Web Enhancement A. NONMEM code for linear splines to describe the input function for Chronogesic sufentanil is shown. This code is used for the analysis in which the linear spline has four knots. HGT1, HGT2, HGT3, and HGT4 represent the heights (release rate) at the knots KNT1, KNT2, KNT3, and KNT4, respectively. Other terms are defined in Web Enhancement B. Similar code is used for the analysis of the linear spline with five knots.

$DES ITIME = T - IMPL

INPUT=HGT1+(HGT2-HGT1)*(ITIME-KNT1)/(KNT2-KNT1)

IF (ITIME.GE.KNT2) INPUT=HGT2+(HGT3-HGT2)*(ITIME-KNT2)/(KNT3-KNT2)

IF (ITIME.GT.KNT3) INPUT=HGT3+(HGT4-HGT3)*(ITIME-KNT3)/(KNT4-KNT3)

IF (T.LT.IMPL) INPUT=0

IF (T.GE.EXPL) INPUT=0

DADT(1) =-(K12*A(1)-K21*A(2)+K13*A(1)-K31*A(3))-K10*A(1)+K41*A(4)

DADT(2) = K12*A(1)-K21*A(2)

DADT(3) = K13*A(1)-K31*A(3)

DADT(4) = INPUT -K41*A(4)