title: Human abuse potential of immediate-release/extended-release versus immediate-release hydrocodone bitartrate/acetaminophen: a randomized controlled trial in recreational users of prescription opioids.
abstract: BACKGROUND
  The abuse potential of prescription opioids is well established. This study compared positive, subjective drug effects of single, equal doses of biphasic immediate release (IR)/extended release (ER) hydrocodone bitartrate (HB)/acetaminophen (acetyl-p-aminophenol [APAP]) 7.5/325 mg tablets versus IR HB/APAP 7.5/325-mg tablets and placebo.
  
  
  METHODS
  Healthy adult recreational users of prescription opioids entered this randomized, double-blind, double-dummy, active- and placebo-controlled, seven-way crossover study. Participants received single, total doses of IR/ER HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), IR HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), and placebo. Peak subjective effects (E(max)); time to peak effects (TE(max)); and area under the drug-effect curves for drug liking, high, and good drug effects were measured using visual analog scales. Median values with 95% confidence interval (CI) were compared using analysis of variance.
  
  
  RESULTS
  Among completers (n = 52), IR/ER HB/APAP produced delayed and lower peak effects compared to equal doses of IR HB/APAP. Comparing intact tablets, the drug liking E(max) (median [95% CI]) was significantly lower for IR/ER HB/APAP 45/1950 mg (78.0 [73.0, 81.0]) than an equal dose of IR HB/APAP (89.5 [85.0, 93.0]; difference, -8.5 [-12.0, -6.0]; P < 0.001). Similar results were observed for intact IR/ER HB/APAP and IR HB/APAP 22.5/975 mg. Crushing IR/ER HB/APAP 45/1950 mg delayed these effects compared with an equal dose of crushed IR HB/APAP and intact IR/ER HB/APAP.
  
  
  CONCLUSIONS
  IR/ER HB/APAP resulted in lower subjective positive drug effects than an equal dose of IR HB/APAP. Crushing IR/ER HB/APAP also delayed the onset of subjective effects compared with intact IR/ER HB/APAP. These findings suggest that biphasic IR/ER HB/APAP has lower abuse potential than IR HB/APAP in single equal doses.
  
  
  BACKGROUND
  This Phase I clinical trial conducted in the USA was not registered.
authors.affiliation: Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals , Hazelwood, MO , USA.
authors.forename: Krishna
authors.initials: K
authors.lastname: Devarakonda
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kostenbader
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jeannie B
authors.initials: JB
authors.lastname: Montgomery
authors.forename: Thomas
authors.initials: T
authors.lastname: Barrett
authors.forename: Jim L
authors.initials: JL
authors.lastname: Young
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Webster
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006853:Hydrocodone / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D019966:Substance-Related Disorders / Q000453:epidemiology* / Q000209:etiology; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D000082:Acetaminophen; D006853:Hydrocodone
keywords: acetaminophen; extended release; fixed-dose combination; human abuse potential; hydrocodone; opioid