Can Saliva Replace Plasma for the Monitoring of Methadone?

Abstract

The aims of this study were to determine the relationship between saliva and plasma methadone concentrations and the influence of variability in saliva pH. Saliva and plasma samples were taken before the daily dose of methadone in 60 patients undergoing methadone maintenance treatment (MMT). Saliva pH was measured immediately after sampling, and concentrations of (RS)-, (R)-, and (S)-methadone in saliva and plasma were assayed by LC/MS. In addition, unbound (R)- and (S)-methadone concentrations were measured in plasma samples by ultrafiltration. Plasma binding and pH differences between plasma and saliva were then used to estimate methadone saliva/plasma ratios and to compare them with observed values. Saliva pH ranged from 5.1 to 7.6 (mean +/- SD, 6.7 +/- 0.5). Plasma and saliva concentrations correlated weakly [(RS)-, r = 0.14, P = 0.007, n = 44; (R)-, r = 0.10, P = 0.04, n = 43; (S)-, r = 0.22, P = 0.002, n = 43], and the mean saliva-to-plasma methadone concentration ratios were 1.1 (+/-1.3 SD), 1.5 (+/-1.5), and 0.8 (+/-0.8), for (RS)-, (R)-, and (S)-methadone, respectively. Corresponding values based on unbound concentrations of methadone in plasma were 21 (+/-20.6, n = 31), 21 (+/-19, n = 34), and 17 (+/-15, n = 36). The salivary concentration-to-dose ratios showed statistically significant but weak inverse correlations with saliva pH [(RS)-, r = 0.27, P < 0.001; (R)-, r = 0.25, P < 0.001; (S)-, r = 0.29, P < 0.001, respectively]. There were significant correlations between predicted and observed saliva/plasma ratios [(RS)-, r = 0.44, P < 0.001, n = 31; (R)-, r = 0.58, P < 0.001, n = 32; (S)-, r = 0.10, P = 0.04, n = 34], but the mean predicted saliva concentrations were about 5 times lower than the mean observed values. The poor correlations between salivary and plasma methadone concentrations observed in this study are partly related to the effect of variable saliva pH. However, saliva pH explained only 10%-36% of the total variation. As a conclusion, monitoring methadone concentrations in saliva may not be a useful alternative to plasma concentration measurements. Correction for saliva pH measured immediately after collection improves the relationship between saliva and plasma methadone concentration, but most of the variation remains unexplained.

Correlation of methadone concentrations in plasma and saliva collected with and without stimulation in pain management patients

“…Salivette ® devices gave the best S/P correlation when compared with the S1 and S2 portions, with mean S/P ratios being 0.9, 0.5, and 0.1, respectively. The S/P ratio of methadone for Salivette ® is in agreement with reported values of 1.1 [3] and 1.3 [4], whereas the ratio obtained for the S1 portion is similar to mean reported values of 0.5 [5] and 0.6 [2]. These findings show that differences in the S/P ratio of methadone could be obtained depending on the technique used for saliva collection.…”

“…A linear relationship was also observed in a previous report [4] where the spitting method was used (r = 0.81, p < 0.001, n = 21). Nevertheless, significant but weak correlations were reported in two other studies [2,3] where a higher number of samples were analyzed. No correlation was found for fractions S1 or S2.…”

“…However, saliva sampling performed without stimulation has been reported as an inappropriate method for monitoring methadone because of wide variability in the saliva-to-plasma (S/P) concentration ratio [2][3][4][5]. Nevertheless, stimulation of salivary flow has several advantages, including increased sample volume and a decrease of inter-subject variability in the S/P ratio for certain drugs [6].…”

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

“…In contrast, a poor correlation between plasma and saliva concentrations of methadone was found in 60 methadone maintenance patients sampled just before their daily methadone dose. Salivary pH explained 10-36% of the total variation [25]. Similarly, no correlation was found between saliva and plasma morphine levels in children receiving a continuous infusion of morphine or adult controls receiving codeine [26].…”

Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

“…ABC transporters are located in several barriers such as superficial columnar epithelial cells in the lumen of the gut, biliary canalicular front of hepatocytes, epithelial cells of small biliary ductules, apical surfaces of epithelial cells of proximal tubules. It has also been reported their presence in ductal cells of salivary glands 10 and several substrates like cyclosporine A 11 and methadone 12 have shown to be preferentially transported to the luminal space.…”