Tramadol

• Moderate to Severe Pain
• Chronic Pain
• Acute Pain Management

Tramadol is a centrally acting analgesic with a dual mechanism of action, combining weak opioid activity with monoamine reuptake inhibition. It is used to treat moderate to moderately severe pain.

Mechanism of Action

Tramadol has two synergistic mechanisms:

• Mu-opioid receptor agonism: Weak binding affinity (6000x less than morphine)
• Serotonin reuptake inhibition: Increases serotonin in descending pain pathways
• Norepinephrine reuptake inhibition: Enhances descending pain inhibition
• Active metabolite (O-desmethyltramadol): Has 200x greater mu-opioid affinity than parent compound

The analgesic effect is only partially antagonized by naloxone, reflecting the non-opioid component.

Available Formulations

• Immediate-release tablets: 50 mg
• Extended-release tablets: 100 mg, 200 mg, 300 mg
• Orally disintegrating tablets: 50 mg
• Combination products: With acetaminophen (Ultracet)

Medical Uses

FDA-Approved Indications:

• Moderate to moderately severe pain (IR formulation)
• Moderate to moderately severe chronic pain requiring around-the-clock treatment (ER formulation)

Dosing Guidelines

Immediate-Release (Adults):

• Initial: 25 mg every morning; increase by 25 mg every 3 days to 25 mg four times daily
• Then increase by 50 mg every 3 days as tolerated
• Maintenance: 50-100 mg every 4-6 hours as needed
• Maximum: 400 mg/day

Extended-Release:

• Initial: 100 mg once daily
• Titrate by 100 mg every 5 days
• Maximum: 300 mg/day

Elderly (>65 years):

• Maximum: 300 mg/day

Renal Impairment (CrCl <30):

• IR: 50-100 mg every 12 hours; max 200 mg/day
• ER: Not recommended

Important Safety Information

Boxed Warnings:

• Addiction, abuse, and misuse (Schedule IV)
• Life-threatening respiratory depression
• Accidental ingestion can cause fatal overdose
• Neonatal opioid withdrawal syndrome
• Concomitant use with benzodiazepines or CNS depressants
• CYP2D6 ultra-rapid metabolizers may have life-threatening respiratory depression

Contraindications:

• Children <12 years
• Postoperative pain in children <18 years after tonsillectomy/adenoidectomy
• Significant respiratory depression
• Acute or severe bronchial asthma without monitoring
• Concurrent use of MAOIs or within 14 days
• Known or suspected GI obstruction

Warnings:

• Seizure risk: Lower threshold, especially with SSRIs, SNRIs, TCAs, or at higher doses
• Serotonin syndrome risk with serotonergic drugs
• CYP2D6 pharmacogenomics affects efficacy and toxicity

Drug Interactions

• MAOIs: Contraindicated (serotonin syndrome, seizures)
• Serotonergic drugs (SSRIs, SNRIs, triptans): Increased serotonin syndrome risk
• CNS depressants: Enhanced respiratory depression
• CYP3A4 inhibitors: May increase tramadol levels
• CYP2D6 inhibitors (paroxetine, fluoxetine): Reduce active metabolite; may decrease efficacy and increase seizure risk
• Carbamazepine: Significantly reduces tramadol effect

Special Populations

• CYP2D6 Ultra-Rapid Metabolizers: Contraindicated in children; risk of life-threatening respiratory depression
• Hepatic Impairment: Reduce dose; extended intervals for severe impairment
• Renal Impairment: Reduce dose and extend intervals; ER not recommended if CrCl <30
• Elderly: Maximum 300 mg/day
• Pregnancy: May cause neonatal withdrawal
• Lactation: Present in milk; avoid breastfeeding