title: Cytotoxicity of Oxycodone and Morphine in Human Neuroblastoma and Mouse Motoneuronal Cells: A Comparative Approach.
abstract: OBJECTIVE
  Oxycodone is the mo st commonly used opioid for the treatment of moderate to severe pain. The peak cerebrospinal fluid concentration after epidural oxycodone was reported to be 300-fold greater (0.025 mM) than when administered intravenously after gynecologic surgery. Additionally, those patients administered epidural oxycodone had lower pain scores, needed less rescue analgesics and had fewer adverse effects compared with intravenous administration. However, oxycodone neurotoxicity requires evaluation before intrathecal implementation for routine clinical use.
  
  
  METHODS
  We used two in vitro cell culture models to compare the cytotoxicity of oxycodone with that of morphine, and to study the mechanisms underlying toxicity. Human neuroblastoma cells and mouse motoneuronal cells were treated with increasing concentrations (0.0125-2 mM) of oxycodone or morphine, and were harvested at 24, 48 or 96 h. Cell cultures were evaluated with 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide and resazurin reduction assays.
  
  
  RESULTS
  Both morphine and oxycodone decreased cell viability in a dose-dependent manner at concentrations between 0.5 and 2 mM. Morphine increased the number of apoptotic cells compared with oxycodone when assessed by flow cytometry, and transmission electron microscopy images revealed that exposure to both opioids evoked the appearance of numerous electron-dense, probable autophagic vacuoles in the cytoplasm of the cells.
  
  
  CONCLUSIONS
  Based on these results, it seems that the cytotoxicity of oxycodone in motoneuronal cells is similar to or less than that of morphine, and occurs only at concentrations above the peak clinical concentration in the cerebrospinal fluid after epidural administration.
authors.affiliation: Anaesthesiology and Intensive Care Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.|Department of Anesthesia and Operative Services, Kuopio University Hospital, PO Box 100, 70029 KYS, Kuopio, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Kokki
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Pesonen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Piia
authors.initials: P
authors.lastname: Vehviläinen
authors.affiliation: Anaesthesiology and Intensive Care Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.|Department of Anesthesia and Operative Services, Kuopio University Hospital, PO Box 100, 70029 KYS, Kuopio, Finland.|School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Litmala
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Pasanen
authors.affiliation: Anaesthesiology and Intensive Care Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland. hannu.kokki@uef.fi.|Department of Anesthesia and Operative Services, Kuopio University Hospital, PO Box 100, 70029 KYS, Kuopio, Finland. hannu.kokki@uef.fi.
authors.forename: Hannu
authors.initials: H
authors.lastname: Kokki
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D009020:Morphine / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D009046:Motor Neurons / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology; D010098:Oxycodone / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D010098:Oxycodone