title: The Efficacy and Safety of the Novel Peripheral Analgesic Isovaline as an Adjuvant to Propofol for General Anesthesia and Conscious Sedation: A Proof-of-Principle Study in Mice.
abstract: BACKGROUND
  The combination of propofol and an opioid analgesic is widely used for procedural sedation, as well as total IV anesthesia. However, opioids produce respiratory depression, a primary cause of death due to these agents. We recently reported on the antinociceptive actions of isovaline, a small nonbiogenic amino acid that does not readily cross the blood-brain barrier and acts on peripheral γ-aminobutyric acid type B receptors. Here, we explored the possibility that isovaline may be an effective and safe alternative to opioids as an adjunct to propofol for producing anesthesia.
  
  
  METHODS
  With approval from our Animal Care Committee, we conducted an in vivo study in adult female CD-1 mice using Dixon's "up-and-down" method for dose assessment. Animals received intraperitoneal saline, propofol, isovaline, fentanyl, or coadministration of propofol with isovaline or fentanyl. We assessed hypnosis by a loss of righting reflex and immobility by an absence of motor response to tail clip application. General anesthesia was defined as the presence of both hypnosis and immobility. We assessed conscious sedation as a decrease in time on a rotarod. The maximal dose without respiratory rates of <4 per minute, apnea, or death was defined as the maximal tolerated dose.
  
  
  RESULTS
  Either isovaline or fentanyl coadministered with propofol at its half-maximal effective dose (ED50) for hypnosis produced general anesthesia (isovaline ED50, 96 mg/kg [95% confidence interval {CI}, 88-124 mg/kg]; fentanyl ED50, 0.12 mg/kg [95% CI, 0.08-3.5 mg/kg]). Propofol produced hypnosis (ED50, 124 mg/kg [95% CI, 84-3520 mg/kg]) but did not block responses to tail clip application. Neither isovaline nor fentanyl produced hypnosis at doses which produced immobility (isovaline ED50, 350 mg/kg [95% CI, 286-1120 mg/kg]; fentanyl ED50, 0.35 mg/kg [95% CI, 0.23-0.51 mg/kg]). Isovaline at its analgesic ED50, coadministered with a subhypnotic dose of propofol (40 mg/kg), did not exacerbate propofol-induced deficits in rotarod performance. The median maximal tolerated dose of fentanyl coadministered with the hypnotic ED50 of propofol was 11 mg/kg (95% CI, 8-18 mg/kg). Isovaline at a maximal deliverable (soluble) dose of 5000 mg/kg produced no apparent respiratory depression or other adverse effects.
  
  
  CONCLUSIONS
  The novel analgesic, isovaline, coadministered with propofol, produced general anesthesia and conscious sedation in mice. The margin of safety for propofol-isovaline was considerably higher than that for propofol-fentanyl. This study's results show that propofol-based sedation and general anesthesia can be effectively and safely produced by replacing the conventional opioid component with a brain-impermeant peripherally acting γ-aminobutyric acid type B receptor agonist. The results provide proof of the principle of combining a peripheral analgesic with a centrally acting hypnotic to produce general anesthesia. This principle suggests a novel approach to clinical general anesthesia and conscious sedation.
authors.affiliation: From the *Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada; and †Department of Anesthesia, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Whitehead
authors.forename: Stephan K W
authors.initials: SK
authors.lastname: Schwarz
authors.forename: Yahya I
authors.initials: YI
authors.lastname: Asiri
authors.forename: Timothy
authors.initials: T
authors.lastname: Fung
authors.forename: Ernest
authors.initials: E
authors.lastname: Puil
authors.forename: Bernard A
authors.initials: BA
authors.lastname: MacLeod
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000633:toxicity; D000768:Anesthesia, General / Q000009:adverse effects / Q000379:methods*; D018686:Anesthetics, Intravenous / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D016292:Procedural Sedation / Q000009:adverse effects / Q000379:methods*; D005260:Female; D051379:Mice; D015742:Propofol / Q000494:pharmacology* / Q000633:toxicity; D016896:Treatment Outcome; D014474:Unconsciousness / Q000139:chemically induced; D014633:Valine / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000700:Analgesics; D018686:Anesthetics, Intravenous; C032737:isovaline; D014633:Valine; D015742:Propofol