title: Analysis of opioid consumption in clinical trials: a simulation based analysis of power of four approaches.
abstract: Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15-62% reduction in morphine consumption. Trials were simulated with duration of 24-96 h. Monte Carlo simulation and re-estimation were performed to determine sample size required to demonstrate efficacy with 80% power using t test, Mann-Whitney rank sum test, time-to-event (TTE) modeling and RTTE modeling. Precision of efficacy estimates for RTTE models were evaluated in 500 simulations. A sample size of 50 patients was required to detect 37% morphine sparing effect with at least 80% power in a 24 h trial with RTTE modeling whereas the required sample size was 200 for Mann-Whitney, 180 for t-test and 76 for TTE models. Extending the trial duration from 24 to 96 h reduced the required sample size by 3.1 fold with RTTE modeling. Precise estimate of potency was obtained with a RTTE model accounting for both morphine effects and time-varying covariates on opioid consumption. An RTTE analysis approach proved better suited for demonstrating efficacy of opioid sparing analgesics than traditional statistical tests as a lower sample size was required due the ability to account for time-varying factors including PK.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, Copenhagen, Denmark.
authors.forename: Rasmus Vestergaard
authors.initials: RV
authors.lastname: Juul
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Nyberg
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, Copenhagen, Denmark.
authors.forename: Lona Louring
authors.initials: LL
authors.lastname: Christrup
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ulrika S H
authors.initials: USH
authors.lastname: Simonsson
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, Copenhagen, Denmark. trine.lund@sund.ku.dk.
authors.forename: Trine Meldgaard
authors.initials: TM
authors.lastname: Lund
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003198:Computer Simulation / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics; D018401:Sample Size; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: Analgesics; Clinical trial simulation; Monte Carlo Mapped Power; Postoperative pain; Repeated time-to-event modeling