EpistemisMorphine
Morphine is the reference analgesic alkaloid extracted from Papaver somniferum. It acts as the gold standard in the control of severe oncological, acute postoperative and myocardial infarction pain, but its management requires mastering its active metabolization profile and the risk of respiratory depression.
Mechanism
💊 Common Business NamesMST Continus, Sevredol, Oramorph, Morfina Kern, Dolantin.
🔬 Pharmacological GroupPure agonist of the µ opioid receptor (MOP). Natural narcotic of the phenanthrene class.
Mechanism of Action
Morphine exerts its action through direct coupling to specific transmembrane receptors:
- Pure agonist of µ opioid receptors (MOP) at central and peripheral level: It binds selectively and with high affinity to µ receptors coupled to G proteins of the inhibitory type (Gi/Go). This binding stimulates the exchange of GDP for GTP and inhibits the activity of cellular adenylate cyclase, plummeting cyclic AMP (cAMP) concentrations.
- Dual Electrophysiological Modulation: Blocks N-type voltage-gated calcium channels at the presynaptic level (preventing the release of glutamate and substance P) and opens GIRK-type internal rectifier potassium channels at the postsynaptic level, hyperpolarizing the neuron and attenuating the afferent propagation of nociceptive impulses through the spinothalamic tract.
Pharmacokinetics
Key Pharmacokinetics
| Parameter | Quantitative Pharmacokinetic Profile |
|---|---|
| Routes of Administration | Intravenous (IV), Subcutaneous (SC), Epidural, Intrathecal, Oral (immediate and prolonged release forms). |
| Oral Bioavailability | Low and highly variable (20 - 40%) due to a marked and intense hepatic first pass effect. The oral dosage should be consequently higher than the parenteral dosage (approximate potency ratio 3:1 or 2:1 in long-term treatments). |
| Protein Distribution and Binding | Moderate to low binding to plasma albumin (30-35%). Volume of distribution (Vd): relatively large, 3 - 5 L/kg. It slowly crosses the blood-brain barrier due to its moderately hydrophilic nature compared to fentanyl. |
| Metabolism and Active Metabolites | Hepatic metabolism by glucuronidation mediated by UGT2B7: Generates two main clinically critical metabolites:
|
| Excretion and Half-Life | Predominant renal excretion (>90% in the form of metabolites M3G and M6G). Elimination half-life of parental morphine (t1/2): short, 2.0 - 3.5 hours. However, the biological half-life of active metabolites is markedly prolonged in nephropathies. |
Indicators and dose
Dosage and Adjustment
- Adults (Treatment of Severe Acute Pain):
- Direct Intravenous Route: 2.5 mg to 5 mg diluted in saline administered slowly over 5 minutes, repeating every 5-10 minutes until pain control is achieved (rapid titration).
- Oral Route (Immediate Release): 5 mg to 10 mg every 4 hours.
- Oral Route (Extended Release - Tolerant Patients): Total daily dose calculated based on previous requirements administered every 12 or 24 hours.
- Pediatrics: Use reserved for specialized units at rapid titration intravenous doses of 0.05 - 0.1 mg/kg administered slowly.
- Adjustment in Kidney Failure:
- Clcr 30-50 mL/min: Reduce the initial dose to 50-75% of the standard and space the dosing intervals every 6 or 8 hours.
- Clcr < 30 mL/min: Reduce the initial dose to 25% of the standard dose and space it at least every 8 or 12 hours. Substitution with inactive liver clearance alternatives such as Fentanyl or Methadone is preferably recommended.
- Adjustment in Liver Failure: Reduce the initial dose to 50% of the standard dose in moderate liver disease due to the risk of secondary portosystemic encephalopathy.
Security
Metabolite Toxicity in Renal Failure
The metabolites M3G (neurotoxic) and M6G (potent analgesic and respiratory depressant) depend on renal glomerular excretion for their plasma clearance. In patients with moderate or severe renal failure (Clcr < 50 mL/min), these compounds progressively accumulate in the plasma, crossing the blood-brain barrier in a delayed manner. This induces a severe picture of late opioid toxicity characterized by myoclonus, refractory hallucinations, delirium and fatal respiratory depression at previously well-tolerated doses. For this reason, morphine is relatively contraindicated or requires drastic dose reductions in kidney patients.
Contraindications
- Absolute: Acute or chronic decompensated respiratory failure; severe bronchial asthma; airway obstruction; traumatic brain injury with intracranial hypertension (morphine induces hypercapnia due to hypoventilation that dilates cerebral vessels, worsening edema); active paralytic ileus or known gastrointestinal obstruction; simultaneous or recent administration (less than 14 days) of Monoamine Oxidase Inhibitors (MAOIs).
- Relative: Moderate to severe renal failure (Clcr < 30 mL/min); severe hypothyroidism; Addison's disease; prostatic hypertrophy (risk of acute urinary retention); cholelithiasis or sphincter of Oddi dysfunction (morphine temporarily induces biliary spasm).
Adverse Effects (ADR)
- Frequent / Tolerable: Persistent constipation (due to activation of the µ receptors of the intestinal myenteric plexus, reducing motility and increasing the tone of the anal sphincter); nausea and vomiting (induced by direct stimulation of the chemoreceptor trigger zone in the area postrema); drowsiness, xerostomia, pruritus (due to systemic release of non-immunological histamine); pupillary miosis ("pinpoint pupils" due to activation of the Edinger-Westphal nucleus).
- Rare / Serious: Dose-dependent respiratory depression (due to annulment of the sensitivity of the respiratory center of the brainstem to carbon dioxide levels CO2); severe orthostatic hypotension; Irreversible paralytic ileus. Physical and psychological dependence, tolerance.
Management of Opioid Overdose and Respiratory Depression: Naloxone
Severe respiratory depression is clinically defined by a respiratory rate less than 8 breaths per minute, bilateral symmetric miosis, and obtundation or deep coma. Immediate treatment requires patenting the airway and intravenously administering the specific competitive antagonist of opioid receptors: Naloxone. The initial dosage is 0.4 mg IV, which can be repeated every 2-3 minutes until the respiratory pattern is normalized without triggering an acute withdrawal syndrome. The half-life of naloxone (t1/2: 60 min) is significantly shorter than that of morphine, requiring close monitoring due to the risk of analgesic rebound.
Drug Interactions
- CNS Depressants (Benzodiazepines, Barbiturates, Alcohol): Extremely dangerous pharmacodynamic synergism that critically increases the incidence of profound sedation, coma and fatal respiratory depression.
- MAOI (Phenelzine, Selegiline): Co-administered can induce CNS excitation, psychotic delirium, profound muscle rigidity and autonomic instability. Absolutely contraindicated.
- 1st Generation Neuroleptics / Antihistamines: Synergism in the sedative effect and marked increase in intestinal constipation.
Pregnancy and Breastfeeding
Classified in FDA Category C. It easily crosses the placental barrier. Its prolonged use during pregnancy can induce physical dependence in the fetus and cause a neonatal abstinence syndrome characterized by neuromuscular irritability, high-pitched inconsolable crying, diarrhea and food refusal. Its peripartum use can induce neonatal respiratory depression. Breastfeeding: Compatible with strict caution and minimum doses; It is excreted in breast milk in moderate concentrations that require monitoring of the infant's sedation and respiratory rate.
Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.
- System
- Pain, Inflammation and Rheumatology
- Cluster
- Potent Major Opioid Analgesic (Narcotic)