Loxapine for treatment of patients with refractory, chemotherapy-induced neuropathic pain : a prematurely terminated pilot study showing efficacy but limited tolerability

  • Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (KNa1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20–30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.

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Author:Sven Schmiedl, David Peters, Oliver Schmalz, Anke Mielke, Tanja Rossmanith, Shirin Diop, Martina Piefke, Petra Thürmann, Achim SchmidtkoORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31402867
Parent Title (English):Frontiers in pharmacology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Francisco Lopez-Munoz
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/07/25
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/08/29
Tag:Slack channel; analgesia; loxapine; neuropathic pain; tolerability and safety
Issue:Art. 838
Page Number:8
First Page:1
Last Page:8
Copyright © 2019 Schmiedl, Peters, Schmalz, Mielke, Rossmanith, Diop, Piefke, Thürmann and Schmidtko. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0