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569 EFFECTS OF A SPINAL CORD INJURY ON THE PERIPHERAL NERVOUS SYSTEM OF THE RAT
Poster Sessions / European Journal of Pain 13 (2009) S55–S285
(PHN) compared with gabapentin (2.100 mg/day) and pregabalin (PG; 300 mg/day and 600 mg/day) from the Spanish Health System perspective. Methods: A Markov model was constructed to calculate the costeffectiveness of gabapentin, PG and lidocaine plaster in terms of the cost per quality-adjusted life-year (QALY) gained when used over a six-month time horizon in patients with PHN. The model structure allowed for differences in costs, utilities and transition probabilities between the initial 30-day run-in period and maintenance therapy. Most transition probabilities were based on clinical trials identified through a systematic literature review. Missing data, including resource utilization, were obtained from a Delphi panel and costs from price tariffs/lists. Utilities derived from the literature were adjusted for age, and were supplemented and validated by the panel. Results: The total cost of treatment with the lidocaine plaster was €1861 per patient, compared with €1296 for gabapentin, €1488 for PG300 mg and €1599 for PG600 mg. Lidocaine plaster generated 0.384 QALYs, compared with 0.322 for gabapentin, 0.325 for PG300 mg and 0.322 for PG600 mg. Lidocaine plaster therefore costs €9113 per QALY gained relative to gabapentin, €6322/QALY relative to PG300 mg and €4226/QALY relative to PG600 mg. Scenario analyses and extensive one-way sensitivity analyses on all parameters including the time horizon confirmed the robustness of the results. Conclusions: The lidocaine 5% plaster is a highly cost-effective treatment for PHN in Spain. Study partially financed by Grunenthal ¨ 569 EFFECTS OF A SPINAL CORD INJURY ON THE PERIPHERAL NERVOUS SYSTEM OF THE RAT ´ J. Mazar´ıo *, G. Avila-Mart´ ın, M. Suard´ıaz, J. Taylor. Laboratorio de Funci´ on Sensitivomotora Hospital Nacional de Parapl´ejicos, Toledo, Spain Neuropathic pain associated with spinal cord injury (SCI) is a symptom that interferes with the integral rehabilitation of the patients due to the progressive worsening of their quality of life. Most of the studies researching the development of neuropathic pain after SCI focus on the changes induced in the central nervous system after the injury, forgetting that this same injury also affects the central branches of the sensory neurons whose somata may be localized in dorsal root ganglia (DRGs) far away from the damaged area. In addition, neurochemical changes that occur after the injury alter the environment of the dorsal root ganglia therefore affecting neurons whose axons were not damaged by the injury. We studied the effects of a contusion injury to the T9 segment of the spinal cord of rats on the neurochemical properties of DRG neurons. We observed that injured animals developed hypersensitivity to cold (0º C) that was maximal 3 weeks after the lesion. 4 weeks after the lesion the proportion of L5 DRG neurons coexpressing neurofilament 200 and TRPV1 had doubled when compared to sham operated rats (3.7%±0.3 vs 7.9%±0.4 of all the labelled neurons for sham and SCI animals respectively, p < 0.01). No significant differences were observed on the proportion of T9 DRG neurons coexpressing these two markers between sham operated and SCI rats (5.1±0.5% vs 4.4±0.6% respectively). We conclude that a SCI can induce changes on the peripheral nervous system well below the level of the lesion. 570 LOW-DOSE KETAMINE-DRIP AS TREATMENT FOR CENTRAL NEUROPATHIC PAIN A. Moesker *. Pain Research, Stadskanaal, Netherlands Background: Neuropathic pain in case of complex regional pain syndrome (CRPS) is difficult to treat Blocking NMDA receptors
S167
by intravenous (iv) ketamine seems to be a new therapeutic possibility. Method: A 30-year-old female patient had debilitating CRPS of the right foot for 6 years. Our treatment consisted of an appropriate dose of iv ketamine such that the patient can still perform activities of daily living. Because of increasing awareness of the role that 5-HT2A receptors (peripheral and central) play in the case of neuropathic pain, we first blocked these receptors by the selective 5-HT2A receptor blocker ketanserin (6 mg/h iv) for three days. With this pre-treatment we were more certain that the remaining neuropathic pain in this patient was mediated by NMDA receptors. The ketamine infusion was then started at 0.9 m/kg/min and was maximally 4.8 m/kg/min; after two days the VAS pain score was zero. The ketamine infusion was continued for another 3 days. There were no serious side-effects. Results: In this patient, after decreasing the ketamine infusion to zero the neuropathic pain remained absent for 3 weeks. After repeating the infusion therapy the neuropathic pain was absent for 3 months and after a third treatment for as long as 6 months. Conclusion: In CRPS cases of otherwise untreatable central neuropathic pain ketamine infusion treatment, after pre-treatment with ketanserin, could be a suitable option. 571 LOSS OF SEROTONINERGIC AND NORADRENERGIC BRAINSTEM NEURONS DURING PAINFUL DIABETIC NEUROPATHY: A STUDY IN STREPTOZOTOCIN-INDUCED DIABETIC RAT C. Morgado *, P. Pereira-Terra, F. Neto, I. Tavares. Institute of Histology and Embryology, Faculty of Medicine of Porto and IBMC, Porto, Portugal Painful diabetic neuropathy was recently shown to be due to central mechanisms both in humans and animals. Neuronal hyperactivity was reported at the spinal cord of streptozotocin-diabetic rats (STZrats), which may account for pain and be caused by dysfunctions in inhibitory descending modulation. Here, we quantified the serotoninergic and noradrenergic levels in brainstem centres involved in descending pain control in STZ rats by immunodetection of their synthesizing enzymes tryptophan hydroxilase (TpH) and tyrosine hydroxilase (TH), respectively. Male Wistar rats were injected with streptozotocin (60 mg/kg) or saline and were sacrificed at 10 weeks post-injection. Neurons immunoreactive for TpH (TpH-IR) were counted in dorsal raphe nucleus (DRN), median raphe nucleus (MRN), caudal linear raphe (CLR), nucleus of the tractus solitarius (NTS), rostroventromedial medulla (RVM) and caudal ventrolateral medulla (CVLM). Neurons immunoreactive for TH (TH-IR) were counted in A1, A2, A5 and A7 noradrenergic cell groups. Besides marked hyperglycaemia and behavioural signs of painful diabetic neuropathy, STZ-rats presented significantly lower numbers of TpH-IR neurons at the DRN, RVM, and CVLM. Regarding the noradrenergic cell groups, significant low numbers of TH-IR neurons were detected at the A1, A2 and A5. These findings point to a deficient inhibitory descending modulation in STZ rats, which may account to the spinal cord hyperactivity and concur to spontaneous pain during diabetes. The value of therapeutic strategies aimed at serotonergic and noradrenergic neurotransmission in diabetic neuropathy is reinforced by these data. Support: FCT project – PTDC/SAU/64643/2006.
(PHN) compared with gabapentin (2.100 mg/day) and pregabalin (PG; 300 mg/day and 600 mg/day) from the Spanish Health System perspective. Methods: A Markov model was constructed to calculate the costeffectiveness of gabapentin, PG and lidocaine plaster in terms of the cost per quality-adjusted life-year (QALY) gained when used over a six-month time horizon in patients with PHN. The model structure allowed for differences in costs, utilities and transition probabilities between the initial 30-day run-in period and maintenance therapy. Most transition probabilities were based on clinical trials identified through a systematic literature review. Missing data, including resource utilization, were obtained from a Delphi panel and costs from price tariffs/lists. Utilities derived from the literature were adjusted for age, and were supplemented and validated by the panel. Results: The total cost of treatment with the lidocaine plaster was €1861 per patient, compared with €1296 for gabapentin, €1488 for PG300 mg and €1599 for PG600 mg. Lidocaine plaster generated 0.384 QALYs, compared with 0.322 for gabapentin, 0.325 for PG300 mg and 0.322 for PG600 mg. Lidocaine plaster therefore costs €9113 per QALY gained relative to gabapentin, €6322/QALY relative to PG300 mg and €4226/QALY relative to PG600 mg. Scenario analyses and extensive one-way sensitivity analyses on all parameters including the time horizon confirmed the robustness of the results. Conclusions: The lidocaine 5% plaster is a highly cost-effective treatment for PHN in Spain. Study partially financed by Grunenthal ¨ 569 EFFECTS OF A SPINAL CORD INJURY ON THE PERIPHERAL NERVOUS SYSTEM OF THE RAT ´ J. Mazar´ıo *, G. Avila-Mart´ ın, M. Suard´ıaz, J. Taylor. Laboratorio de Funci´ on Sensitivomotora Hospital Nacional de Parapl´ejicos, Toledo, Spain Neuropathic pain associated with spinal cord injury (SCI) is a symptom that interferes with the integral rehabilitation of the patients due to the progressive worsening of their quality of life. Most of the studies researching the development of neuropathic pain after SCI focus on the changes induced in the central nervous system after the injury, forgetting that this same injury also affects the central branches of the sensory neurons whose somata may be localized in dorsal root ganglia (DRGs) far away from the damaged area. In addition, neurochemical changes that occur after the injury alter the environment of the dorsal root ganglia therefore affecting neurons whose axons were not damaged by the injury. We studied the effects of a contusion injury to the T9 segment of the spinal cord of rats on the neurochemical properties of DRG neurons. We observed that injured animals developed hypersensitivity to cold (0º C) that was maximal 3 weeks after the lesion. 4 weeks after the lesion the proportion of L5 DRG neurons coexpressing neurofilament 200 and TRPV1 had doubled when compared to sham operated rats (3.7%±0.3 vs 7.9%±0.4 of all the labelled neurons for sham and SCI animals respectively, p < 0.01). No significant differences were observed on the proportion of T9 DRG neurons coexpressing these two markers between sham operated and SCI rats (5.1±0.5% vs 4.4±0.6% respectively). We conclude that a SCI can induce changes on the peripheral nervous system well below the level of the lesion. 570 LOW-DOSE KETAMINE-DRIP AS TREATMENT FOR CENTRAL NEUROPATHIC PAIN A. Moesker *. Pain Research, Stadskanaal, Netherlands Background: Neuropathic pain in case of complex regional pain syndrome (CRPS) is difficult to treat Blocking NMDA receptors
S167
by intravenous (iv) ketamine seems to be a new therapeutic possibility. Method: A 30-year-old female patient had debilitating CRPS of the right foot for 6 years. Our treatment consisted of an appropriate dose of iv ketamine such that the patient can still perform activities of daily living. Because of increasing awareness of the role that 5-HT2A receptors (peripheral and central) play in the case of neuropathic pain, we first blocked these receptors by the selective 5-HT2A receptor blocker ketanserin (6 mg/h iv) for three days. With this pre-treatment we were more certain that the remaining neuropathic pain in this patient was mediated by NMDA receptors. The ketamine infusion was then started at 0.9 m/kg/min and was maximally 4.8 m/kg/min; after two days the VAS pain score was zero. The ketamine infusion was continued for another 3 days. There were no serious side-effects. Results: In this patient, after decreasing the ketamine infusion to zero the neuropathic pain remained absent for 3 weeks. After repeating the infusion therapy the neuropathic pain was absent for 3 months and after a third treatment for as long as 6 months. Conclusion: In CRPS cases of otherwise untreatable central neuropathic pain ketamine infusion treatment, after pre-treatment with ketanserin, could be a suitable option. 571 LOSS OF SEROTONINERGIC AND NORADRENERGIC BRAINSTEM NEURONS DURING PAINFUL DIABETIC NEUROPATHY: A STUDY IN STREPTOZOTOCIN-INDUCED DIABETIC RAT C. Morgado *, P. Pereira-Terra, F. Neto, I. Tavares. Institute of Histology and Embryology, Faculty of Medicine of Porto and IBMC, Porto, Portugal Painful diabetic neuropathy was recently shown to be due to central mechanisms both in humans and animals. Neuronal hyperactivity was reported at the spinal cord of streptozotocin-diabetic rats (STZrats), which may account for pain and be caused by dysfunctions in inhibitory descending modulation. Here, we quantified the serotoninergic and noradrenergic levels in brainstem centres involved in descending pain control in STZ rats by immunodetection of their synthesizing enzymes tryptophan hydroxilase (TpH) and tyrosine hydroxilase (TH), respectively. Male Wistar rats were injected with streptozotocin (60 mg/kg) or saline and were sacrificed at 10 weeks post-injection. Neurons immunoreactive for TpH (TpH-IR) were counted in dorsal raphe nucleus (DRN), median raphe nucleus (MRN), caudal linear raphe (CLR), nucleus of the tractus solitarius (NTS), rostroventromedial medulla (RVM) and caudal ventrolateral medulla (CVLM). Neurons immunoreactive for TH (TH-IR) were counted in A1, A2, A5 and A7 noradrenergic cell groups. Besides marked hyperglycaemia and behavioural signs of painful diabetic neuropathy, STZ-rats presented significantly lower numbers of TpH-IR neurons at the DRN, RVM, and CVLM. Regarding the noradrenergic cell groups, significant low numbers of TH-IR neurons were detected at the A1, A2 and A5. These findings point to a deficient inhibitory descending modulation in STZ rats, which may account to the spinal cord hyperactivity and concur to spontaneous pain during diabetes. The value of therapeutic strategies aimed at serotonergic and noradrenergic neurotransmission in diabetic neuropathy is reinforced by these data. Support: FCT project – PTDC/SAU/64643/2006.