Table 3 Twenty most frequently observed methadone-drug interactions (MDIs) among co-medication subpopulation in the MMTP (128 patients)

Tramadol

1

42 (6.0)

Concomitant administration of methadone and tramadol may result in withdrawal symptoms; methadone (moderate CYP 2D6 inhibitor) may decrease the metabolism of tramadol

Chlorpromazine

1

22 (3.1)

The concomitant use of methadone and chlorpromazine may cause additive CNS and respiratory depression

Levofloxacin

1

16 (2.3)

Levofloxacin may increase the QTc prolonging effects of methadone

Prochlorperazine

1

12 (1.7)

The concomitant use of methadone and prochlorperazine may cause additive CNS and respiratory depression

Alprazolam

2

99 (14.2)

Alprazolam may cause additive CNS depression

Cimetidine

2

84 (12.0)

Cimetidine (moderate CYP 3A4 and 2D6 inhibitor) may decrease the metabolism of methadone, raise serum methadone concentrations and consequently increase the toxicity of methadone

Dexamethasone

2

48 (6.9)

Dexamethasone (moderate CYP 3A4 and 2B6 inducer) may increase the metabolism of methadone, lower serum methadone concentrations and result in withdrawal symptoms

Estazolam

2

40 (5.7)

Estazolam may cause additive CNS depression

Fusidic acid

2

26 (3.7)

Fusidic acid may induce CYP enzyme

Pethidine

2

25 (3.6)

Interaction probably occurs due to additive opioid effects

Diltiazem

2

23 (3.3)

Diltiazem (moderate CYP 3A4 inhibitor) may decrease the metabolism of methadone, raise serum methadone concentrations and consequently increase the toxicity of methadone

Carbamazepine

2

22 (3.1)

Carbamazepine (strong CYP 2B6 inducer) may increase the metabolism of methadone, lower serum methadone concentrations and result in withdrawal symptoms

Imipramine

2

22 (3.1)

Imipramine (moderate CYP 2D6 inhibitor) may decrease the metabolism of methadone; combination with methadone increases tricyclic antidepressant (TCA) toxicity

Risperidone

2

20 (2.9)

Risperidone accelerates methadone metabolism via interfering with absorption or displacing methadone from plasma protein binding sites and results in withdrawal symptoms

Midazolam

2

19 (2.7)

Midazolam may cause additive CNS depression

Nifedipine

3

18 (2.6)

Methadone possibly increases the effects of nifidepine and increase the toxicity of nifedipine

Morphine

2

13 (1.9)

Interaction probably occurs due to additive opioid effects

Paroxetine

2

12 (1.7)

Paroxetine (moderate CYP 2B6 and 2D6 inhibitor) may decrease the metabolism of methadone and raise serum methadone concentrations and consequently increase the toxicity of methadone

Erythromycin

2

12 (1.7)

Erythromycin (CYP 3A4 inhibitor) may decrease the metabolism of methadone, raise serum methadone concentrations and consequently increase the toxicity of methadone

Dextromethorphan

3

25 (3.6)

Methadone may increase the levels/effects of dextromethorphan and increase the toxicity of dextromethorphan

Diazepam

3

15 (2.1)

Diazepam may increase the methadone effects and consequently increase the toxicity of methadone