Repeated Time-to-event Analysis of Consecutive Analgesic Events in Postoperative Pain.
BACKGROUND
Reduction in consumption of opioid rescue medication is often used as an endpoint when investigating analgesic efficacy of drugs by adjunct treatment, but appropriate methods are needed to analyze analgesic consumption in time. Repeated time-to-event (RTTE) modeling is proposed as a way to describe analgesic consumption by analyzing the timing of consecutive analgesic events.


METHODS
Retrospective data were obtained from 63 patients receiving standard analgesic treatment including morphine on request after surgery following hip fracture. Times of analgesic events up to 96 h after surgery were extracted from hospital medical records. Parametric RTTE analysis was performed with exponential, Weibull, or Gompertz distribution of analgesic events using NONMEM, version 7.2 (ICON Development Solutions, USA). The potential influences of night versus day, sex, and age were investigated on the probability.


RESULTS
A Gompertz distribution RTTE model described the data well. The probability of having one or more analgesic events within 24 h was 80% for the first event, 55% for the second event, 31% for the third event, and 18% for fourth or more events for a typical woman of age 80 yr. The probability of analgesic events decreased in time, was reduced to 50% after 3.3 days after surgery, and was significantly lower (32%) during night compared with day.


CONCLUSIONS
RTTE modeling described analgesic consumption data well and could account for time-dependent changes in probability of analgesic events. Thus, RTTE modeling of analgesic events is proposed as a valuable tool when investigating new approaches to pain management such as opioid-sparing analgesia.
From the Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (R.V.J., M.K., L.L.C., T.M.L.); Orthopaedic Surgery Research Unit and Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark (S.R.); and Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden (U.S.H.S.).
Rasmus Vestergaard
RV
Juul
Sten
S
Rasmussen
Mads
M
Kreilgaard
Lona Louring
LL
Christrup
Ulrika S H
US
Simonsson
Trine Meldgaard
TM
Lund
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000698:Analgesia / Q000706:statistics & numerical data*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D005260:Female; D006620:Hip Fractures / Q000601:surgery*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use; D010149:Postoperative Pain / Q000188:drug therapy*; D010507:Periodicity; D012189:Retrospective Studies; D012737:Sex Factors; D013997:Time Factors; D055815:Young Adult
D000701:Analgesics, Opioid; D009020:Morphine