Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk.

BACKGROUND: The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.

RESEARCH DESIGN AND METHODS: Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.

RESULTS: Thirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R2  = 0.239, p = 0.018; R2  = 0.513, p = 0.006) was shown, and it remained so if the concentration of diazepam was included (R2  = 0.347, p = 0.026, R2  = 0.513, p = 0.009).

CONCLUSIONS: The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.