicine and Surgery and Pain Center, 2 Department of Anesthesiology and Intensive Care, Karolinska University Hospital, Solna/Karolinska Institutet, Stockholm, Sweden; 3 Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA; 4 INSERM U-987, Hopital Ambroise Par´e, Boulogne-Billancourt, France There is currently lack of widely accepted consensus by experts on how to diagnos neuropathic pain. Recently the IASP definition of neuropathic pain (Merskey & Bogduk, 1994) was challenged by a group of neuroscientists and clinicians who also put forth a diagnostic work-up algorithm (Treede et al. 2008). Dr. Hansson will introduce important features of the output of this group. Dr. Backonja will then highlight the neurological decision making process, built on a strong and longstanding neurological tradition, starting with the interview to extract sensory symptoms relevant to neuropathic pain followed by the basic principles of conducting sensory examination with the goal of determining type and extent of sensory abnormalities. Symptoms are often distressing and confusing to patients who have great difficulties in understanding conflicting symptoms (“The skin is numb, I don’t feel it but it hurts”). Though important information is gained from sensory symptoms the critical step leading to confirmation of the diagnosis is somatosensory examination and such measures should be performed to allow detection of both positive and negative signs. The integration of all findings serves as a basis to deduce whether the diagnosis of neuropathic pain is justified. The final step to consider is the likelihood that each patient has more than one type of pain at any given time and that non-neuropathic types of pain also can manifest with sensory abnormalities, thus mimicking neuropathic pain. Dr. Bouhassira will discuss the usefulness and limitations of neuropathic pain questionnaires in light of the recently proposed new definition and graded diagnostic system of neuropathic pain (Treede et al. 2008). The suggested work-up of mainly relies on identification of a neurological lesion or disease and does not take into account the characteristics of pain. Over the last few years, a series of studies have demonstrated that some symptoms (i.e. pain descriptors) can discriminate between neuropathic and non neuropathic pain. This finding allowed the development and validation of a series of simple clinical tools, in the form of questionnaires. Although none of the single pain descriptors was specific, these studies showed consistently that the combination of a relatively small number of items was sufficient to discriminate pain due to a definite neurological lesion. The fact that these different questionnaires, developed independently and in parallel in different countries, share a large number of items strongly supports the validity of this approach. 24 CLINICAL APPLICATIONS OF NEUROPATHIC PAIN QUESTIONNAIRES D. Bouhassira. INSERM U987 Centre d’Evaluation et Traitement de la Douleur, CHU Ambroise Par´e, Boulogne-Billancourt, France According to the new definition and graded diagnostic system proposed recently (Treede et al. 2008), the diagnosis of neuropathic pain should rely on identification of a neurological lesion or disease. One limitation of this proposal is that it does not take into account the characteristics of pain. Over the last few years, a series of studies have demonstrated that, despite its numerous causes, neuropathic pain is characterized by the combination of a relatively small number of ‘core’ symptoms (particularly burning pain, electric
21 CAN SHARED MECHANISMS AND SUBSTRATES INFORM ON TREATMENTS? A. Dickenson. Neuroscience, Physiology, Pharmacology, University College London, London, UK Organisms need to respond to the external world and then process incoming sensory information. It is not surprising then, that commonalities may occur between pain processes and other CNS functions. Many of the peripheral pain receptors arose from families of sensors that allowed organisms to sense their environment. The ability of the spinal cord to increase sensitivity is thought to have its origins in associative learning in primitive organisms. Changes in genes in the spinal cord after persistent inputs include those also associated with chemical sense of smell and memory. Many of these outputs to the brain arrive in limbic areas where affective and vegatative functions reside. Descending controls, originating in these midbrain and brainstem regions and projecting to spinal cord are key links in multiple neural networks that interact to produce the overall pain experience. The balance between descending controls, both excitatory and inhibitory, are altered in various pain states ranging from nerve injury to cancer pain. The potential for higher cognitive function through cortical controls that project to shift descending controls allows for “top-down” processing of pain pathways to alter spinal sensitization, has been shown for placebo. The major transmitter systems implicated in the descending controls are the monoamines, noradrenaline and 5-HT and opioids, also implicated in the pain induced co-morbidities of sleep problems, anxiety and depression. Indeed, increasing NA alters bitter and sour tastes whereas 5HT regulates sweet. Opioids alter taste perception. Broadly, NA and 5HT can alter CNS processes in opposite or complementary directions, with 5HT able to enhance pain whereas NA is generally inhibitory. Preclinical data can explain this on the basis that descending NA actions clearly mediate inhibitions through spinal alpha-2 adrenoceptor receptors whereas 5HT, via 5HT2 and 3 receptors, is the key transmitter in descending facilitations. A number of analgesic drugs interact with descending controls: opioids have direct supraspinal interactions with brainstem systems, pregabalin and gabapentin actions are regulated by descending NA and 5HT pathways and the TCA and SNRI alter synaptic levels of NA and 5HT. Tramadol and tapentadol have mixed mu opioid receptor and reuptake inhibition actions, the former with dual NA/5HT actions, the latter with NA only. TCA and SNRI have greater efficacy than SSRI in neuropathic pain and tapentadol is more powerful than tramadol. Thus increasing 5HT levels appears to reduce the analgesic effects of various molecules, enhance pain and favour negative functions. 22 SHARED MECHANISMS, SHARED TREATMENTS: NEUROPATHIC PAIN AND OTHER PATHOPHYSIOLOGIES J. Hathornthwaite. Center for Mind Body Research, Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA Nerve injuries can precipitate sensitisation in peripheral and central nervous systems so that pain signals are exacerbated (hyperalgesia) or are newly evoked by non-noxious stimuli (allodynia). Similarly, the experience of pain can evoke emotional, behavioral and cognitive responses that may further sensitize these systems and enhance pain. Negative emotions (e.g., anxiety or depression), pain-specific cognitions (e.g., catastrophizing), and behavioral perturbations (e.g., sleep disturbance) are examples of behavioral responses to pain that can further exacerbate pain and have been increasingly linked to alterations in pain modulation. Recent studies of these behavioral processes have direct relevance to the onset and persistence of neuropathic pain, as well as implications for treatment.
7
A2. How to Diagnose Neuropathic Pain 23 WORKSHOP SUMMARY: HOW TO DIAGNOSE NEUROPATHIC PAIN P. Hansson1,2 , M. Backonja3 , D. Bouhassira4 . 1 Department of Molecular Medicine and Surgery and Pain Center, 2 Department of Anesthesiology and Intensive Care, Karolinska University Hospital, Solna/Karolinska Institutet, Stockholm, Sweden; 3 Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA; 4 INSERM U-987, Hopital Ambroise Par´e, Boulogne-Billancourt, France There is currently lack of widely accepted consensus by experts on how to diagnos neuropathic pain. Recently the IASP definition of neuropathic pain (Merskey & Bogduk, 1994) was challenged by a group of neuroscientists and clinicians who also put forth a diagnostic work-up algorithm (Treede et al. 2008). Dr. Hansson will introduce important features of the output of this group. Dr. Backonja will then highlight the neurological decision making process, built on a strong and longstanding neurological tradition, starting with the interview to extract sensory symptoms relevant to neuropathic pain followed by the basic principles of conducting sensory examination with the goal of determining type and extent of sensory abnormalities. Symptoms are often distressing and confusing to patients who have great difficulties in understanding conflicting symptoms (“The skin is numb, I don’t feel it but it hurts”). Though important information is gained from sensory symptoms the critical step leading to confirmation of the diagnosis is somatosensory examination and such measures should be performed to allow detection of both positive and negative signs. The integration of all findings serves as a basis to deduce whether the diagnosis of neuropathic pain is justified. The final step to consider is the likelihood that each patient has more than one type of pain at any given time and that non-neuropathic types of pain also can manifest with sensory abnormalities, thus mimicking neuropathic pain. Dr. Bouhassira will discuss the usefulness and limitations of neuropathic pain questionnaires in light of the recently proposed new definition and graded diagnostic system of neuropathic pain (Treede et al. 2008). The suggested work-up of mainly relies on identification of a neurological lesion or disease and does not take into account the characteristics of pain. Over the last few years, a series of studies have demonstrated that some symptoms (i.e. pain descriptors) can discriminate between neuropathic and non neuropathic pain. This finding allowed the development and validation of a series of simple clinical tools, in the form of questionnaires. Although none of the single pain descriptors was specific, these studies showed consistently that the combination of a relatively small number of items was sufficient to discriminate pain due to a definite neurological lesion. The fact that these different questionnaires, developed independently and in parallel in different countries, share a large number of items strongly supports the validity of this approach. 24 CLINICAL APPLICATIONS OF NEUROPATHIC PAIN QUESTIONNAIRES D. Bouhassira. INSERM U987 Centre d’Evaluation et Traitement de la Douleur, CHU Ambroise Par´e, Boulogne-Billancourt, France According to the new definition and graded diagnostic system proposed recently (Treede et al. 2008), the diagnosis of neuropathic pain should rely on identification of a neurological lesion or disease. One limitation of this proposal is that it does not take into account the characteristics of pain. Over the last few years, a series of studies have demonstrated that, despite its numerous causes, neuropathic pain is characterized by the combination of a relatively small number of ‘core’ symptoms (particularly burning pain, electric