Tramadol (Ultram®)
| Tramadol |  |
|---|---|
| Brand Names | Ultram®, ConZip® |
| Drug Class | Opioid (Weak μ-agonist, Dual Mechanism) |
| Primary Indication | Moderate Pain |
| Relative Potency | ~0.1× Morphine |
| Mechanism | Weak μ agonist + SNRI |
| Seizure Risk | Yes |
| Serotonin Syndrome Risk | Yes |
| Controlled Substance | Schedule IV |
| FDA Approval | 1995 |
Overview
Tramadol is a centrally acting analgesic with a dual mechanism of action:
- Weak μ-opioid receptor agonism
- Inhibition of serotonin and norepinephrine reuptake
It provides modest analgesia and carries unique risks not seen with traditional opioids, including seizures and serotonin syndrome.
Mechanism of Action
Receptor Activity
- Weak μ-opioid receptor agonist
Monoamine Effects
- Inhibits serotonin reuptake
- Inhibits norepinephrine reuptake
Metabolism
- CYP2D6 converts tramadol → O-desmethyltramadol (active metabolite with stronger μ activity)
Analgesic effect is partly dependent on CYP2D6 activity.
Indications
- Moderate acute pain
- Chronic musculoskeletal pain
- Neuropathic pain (limited evidence)
Not appropriate for severe pain requiring potent opioid therapy.
Contraindications
Absolute:
- Concomitant MAOI use
- Severe respiratory depression
- Acute intoxication with CNS depressants
Relative / Caution:
- Seizure disorders
- Concurrent SSRI/SNRI use
- Hepatic impairment
- Renal impairment
- CYP2D6 ultra-rapid metabolizers
Dosing
Immediate-Release:
- 50–100 mg every 4–6 hours
Maximum:
- 400 mg/day (lower in elderly)
Renal impairment:
- Dose adjustment required
Extended-release:
- Once daily dosing
Pharmacokinetics
Absorption:
- Oral
Metabolism:
- CYP2D6 → active metabolite
- CYP3A4 involvement
Half-life:
- ~6 hours
Elimination:
- Renal
CYP2D6 poor metabolizers → reduced analgesic effect CYP2D6 ultra-rapid metabolizers → increased toxicity risk
Adverse Effects
Common:
- Nausea
- Dizziness
- Sedation
- Constipation
Serious:
- Seizures
- Serotonin syndrome
- Respiratory depression (less than full agonists)
- Physical dependence
Seizure risk increases with:
- High doses
- SSRIs/SNRIs
- TCAs
- Bupropion
Drug Interactions
Increased serotonin syndrome risk:
- SSRIs
- SNRIs
- MAOIs
- Linezolid
- St. John’s Wort
CYP2D6 inhibitors (↓ analgesia):
- Fluoxetine
- Paroxetine
CNS depressants:
- Benzodiazepines
- Alcohol
Monitoring
Clinical:
- Pain response
- Sedation
- Signs of serotonin toxicity
High-risk patients:
- History of seizures
- Polypharmacy
Clinical Pearls
- Weak μ agonist + SNRI mechanism.
- Analgesia depends partly on CYP2D6 activation.
- Higher seizure risk than other opioids.
- Risk of serotonin syndrome with SSRIs/SNRIs.
- Schedule IV (lower abuse potential than Schedule II opioids).
- Not appropriate for severe acute pain.
Toxicity
Overdose may present with:
- CNS depression
- Seizures
- Serotonin syndrome
- Respiratory depression
Naloxone may reverse respiratory depression but does NOT treat seizures.
See:
Comparison Within Class
Compared to Morphine:
- Much weaker
- Has serotonergic activity
Compared to Tapentadol:
- More serotonergic
- Higher seizure risk
Compared to Codeine:
- Similar potency
- More complex mechanism