DOLOPHINE HYDROCHLORIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DOLOPHINE HYDROCHLORIDE (DOLOPHINE HYDROCHLORIDE).
Methadone is a mu-opioid receptor agonist with additional NMDA receptor antagonism and serotonin/norepinephrine reuptake inhibition. It also binds to delta and kappa opioid receptors, producing analgesic and antitussive effects.
| Metabolism | Primarily hepatic via CYP3A4, CYP2B6, and CYP2C19 to inactive metabolites (EDDP and EMDP). Also undergoes N-demethylation. It is a substrate for P-glycoprotein. |
| Excretion | Primarily renal elimination of unchanged drug (approximately 50-60%) and metabolites (including the inactive metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine). Fecal excretion accounts for about 10-20%. Biliary excretion contributes minimally (<5%) to overall elimination. |
| Half-life | Terminal elimination half-life: 15 to 60 hours (average 24-36 hours). Clinical context: Prolonged half-life due to extensive tissue binding and redistribution; accumulates with repeated dosing, requiring careful titration to avoid toxicity. |
| Protein binding | Approximately 85-90% bound to alpha1-acid glycoprotein (orosomucoid) and, to a lesser extent, albumin. |
| Volume of Distribution | 4-7 L/kg. Clinical meaning: Large Vd indicates extensive tissue distribution (e.g., liver, kidney, lung, spleen) and storage in peripheral compartments; contributes to prolonged elimination half-life. |
| Bioavailability | Oral: 41-99% (mean ~80%). Rectal: approximately 60%. |
| Onset of Action | Oral: 30-60 minutes. Intravenous: 5-10 minutes. Intramuscular: 10-20 minutes. Subcutaneous: 10-20 minutes. |
| Duration of Action | Oral: 4-8 hours (analgesic), 12-24 hours (suppression of opioid withdrawal). Intravenous: 3-5 hours (analgesic) due to redistribution; duration for withdrawal suppression may extend up to 24 hours with repeated dosing. Clinical notes: Long half-life may cause delayed toxicity; monitor for respiratory depression and QT prolongation. |
Initial: 2.5-10 mg orally every 8-12 hours, titrating to effect. Maintenance: 5-20 mg orally every 8-12 hours. For severe chronic pain, dosing interval may be extended to every 12-24 hours due to long half-life. Not recommended for acute pain or as PRN analgesia.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-60 mL/min: Administer 50-75% of usual dose and extend dosing interval to every 12-24 hours. GFR <30 mL/min: Administer 25-50% of usual dose and extend interval to every 24-36 hours. Hemodialysis: Not dialyzable; avoid use or reduce dose by 50% and monitor closely. |
| Liver impairment | Child-Pugh Class A: No adjustment typically needed. Class B: Reduce starting dose by 50% and titrate cautiously; extend dosing interval to every 12-24 hours. Class C: Avoid use or administer with extreme caution; use 25% of usual dose with extended intervals (every 24-48 hours) and close monitoring. |
| Pediatric use | Not FDA-approved for children under 18 years. Limited data: 0.1-0.2 mg/kg/dose orally every 8-12 hours, titrate to effect. Maximum single dose: 5 mg. Not recommended for acute pain management. |
| Geriatric use | Initial dose should be reduced by 50% (e.g., 2.5 mg orally every 12-24 hours). Titrate slowly due to increased sensitivity and prolonged half-life. Maximum daily dose: 20 mg. Monitor for sedation, respiratory depression, and constipation. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DOLOPHINE HYDROCHLORIDE (DOLOPHINE HYDROCHLORIDE).
| Breastfeeding | Methadone is excreted into breast milk with an M/P ratio of approximately 0.5. Concentrations are low (2-5% of maternal weight-adjusted dose). Breastfeeding is encouraged in stable mothers on low doses, but infants must be monitored for sedation and withdrawal. The benefits outweigh risks if mothers are on a stable methadone regimen without other substances. |
| Teratogenic Risk | First trimester: Limited data; methadone is not a major human teratogen, but neonatal abstinence syndrome (NAS) is expected with chronic use. Second/third trimester: Continued risk of NAS; no structural malformations consistently associated. Chronic use may lead to fetal growth restriction and preterm birth. |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; PROLONGED QT INTERVAL; ADRENAL INSUFFICIENCY; SEVERE HYPERSENSITIVITY; RAPID WITHDRAWAL; NEUROTOXICITY (see full prescribing information for complete boxed warning).
| Common Effects | Stomach pain Nausea Vomiting |
| Serious Effects |
["Hypersensitivity to methadone or any component of the formulation","Significant respiratory depression (in unmonitored setting or absence of resuscitative equipment)","Acute or severe bronchial asthma in unmonitored setting","Known or suspected gastrointestinal obstruction, including paralytic ileus","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy","Prolonged QT interval (QTc > 500 ms) or history of torsades de pointes","Moderate to severe hepatic impairment (Child-Pugh class B or C) unsupervised","Concomitant use of CYP3A4 inducers or inhibitors without dose adjustment","Neonates with respiratory depression or risk of withdrawal (relative)"]
| Precautions |
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| Fetal Monitoring | Maternal: Liver function tests, ECG for QTc interval, drug levels (trough) to assess stability, and respiratory status. Fetal: Ultrasound for growth and anatomy, nonstress test or biophysical profile in third trimester for chronic use. Neonatal: Monitor for NAS using Finnegan or ESC score for at least 48-72 hours postpartum. |
| Fertility Effects | Methadone may cause menstrual irregularities and reduce libido in females, potentially impacting fertility. In males, it can decrease testosterone levels, leading to erectile dysfunction and reduced sperm count. These effects are reversible upon dose reduction or discontinuation. |
| ["Life-threatening respiratory depression, especially during initiation or dose escalation","Prolonged QT interval and risk of torsades de pointes, particularly at high doses or with electrolyte abnormalities","Adrenal insufficiency with prolonged use","Severe hypotension, including orthostatic hypotension and syncope","Seizures in patients with seizure disorders or taking other medications that lower seizure threshold","Serotonin syndrome with concomitant serotonergic drugs","Neonatal opioid withdrawal syndrome with prolonged use during pregnancy","Risk of overdose and death with accidental ingestion, especially in children","Monitor for signs of misuse, abuse, and addiction","Do not abruptly discontinue; taper gradually"] |