N Kerckhove1,2, B Pereira1, S Soriot-Thomas3, H Alchaar4, R Deleens5, V S Hieng6, E Serra3, M Lanteri-Minet1,4, P Arcagni7, P Picard1, D Lefebvre-Kuntz8, C Maindet9, G Mick10, L Balp11, C Lucas12, C Creach7, M Letellier13, V Martinez14, M Navez7, D Delbrouck8, E Kuhn13, E Piquet4, E Bozzolo4, C Brosse7, B Lietar7, F Marcaillou1, A Hamdani8, N Leroux-Bromberg8, Y Perier15, P Vergne-Salle16, C Gov17, N Delage1, D Gillet10, S Romettino4, D Richard1, C Mallet1, L Bernard1, C Lambert1, C Dubray1,2, C Duale1,2, A Eschalier1,2. 1. Service de Pharmacologie Médicale, Direction de la Recherche Clinique et de l'Innovation, CETD, CIC, CNRS, SIGMA Clermont, ICCF, Service de Pharmacie, Université Clermont Auvergne, CHU Clermont-Ferrand, INSERM - NEURO-DOL, Clermont-Ferrand, France. 2. Analgesia Institute, Université Clermont Auvergne, Clermont-Ferrand, France. 3. CHU Amiens Picardie, CETD, CRC, Amiens, France. 4. Université Nice Côte-d'Azur, CHU Nice - Hôpital de Cimiez, Fédération Hospitalo-Universitaire INOVPAIN, CETD, Nice, France. 5. CHU Rouen, CETD, Rouen, France. 6. CH Lisieux, Lisieux, France. 7. CHU Saint-Etienne, CETD, Saint-Etienne, France. 8. Cancer Centre Oscar-Lambret, Lille, France. 9. CHU Grenoble Alpes, CETD, Grenoble, France. 10. CH Voiron, UETD, Voiron, France. 11. CH Lons-le-Saunier, CETD, Lons-le-Saunier, France. 12. Université Lille Nord de France, CHRU Lille, CETD, Lille, France. 13. CHU Nantes, CETD, Nantes, France. 14. AP-HP - Hôpital Raymond Poincaré, CETD, Paris, France. 15. CH Avranches, CETD, Avranches, France. 16. CHU Limoges, CETD, Limoges, France. 17. HCL - Hôpital Neurologique, CETD, Lyon, France.
Abstract
BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION:Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.
RCT Entities:
BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION:Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.
Authors: Marena Montera; Aleyah Goins; Leos Cmarko; Norbert Weiss; Karin N Westlund; Sascha R A Alles Journal: Channels (Austin) Date: 2021-12 Impact factor: 2.581
Authors: Giulia Di Stefano; Andrea Di Lionardo; Giuseppe Di Pietro; Giorgio Cruccu; Andrea Truini Journal: Pain Res Manag Date: 2021-04-26 Impact factor: 3.037