Morphine is a strong opioid analgesic used to relieve severe acute or chronic pain that does not respond to weaker painkillers. It acts on the brain and spinal cord to reduce the perception of pain. It is a controlled substance (narcotic): it can cause dependence, drowsiness, constipation and, at high doses, potentially fatal respiratory depression. It must be used under medical prescription and supervision, at the lowest effective dose for the shortest possible time.
Also known as: morphine, morphine sulfate, MS Contin
Hydroxyzine plus morphine increases the risk of profound sedation, hypotension and respiratory depression.
Opioid plus sedating antihistamine: additive depression of the CNS and respiratory centre.
Level of consciousness, respiratory rate, blood pressure.
Extreme drowsiness, slow breathing, hypotension.
If the combination is needed (analgesic premedication), reduce doses and monitor respiration.
DailyMed — Morphine Sulfate Injection [Fresenius Kabi] label (additive CNS depressants) and Hydroxyzine Pamoate [RemedyRepack]: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f53de80-efc8-4930-b3e3-fba0d026af05
Sedating antihistamine + opioid: additive CNS depression.
The diphenhydramine label documents that "diphenhydramine has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.)" and the morphine label classifies "Benzodiazepines and Other Central Nervous System (CNS) Depressants" as an interaction with risk of "profound sedation, respiratory depression, coma, and death" due to additive pharmacologic effect. Diphenhydramine is an H1 antihistamine with central sedative effect and morphine is an opioid with CNS and respiratory depression — the sum is particularly risky in the elderly, patients with COPD, sleep apnoea or polypharmacy. Avoid whenever possible; if unavoidable (e.g., uraemic pruritus or allergic reaction in a patient on morphine), use the lowest dose, watch for sedation and respiratory rate, and inform the patient not to drive or operate machinery. Consider non-sedative alternatives (second-generation H1 antihistamines, such as cetirizine, for pruritus).
Diphenhydramine + morphine: additive sedation and CNS depression. Risk of somnolence, dizziness and respiratory depression. Avoid or monitor closely.
Both depress the CNS, potentiating sedation and respiratory depression.
Level of consciousness, respiratory rate, oximetry.
Deep drowsiness, bradypnoea, confusion.
Avoid the combination; if unavoidable, use the lowest dose and watch sedation/respiration.
DailyMed (FDA) — approved Diphenhydramine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d8944f3c-acef-4ebe-9633-7d641ae95edf ; approved Morphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57ee014e-744e-65e1-e063-6394a90a8c93 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining morphine with alprazolam increases the risk of profound sedation, respiratory depression, coma and death.
Morphine and alprazolam depress the central nervous system and the respiratory centre through complementary mechanisms (mu opioid receptor agonism and GABA potentiation at the GABA-A receptor). The FDA issued a boxed warning for the combination of opioids with benzodiazepines: a substantial proportion of overdose deaths involves both groups together. Whenever possible, avoid co-administration; if clinically unavoidable, use the lowest effective doses for the shortest time, inform the patient and family, and monitor sedation, respiratory rate and oxygen saturation. Naloxone should be available when the opioid is used at a relevant dose.
Benzodiazepine + opioid: additive CNS and respiratory depression, with risk of deep sedation, coma and death. Avoid the combination; if unavoidable, use the lowest effective doses and monitor sedation and breathing closely.
Additive effect of opioids and benzodiazepines on central nervous system and respiratory depression.
Respiratory rate, oxygen saturation, level of sedation and pupillary response.
Respiratory depression (rate < 10/min), deep sedation or coma require urgent assessment and reversal with naloxone.
Avoid the combination whenever possible; if unavoidable, use the lowest effective doses and monitor closely.
DailyMed/FDA (NIH/NLM) — approved Morphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57ee014e-744e-65e1-e063-6394a90a8c93 ; approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
CYP3A4 inhibitor + opioid: active metabolite may accumulate.
Fluconazole moderately inhibits UGT2B7, potentially increasing morphine-6-glucuronide levels. The effect is less pronounced than with ritonavir.
Respiratory rate, sedation.
Respiratory depression.
Monitor for signs of respiratory depression. Consider reducing dose by 25%.
DailyMed/FDA — approved Morphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=41bf125b
CYP3A4 inhibitor + opioid: active metabolite morphine-6-glucuronide levels increased. Serious respiratory depression.
Morphine is metabolised by glucuronidation (UGT2B7) to two metabolites: morphine-3-glucuronide (inactive, ~60%) and morphine-6-glucuronide (active, ~10%, more potent than morphine). Ritonavir inhibits UGT2B7, reducing morphine clearance and increasing active metabolite levels. The effect is prolonged (morphine-6-glucuronide has longer half-life than morphine). Complications: prolonged respiratory depression, paralytic ileus, urinary retention. Monitor closely.
UGT2B7 inhibitor + opioid: active metabolite morphine-6-glucuronide accumulates. Prolonged respiratory depression and paralytic ileus.
Morphine is metabolised by glucuronidation (UGT2B7) to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active, more potent than morphine). Ritonavir inhibits UGT2B7, increasing active metabolite levels. Risk of prolonged respiratory depression.
Respiratory rate, O2 saturation, consciousness level, gut transit time.
Respiratory depression, severe paralytic ileus.
Avoid combination if possible. If necessary, reduce morphine dose by 50% and monitor closely.
DailyMed/FDA — approved Morphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=41bf125b
Alcohol enhances the CNS-depressant effects of morphine, with risk of sedation and respiratory depression.
Advise avoiding alcohol consumption during treatment.
EMC-UK (MHRA) — approved MST Continus (Morphine) SmPC: https://www.medicines.org.uk/emc/product/7664/smpc
Morphine may cause or worsen respiratory depression, a risk in patients with respiratory insufficiency.
Contraindicated in severe respiratory depression; use with extreme caution in other respiratory insufficiency.
EMC-UK (MHRA) — approved MST Continus SmPC: https://www.medicines.org.uk/emc/product/7664/smpc
Opioids reduce gastrointestinal motility and may cause or worsen paralytic ileus.
Contraindicated in paralytic ileus; monitor for severe constipation.
EMC-UK (MHRA) — approved MST Continus SmPC: https://www.medicines.org.uk/emc/product/7664/smpc
Morphine crosses the placenta; chronic use may cause neonatal withdrawal syndrome and respiratory depression in the neonate.
Not recommended unless benefit outweighs risk; use in labour may depress neonatal respiration.
Excreted into breast milk; not recommended while breastfeeding.
With chronic use, advise on effective contraception.
EMC-UK (MHRA) — approved MST Continus (Morphine) SmPC: https://www.medicines.org.uk/emc/product/7664/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 1, Drugs and Pregnancy: Avoid; potent uterine stimulant (has been used to induce abortion and may cause stillbirths).
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Reference mu opioid agonist: potent analgesia, sedation and euphoria, with dose-dependent respiratory depression (the limiting effect). Peak analgesic effect occurs ~60 min after oral dosing and the duration of effect is 4-6 h. It causes constipation (reduced peristalsis), miosis, nausea/vomiting and histamine release (pruritus).
Selective agonist of mu (μ) opioid receptors in the CNS and periphery, with lower affinity for delta and kappa. It activates descending pain-inhibitory pathways and inhibits the release of pro-nociceptive neurotransmitters (e.g., substance P) from primary afferents, reducing pain signal transmission in the spinal cord.
About two-thirds of an oral dose is absorbed from the GI tract; oral bioavailability <40% with large inter-individual variability (extensive pre-systemic metabolism). Food does not change the extent of absorption (AUC). Steady state reached within ~48 h with 6-hourly dosing.
Hepatic conjugation with glucuronic acid: morphine-3-glucuronide (M3G, ~50%, no analgesic activity) and morphine-6-glucuronide (M6G, ~15%, analgesic activity but poor blood-brain barrier penetration); <5% demethylation. Renal excretion of glucuronides; M3G/M6G accumulation in renal impairment.
Elimination half-life ~2 h after IV administration; the duration of analgesic effect is 4-6 h (extended-release formulations extend the dosing interval). Volume of distribution 1-6 L/kg; protein binding 20-35%.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
