title: Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs.
abstract: To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extended-release and immediate-release oxycodone/acetaminophen fixed-dose combination analgesicsDesign. Randomized, double-blind, active- and placebo-controlled, 7-way crossover studySetting. Contract research organizationSubjects. Nondependent recreational users of prescription opioids.
  
  
  
  Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored.
  
  
  
  Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax(tmax) was significantly longer (P<0.001) for intact immediate-release/extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmaxfor immediate-release/extended-release oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmaxand area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711-0.997).
  
  
  
  Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmaxand longer tmaxthan immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.
authors: *Department of Clinical Pharmacology, terri.morton@mallinckrodt.com.
authors: Terri L
authors: TL
authors: Morton
authors: *Department of Clinical Pharmacology.
authors: Krishna
authors: K
authors: Devarakonda
authors: Contract Medical Monitor, and.
authors: Kenneth
authors: K
authors: Kostenbader
authors: Clinical Trial Manager, Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, Missouri, USA.
authors: Jeannie
authors: J
authors: Montgomery
authors: Clinical Trial Manager, Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, Missouri, USA.
authors: Thomas
authors: T
authors: Barrett
authors: Scientific Affairs, PRA Health Sciences, Salt Lake City, Utah, USA.
authors: Lynn
authors: L
authors: Webster
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood*; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood*; D018592:Cross-Over Studies; D059026:Diagnostic Self Evaluation; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D013287:Illicit Drugs / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010098:Oxycodone / Q000008:administration & dosage / Q000097:blood*; D055553:Prescription Drugs / Q000008:administration & dosage / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D004338:Drug Combinations; D013287:Illicit Drugs; D055553:Prescription Drugs; C514822:oxycodone-acetaminophen; D000082:Acetaminophen; D010098:Oxycodone
keywords: Abuse Potential; Acetaminophen; Oxycodone; Pharmacokinetics; Subjective Effects