- Email: [email protected]
T157 DYNAMIC MECHANICAL ALLODYNIA: THE ROLE OF UNMYELINATED TACTILE (CT) AFFERENTS
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
that the two responses reflect the entrainment of distinct neuronal populations. For both types of SSEPs, the signal-to-noise was smaller at 7 and 13 Hz, possibly because of background alpha-band activity. Unlike conventional nociceptive event-related potentials, nociceptive SSEPs did not habituate, suggesting that they reflect more obligatory stages of sensory-processing. Conclusions: The recording of nociceptive and non-nociceptive somatosensory SSEPs offers a unique opportunity to study the cortical representation of nociception and touch in humans. Disclosure: None declared
T155 MAPPING OF CENTRAL CHANGES, USING cASL, INDUCED BY POST-SURGICAL PAIN AFTER THIRD MOLAR SURGERY BEFORE AND AFTER PARACETAMOL INFUSION N. Khawaja1 *, M. Howard2 , S. Williams2 , T. Renton1 . 1 Oral Surgery, King’s College London, 2 Department of Neuroimaging, King’s College London, Institute of Psychiatry, London, UK Background and Aims: Continuous arterial spin labelling (cASL), a perfusion MRI technique, provides quantitative measurements of regional cerebral blood flow (rCBF) throughout the brain. Previously we demonstrated the sensitivity of the technique to represent acute ongoing post-surgical pain. Here we intended to assess the sensitivity of cASL to represent changes in rCBF associated with a reduction in pain following administration of an analgesic. Intravenous paracetamol is one of the most commonly used analgesics in general surgery. However, its mechanism of action is not fully understood. This study examines the cerebral representation of paracetamol infusion resulting from attenuation of pain following third molar surgery (TMS). Methods: Prior to and following TMS, 15 right handed males underwent a series of cASL scans during which they received saline and paracetamol infusions. Participants provided VAS estimates of pain intensity during scanning. Results: There was a marked reduction in pain scores following paracetamol infusion from 8/10 to 0.5/10. Preliminary results indicate that cASL detects a differential effect of intravenous paracetamol on pain following TMS. This is reflected by changes in rCBF between the saline and paracetamol infusions in brain regions including the anterior cingulate, somatosensory and insula cortices, and brainstem (Fig. 1).
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Conclusions: We provide early indications demonstrating that cASL is a sensitive marker for pharmacological modulation of brain activity as a result of attenuation of pain. This study provides scope for developing this technique as a pain biomarker in the development of novel analgesics. Disclosure: None declared
T156 LIMBIC STRUCTURES AND RESPONSE TO ANTI-TNF TREATMENT K. Wartolowska1 *, P. Wordsworth2 , I. Tracey1 . 1 NDA, NDCS, 2 National Institute for Health Research Oxford Musculoskeletal Biomechanical Research Unit, Nuffield Orthopaedic Centre, Oxford, UK Background and Aims: Tumor necrosis factor (TNF) is a key cytokine in joint inflammation. TNF blockers suppress disease activity in severe rheumatoid arthritis (RA) by reducing both joint pain and inflammation. In this study we used functional magnetic resonance imaging (FMRI) to investigate changes in brain activation in response to joint pressure pain and to examine whether brain activation pattern could differentiate responders from non-responders. Methods: Fifteen patients have responded to the treatment and completed the follow up visit 6–10 months after the start of the anti-TNF. Five patients did not respond and had their medication changed. During the imaging session, the most painful joint of patient’s right hand was pressed with a purpose-built device. We have analysed changes in pressure-evoked brain activation before, i.e. at the baseline, and after treatment in the responders group. We have also compared brain activation at the baseline in the responders and non-responders group. Results: In the responders group, treatment resulted in a decrease in brain activation in the primary motor, premotor, primary somatosensory and insular cortices as well as in the hippocampus and the amygdala. At the baseline, the hippocampus, the amygdala and the insular cortex showed stronger activation in the responders group, whereas the medial prefrontal cortex was activated stronger in the non-responders group. Conclusions: We observed a reduction in brain activation in response to pressure stimulus. The decrease was most pronounced in the hippocampus and the amygdala – the same regions that differentiated responders and non-responders at the baseline. Disclosure: None declared
T157 DYNAMIC MECHANICAL ALLODYNIA: THE ROLE OF UNMYELINATED TACTILE (CT) AFFERENTS L. Loken *, E. Duff, I. Tracey. Department of Clinical Neurosciences, University of Oxford, Oxford, UK
Figure: Post-surgical CBF changes after IV paracetamol.
Background and Aims: The mechanisms underlying primary dynamic mechanical allodynia remains elusive. Previous microneurography recordings during soft brush stroking has shown that discharge rates in unmyelinated tactile (CT) afferents respond optimally to soft brush stroking with velocities at 1–10 cm/s whereas myelinated afferents increase their firing rate with increasing stimulus velocity (Loken et al., Nat Neurosci 2009). Here, we adressed the relationship between firing rate and unpleasantness of primary dynamic mechanical allodynia. Methods: To evoke dynamic-mechanical allodynia, capsaicin cream (1%) was topically applied to one of two areas marked on the forearm in 8 healthy participants. Brush strokings (soft goat hair, 30 mm) were applied manually over a distance of 6 cm with velocities of 0.3, 1, 3, 10 or 30 cm/s. Stroking stimuli were alternated between capsaicin treated and non-treated skin. Following each stimulation, the participant rated perception of the brush stroking on a visual analog scale (VAS) with the endpoints “unpleasant” and “pleasant”. Results: At the non-treated area, participants perceived brush stroking as pleasant at velocities optimal to elicit CT afferent
32
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
activation (1–10 cm/s). At the capsaicin treated area, participants rating pattern across velocities deviated markedly from hedonic touch. Specifically, velocities of 0.3 cm/s elicited the most painful sensation which decreased as velocity increased. Conclusions: These results indicate that primary dynamic mechanical allodynia is most efficiently evoked at slow stimulus velocities, where discharge rates in CT and myelinated afferents are low. In contrast, stimulus velocities optimal for eliciting high discharge rates in myelinated afferents were percieved as relieving. Disclosure: None declared
T158 THE RELATIONSHIP BETWEEN RESTING BLOOD PRESSURE AND COLD PAIN SENSITIVITY IN A GENERAL POPULATION. THE TROMSØ STUDY R.B. Olsen1 *, C.S. Nielsen2 , A. Johansen3 , L.A. Rosseland1 , A. Stubhaug1 . 1 Division of Critical Care, Oslo University Hospital, Rikshospitalet, Norway; 2 Division of Mental Health, Norwegian Institute of Public Health, Oslo, 3 Division of Surgical Medicine and Intensive Care, University Hospital of North Norway, Tromsø, Norway Background and Aims: Elevated resting blood pressure (BP) is associated with reduced acute pain sensitivity in healthy normotensive individuals. We examined the relationship between resting BP and acute cold pain sensitivity in a population-based study. Methods: The sixth survey of the Tromsø Study was conducted in 2007–8 and included a total of 12,982 participants (46.6% men and 53.4% women), aged 30–87 years. We studied 10,265 of these with the Cold pressor test (3°C, maximum 106 seconds). Pain intensity ratings (NRS 0–10) were obtained after 4 seconds and every 9 seconds thereafter. Pain sensitivity was calculated as a mean of all 12 NRS ratings. If the subject withdrew before the full 106 seconds the missing values were set to NRS = 10. Three resting BP determinations were made, and the mean of the last two were used for analysis. Results: In a linear regression analysis adjusted for age, sex and BMI, the acute cold pain sensitivity decreased with increasing BP. This was the case for both systolic (b = −0.009, 95% CI: −0.011 to −0.007, P < 0.001) and diastolic (b = −0.014, 95% CI: −0.018 to −0.010, P < 0.001) BP. Conclusions: This study in a general population confirms that hypoalgesia is associated with elevated resting BP, as previously found in smaller samples. Disclosure: None declared
T159 A NOVEL METHOD FOR EXAMINING VISCERAL HYPERALGESIA COMBINED WITH VISUAL INSPECTION IN THE HEALTHY HUMAN OESOPHAGUS A.L. Krarup *, F.H. Lundager, A.M. Drewes. Aalborg Hopsital, Aarhus University, Aalborg, Denmark Background and Aims: The multimodal oesophageal pain model can induce hyperalgesia with an acid perfusion, but visual inspection of mucosal redness has not before been built into the probe. The aims were to develop a new technique for inducing hyperalgesia in the oesophagus combined with continuous visual inspection of the mucosa. Methods: A probe (picture) was constructed combining the multimodal oesophageal probe with a PillCam SB mini-videocamera (Given Imaging). A 0.6 cm thin probe was fitted with a PillCam on the tip facing distal and recording 2 pictures/second. A bag was mounted 2–7 cm proximal to the PillCam, electrodes 11 cm and 20 cm, and a hole for acid perfusion 12 cm proximal to it. A syringe pump controlled water infusion and deflation. Electrical stimuli were applied by a constant current generator. Four healthy volunteers were studied; the probe positioned with the bag 8 cm proximal to the oesophago-gastric junction using the PillCam.
Pain to distension, heat, and electrical current was evoked before and after an acid perfusion inducing hyperalgesia. Simultaneously mucosa colour changes were recorded. Results: In all four subjects acid induced hyperalgesia was measured and increased mucosal redness observed with PillCam pictures. The recorded pictures were of quality comparable to endoscopy. Conclusions: The constructed probe enabled: 1. easy placement, 2. continuous verification of placement during distension, heat, electrical and acid stimulations, and 3. simultaneous visual inspection of the mucosa. With this new feature it will be possible to study oesophageal hyperalgesia in greater detail.
Figure: Probe for visual inspection of the mucosa. Disclosure: None declared
T160 THE ROLE OF DOPAMINE IN PLACEBO ANALGESIA N. Wrobel1,2 *, C. Ritter1,2 , K. Wiech3,4 , U. Bingel1,2 . 1 Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, 2 Department of Neurology, University Medical Center Hamburg Eppendorf, Hamburg, Germany; 3 Nuffield Department of Anaesthetics, University of Oxford, 4 Department of Clinical Neurology, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, John Radcliffe Hospital, Oxford, UK Background: Eventhough numerous studies have underlined the importance of the endogenous opioid system for placebo analgesia (PA), involvement of other neurotransmitter systems such as the dopaminergic system (DS) has been suggested for PA (Scott et al, 2007). Specifically, PA has been associated with increasing dopaminergic activity in the nucleus accumbens, which correlates with the individual magnitude of the placebo response. Our study aims to unravel the functional significance of dopaminergic neurotransmission for PA: is dopamineric activity causally related to the antinociceptive effect, or simply an “epiphenomenon” reflecting the expectancy of reward inherent to the pain relief during PA. Methods: In this fMRI study 49 participants completed a wellestablished placebo paradigm (Eippert et al., 2009). Prior to fMRI scanning, the DS was modulated by the oral administration of the D2-antagonist haloperidol (2 mg) using a randomized, double blind design. Results: On the behavioural level a significant placebo response could be elicited in the haloperidol and control group. Side effect profiles, mood scales and haloperidol plasma levels indicate a successful pharmacological modulation of the DS. However, haloperidol did not significantly change the placebo response. Furthermore, no differences in the perception of pain applied in the control (no placebo) condition or heat pain thresholds were observed. The ongoing fMRI data analysis will be presented. Conclusions: The behavioural results indicate that the antinociceptive effect during PA does not depend on dopaminergic neurotransmission, as challended in our paradigm but with the reward component of PA.
that the two responses reflect the entrainment of distinct neuronal populations. For both types of SSEPs, the signal-to-noise was smaller at 7 and 13 Hz, possibly because of background alpha-band activity. Unlike conventional nociceptive event-related potentials, nociceptive SSEPs did not habituate, suggesting that they reflect more obligatory stages of sensory-processing. Conclusions: The recording of nociceptive and non-nociceptive somatosensory SSEPs offers a unique opportunity to study the cortical representation of nociception and touch in humans. Disclosure: None declared
T155 MAPPING OF CENTRAL CHANGES, USING cASL, INDUCED BY POST-SURGICAL PAIN AFTER THIRD MOLAR SURGERY BEFORE AND AFTER PARACETAMOL INFUSION N. Khawaja1 *, M. Howard2 , S. Williams2 , T. Renton1 . 1 Oral Surgery, King’s College London, 2 Department of Neuroimaging, King’s College London, Institute of Psychiatry, London, UK Background and Aims: Continuous arterial spin labelling (cASL), a perfusion MRI technique, provides quantitative measurements of regional cerebral blood flow (rCBF) throughout the brain. Previously we demonstrated the sensitivity of the technique to represent acute ongoing post-surgical pain. Here we intended to assess the sensitivity of cASL to represent changes in rCBF associated with a reduction in pain following administration of an analgesic. Intravenous paracetamol is one of the most commonly used analgesics in general surgery. However, its mechanism of action is not fully understood. This study examines the cerebral representation of paracetamol infusion resulting from attenuation of pain following third molar surgery (TMS). Methods: Prior to and following TMS, 15 right handed males underwent a series of cASL scans during which they received saline and paracetamol infusions. Participants provided VAS estimates of pain intensity during scanning. Results: There was a marked reduction in pain scores following paracetamol infusion from 8/10 to 0.5/10. Preliminary results indicate that cASL detects a differential effect of intravenous paracetamol on pain following TMS. This is reflected by changes in rCBF between the saline and paracetamol infusions in brain regions including the anterior cingulate, somatosensory and insula cortices, and brainstem (Fig. 1).
31
Conclusions: We provide early indications demonstrating that cASL is a sensitive marker for pharmacological modulation of brain activity as a result of attenuation of pain. This study provides scope for developing this technique as a pain biomarker in the development of novel analgesics. Disclosure: None declared
T156 LIMBIC STRUCTURES AND RESPONSE TO ANTI-TNF TREATMENT K. Wartolowska1 *, P. Wordsworth2 , I. Tracey1 . 1 NDA, NDCS, 2 National Institute for Health Research Oxford Musculoskeletal Biomechanical Research Unit, Nuffield Orthopaedic Centre, Oxford, UK Background and Aims: Tumor necrosis factor (TNF) is a key cytokine in joint inflammation. TNF blockers suppress disease activity in severe rheumatoid arthritis (RA) by reducing both joint pain and inflammation. In this study we used functional magnetic resonance imaging (FMRI) to investigate changes in brain activation in response to joint pressure pain and to examine whether brain activation pattern could differentiate responders from non-responders. Methods: Fifteen patients have responded to the treatment and completed the follow up visit 6–10 months after the start of the anti-TNF. Five patients did not respond and had their medication changed. During the imaging session, the most painful joint of patient’s right hand was pressed with a purpose-built device. We have analysed changes in pressure-evoked brain activation before, i.e. at the baseline, and after treatment in the responders group. We have also compared brain activation at the baseline in the responders and non-responders group. Results: In the responders group, treatment resulted in a decrease in brain activation in the primary motor, premotor, primary somatosensory and insular cortices as well as in the hippocampus and the amygdala. At the baseline, the hippocampus, the amygdala and the insular cortex showed stronger activation in the responders group, whereas the medial prefrontal cortex was activated stronger in the non-responders group. Conclusions: We observed a reduction in brain activation in response to pressure stimulus. The decrease was most pronounced in the hippocampus and the amygdala – the same regions that differentiated responders and non-responders at the baseline. Disclosure: None declared
T157 DYNAMIC MECHANICAL ALLODYNIA: THE ROLE OF UNMYELINATED TACTILE (CT) AFFERENTS L. Loken *, E. Duff, I. Tracey. Department of Clinical Neurosciences, University of Oxford, Oxford, UK
Figure: Post-surgical CBF changes after IV paracetamol.
Background and Aims: The mechanisms underlying primary dynamic mechanical allodynia remains elusive. Previous microneurography recordings during soft brush stroking has shown that discharge rates in unmyelinated tactile (CT) afferents respond optimally to soft brush stroking with velocities at 1–10 cm/s whereas myelinated afferents increase their firing rate with increasing stimulus velocity (Loken et al., Nat Neurosci 2009). Here, we adressed the relationship between firing rate and unpleasantness of primary dynamic mechanical allodynia. Methods: To evoke dynamic-mechanical allodynia, capsaicin cream (1%) was topically applied to one of two areas marked on the forearm in 8 healthy participants. Brush strokings (soft goat hair, 30 mm) were applied manually over a distance of 6 cm with velocities of 0.3, 1, 3, 10 or 30 cm/s. Stroking stimuli were alternated between capsaicin treated and non-treated skin. Following each stimulation, the participant rated perception of the brush stroking on a visual analog scale (VAS) with the endpoints “unpleasant” and “pleasant”. Results: At the non-treated area, participants perceived brush stroking as pleasant at velocities optimal to elicit CT afferent
32
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
activation (1–10 cm/s). At the capsaicin treated area, participants rating pattern across velocities deviated markedly from hedonic touch. Specifically, velocities of 0.3 cm/s elicited the most painful sensation which decreased as velocity increased. Conclusions: These results indicate that primary dynamic mechanical allodynia is most efficiently evoked at slow stimulus velocities, where discharge rates in CT and myelinated afferents are low. In contrast, stimulus velocities optimal for eliciting high discharge rates in myelinated afferents were percieved as relieving. Disclosure: None declared
T158 THE RELATIONSHIP BETWEEN RESTING BLOOD PRESSURE AND COLD PAIN SENSITIVITY IN A GENERAL POPULATION. THE TROMSØ STUDY R.B. Olsen1 *, C.S. Nielsen2 , A. Johansen3 , L.A. Rosseland1 , A. Stubhaug1 . 1 Division of Critical Care, Oslo University Hospital, Rikshospitalet, Norway; 2 Division of Mental Health, Norwegian Institute of Public Health, Oslo, 3 Division of Surgical Medicine and Intensive Care, University Hospital of North Norway, Tromsø, Norway Background and Aims: Elevated resting blood pressure (BP) is associated with reduced acute pain sensitivity in healthy normotensive individuals. We examined the relationship between resting BP and acute cold pain sensitivity in a population-based study. Methods: The sixth survey of the Tromsø Study was conducted in 2007–8 and included a total of 12,982 participants (46.6% men and 53.4% women), aged 30–87 years. We studied 10,265 of these with the Cold pressor test (3°C, maximum 106 seconds). Pain intensity ratings (NRS 0–10) were obtained after 4 seconds and every 9 seconds thereafter. Pain sensitivity was calculated as a mean of all 12 NRS ratings. If the subject withdrew before the full 106 seconds the missing values were set to NRS = 10. Three resting BP determinations were made, and the mean of the last two were used for analysis. Results: In a linear regression analysis adjusted for age, sex and BMI, the acute cold pain sensitivity decreased with increasing BP. This was the case for both systolic (b = −0.009, 95% CI: −0.011 to −0.007, P < 0.001) and diastolic (b = −0.014, 95% CI: −0.018 to −0.010, P < 0.001) BP. Conclusions: This study in a general population confirms that hypoalgesia is associated with elevated resting BP, as previously found in smaller samples. Disclosure: None declared
T159 A NOVEL METHOD FOR EXAMINING VISCERAL HYPERALGESIA COMBINED WITH VISUAL INSPECTION IN THE HEALTHY HUMAN OESOPHAGUS A.L. Krarup *, F.H. Lundager, A.M. Drewes. Aalborg Hopsital, Aarhus University, Aalborg, Denmark Background and Aims: The multimodal oesophageal pain model can induce hyperalgesia with an acid perfusion, but visual inspection of mucosal redness has not before been built into the probe. The aims were to develop a new technique for inducing hyperalgesia in the oesophagus combined with continuous visual inspection of the mucosa. Methods: A probe (picture) was constructed combining the multimodal oesophageal probe with a PillCam SB mini-videocamera (Given Imaging). A 0.6 cm thin probe was fitted with a PillCam on the tip facing distal and recording 2 pictures/second. A bag was mounted 2–7 cm proximal to the PillCam, electrodes 11 cm and 20 cm, and a hole for acid perfusion 12 cm proximal to it. A syringe pump controlled water infusion and deflation. Electrical stimuli were applied by a constant current generator. Four healthy volunteers were studied; the probe positioned with the bag 8 cm proximal to the oesophago-gastric junction using the PillCam.
Pain to distension, heat, and electrical current was evoked before and after an acid perfusion inducing hyperalgesia. Simultaneously mucosa colour changes were recorded. Results: In all four subjects acid induced hyperalgesia was measured and increased mucosal redness observed with PillCam pictures. The recorded pictures were of quality comparable to endoscopy. Conclusions: The constructed probe enabled: 1. easy placement, 2. continuous verification of placement during distension, heat, electrical and acid stimulations, and 3. simultaneous visual inspection of the mucosa. With this new feature it will be possible to study oesophageal hyperalgesia in greater detail.
Figure: Probe for visual inspection of the mucosa. Disclosure: None declared
T160 THE ROLE OF DOPAMINE IN PLACEBO ANALGESIA N. Wrobel1,2 *, C. Ritter1,2 , K. Wiech3,4 , U. Bingel1,2 . 1 Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, 2 Department of Neurology, University Medical Center Hamburg Eppendorf, Hamburg, Germany; 3 Nuffield Department of Anaesthetics, University of Oxford, 4 Department of Clinical Neurology, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, John Radcliffe Hospital, Oxford, UK Background: Eventhough numerous studies have underlined the importance of the endogenous opioid system for placebo analgesia (PA), involvement of other neurotransmitter systems such as the dopaminergic system (DS) has been suggested for PA (Scott et al, 2007). Specifically, PA has been associated with increasing dopaminergic activity in the nucleus accumbens, which correlates with the individual magnitude of the placebo response. Our study aims to unravel the functional significance of dopaminergic neurotransmission for PA: is dopamineric activity causally related to the antinociceptive effect, or simply an “epiphenomenon” reflecting the expectancy of reward inherent to the pain relief during PA. Methods: In this fMRI study 49 participants completed a wellestablished placebo paradigm (Eippert et al., 2009). Prior to fMRI scanning, the DS was modulated by the oral administration of the D2-antagonist haloperidol (2 mg) using a randomized, double blind design. Results: On the behavioural level a significant placebo response could be elicited in the haloperidol and control group. Side effect profiles, mood scales and haloperidol plasma levels indicate a successful pharmacological modulation of the DS. However, haloperidol did not significantly change the placebo response. Furthermore, no differences in the perception of pain applied in the control (no placebo) condition or heat pain thresholds were observed. The ongoing fMRI data analysis will be presented. Conclusions: The behavioural results indicate that the antinociceptive effect during PA does not depend on dopaminergic neurotransmission, as challended in our paradigm but with the reward component of PA.