Tramadol

Mechanism

💊 Common Business Names

Adolonta, Tramal, Tradonal, Ceparadin, Dolpar, Zytram.

🔬 Pharmacological Group

Synthetic atypical opioid agonist. Dual mechanism analgesic of the cyclohexanol class.

Mechanism of Action

Tramadol exerts its synergistic therapeutic action through two distinct complementary mechanisms:

• Atypical agonism on µ opioid receptors (MOP): It has a low affinity for this receptor (approximately 6000 times lower than morphine). However, its main active metabolite, O-desmethyltramadol (M1), has an affinity for the μ receptor up to 200 times higher than that of unchanged tramadol itself, which supports most of its opioid analgesic efficacy.
• Inhibition of monoamine reuptake in the descending analgesic pathway: Blocks the reuptake of serotonin (5-HT) and complementary inhibits the reuptake of norepinephrine (NE) at the level of the synaptic cleft of the dorsal horn of the spinal cord. By increasing local concentrations of these neurotransmitters, endogenous inhibition of afferent pain signals is optimized.

Pharmacokinetics

Key Pharmacokinetics

Indicators and dose

Dosage and Adjustment

• Adults (Moderate Pain):
  • Oral Route (Immediate Release): 50 mg to 100 mg every 6 or 8 hours.
  • Parenteral route (IV/IM): 100 mg administered as a slow infusion over 15-20 minutes every 6 or 8 hours. Absolute maximum recommended dose: 400 mg/day in healthy adults; limit to 300 mg/day in elderly people over 75 years of age.
• Pediatrics: Not generally recommended for children under 12 years of age. Absolutely contraindicated in children under 18 years of age undergoing tonsillectomy or adenoidectomy due to the extreme risk of fatal respiratory depression in ultra-rapid metabolizers of CYP2D6.
• Adjustment in Kidney Failure:
  • Cl_cr ≥ 30 mL/min: No adjustment required for short therapies.
  • Cl_cr < 30 mL/min: Extend the dosing interval to a minimum of every 12 hours, and strictly limit the daily cumulative dose to a maximum of 200 mg/day. Avoid extended release formulations.
• Adjustment in Hepatic Insufficiency: In moderate hepatic insufficiency (Child-Pugh B), extend the dosing interval to every 12 hours. Contraindicated in severe decompensated cirrhosis (Child-Pugh C).

Security

Contraindications

• Absolute: Acute intoxication by alcohol, hypnotics, central analgesics or opioids; simultaneous use of Monoamine Oxidase Inhibitors (MAOIs) or within 14 days after their withdrawal; active epilepsy not optimally controlled; severe respiratory failure; active dependence on opiates.
• Relative: Personal history of seizures or associated clinical conditions that reduce the epileptic threshold (head trauma, CNS tumors, alcohol or benzodiazepine withdrawal); moderate to severe kidney or liver failure.

Adverse Effects (ADR)

• Frequent / Tolerable: Nausea, vomiting, xerostomia, postural vertigo, headache, profuse sweating, drowsiness, mild confusion.
• Rare / Severe: Generalized tonic-clonic seizures (induced by the inhibition of monoamine reuptake that alters the cortical GABAergic balance; dose-dependent and favored by interactions); anaphylactic shock; serotonin syndrome. Mild respiratory depression (but severe in CYP2D6 ultra-rapid metabolizers).

Critical Risk of Serotonin Syndrome

Due to its ability to potently inhibit serotonin reuptake, concomitant administration of tramadol with other serotonergic acting agents (Selective Serotonin Reuptake Inhibitors [SSRIs] such as sertraline, Serotonin and Norepinephrine Reuptake Inhibitors [SNRIs] such as duloxetine, tricyclic antidepressants, triptans or linezolid) may trigger serotonin reuptake. Serotoninergic Syndrome. This potentially fatal clinical condition is manifested by mental agitation, severe hyperthermia, diaphoresis, spontaneous or inducible clonus, neuromuscular hyperreflexia and marked hemodynamic instability.

Drug Interactions

• Potent CYP2D6 Inhibitors (Fluoxetine, Paroxetine, Quinidine, Bupropion): They block the biotransformation of tramadol into its active metabolite M1, nullifying the effectiveness of the opioid analgesic component.
• CYP3A4 inducers (Rifampicin, Carbamazepine): They divert metabolism towards the inactive N-demethylation pathway, notably reducing the effective plasma concentrations of tramadol.
• Drugs that Reduce the Seizure Threshold (Neuroleptics, Antidepressants, Theophylline): Deleterious pharmacodynamic synergism that increases the risk of inducing generalized epileptic seizures.

Pregnancy and Breastfeeding

Classified in FDA Category C. It easily crosses the placenta. Prolonged use during pregnancy can induce dependence and neonatal withdrawal syndrome. Absolutely contraindicated during breastfeeding due to the unpredictable risk of deep sedation, apnea and sudden infant death in the case of mothers who present phenotypes of ultra-rapid metabolizers of CYP2D6.

Clinical

Clinical Impact of the CYP2D6 Genetic Polymorphism

The CYP2D6 isoenzyme presents a marked polymorphism in the human population that substantially alters the response profile to tramadol:

• Slow Metabolizers (PM - ~7-10% of the Caucasian population): They have loss-of-function mutations in CYP2D6. By not being able to form the active metabolite O-desmethyltramadol (M1) sufficiently, they experience a marked analgesic ineffectiveness of the opioid component of the drug.
• Ultra-rapid metabolizers (UM - ~1-10% in various ethnicities, up to 29% in populations of African/Oriental origin): They present active gene duplications of CYP2D6. They convert tramadol into M1 massively and ultra-rapidly, reaching toxic serum concentrations of the metabolite that induce acute-onset respiratory depression and deep sedation even at low doses.