Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling

Abstract

IMPORTANCE 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 Na V 1.7 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. DESIGN, SETTING, AND PARTICIPANTS Pain in 2 patients with IEM due to the Na V 1.7 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. MAIN OUTCOMES AND MEASURES 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 Na V 1.7 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 Na V 1.7 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 Na V 1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine. CONCLUSIONS AND RELEVANCE Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neu...

Current pain management strategies for patients with erythromelalgia: a critical review

“…These are undergoing clinical trials 2,91. Finally, advancement in electrophysiology, molecular modeling, thermodynamic analysis, and functional analyses profiling is improving our understanding of the molecular mechanisms underlying pain in EM 51. These studies are much needed to address the pain and significant comorbidity in patients with EM.…”

“…Carbamazepine has not been found to have significant effects on pain in EM. However, there is some evidence suggesting that individuals who carry a specific mutation on the Nav1.7 sodium channel (V400M) may be more responsive to carbamezepine 49–51. Oxcarbazepine has been used in inherited EM.…”

Sodium channels in pain disorders: pathophysiology and prospects for treatment

“…Patients with IEM start to exhibit symptoms as early as 1 year of age and as late as late-teens, and episodes of burning pain are triggered by mild warmth or exercise together with erythema and mild swelling in the hands and feet, with partial relief of symptoms by cooling affected extremities [45]. Despite the apparent uniformity of these symptoms, one recent study that looked in more details into the natural history of IEM in a cohort of 13 patients from four families demonstrated substantial variability in symptom presentation and triggers among members of the same family, including, for example, patients who reported that cooling evokes pain rather than relieves pain [82], while another study on two patients (parent/child) showed large variability in the severity of ongoing pain and in the number of nightly awakening due to pain [55]. The distinct patterns of affected body regions in IEM and PEPD, and the substantial variability of pain symptoms among members of the same family with the same mutation in IEM, suggest additional factors that regulate the severity of the symptoms and which parts of the body are affected.…”

“…The lack of efficacy of sodium channel blockers in patients with Na v 1.7 IEM mutations is not well understood, albeit in one case it has been linked to a reduced affinity of the mutant channel, Asn395Lys, to sodium channel blockers that bind at the local anesthetic binding site [102]. However, there are case reports of effective treatment with mexiletine in a patient carrying the Val872Gly [27], and CBZ in patients carrying the mutations Val400Met [52] and Ser241Thr [55]. The efficacy of mexiletine in the patient carrying the Val872Gly mutation has been linked to a stronger use-dependent fall-off in the current [27].…”

The AMPK Activator A769662 Blocks Voltage-Gated Sodium Channels: Discovery of a Novel Pharmacophore with Potential Utility for Analgesic Development

“…Inhibiting VGSCs with small molecules reduces sensory neuron excitability [17,18,19]. Further, block of the channel by small molecules shows that Na v 1.7 contributes to the major TTX-sensitive Na + current in both small-diameter mouse and human DRG neurons [20,21,22]. In mice, the genetic deletion of VGSCs produces striking decreases in normal and pathological pain [23,24,25,26].…”