====== Tramadol (Ultram®) ======

<WRAP right 340px>
<WRAP infobox>
^ Tramadol | {{ :neuro:opioids:tramadol_as_a_racemic_mixture.svg?200 |}} |
| Brand Names | Ultram®, ConZip® |
| Drug Class | [[neuro:opioids:start|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 |
</WRAP>
</WRAP>

===== 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.

<WRAP clear></WRAP>

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===== 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.

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===== Indications =====

  * Moderate acute pain  
  * Chronic musculoskeletal pain  
  * Neuropathic pain (limited evidence)  

Not appropriate for severe pain requiring potent opioid therapy.

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<WRAP contra>
===== 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  

</WRAP>

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<WRAP details>
===== 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  

</WRAP>

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<WRAP details>
===== 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  

</WRAP>

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<WRAP details>
===== 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  

</WRAP>

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<WRAP details>
===== Drug Interactions =====

Increased serotonin syndrome risk:
  * SSRIs  
  * SNRIs  
  * MAOIs  
  * Linezolid  
  * St. John’s Wort  

CYP2D6 inhibitors (↓ analgesia):
  * Fluoxetine  
  * Paroxetine  

CNS depressants:
  * Benzodiazepines  
  * Alcohol  

</WRAP>

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<WRAP monitoring>
===== Monitoring =====

Clinical:
  * Pain response  
  * Sedation  
  * Signs of serotonin toxicity  

High-risk patients:
  * History of seizures  
  * Polypharmacy  

</WRAP>

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<WRAP pearls>
===== 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.  

</WRAP>

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===== Toxicity =====

Overdose may present with:
  * CNS depression  
  * Seizures  
  * Serotonin syndrome  
  * Respiratory depression  

Naloxone may reverse respiratory depression but does NOT treat seizures.

See:
  * [[neuro:opioids:naloxone|Naloxone]]

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===== Comparison Within Class =====

Compared to [[neuro:opioids:morphine|Morphine]]:
  * Much weaker  
  * Has serotonergic activity  

Compared to [[neuro:opioids:tapentadol|Tapentadol]]:
  * More serotonergic  
  * Higher seizure risk  

Compared to [[neuro:opioids:codeine|Codeine]]:
  * Similar potency  
  * More complex mechanism  

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===== Related =====

  * [[neuro:opioids:start|Opioids]]
  * [[neuro:opioids:tapentadol|Tapentadol]]
  * [[neuro:opioids:morphine|Morphine]]
  * [[neuro:opioids:naloxone|Naloxone]]