Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia

A randomized controlled trial

Jeffrey M. Statland, Brian N. Bundy, Yunxia Wang, Dipa Raja Rayan, Jaya R. Trivedi, Valeria A. Sansone, Mohammad K. Salajegheh, Shannon L. Venance, Emma Ciafaloni, Emma Matthews, Giovanni Meola, Laura Herbelin, Robert C. Griggs, Richard J. Barohn, Michael G. Hanna

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Context: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. Design, Setting, and Participants: A randomized, double-blind, placebocontrolled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health - funded Rare Disease Clinical Research Network. Intervention: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. Main Outcome Measures Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1=minimal to 9=worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL - QOL, percentage of maximal detrimental impact). Results: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P<.001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68;95% CI, -3.85 to -0.139; P=.04). Mexiletine improved the INQOL - QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P<.001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P<.001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. Conclusion: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration: clinicaltrials.gov Identifier: NCT00832000

Original languageEnglish (US)
Pages (from-to)1357-1365
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume308
Issue number13
DOIs
StatePublished - Oct 3 2012

Fingerprint

Myotonia
Mexiletine
Signs and Symptoms
Randomized Controlled Trials
Placebos
Rare Diseases
Quality of Life
Nondystrophic myotonia
Pain
Muscle Relaxation
Sodium Channels
National Institutes of Health (U.S.)
Ion Channels
Cross-Over Studies
Capsules
Skeletal Muscle
Referral and Consultation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia : A randomized controlled trial. / Statland, Jeffrey M.; Bundy, Brian N.; Wang, Yunxia; Rayan, Dipa Raja; Trivedi, Jaya R.; Sansone, Valeria A.; Salajegheh, Mohammad K.; Venance, Shannon L.; Ciafaloni, Emma; Matthews, Emma; Meola, Giovanni; Herbelin, Laura; Griggs, Robert C.; Barohn, Richard J.; Hanna, Michael G.

In: JAMA - Journal of the American Medical Association, Vol. 308, No. 13, 03.10.2012, p. 1357-1365.

Research output: Contribution to journalArticle

Statland, JM, Bundy, BN, Wang, Y, Rayan, DR, Trivedi, JR, Sansone, VA, Salajegheh, MK, Venance, SL, Ciafaloni, E, Matthews, E, Meola, G, Herbelin, L, Griggs, RC, Barohn, RJ & Hanna, MG 2012, 'Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: A randomized controlled trial', JAMA - Journal of the American Medical Association, vol. 308, no. 13, pp. 1357-1365. https://doi.org/10.1001/jama.2012.12607
Statland, Jeffrey M. ; Bundy, Brian N. ; Wang, Yunxia ; Rayan, Dipa Raja ; Trivedi, Jaya R. ; Sansone, Valeria A. ; Salajegheh, Mohammad K. ; Venance, Shannon L. ; Ciafaloni, Emma ; Matthews, Emma ; Meola, Giovanni ; Herbelin, Laura ; Griggs, Robert C. ; Barohn, Richard J. ; Hanna, Michael G. / Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia : A randomized controlled trial. In: JAMA - Journal of the American Medical Association. 2012 ; Vol. 308, No. 13. pp. 1357-1365.
@article{5681ec830c474564a6d03ffb9e8875d4,
title = "Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: A randomized controlled trial",
abstract = "Context: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. Design, Setting, and Participants: A randomized, double-blind, placebocontrolled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health - funded Rare Disease Clinical Research Network. Intervention: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. Main Outcome Measures Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1=minimal to 9=worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL - QOL, percentage of maximal detrimental impact). Results: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95{\%} CI, -2.66 to -0.706; P<.001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68;95{\%} CI, -3.85 to -0.139; P=.04). Mexiletine improved the INQOL - QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95{\%} CI, -4.07 to -1.30; P<.001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95{\%} CI, -0.633 to -0.142; P<.001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. Conclusion: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration: clinicaltrials.gov Identifier: NCT00832000",
author = "Statland, {Jeffrey M.} and Bundy, {Brian N.} and Yunxia Wang and Rayan, {Dipa Raja} and Trivedi, {Jaya R.} and Sansone, {Valeria A.} and Salajegheh, {Mohammad K.} and Venance, {Shannon L.} and Emma Ciafaloni and Emma Matthews and Giovanni Meola and Laura Herbelin and Griggs, {Robert C.} and Barohn, {Richard J.} and Hanna, {Michael G.}",
year = "2012",
month = "10",
day = "3",
doi = "10.1001/jama.2012.12607",
language = "English (US)",
volume = "308",
pages = "1357--1365",
journal = "JAMA - Journal of the American Medical Association",
issn = "0098-7484",
publisher = "American Medical Association",
number = "13",

}

TY - JOUR

T1 - Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia

T2 - A randomized controlled trial

AU - Statland, Jeffrey M.

AU - Bundy, Brian N.

AU - Wang, Yunxia

AU - Rayan, Dipa Raja

AU - Trivedi, Jaya R.

AU - Sansone, Valeria A.

AU - Salajegheh, Mohammad K.

AU - Venance, Shannon L.

AU - Ciafaloni, Emma

AU - Matthews, Emma

AU - Meola, Giovanni

AU - Herbelin, Laura

AU - Griggs, Robert C.

AU - Barohn, Richard J.

AU - Hanna, Michael G.

PY - 2012/10/3

Y1 - 2012/10/3

N2 - Context: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. Design, Setting, and Participants: A randomized, double-blind, placebocontrolled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health - funded Rare Disease Clinical Research Network. Intervention: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. Main Outcome Measures Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1=minimal to 9=worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL - QOL, percentage of maximal detrimental impact). Results: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P<.001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68;95% CI, -3.85 to -0.139; P=.04). Mexiletine improved the INQOL - QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P<.001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P<.001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. Conclusion: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration: clinicaltrials.gov Identifier: NCT00832000

AB - Context: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. Design, Setting, and Participants: A randomized, double-blind, placebocontrolled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health - funded Rare Disease Clinical Research Network. Intervention: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. Main Outcome Measures Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1=minimal to 9=worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL - QOL, percentage of maximal detrimental impact). Results: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P<.001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68;95% CI, -3.85 to -0.139; P=.04). Mexiletine improved the INQOL - QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P<.001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P<.001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. Conclusion: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration: clinicaltrials.gov Identifier: NCT00832000

UR - http://www.scopus.com/inward/record.url?scp=84866919087&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866919087&partnerID=8YFLogxK

U2 - 10.1001/jama.2012.12607

DO - 10.1001/jama.2012.12607

M3 - Article

VL - 308

SP - 1357

EP - 1365

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0098-7484

IS - 13

ER -