title: Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling.
abstract: OBJECTIVE
  There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable.
  
  
  OBJECTIVE
  To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling.
  
  
  METHODS
  Pain in 2 patients with IEM due to the NaV1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels.
  
  
  METHODS
  Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels.
  
  
  RESULTS
  This study included 2 patients from the same family with IEM and the S241T NaV1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T NaV1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400 mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400 mg then 200 mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine. Patient 1 reported a reduction of mean episode duration, from 615 minutes while taking placebo to 274.1 minutes while taking carbamazepine, while patient 2 reported a reduction of the mean episode duration from 91.5 minutes while taking placebo to 45.3 minutes while taking carbamazepine. Patient 1, who had a history of night awakenings from pain, reported 101 awakenings owing to pain while taking placebo during the maintenance period and 32 awakenings while taking carbamazepine. Attenuation of pain was paralleled by a shift in brain activity from valuation and pain areas to primary and secondary somatosensory, motor, and parietal attention areas. Firing of DRG neurons expressing the S241T NaV1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine.
  
  
  CONCLUSIONS
  Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut2The John B. Pierce Laboratory, New Haven, Connecticut.
authors.forename: Paul
authors.initials: P
authors.lastname: Geha
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: Mark
authors.initials: M
authors.lastname: Estacion
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: Betsy R
authors.initials: BR
authors.lastname: Schulman
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: Hajime
authors.initials: H
authors.lastname: Tokuno
authors.affiliation: Department of Physiology, Northwestern University, Chicago, Illinois.
authors.forename: A Vania
authors.initials: AV
authors.lastname: Apkarian
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002220:Carbamazepine / Q000627:therapeutic use*; D059350:Chronic Pain / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology*; D004252:DNA Mutational Analysis; D004311:Double-Blind Method; D004558:Electric Stimulation; D004916:Erythromelalgia / Q000150:complications* / Q000235:genetics; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics; D010147:Pain Measurement; D012044:Regression Analysis; D011984:Sensory Receptor Cells / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D002220:Carbamazepine