- Email: [email protected]
69 GENETICS OF NEUROPATHIC PAIN
Oral presentations / European Journal of Pain Supplements 4 (2010) 1–46
Similarly in Study C117, patients with PHN achieved rapid and prolonged pain relief for 12 weeks with a single 60-minute QUTENZA application. A significantly greater reduction in NPRS score from baseline for Weeks 2–8, the primary efficacy endpoint, was observed with QUTENZA compared with control (−32.0% vs −24.4%; p = 0.011). An integrated efficacy analysis (n = 1079) pooled the results of these pivotal Phase III studies with previous double-blind, controlled Phase II/III and III studies in patients with PHN, C108 and C110. These data further confirmed that a single 60-minute application of QUTENZA significantly reduced pain, regardless of gender, age, baseline pain score or concomitant neuropathic pain medication use. QUTENZA has a rapid onset of action with pain relief observed at Day 2 and maintained for 12 weeks. QUTENZA was well tolerated with only mild and transient local application site reactions reported as the most common adverse events. [1] The results from the pivotal studies investigating QUTENZA in patients with PHN and HIV-AN demonstrate that targeting the nociceptive TRPV1 channel directly at the source of pain is an effective treatment for peripheral neuropathic pain. QUTENZA may therefore be a suitable treatment option for other peripheral neuropathic pain conditions suggesting that further clinical studies may be warranted to investigate other potential uses for QUTENZA. Reference(s) [1] Backonja M, et al. Lancet Neurol 2008; 7(12): 1106–1112.
T4. Personalized Treatment of Neuropathic Pain: Fiction or Future? 67 WORKSHOP SUMMARY: PERSONALIZED TREATMENT OF NEUROPATHIC PAIN: FICTION OR FUTURE? 3 1 J. Scholz1 , I. Belfer2 , C. Maihofner ¨ . Neurobiology Program, Children’s Hospital Boston, Boston, MA, 2 Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA; 3 Department of Neurology, University of Erlangen, Erlangen, Germany Recent advances in the knowledge of genetic and epigenetic factors that underlie complex disorders or affect the response to drugs raise the prospect of personalized treatment for many diseases including chronic pain. However, only few gene variations associated with an increased risk to develop neuropathic pain have been identified. High costs dampen the expectations for a broad application of pharmacogenetic screens to optimize treatment strategies in individual patients. As a consequence, treatment algorithms for neuropathic pain continue to rely on etiological disease classifications. And therapeutic decisions are usually based on comorbidity and the potential side effects of analgesics, not the specific genetic makeup of patients. We review the challenges and opportunities of genotype-based neuropathic pain treatment. We present new strategies for classifying patients according to their clinical pain phenotype, which reflects the activity of distinct pathophysiological mechanisms independent of disease etiology. We discuss the potential for improving the characterization of a patient’s pain phenotype through the imaging of pain-processing networks in the brain. A standardized classification of neuropathic pain phenotypes may support the development of strategies for targeted analgesic treatment when genetic determinants of pain or treatment response are elusive.
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68 INDIVIDUAL PAIN PHENOTYPES J. Scholz. Neurobiology Program, Children’s Hospital Boston, Boston, MA, USA Current treatment algorithms for neuropathic pain do not consider differences in the phenotype of pain. They usually provide recommendations based on clinical trials performed on study populations with a particular neurological disorder associated with pain or heterogeneous populations with neuropathic pain of diverse etiology. It is assumed that the results of these trials apply to neuropathic pain in general. However, pain-related symptoms and signs vary even between patients with the same disease, indicating substantial differences in the operating pain mechanisms. Because pain mechanisms are the target of pharmacological interventions, interindividual differences in pain mechanisms are likely to contribute to variable treatment response in clinical practice and low average pain reductions in clinical trials. Recently, several new strategies have emerged to characterize the pain phenotype of patients using standardized evaluations of sensory symptoms and signs. This allows a novel approach to the classification of neuropathic pain, one that focuses more on the symptoms and signs that constitute a patient’s pain rather than etiological disease categories. Considering phenotypical differences in clinical trials would raise the possibility to determine the correlation between pain features and treatment response and assess the probability of successful pain reduction in patients with corresponding pain phenotypes. The ability to predict treatment response in individual patients would greatly facilitate the establishment of guidelines for personalized treatment of neuropathic pain. 69 GENETICS OF NEUROPATHIC PAIN I. Belfer. Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA Recent studies have established that both clinical and experimental pain perception are influenced by genetic factors. Since major injuries or disease exposures rarely occur together in sibling pairs, association studies in unrelated subjects are the standard method to identify genetic determinants of neuropathic pain. Several studies used a candidate gene approach to elucidate genetic contribution to neuropathic pain phenotypes; however, the data is limited and inconsistent. Possible reasons include: sample heterogeneity, underpowered study design, population admixture, poor phenotyping, genotyping errors, and statistical analytical mistakes. This presentation discusses current strategies to optimize population-based association studies of human neuropathic pain focusing on selection of genetic markers, genotyping data analysis and follow-up approaches. New powerful methods of molecular epidemiology and unbiased interrogation of the whole genome based on systematically grouped well-phenotyped patients possess enormous potential for progress in understanding neuropathic pain and may lead to personalized pain medicine. 70 FUNCTIONAL IMAGING OF NEUROPATHIC PAIN C. Maihofner. ¨ University of Erlangen, Erlangen, Germany Over the last few years remarkable efforts have been made using functional imaging studies to unravel brain processing of pain and decipher underlying neuronal mechanisms. Cerebral processing in experimental pain models, especially those provoking hyperalgesia, and its pharmacological modulation will form the first part of this talk. In a second part I will address central mechanisms of clinical neuropathic pain. Up to now, there are at least six main mechanisms involved in the chronification of neuropathic pain: (i) activity increase in areas of the pain neuromatrix, (ii) recruitment of additional cortical areas beyond the classical pain neuromatrix, (iii) cortical reorganization andmaladaptive neuroplasticity, (iv) alterations in neurochemistry (v) structural
Similarly in Study C117, patients with PHN achieved rapid and prolonged pain relief for 12 weeks with a single 60-minute QUTENZA application. A significantly greater reduction in NPRS score from baseline for Weeks 2–8, the primary efficacy endpoint, was observed with QUTENZA compared with control (−32.0% vs −24.4%; p = 0.011). An integrated efficacy analysis (n = 1079) pooled the results of these pivotal Phase III studies with previous double-blind, controlled Phase II/III and III studies in patients with PHN, C108 and C110. These data further confirmed that a single 60-minute application of QUTENZA significantly reduced pain, regardless of gender, age, baseline pain score or concomitant neuropathic pain medication use. QUTENZA has a rapid onset of action with pain relief observed at Day 2 and maintained for 12 weeks. QUTENZA was well tolerated with only mild and transient local application site reactions reported as the most common adverse events. [1] The results from the pivotal studies investigating QUTENZA in patients with PHN and HIV-AN demonstrate that targeting the nociceptive TRPV1 channel directly at the source of pain is an effective treatment for peripheral neuropathic pain. QUTENZA may therefore be a suitable treatment option for other peripheral neuropathic pain conditions suggesting that further clinical studies may be warranted to investigate other potential uses for QUTENZA. Reference(s) [1] Backonja M, et al. Lancet Neurol 2008; 7(12): 1106–1112.
T4. Personalized Treatment of Neuropathic Pain: Fiction or Future? 67 WORKSHOP SUMMARY: PERSONALIZED TREATMENT OF NEUROPATHIC PAIN: FICTION OR FUTURE? 3 1 J. Scholz1 , I. Belfer2 , C. Maihofner ¨ . Neurobiology Program, Children’s Hospital Boston, Boston, MA, 2 Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA; 3 Department of Neurology, University of Erlangen, Erlangen, Germany Recent advances in the knowledge of genetic and epigenetic factors that underlie complex disorders or affect the response to drugs raise the prospect of personalized treatment for many diseases including chronic pain. However, only few gene variations associated with an increased risk to develop neuropathic pain have been identified. High costs dampen the expectations for a broad application of pharmacogenetic screens to optimize treatment strategies in individual patients. As a consequence, treatment algorithms for neuropathic pain continue to rely on etiological disease classifications. And therapeutic decisions are usually based on comorbidity and the potential side effects of analgesics, not the specific genetic makeup of patients. We review the challenges and opportunities of genotype-based neuropathic pain treatment. We present new strategies for classifying patients according to their clinical pain phenotype, which reflects the activity of distinct pathophysiological mechanisms independent of disease etiology. We discuss the potential for improving the characterization of a patient’s pain phenotype through the imaging of pain-processing networks in the brain. A standardized classification of neuropathic pain phenotypes may support the development of strategies for targeted analgesic treatment when genetic determinants of pain or treatment response are elusive.
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68 INDIVIDUAL PAIN PHENOTYPES J. Scholz. Neurobiology Program, Children’s Hospital Boston, Boston, MA, USA Current treatment algorithms for neuropathic pain do not consider differences in the phenotype of pain. They usually provide recommendations based on clinical trials performed on study populations with a particular neurological disorder associated with pain or heterogeneous populations with neuropathic pain of diverse etiology. It is assumed that the results of these trials apply to neuropathic pain in general. However, pain-related symptoms and signs vary even between patients with the same disease, indicating substantial differences in the operating pain mechanisms. Because pain mechanisms are the target of pharmacological interventions, interindividual differences in pain mechanisms are likely to contribute to variable treatment response in clinical practice and low average pain reductions in clinical trials. Recently, several new strategies have emerged to characterize the pain phenotype of patients using standardized evaluations of sensory symptoms and signs. This allows a novel approach to the classification of neuropathic pain, one that focuses more on the symptoms and signs that constitute a patient’s pain rather than etiological disease categories. Considering phenotypical differences in clinical trials would raise the possibility to determine the correlation between pain features and treatment response and assess the probability of successful pain reduction in patients with corresponding pain phenotypes. The ability to predict treatment response in individual patients would greatly facilitate the establishment of guidelines for personalized treatment of neuropathic pain. 69 GENETICS OF NEUROPATHIC PAIN I. Belfer. Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA Recent studies have established that both clinical and experimental pain perception are influenced by genetic factors. Since major injuries or disease exposures rarely occur together in sibling pairs, association studies in unrelated subjects are the standard method to identify genetic determinants of neuropathic pain. Several studies used a candidate gene approach to elucidate genetic contribution to neuropathic pain phenotypes; however, the data is limited and inconsistent. Possible reasons include: sample heterogeneity, underpowered study design, population admixture, poor phenotyping, genotyping errors, and statistical analytical mistakes. This presentation discusses current strategies to optimize population-based association studies of human neuropathic pain focusing on selection of genetic markers, genotyping data analysis and follow-up approaches. New powerful methods of molecular epidemiology and unbiased interrogation of the whole genome based on systematically grouped well-phenotyped patients possess enormous potential for progress in understanding neuropathic pain and may lead to personalized pain medicine. 70 FUNCTIONAL IMAGING OF NEUROPATHIC PAIN C. Maihofner. ¨ University of Erlangen, Erlangen, Germany Over the last few years remarkable efforts have been made using functional imaging studies to unravel brain processing of pain and decipher underlying neuronal mechanisms. Cerebral processing in experimental pain models, especially those provoking hyperalgesia, and its pharmacological modulation will form the first part of this talk. In a second part I will address central mechanisms of clinical neuropathic pain. Up to now, there are at least six main mechanisms involved in the chronification of neuropathic pain: (i) activity increase in areas of the pain neuromatrix, (ii) recruitment of additional cortical areas beyond the classical pain neuromatrix, (iii) cortical reorganization andmaladaptive neuroplasticity, (iv) alterations in neurochemistry (v) structural