Background
Methods
Data sources and study sample
Prescription data
Methadone-drug interactions (MDIs) data
Level | Definition | Drugs |
---|---|---|
1
a
| Drugs should not be coadministered as they might lead to serious adverse events or precipitate opioid withdrawal | Buprenorphine, Tramadol, Nalbuphine, Naloxone, Naltrexone, Amiodarone, Butorphanol, Ciprofloxacin, Chlorpromazine, Cisapride, Dezocine, Dofetilide, Droperidol, Dronedarone, Fentanyl/Droperidol, Fluphenazine, Fospropofol, Gatifloxacin, Halofantrine, Haloperidol, Ibutilide, Iloperidone, Lapatinib, Levofloxacin, Mesoridazine, Moxifloxacin, Nalbuphine, Nilotinib, Paliperidone, Perphenazine, Pimozide, Prochlorperazine, Promazine, Promethazine, Quinidine, Quinine, Ranolazine, Sotalol, Sunitinb, Tapentadol, Telithromycin, Tetrabenazine, Thiethylperazine, Thioridazine, Trifluoperazine, Vardenafil |
2
b
| A potential interaction might modify the dosage; monitor closely to minimize clinical consequences | Alprazolam, Estazolam, Flurazepam, Midazolam, Zopiclone, Clormethiazole, Methylphenidate, Amitriptyline, Desipramine, Imipramine, Nortriptyline, Protriptyline, Phenobarbital, Dexamethasone, Fusidic acid, Rifampicin, Spironolactone, Diltiazem, Cimetidine, Dihydroergotamine, Fluconazole, Ketoconazole, Erythromycin, Clarithromycin, Moclobemide, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Risperidone, Merperidine, Alfentanil, Propoxyphene, Morphine, Carbamazepine, Phenytoin |
3
c
| Minor or unknown interactions | Dextromethorphan, Nifedipine, Diazepam, Metronidazole, Omeprazole, Verapamil |
Statistical analyses
Results
Selected characteristics of MMTP patients
No interaction (n = 43) | Drug interaction (n = 85) |
df
| P-value* | |
---|---|---|---|---|
Mean age, (SD) | 40.7 (6.8) | 39.0 (7.4) | 127 | 0.20 |
Male, n (%) | 36 (83.7) | 75 (88.2) | 1 | 0.47 |
Mean body mass index, kg/m2 (SD) | 23.6 (3.3) | 24.4 (3.9) | 125 | 0.24 |
Education, n (%) | ||||
Less than high school | 26 (60.5) | 47 (55.3) | 1 | 0.58 |
High school or above | 17 (39.5) | 38 (44.7) | ||
Marital status, n (%) | ||||
Married or living with partner | 13 (30.2) | 27 (32.1) | 2 | 0.69 |
Never married | 24 (55.8) | 41 (48.8) | ||
Divorced/widowed | 6 (14.0) | 16 (19.1) | ||
Employment, n (%) | ||||
Employed | 30 (69.8) | 55 (64.7) | 1 | 0.57 |
Other | 13 (30.2) | 30 (35.3) | ||
Current illicit drug use, n (%) | ||||
Heroin | 22 (51.2) | 30 (35.3) | 1 | 0.08 |
Amphetamine(s) | 1 (2.3) | 3 (3.5) | 1 | 0.99 |
Benzodiazepine(s) | 7 (16.3) | 14 (16.5) | 1 | 0.98 |
Heroin use years, (SD) | 9.5 (6.3) | 7.6 (5.1) | 119 | 0.11 |
Drug use in the past, n (%) | ||||
Heroin | 43 (100) | 85 (100) | 1 | -- |
Amphetamine(s) | 26 (60.5) | 56 (65.9) | 1 | 0.55 |
MDMA | 0 (0.0) | 8 (9.4) | 1 | 0.05 |
Ketamine | 1 (2.3) | 10 (11.8) | 1 | 0.10 |
Other substance use, n (%) | ||||
Cigarettes | 33 (83.7) | 73 (85.9) | 1 | 0.75 |
Alcohol | 13 (30.2) | 30 (35.3) | 1 | 0.57 |
Betel quid | 9 (20.9) | 28 (32.9) | 1 | 0.16 |
HCV coinfection, n (%) | 42 (97.7) | 79 (92.9) | 1 | 0.42 |
HBV coinfection (HBsAg-positive), n (%) | 9 (20.9) | 18 (21.2) | 1 | 0.97 |
Current methadone dose, mg (SD) | 53.9 (25.7) | 53.0 (29.7) | 127 | 0.86 |
MMTP participation period, months (SD) | 17.7 (12.5) | 22.8 (13.8) | 126 | 0.04* |
Methadone-drug interactions
Drugs that interact with methadone | Level | n (%) | Mechanisms of MDI |
---|---|---|---|
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 |
Drugs | Frequency | Mechanisms of MDI |
---|---|---|
Tramadol | 42 | Concomitant administration of methadone and tramadol may result in withdrawal symptoms; methadone (moderate CYP 2D6 inhibitor) may decrease the metabolism of tramadol |
Chlorpromazine | 22 | The concomitant use of methadone and chlorpromazine may cause additive CNS and respiratory depression |
Levofloxacin | 16 | Levofloxacin may increase the QTc prolonging effects of methadone |
Prochlorperazine | 12 | The concomitant use of methadone and prochlorperazine may cause additive CNS and respiratory depression |
Moxifloxacin | 6 | Moxifloxacin may increase the QTc prolonging effects of methadone |
Ciprofloxacin | 5 | Ciprofloxacin may increase the QTc prolonging effects of methadone |
Haloperidol | 5 | Haloperidol may increase the QTc prolonging effects of methadone |
Buprenorphine | 1 | Concomitant administration of methadone and buprenorphine may result in withdrawal symptoms |
Droperidol | 1 | Droperidol may increase the QTc prolonging effects of methadone |
Nalbuphine | 1 | Concomitant administration of methadone and nalbuphine may result in withdrawal symptoms |
Thioridazine | 1 | The concomitant use of methadone and thioridazine may cause additive CNS and respiratory depression |
Logistic regression of correlates of coadministration
Characteristic | Adjusted OR (95% CI) |
P-value
|
---|---|---|
Age | 1.02 (0.95 ~ 1.09) | 0.61 |
Sex | ||
Female | 1.00 | - |
Male | 0.63 (0.13 ~ 2.61) | 0.54 |
Education | ||
Less than high school | 1.00 | - |
High school or above | 2.42 (1.00 ~ 6.25) | 0.06 |
Marital status | ||
Married or living with partner | 1.00 | - |
Never married | 0.23 (0.06 ~ 0.72) | 0.02* |
Divorced/widowed | 0.24 (0.06 ~ 0.89) | 0.03* |
Employment | ||
Employed | 1.00 | - |
Other | 1.06 (0.41 ~ 2.66) | 0.91 |
Drug use in the past | ||
Amphetamine | 2.68 (1.15 ~ 6.53) | 0.03* |
MDMA | 0.19 (0.01 ~ 2.85) | 0.26 |
Ketamine | 4.84 (0.42 ~ 132.23) | 0.25 |
Other use substances | ||
Cigarettes | 1.43 (0.46 ~ 4.32) | 0.53 |
Alcohol | 1.01 (0.42 ~ 2.45) | 0.98 |
Betel quid | 1.44 (0.50 ~ 4.36) | 0.50 |
HBV coinfection | 3.08 (1.03 ~ 10.77) | 0.05 |
HCV coinfection | 6.68 (1.56 ~ 31.06) | 0.01* |
MMTP participation period | 1.08 (1.04 ~ 1.12) | < 0.0001** |
Logistic regression of correlates of MDIs
Characteristics | Adjusted OR (95% CI) |
P-value
|
---|---|---|
Age | 0.94 (0.88 ~ 0.99) | 0.07 |
Sex | ||
Female | 1.00 | - |
Male | 4.88 (1.25 ~ 20.17) | 0.02* |
Marital status | ||
Married or living with partner | 1.00 | - |
Divorced/widowed | 2.24 (0.71 ~ 7.94) | 0.19 |
Current illicit drug use | ||
Heroin (yes vs. no) | 0.38 (0.15 ~ 0.94) | 0.04* |
Number of comedications per MMTP participation monthsa | 1.41 (1.17 ~ 1.79) | 0.002* |
Case no. | Suspected Drugs | Mechanisms | Description |
---|---|---|---|
1 | Thioridazine | Additive CNS and respiratory depression | A 38-year-old man was diagnosed with drug-induced psychotic disorder with hallucinations and started on thioridazine, flunitrazepam, and trihexyphenidyl for three months. He then experienced anxiety causing hyperventilation, and was consequently treated with midazolam and oxazolam. |
2 | Chlorpromazine | Additive CNS and respiratory depression | A 31-year-old woman was started on chlorpromazine for insomnia. After three months, she was diagnosed with hyperventilation and tachycardia, which may have been a result of methadone or a methadone-chlorpromazine interaction. |
3 | Tramadol | May result in withdrawal symptoms | A 48-year-old man was started on tramadol for a month. He then felt anxious, which may have been caused by a methadone-tramadol interaction. Upon discontinuing tramadol, no other symptoms related to anxiety persisted. |
Dexamethasone | CYP3A4 strong inducer | This man was started on dexamethasone for intracranial injury. After coadministering methadone with dexamethasone for a month, he started to feel anxious. | |
4 | Tramadol | May result in withdrawal symptoms | A 48-year-old man was prescribed tramadol for a month for fractures of the tibia and fibula. Then, he developed a depressive mood, which may be owing to a methadone-tramadol interaction. |
5 | Paroxetine | CYP2B6 moderate inhibitor | A 38-year-old man was diagnosed with depression and started on paroxetine for several months. When methadone was coadministered with paroxetine, an anxious feeling persisted. |
6 | Ketoconazole | CYP3A4 strong inhibitor | A 41-year-old man's foot was infected with mycoses and was started on ketoconazole for two months. He was then diagnosed with angina pectoris, which may be due to a methadone-ketoconazole interaction. Upon stopping ketoconazole, he did not experience any symptoms related to angina. |