title: Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease.
abstract: Recent evidence of neuropathic pain among adults with sickle cell disease (SCD) reveals a need for adjuvant analgesic treatments for these patients. Ca(2+)/calmodulin protein kinase IIα (CaMKIIα) has a known role in neuropathic pain and trifluoperazine is a potent CaMKIIα inhibitor. The study aim was to determine trifluoperazine's acute effects, primarily on adverse effects and secondarily on pain intensity reduction, in adults with SCD. In a phase I, open-label study of 6 doses of trifluoperazine (0.5, 1, 2, 5, 7.5, 10mg), we obtained 7-hourly and 24-h repeated measures of adverse effects, pain intensity, and supplemental opioid analgesics in 18 adults with SCD (18 hemoglobin SS disease, 15 women, average age 35.8±8.9 years, ranged 23-53) each of whom received a single dose. Data were analyzed with descriptive statistics. Subjects reported moderate to severe sedative effects at 7.5 and 10mg doses, respectively. Eight subjects reported 50% reduction in chronic pain without severe sedation or supplemental opioid analgesics; one of these subjects had dystonia 24.5h after the 10mg dose. The analgesic effect lasted for at least 24h in 3 subjects. Sedation resolved with caffeine and dystonia resolved with diphenhydramine. Adults with SCD experienced minimal adverse effects at doses under 10mg. In this molecular mechanism-driven translational study, trifluoperazine shows promise as an analgesic drug that is worthy of further testing in a randomized controlled study of adults with SCD starting at a dose of 1mg in repeated doses to determine long-term adverse and analgesic effects.
authors.affiliation: University of Illinois at Chicago, College of Medicine, Division of Hematology/Oncology, Chicago, IL, USA; Jesse Brown Veteran's Administration Medical Center, Chicago, IL, USA; University of Illinois at Chicago College of Pharmacy Department of Biopharmaceutical Sciences, Chicago, IL, USA; Comprehensive Sickle Cell Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA. Electronic address: remoloki@uic.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Molokie
authors.affiliation: University of Illinois at Chicago College of Nursing Department of Biobehavioral Health Science, Chicago, IL, USA; Comprehensive Sickle Cell Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Wilkie
authors.affiliation: University of Illinois at Chicago College of Nursing Department of Biobehavioral Health Science, Chicago, IL, USA.
authors.forename: Harriett
authors.initials: H
authors.lastname: Wittert
authors.affiliation: University of Illinois at Chicago College of Nursing Department of Biobehavioral Health Science, Chicago, IL, USA.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Suarez
authors.affiliation: University of Illinois at Chicago College of Nursing Department of Biobehavioral Health Science, Chicago, IL, USA.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Yao
authors.affiliation: University of Illinois at Chicago College of Nursing Department of Biobehavioral Health Science, Chicago, IL, USA.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: University of Illinois at Chicago College of Pharmacy Department of Biopharmaceutical Sciences, Chicago, IL, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: University of Illinois at Chicago College of Pharmacy Department of Biopharmaceutical Sciences, Chicago, IL, USA; Comprehensive Sickle Cell Center, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.
authors.forename: Zaijie J
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D000328:Adult; D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use*; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy*; D014268:Trifluoperazine / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000700:Analgesics; D014268:Trifluoperazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Neuropathic pain; Phase 1 study; Safety; Sickle cell disease; Trifluoperazine