Buprenorphine may be effective for treatment of paramyotonia congenita

Abstract

Introduction/Aims: Paramyotonia congenita (PMC) is a skeletal muscle sodium channelopathy characterized by paradoxical myotonia, cold sensitivity, and exercise/ cold-induced paralysis. Treatment with sodium-channel-blocking antiarrhythmic agents may expose patients to a risk of arrhythmia or may be poorly tolerated or ineffective. In this study we explored the effectiveness of non-antiarrhythmic sodiumchannel blockers in two patients with PMC.Methods: Earlier treatment with mexiletine was discontinued for gastrointestinal side effects in one of the patients and lack of clinical benefit in the other. One patient received lacosamide, ranolazine, and buprenorphine, and the other was given buprenorphine only. Drug efficacy was assessed by clinical scores, timed tests, and by long and short exercise tests. Results:In both patients, buprenorphine improved pain scores by at least 50%, stiffness and weakness levels, and handgrip/eyelid-opening times. The fall in compound muscle action potential (CMAP) during short exercise normalized in both patients at baseline, and improved after cooling. During long exercise, one patient showed an earlier recovery of CMAP, and the other patient had a less severe decrease (<60%).With buprenorphine, the fall in CMAP induced by cooling normalized in one patient (from −72% to −4%) and improved (from −49% to −37%) in the other patient.Discussion: Buprenorphine showed promising results for the treatment of exerciseinduced paralysis and cold intolerance in the two patients assessed. The exercise test may be useful for quantitative assessment of treatment response. Further studies on a larger number of patients, under carefully controlled conditions, should be considered to address the effectiveness and long-term tolerability of this therapeutic option.

Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized double‐blind placebo‐controlled cross‐over study

“…However, we propose the use of MVRC as a biomarker for target engagement of drugs developed to influence muscle excitability, such as novel (subtype‐specific) Na V blockers, 19 , 20 or existing sodium‐ or potassium channel modulating therapies proposed as new treatments for myotonia. 21 , 22 , 23 This biomarker may therefore be used for proof of target engagement but may also facilitate an informed choice of the dose level in the translation from phase I studies in healthy subjects to phase II and III studies in patient populations. Furthermore, MVRCs may also be used in the translational phase between preclinical and clinical studies because the measurement can also be performed in animal studies.…”

“…Whether effects of compounds developed for various NMDs can be detected using MVRC will have to be confirmed in future studies. However, we propose the use of MVRC as a biomarker for target engagement of drugs developed to influence muscle excitability, such as novel (subtype‐specific) Na V blockers, 19,20 or existing sodium‐ or potassium channel modulating therapies proposed as new treatments for myotonia 21–23 . This biomarker may therefore be used for proof of target engagement but may also facilitate an informed choice of the dose level in the translation from phase I studies in healthy subjects to phase II and III studies in patient populations.…”

What Is in the Myopathy Literature?

“…Alternative treatments for myotonia may include ranolazine and lamotrigine which enhance the slow inactivation of sodium channels. 21,22 Ravaglia et al 23 recently reported another possible compound that might be useful in treating stiffness in paramyotonia congenita. They treated 2 patients with buprenorphine, a drug that is typically used for opiate addiction often in combination with naloxone.…”