HYDROMORPHONE HYDROCHLORIDE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Hydromorphone is a full mu-opioid receptor agonist. It binds to mu-opioid receptors in the CNS, activating G-protein coupled receptors that inhibit adenylate cyclase, decrease cAMP production, and modulate ion channels, leading to reduced neurotransmitter release (e.g., substance P, glutamate) and hyperpolarization of neurons. This results in analgesia, sedation, and euphoria.
| Metabolism | Hydromorphone is extensively metabolized in the liver via glucuronidation (primarily UGT2B7) to hydromorphone-3-glucuronide, which is inactive. Minor metabolism via N-demethylation to normorphine (active) and reduction to dihydroisomorphine (active). |
| Excretion | Primarily renal (approximately 90% as hydromorphone-3-glucuronide and other conjugates; <7% as unchanged hydromorphone), with a small amount biliary/fecal. |
| Half-life | Terminal elimination half-life: 2.0–3.0 hours in healthy adults; prolonged in renal impairment (up to 40 hours) and hepatic impairment; clinical context: supports dosing interval of 4–6 hours in normal renal function. |
| Protein binding | Approximately 20–30% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | 1–3 L/kg; indicates extensive tissue distribution and penetration into extravascular tissues, including CNS. |
| Bioavailability | Oral immediate release: 30–40% (extensive first-pass metabolism); Oral extended release: 30–50% (first-pass effect; formulation-dependent); Rectal: approximately 30–40%; IM: nearly 100%; IV: 100%. |
| Onset of Action | IV: 5–10 minutes; IM: 10–15 minutes; Oral immediate release: 15–30 minutes; Oral extended release: 30–60 minutes; Rectal: 20–30 minutes. |
| Duration of Action | IV/IM: 3–4 hours; Oral immediate release: 4–5 hours; Oral extended release: 12–24 hours (formulation-dependent); Rectal: 4–6 hours. Note: Duration increases with repeated dosing due to accumulation. |
Initial: 2-4 mg orally every 3-4 hours; 1-2 mg intravenously/subcutaneously/intramuscularly every 2-4 hours. For opioid-naive patients, lower starting doses (e.g., 1-2 mg oral, 0.2-0.5 mg parenteral) are recommended.
| Dosage form | TABLET |
| Renal impairment | For GFR 30-59 mL/min: administer 75% of usual dose every 4-6 hours; for GFR 10-29 mL/min: administer 50% of usual dose every 6-8 hours; for GFR <10 mL/min: administer 25% of usual dose every 8-12 hours. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 25-50% and increase dosing interval; Class C: avoid use or reduce dose by 75% with extended intervals. |
| Pediatric use | Oral: 0.03-0.08 mg/kg/dose every 3-4 hours; Intravenous/Intramuscular: 0.015-0.02 mg/kg/dose every 4-6 hours. Maximum single dose not to exceed 5 mg. |
| Geriatric use | Start at 25-50% of adult dose; increase cautiously. For oral, start with 1-2 mg every 4-6 hours. For parenteral, use 0.2-0.5 mg every 4-6 hours. Monitor for respiratory depression and constipation. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
| Breastfeeding | Hydromorphone is excreted into breast milk in low concentrations. The M/P ratio is not well established but estimated to be approximately 0.7-1.0. Relative infant dose is less than 2-3% of maternal weight-adjusted dose, considered compatible with breastfeeding. Monitor infant for drowsiness, respiratory depression, and feeding difficulties. Use caution with prolonged therapy. |
| Teratogenic Risk | Hydromorphone crosses the placenta. First trimester: no clear evidence of major malformations in human studies, but opioid use in pregnancy is associated with a small increased risk of neural tube defects and congenital heart defects. Second and third trimesters: chronic use may lead to fetal dependence and neonatal opioid withdrawal syndrome (NOWS). Use near term may cause neonatal respiratory depression. |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS. Hydromorphone exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Serious, life-threatening, or fatal respiratory depression may occur. Accidental ingestion, especially by children, can result in fatal overdose. Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome. Concomitant use with benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death.
| Common Effects | Constipation |
| Serious Effects |
["Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Known or suspected gastrointestinal obstruction, including paralytic ileus","Hypersensitivity to hydromorphone or any component of the formulation","Concurrent use of MAOIs or within 14 days of such therapy"]
| Precautions |
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| Fetal Monitoring | Monitor maternal respiratory status, sedation level, and signs of opioid toxicity. For fetus: assess fetal heart rate patterns, consider fetal nonstress testing or biophysical profile if chronic maternal use. Neonates: observe for signs of neonatal opioid withdrawal syndrome (e.g., irritability, poor feeding, tremors) for at least 48 hours after birth if maternal use >7 days. |
| Fertility Effects | Chronic opioid use may impair fertility by disrupting hypothalamic-pituitary-gonadal axis, causing decreased libido, anovulation, or menstrual irregularities. Withdrawal may restore function. No specific animal fertility studies for hydromorphone, but class effect likely. |
| ["Addiction, abuse, and misuse","Life-threatening respiratory depression","Accidental ingestion","Neonatal opioid withdrawal syndrome","Risks from concomitant use with benzodiazepines or other CNS depressants","Interaction with MAOIs","Increased intracranial pressure","Adrenal insufficiency","Severe hypotension","Seizures","Biliary tract disease","Use in patients with gastrointestinal obstruction","Impaired renal or hepatic function","Elderly and debilitated patients","Driving and operating machinery"] |