Does tramadol contain codeine?

Tramadol Does Not Contain Codeine

No, tramadol does not contain codeine. Tramadol is a synthetic opioid analgesic with a distinct chemical structure and mechanism of action from codeine. 1

Pharmacological Differences Between Tramadol and Codeine

Tramadol's Mechanism of Action

• Tramadol is a synthetic analog with a dual mechanism of action:
  • Weak mu-opioid receptor agonist (approximately one-tenth as potent as morphine)
  • Inhibits reuptake of norepinephrine and serotonin 1, 2
• Tramadol consists of two enantiomers that contribute differently to its analgesic effect:
  • (+)-Tramadol and its metabolite (+)-O-desmethyl-tramadol (M1) act on mu opioid receptors
  • (+)-Tramadol inhibits serotonin reuptake
  • (-)-Tramadol inhibits norepinephrine reuptake 2

Codeine's Mechanism of Action

• Codeine is a naturally occurring opioid that functions as a prodrug
• Requires metabolism by CYP2D6 enzyme to be converted to morphine to achieve analgesic effects 3
• Has high lipophilicity and weak protein binding 3

Clinical Implications of the Differences

Metabolism Considerations

• Tramadol is metabolized primarily through:
  • O-demethylation to M1 (via CYP2D6)
  • N-demethylation (via CYP2B6 and CYP3A4) 2
• Codeine requires CYP2D6 metabolism to convert to morphine for analgesic effect
• This difference is clinically significant because:
  • Patients with CYP2D6 polymorphism (more common among Asians) may have less response to codeine 3
  • Poor CYP2D6 metabolizers may have decreased clearance of oxycodone and codeine 3
  • Ultrarapid metabolizers may have higher concentrations of active metabolites, potentially leading to toxicity 3

Safety Profile Differences

• Tramadol has:
  • Lower risk of respiratory depression compared to traditional opioids
  • Higher risk of seizures and serotonin syndrome 1, 4
• Codeine has:
  • Higher risk of respiratory depression
  • Potential for severe neonatal depression in breastfeeding infants 3

Prescribing Considerations

Tramadol Dosing

• Initial dose: 50 mg every 4-6 hours as needed
• Maximum daily dose: 400 mg for immediate-release formulations
• Reduced dosing for elderly patients (>75 years): maximum 300 mg/day 1

Important Contraindications and Warnings

• Tramadol should not be used with:
  • Monoamine oxidase inhibitors (MAOIs) due to risk of adverse interactions
  • Caution with other serotonergic medications due to risk of serotonin syndrome 1
• Increased seizure risk, especially in patients with:
  • History of seizures
  • Head trauma
  • Metabolic disorders
  • Concurrent medications that lower seizure threshold 1, 4

Common Clinical Confusion

A common source of confusion is that both medications:

• Are considered "weak" opioids
• Were traditionally part of the WHO pain ladder's "Step 2" medications
• Are often combined with acetaminophen in formulations
• Require consideration of CYP2D6 metabolism

However, they are distinctly different medications with different chemical structures, mechanisms of action, and side effect profiles.