Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial

Abstract

Aims: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a “target” plasma R-methadone level (80–250 ng/mL). Methods: A multicenter randomized controlled trial was organized. Results: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the “target range” at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. ­Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.

Response to Letter to the Editor by Ernesto de Bernadis

“…The upper limit remained at 250 ng/mL, but in our population, a very limited number of patients reached such levels (Fig. 3a in Mannaioni et al [1]). Furthermore, we confirmed that plasma concentrations above 200 ng/mL were reached in patients with an oral methadone dose intake of as low as 60 or as high as 200 mg/day (see the above-mentioned Fig.…”

“…The target therapeutic plasma R-methadone concentration for the treatment of severe heroin users in the methadone maintenance program (MMT) described in Mannaioni et al [1] was set at 80–250 ng/mL. The comment letter of de Bernardis suggests that by further increasing plasma R-methadone concentrations, a better therapeutic outcome could possibly be obtained.…”

Comment on “Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial”

“…More recently, Meini et al [3], also acknowledged by Mannaioni et al [1], confirmed Eap’s results, showing in their sample of methadone-treated patients the presence of a R-methadone threshold of 200 ng/mL for absence of heroin use, and 250 ng/mL for absence of craving. According to Meini’s published data on graph, more than 40% of the heroin-using patients in his sample had trough R-methadone levels falling between 80 and 250 ng/mL.…”

“…Mannaioni et al [1], in their recent ­randomised clinical trial on methadone dosing adjusted according to serum ­R-methadone levels, chose a target window of 80–250 ng/mL R-methadone based on results by Eap et al [2]. …”

“…Thus, it is conceivable that the target therapeutic window chosen by Mannaioni et al [1], starting at less than one third of the optimal threshold level and ending just at it, might have been too low to deliver a clear effect in comparison with controls, both on retention in treatment and on use of illegal psychoactive substances.…”