Table 3.

(R)/(S) enantiomeric ratio at peak and trough concentrations following chronic dosing of between 7.5 mg and 130 mg rac-methadone once daily in 18 patients enrolled in a maintenance programme.

Parameter1	Mean	Range	%CV	P value2 (mean difference; 95% CI)
${\mathrm{R}}_{\min \left(\mathrm{first}\right)}^{\mathrm{ss}}/{\mathrm{S}}_{\min \left(\mathrm{first}\right)}^{\mathrm{ss}}$	1.07	0.68–2.28	34	0.57 (−0.02; −0.10, 0.06)
${\mathrm{R}}_{\min \left(\mathrm{last}\right)}^{\mathrm{ss}}/{\mathrm{S}}_{\min \left(\mathrm{last}\right)}^{\mathrm{ss}}$	1.10	0.70–1.97	27
${\mathrm{R}}_{\max }^{\mathrm{ss}}/{\mathrm{S}}^{\mathrm{ss}}$	0.88	0.68–1.40	19	< 0.0001 (−0.21; −0.30, −0.13)
${\mathrm{R}}^{\mathrm{ss}}/{\mathrm{S}}_{\max }^{\mathrm{ss}}$	0.843	0.66–1.07	15	0.0002 (−0.26; −0.38, −0.15)
${\mathrm{R}}_{{\min \left(\mathrm{first}\right)}_u}^{\mathrm{ss}}/{\mathrm{S}}_{{\min \left(\mathrm{first}\right)}_u}^{\mathrm{ss}}$	1.91	1.20–4.11	38	0.52 (−0.05; −0.20, 0.10)
${\mathrm{R}}_{{\min \left(\mathrm{last}\right)}_u}^{\mathrm{ss}}/{\mathrm{S}}_{{\min \left(\mathrm{last}\right)}_u}^{\mathrm{ss}}$	1.96	1.24–3.54	33
${\mathrm{R}}_{{\max }_u}^{\mathrm{ss}}/{\mathrm{S}}_{\mathrm{u}}^{\mathrm{ss}}$	1.55	1.09–2.52	26	0.0003 (−0.41; −0.60, −0.22)
${\mathrm{R}}_{\mathrm{u}}^{\mathrm{ss}}/{\mathrm{S}}_{{\max }_u}^{\mathrm{ss}}$	1.454	1.09–2.04	20	0.0008 (−0.51; −0.77, −0.25)

¹${\mathrm{R}}_{\min \left(\mathrm{first}\right)}^{\mathrm{ss}}/{\mathrm{S}}_{\min \left(\mathrm{first}\right)}^{\mathrm{ss}}$=ratio of (R)- to (S)-methadone plasma concentrations predose; ${\mathrm{R}}_{\min \left(\mathrm{last}\right)}^{\mathrm{ss}}/{\mathrm{S}}_{\min \left(\mathrm{last}\right)}^{\mathrm{ss}}$=ratio of (R)- to (S)-methadone plasma concentrations 24 h after dosing; ${\mathrm{R}}_{\max }^{\mathrm{ss}}/{\mathrm{S}}^{\mathrm{ss}}$=ratio of (R)-methadone ${\mathrm{C}}_{\max }^{\mathrm{ss}}$ and the corresponding (S)-methadone concentration at (R)-methadone t_max; ${\mathrm{R}}^{\mathrm{ss}}/{\mathrm{S}}_{\max }^{\mathrm{ss}}$=ratio of (R)-methadone concentration at the (S)-methadone t_max and (S)-methadone ${\mathrm{C}}_{\max }^{\mathrm{ss}}$;${\mathrm{R}}_{{\min \left(\mathrm{first}\right)}_u}^{\mathrm{ss}}/{\mathrm{S}}_{{\min \left(\mathrm{first}\right)}_u}^{\mathrm{ss}}$=ratio of (R)- to (S)- methadone plasma concentrations of the unbound drug predose; ${\mathrm{R}}_{{\min \left(\mathrm{last}\right)}_u}^{\mathrm{ss}}/{\mathrm{S}}_{{\min \left(\mathrm{last}\right)}_u}^{\mathrm{ss}}$=ratio of (R)- to (S)-methadone plasma concentrations of the unbound drug 24 h after dosing; ${\mathrm{R}}_{{\max }_u}^{\mathrm{ss}}/{\mathrm{S}}_{\mathrm{u}}^{\mathrm{ss}}$=ratio of (R)-methadone ${\mathrm{C}}_{{\max }_u}^{\mathrm{ss}}$ and the corresponding (S)-methadone concentration of the unbound drug at (R)-methadone t_max; ${\mathrm{R}}_{\mathrm{u}}^{\mathrm{ss}}/{\mathrm{S}}_{{\max }_u}^{\mathrm{ss}}$=ratio of (R)-methadone concentration of the unbound drug at the (S)-methadone t_max and (S)- methadone ${\mathrm{C}}_{{\max }_u}^{\mathrm{ss}}$

²Comparison within each group vs the parameter with a blank cell in the P value column

³Statistically significant difference (P value, mean difference; 95% CI) compared with${\mathrm{R}}_{\max }^{\mathrm{ss}}/{\mathrm{S}}^{\mathrm{ss}}$ (P =0.043, 0.048; 0.002, 0.094)

⁴statistically significant difference compared with ${\mathrm{R}}_{{\max }_u}^{\mathrm{ss}}/{\mathrm{S}}_{\mathrm{u}}^{\mathrm{ss}}$ (P = 0.047, 0.098; 0.002, 0.195).