- Email: [email protected]
339 Case report: Ziconotide treatment for a neuropathic and a degenerative pain problem
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Poster Presentations / Molecular / Cellular studies I & II / European Journal of Pain 11(S1) (2007) S59–S207
337 THE UTILITY OF PREGABALIN IN NEUROPATHIC PAIN PATIENTS – DEGREE OF BENEFIT IN RESPONDERS AND NON-RESPONDERS TO GABAPENTIN C. Toth Department of Clinical Neurosciences, Foothills Medical Complex, Calgary, AB, Canada Background. The new gabapentinoid, pregabalin (PGB), is effective in therapy of neuropathic pain (NeP) in patients with diabetic peripheral neuropathy (DPN), and possibly in patients with other forms of peripheral neuropathy (PN). It is uncertain as to whether PGB is more effective and better tolerated than gabapentin (GBP) in this patient population. Methods. Patients with NeP due to PN diagnosed at a tertiary care neuromuscular clinic were initially treated with GBP, with a minimum dose of 1200 mg daily. Both responders [defined as >30% decrease in visual analog score (VAS) of pain], and non-responders had therapy exchanged for PGB, which was commenced immediately with discontinuation of GBP, no washout period, and no overlap of therapy. Results. A total of 23 responders and 10 nonresponders to GBP were switched to PGB. Approximately 40% of patients had a diagnosis of DPN, with other various forms of neuropathy identified. The duration of PGB therapy averaged 6 months. The average dose of 2000 mg of GBP was replaced by an average dose of 375 mg of PGB, with a further 25% improvement in VAS in responders, and 21% in non-responders over GBP. Sixty percent of GBP non-responders were deemed a successful responder to PGB. Side effects due to either GBP or PGB were more common in non-responders to GBP, and discontinuations were only identified in GBP non-responders. Conclusion. PGB may improve NeP relief in both responders and non-responders to GBP. Future studies are needed which include quality of life assessments and head-to-head comparisons. doi:10.1016/j.ejpain.2007.03.352
338 OXYCODONE IN NEUROPATHIC CLINICAL EXPERIENCE D. Ventura Vargas *, S. Martin Sanchez
PAIN:
A
Department of Anaesthesiology, Hospital De Puerto Real, Puerto Real, Spain Background and aims. The aim of this study is to prove the need of opioids, oxycodone in this case, as a coadjuvant treatment in neuropathic pain.
Methods. Fifty patients with neuropathic pain between 50 and 60 years old were selected, all of them with an unremarkable clinical history except a bilateral radiculopathy in both legs secondary to a lumbar disc hernia at L3–L4 level. These patients were treated with Oxycodone, Pregabalin, Duloxetine. A VAS assessment and a Lattinen test were performed at the beginning of the study and after 2 months of treatment. Results. A mean decrease in VAS of 3 points ± SD was obtained in 80% of cases and of 5 points ± SD in Lattinen. A 15% of cases presented adverse reactions. A 5% of cases did not experience any improvement. Conclusion. Oxycodone is an acceptable option in association with Pregabalin and Duloxetine in neuropathic pain due to lumbar discopathy. doi:10.1016/j.ejpain.2007.03.353
339 CASE REPORT: ZICONOTIDE TREATMENT FOR A NEUROPATHIC AND A DEGENERATIVE PAIN PROBLEM A. Ver Donck Multidisciplinary Pain Centre, AZ Sint Jan, Brugge, Belgium Background. Ziconotide, an intrathecal non-opioid analgesic, was approved in the European Union in 2005 for severe, chronic pain. Case report. Following three unsuccessful operations for herniated discs, RS was diagnosed in 2001 with bilateral neuralgia in the T5–T8 region. In 2002, thoracic pain was compounded with low back and leg pain due to L5–S1 disc degeneration. Spinal cord stimulation was not effective, obesity was a contraindication for morphine and surgery was not advised. The multidisciplinary team recommended enrollment into a randomised controlled trial with ziconotide. At study start (January 2005), RS was receiving tramadol, gabapentin, chlorothiazide, morphine immediate release, paracetamol/codeine, indomethacin and sertraline. Ziconotide was titrated over 25 days via an IT catheter, placed at the T9–T10 level, and external pump from a starting dose of 2.4 lg/day to 3.12 lg/ day. RS responded favourably, with Visual Analogue Scale of Pain Intensity (VASPI) being reduced from 84 mm to 45 mm. A SynchroMedÒ infusion system was implanted and RS was enrolled in a follow-up study, during which ziconotide was titrated from 2.4 lg/day to 6.0 lg/day. VASPI varied between 65 mm and 46 mm. RS is currently on ziconotide 8.4 lg/day. Gabapentin, morphine and paracetamol/
Poster Presentations / Molecular / Cellular studies I & II / European Journal of Pain 11(S1) (2007) S59–S207
codeine have been withdrawn. Side effects, e.g. dizziness and blurred vision, have been successfully managed by dose reduction. Conclusion. A stable dose of ziconotide has provided an acceptable level of pain reduction in a dual problem: neuropathic pain on a thoracic level and degenerative low back and leg pain. doi:10.1016/j.ejpain.2007.03.354
Poster Session 2: Molecular/Cellular studies I & II 340 NUMBERS, DENSITIES AND CO-LOCALIZATION OF AMPA AND NMDA RECEPTORS AT INDIVIDUAL SYNAPTIC CONTACT AREAS IN THE SUPERFICIAL SPINAL DORSAL HORN M. Antal *,a, Y. Fukozawa b, M. Eo¨rdo¨gh a, R. Shigemoto b a
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Hungary b Division of Cerebral Structures, National Institutes for Physiological Sciences, Myodaiji, Okazaki, Japan The well established role of AMPA- and NMDA-type ionotropic glutamate receptor mechanisms in the induction of spinal LTP and consecutive pain makes these receptors exceptionally important in spinal processing of nociceptive sensory signals. Here we applied the SDS-FRL method to laminae I–II of the spinal dorsal horn of rats and investigated the numbers, densities and co-localization of AMPA and NMDA receptors at individual postsynaptic active zones with a high molecular resolution. We demonstrated that the average surface area of glutamatergic postsynaptic active zones in laminae I–II was 0.0546 lm2. We also showed that all glutamatergic postsynaptic membranes in laminae I–II expressed AMPA receptors, and most of them (96.2%) were immunostained also for the NR1 subunit of NMDA receptors. The numbers of gold particles labeling AMPAand NMDA-type glutamate receptor ion channels at individual postsynaptic membranes varied in the range of 8–214 and 5–232 with mean values of 50.98 and 41.6, whereas their densities varied in the range of 325– 3365 lm 2 and 84–2263 lm 2 with a mean of 1136.2 lm 2 and 786.8 lm 2, respectively. Concerning the subunits of AMPA receptors, it was revealed that virtually all (98.8%) investigated postsynaptic membranes expressed GluR2 subunits, and most of them (90.4%) were also immunoreactivity for GluR1. The size of postsynaptic surface areas showed a more or less linear correlation with the numbers of AMPA and NMDA
S151
receptors. However, GluR1 expression was exceptionally low in postsynaptic active zones larger than 0.1 lm2. doi:10.1016/j.ejpain.2007.03.355
341 NEUROPATHIC PAIN AND SPINAL GLIA: CHARACTERIZATION OF C-JUN N-TERMINAL KINASE (JNK) ACTIVATION IN ASTROCYTE CULTURES A.T. Beggah *,a,b, A. Parent c, M. Pertin a,b, C. Bonny d,e, L. Pellerin c, R.R. Ji f, I. Decosterd a,b a
Anesthesiology Department, Lausanne University, Switzerland b Department of Cellular Biology and Morphology, Lausanne University, Switzerland c Department of Physiology, Lausanne University, Switzerland d Unit of Medical Genetics, Lausanne University, Switzerland e Xigen S.A., Lausanne, Switzerland f Department of Anesthesiology, Pain Research Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA Pain hypersensitivity and central changes following peripheral nerve injury are not only mediated by neurons. Recent evidence has demonstrated the activation of glia plays an important role in the generation/maintenance of neuropathic pain. For instance, spinal nerve ligation induces activation of JNK in spinal astrocytes and intrathecal administration of JNK inhibitors can alleviate neuropathic pain. In order to define how JNK is activated in spinal astrocytes, we set up an in vitro assay to study JNK activation. Primary cultures of astrocytes from neonatal mice were stimulated with proinflammatory cytokines and trophic factors (TNFalpha, IL-1beta, BDNF, FGF and IL-6). The astrocyte cultures were harvested at different times after stimulation. The activation of JNK pathway was assessed by Western blot using antibodies against the phosphorylated forms of JNK (pJNK) and c-jun (p-c-jun). Data obtained from triplicate wells showed that among these agents, TNFalpha induced a substantial and reproducible increase of both p-JNK and p-c-jun levels at 15 min and 30 min. These data have demonstrated that in cultured astrocytes JNK pathway is readily activated by physiologically-relevant mediators. This in vitro model of JNK activation is valuable to determine downstream mechanisms of JNK activation. We are currently assessing JNK-mediated transcriptional regulation of targeted genes with quantitative RT-PCR after blocking the JNK pathway with the peptide inhibitor D-JNKI-1. The identification of downstream elements of JNK pathway in astrocytes will pro-
Poster Presentations / Molecular / Cellular studies I & II / European Journal of Pain 11(S1) (2007) S59–S207
337 THE UTILITY OF PREGABALIN IN NEUROPATHIC PAIN PATIENTS – DEGREE OF BENEFIT IN RESPONDERS AND NON-RESPONDERS TO GABAPENTIN C. Toth Department of Clinical Neurosciences, Foothills Medical Complex, Calgary, AB, Canada Background. The new gabapentinoid, pregabalin (PGB), is effective in therapy of neuropathic pain (NeP) in patients with diabetic peripheral neuropathy (DPN), and possibly in patients with other forms of peripheral neuropathy (PN). It is uncertain as to whether PGB is more effective and better tolerated than gabapentin (GBP) in this patient population. Methods. Patients with NeP due to PN diagnosed at a tertiary care neuromuscular clinic were initially treated with GBP, with a minimum dose of 1200 mg daily. Both responders [defined as >30% decrease in visual analog score (VAS) of pain], and non-responders had therapy exchanged for PGB, which was commenced immediately with discontinuation of GBP, no washout period, and no overlap of therapy. Results. A total of 23 responders and 10 nonresponders to GBP were switched to PGB. Approximately 40% of patients had a diagnosis of DPN, with other various forms of neuropathy identified. The duration of PGB therapy averaged 6 months. The average dose of 2000 mg of GBP was replaced by an average dose of 375 mg of PGB, with a further 25% improvement in VAS in responders, and 21% in non-responders over GBP. Sixty percent of GBP non-responders were deemed a successful responder to PGB. Side effects due to either GBP or PGB were more common in non-responders to GBP, and discontinuations were only identified in GBP non-responders. Conclusion. PGB may improve NeP relief in both responders and non-responders to GBP. Future studies are needed which include quality of life assessments and head-to-head comparisons. doi:10.1016/j.ejpain.2007.03.352
338 OXYCODONE IN NEUROPATHIC CLINICAL EXPERIENCE D. Ventura Vargas *, S. Martin Sanchez
PAIN:
A
Department of Anaesthesiology, Hospital De Puerto Real, Puerto Real, Spain Background and aims. The aim of this study is to prove the need of opioids, oxycodone in this case, as a coadjuvant treatment in neuropathic pain.
Methods. Fifty patients with neuropathic pain between 50 and 60 years old were selected, all of them with an unremarkable clinical history except a bilateral radiculopathy in both legs secondary to a lumbar disc hernia at L3–L4 level. These patients were treated with Oxycodone, Pregabalin, Duloxetine. A VAS assessment and a Lattinen test were performed at the beginning of the study and after 2 months of treatment. Results. A mean decrease in VAS of 3 points ± SD was obtained in 80% of cases and of 5 points ± SD in Lattinen. A 15% of cases presented adverse reactions. A 5% of cases did not experience any improvement. Conclusion. Oxycodone is an acceptable option in association with Pregabalin and Duloxetine in neuropathic pain due to lumbar discopathy. doi:10.1016/j.ejpain.2007.03.353
339 CASE REPORT: ZICONOTIDE TREATMENT FOR A NEUROPATHIC AND A DEGENERATIVE PAIN PROBLEM A. Ver Donck Multidisciplinary Pain Centre, AZ Sint Jan, Brugge, Belgium Background. Ziconotide, an intrathecal non-opioid analgesic, was approved in the European Union in 2005 for severe, chronic pain. Case report. Following three unsuccessful operations for herniated discs, RS was diagnosed in 2001 with bilateral neuralgia in the T5–T8 region. In 2002, thoracic pain was compounded with low back and leg pain due to L5–S1 disc degeneration. Spinal cord stimulation was not effective, obesity was a contraindication for morphine and surgery was not advised. The multidisciplinary team recommended enrollment into a randomised controlled trial with ziconotide. At study start (January 2005), RS was receiving tramadol, gabapentin, chlorothiazide, morphine immediate release, paracetamol/codeine, indomethacin and sertraline. Ziconotide was titrated over 25 days via an IT catheter, placed at the T9–T10 level, and external pump from a starting dose of 2.4 lg/day to 3.12 lg/ day. RS responded favourably, with Visual Analogue Scale of Pain Intensity (VASPI) being reduced from 84 mm to 45 mm. A SynchroMedÒ infusion system was implanted and RS was enrolled in a follow-up study, during which ziconotide was titrated from 2.4 lg/day to 6.0 lg/day. VASPI varied between 65 mm and 46 mm. RS is currently on ziconotide 8.4 lg/day. Gabapentin, morphine and paracetamol/
Poster Presentations / Molecular / Cellular studies I & II / European Journal of Pain 11(S1) (2007) S59–S207
codeine have been withdrawn. Side effects, e.g. dizziness and blurred vision, have been successfully managed by dose reduction. Conclusion. A stable dose of ziconotide has provided an acceptable level of pain reduction in a dual problem: neuropathic pain on a thoracic level and degenerative low back and leg pain. doi:10.1016/j.ejpain.2007.03.354
Poster Session 2: Molecular/Cellular studies I & II 340 NUMBERS, DENSITIES AND CO-LOCALIZATION OF AMPA AND NMDA RECEPTORS AT INDIVIDUAL SYNAPTIC CONTACT AREAS IN THE SUPERFICIAL SPINAL DORSAL HORN M. Antal *,a, Y. Fukozawa b, M. Eo¨rdo¨gh a, R. Shigemoto b a
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Hungary b Division of Cerebral Structures, National Institutes for Physiological Sciences, Myodaiji, Okazaki, Japan The well established role of AMPA- and NMDA-type ionotropic glutamate receptor mechanisms in the induction of spinal LTP and consecutive pain makes these receptors exceptionally important in spinal processing of nociceptive sensory signals. Here we applied the SDS-FRL method to laminae I–II of the spinal dorsal horn of rats and investigated the numbers, densities and co-localization of AMPA and NMDA receptors at individual postsynaptic active zones with a high molecular resolution. We demonstrated that the average surface area of glutamatergic postsynaptic active zones in laminae I–II was 0.0546 lm2. We also showed that all glutamatergic postsynaptic membranes in laminae I–II expressed AMPA receptors, and most of them (96.2%) were immunostained also for the NR1 subunit of NMDA receptors. The numbers of gold particles labeling AMPAand NMDA-type glutamate receptor ion channels at individual postsynaptic membranes varied in the range of 8–214 and 5–232 with mean values of 50.98 and 41.6, whereas their densities varied in the range of 325– 3365 lm 2 and 84–2263 lm 2 with a mean of 1136.2 lm 2 and 786.8 lm 2, respectively. Concerning the subunits of AMPA receptors, it was revealed that virtually all (98.8%) investigated postsynaptic membranes expressed GluR2 subunits, and most of them (90.4%) were also immunoreactivity for GluR1. The size of postsynaptic surface areas showed a more or less linear correlation with the numbers of AMPA and NMDA
S151
receptors. However, GluR1 expression was exceptionally low in postsynaptic active zones larger than 0.1 lm2. doi:10.1016/j.ejpain.2007.03.355
341 NEUROPATHIC PAIN AND SPINAL GLIA: CHARACTERIZATION OF C-JUN N-TERMINAL KINASE (JNK) ACTIVATION IN ASTROCYTE CULTURES A.T. Beggah *,a,b, A. Parent c, M. Pertin a,b, C. Bonny d,e, L. Pellerin c, R.R. Ji f, I. Decosterd a,b a
Anesthesiology Department, Lausanne University, Switzerland b Department of Cellular Biology and Morphology, Lausanne University, Switzerland c Department of Physiology, Lausanne University, Switzerland d Unit of Medical Genetics, Lausanne University, Switzerland e Xigen S.A., Lausanne, Switzerland f Department of Anesthesiology, Pain Research Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA Pain hypersensitivity and central changes following peripheral nerve injury are not only mediated by neurons. Recent evidence has demonstrated the activation of glia plays an important role in the generation/maintenance of neuropathic pain. For instance, spinal nerve ligation induces activation of JNK in spinal astrocytes and intrathecal administration of JNK inhibitors can alleviate neuropathic pain. In order to define how JNK is activated in spinal astrocytes, we set up an in vitro assay to study JNK activation. Primary cultures of astrocytes from neonatal mice were stimulated with proinflammatory cytokines and trophic factors (TNFalpha, IL-1beta, BDNF, FGF and IL-6). The astrocyte cultures were harvested at different times after stimulation. The activation of JNK pathway was assessed by Western blot using antibodies against the phosphorylated forms of JNK (pJNK) and c-jun (p-c-jun). Data obtained from triplicate wells showed that among these agents, TNFalpha induced a substantial and reproducible increase of both p-JNK and p-c-jun levels at 15 min and 30 min. These data have demonstrated that in cultured astrocytes JNK pathway is readily activated by physiologically-relevant mediators. This in vitro model of JNK activation is valuable to determine downstream mechanisms of JNK activation. We are currently assessing JNK-mediated transcriptional regulation of targeted genes with quantitative RT-PCR after blocking the JNK pathway with the peptide inhibitor D-JNKI-1. The identification of downstream elements of JNK pathway in astrocytes will pro-