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Original Investigation |

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

Paul Geha, MD1,2; Yang Yang, PhD3,4; Mark Estacion, PhD3,4; Betsy R. Schulman, PhD3,4; Hajime Tokuno, MD3,4; A. Vania Apkarian, PhD5; Sulayman D. Dib-Hajj, PhD3,4; Stephen G. Waxman, MD, PhD3,4
[+] Author Affiliations
1Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
2The John B. Pierce Laboratory, New Haven, Connecticut
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
4Neurorehabilitation Research Center, Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut
5Department of Physiology, Northwestern University, Chicago, Illinois
JAMA Neurol. 2016;73(6):659-667. doi:10.1001/jamaneurol.2016.0389.
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Published online

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 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.

Design, Setting, and Participants  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.

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 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 and Relevance  Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.

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Figures

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Figure 1.
Inherited Erythromelalgia Pain Rating

An example of rating of pain fluctuations after an episode is elicited with the thermal boot. The rating shown here was recorded after the thermal stimulus was switched off. gLMS indicates generalized Labeled Magnitude Scale.

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Figure 2.
Pain Characteristics in Patients 1 and 2

Pain characteristics and effects of carbamazepine treatment vs placebo for patients 1 and 2. A, Time in pain as reported in patients’ diaries during the 3 phases of treatment ramp-up, maintenance, and taper. Histograms represent means. B, Same as in panel A for the reported duration of inherited erythromelalgia episodes. C, Number of awakenings due to pain during 3 phases of ramp-up, maintenance, and taper.

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Figure 3.
Brain Activity Modulation With Carbamazepine (CBZ)

Treatment effects of CBZ vs baseline. A, Brain activity obtained when contrasting baseline to carbamazepine (baseline > CBZ) (paired t test; n = 2; fixed effects; P < .05, corrected for multiple comparisons). The bar plot shows mean (SEM) brain activity in z scores during pain rating (blue) and visual tracking (white) within the left (L) nucleus accumbens (NAc) (blue arrowhead) plotted for baseline (BL, left), chronic CBZ treatment (CBZ, middle), and chronic placebo (PL, right) treatment, respectively. B, Brain activity when contrasting CBZ > baseline; the bar plot depicts mean activity within primary somatosensory area (SI) (red arrowhead). MI indicates primary motor cortex; PCC, posterior cingulate cortex; PC, parietal cortex; R, right; rACC, rostral anterior cingulate cortex; and SI, primary somatosensory cortex.

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Figure 4.
Brain Activity Modulation by Placebo

A, Treatment effects of placebo vs baseline. Areas shown in red to yellow represent the contrast (baseline > placebo) and areas shown in blue to green represent the contrast (placebo > baseline). Unlike carbamazepine, placebo decreases activity in somatosensory parietal areas and increases activity in the posterior cingulate cortex and medial prefrontal cortex, among others. B, Contrast results between placebo scans (placebo > carbamazepine, red to yellow) and carbamazepine scans (carbamazepine > placebo, blue to green). Differences in activations are similar to those shown in Figure 3 for carbamazepine and baseline.

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Figure 5.
Brain Activity Associated With Decreased Pain

A, Regression of brain activity during pain rating scans across all visits against pain intensity reported during scanning. B, Regression of brain activity against time in pain as reported in patients’ diaries after masking with results shown in panel A. Areas in red to yellow represent positive correlations, whereas areas in blue to green represent negative correlations.

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Figure 6.
Carbamazepine Attenuation of Warmth-Evoked Firing in Dorsal Root Ganglion Neurons Expressing Nav1.7 S241T Mutant Channels

A-C, Heat maps of a representative multielectrode array recording of dorsal root ganglion neurons expressing NaV1.7 S241T before carbamazepine treatment (upper panels). The firing frequency of each active electrode is color coded with white/red representing high firing frequency and blue/black representing low firing frequency. Each circle corresponds to an active electrode within an 8 × 8 electrode array. There is only 1 active electrode in the heat map at 33°C (A). The number of active electrodes and firing frequency increase at 37°C (B) and 40°C (C). D-F, Heat maps of the same multielectrode array recording well after (30-µM) carbamazepine treatment (upper panels). The number of active electrodes and firing frequency of neurons are both markedly reduced at all 3 temperatures: 33°C (D), 37°C (E), and 40°C (F). White arrowheads indicate silent neurons after carbamazepine treatment. In the lower panels in A-F, recordings from a representative neuron in the heat map indicated by yellow arrowheads are shown. Note increased firing as temperature increased in the absence of carbamazepine (A-C) and attenuation of firing by carbamazepine (D-F).

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Figure 7.
Firing Frequency

Mean firing frequency of neurons (n = 98) expressing NaV1.7 S241T before and after carbamazepine treatment at all 3 temperatures.

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