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Clinical Trial ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00838

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

 Sven Schmiedl1, 2*, David Peters1, 3, Oliver Schmalz4,  Anke Mielke5, Tanja Rossmanith6,  Shirin Diop7,  Martina Piefke7, Petra Thürmann3, 8 and  Achim Schmidtko9, 10
  • 1Philipp Klee-Institute for Clinical Pharmacology, Helios Klinikum Wuppertal, Germany
  • 2Department of Clinical Pharmacology, School of Medicine, Faculty of Health,, Witten/Herdecke University, Germany
  • 3Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Germany
  • 4Clinic of Internal Medicine I, Division of Oncology and Palliative Care, Helios Klinikum Wuppertal, Germany
  • 5Clinic for Anesthesiology, Pain Management Unit, Helios Klinikum Wuppertal, Germany
  • 6branch for Translational Medicine and Pharmacology of the Fraunhofer IME, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Germany
  • 7Neurobiology and Genetics of Behavior, Department of Psychology and Psychotherapy, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Germany
  • 8Philipp Klee-Institute for Clinical Pharmacology,, Helios Klinikum Wuppertal, Germany
  • 9Institute of Pharmacology and Clinical Pharmacy, College of Pharmacy, Goethe University Frankfurt, Germany
  • 10Institute of Pharmacology and Toxicology, Centre for Biomedical Education and Research (ZBAF), School of Medicine, Faculty of Health, Witten/Herdecke University, Germany

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 a 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 (4 treatment episodes à 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 which 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 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. (EudraCT Number: 2014-005440-17 (, NCT02820519 (

Keywords: Loxapine, Neuropathic pain (NP), Slack channel, Analgesia, Tolerability and safety

Received: 22 Feb 2019; Accepted: 01 Jul 2019.

Edited by:

Francisco Lopez-Munoz, Camilo José Cela University, Spain

Reviewed by:

Jose A. Guerra, Faculty of Pharmacy, Complutense University of Madrid, Spain
Guy H. Hans, Antwerp University Hospital, Belgium  

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.

* Correspondence: Dr. Sven Schmiedl, Helios Klinikum Wuppertal, Philipp Klee-Institute for Clinical Pharmacology, Wuppertal, 42283, North Rhine-Westphalia, Germany,