What is the evidence for using tramadol (opioid analgesic) and codeine (opioid analgesic) in pain control?

Evidence for Tramadol and Codeine in Pain Control

Tramadol: Limited Role with Significant Caveats

Tramadol is not recommended as first-line treatment for moderate to severe pain and should be reserved only for mild to moderate pain when other options are inadequate, with careful attention to its numerous drug interactions and adverse effects. 1

Efficacy and Clinical Position

• Tramadol is classified as a WHO level 2 "weak" opioid with approximately one-tenth the potency of morphine 1, 2
• In single-dose studies of postoperative pain, tramadol 100 mg was less effective than aspirin 650 mg combined with codeine 60 mg 3
• Long-term controlled trials showed tramadol 250 mg daily in divided doses was generally comparable to acetaminophen/codeine combinations, but effectiveness typically plateaus after 30-40 days in cancer patients 4, 1
• When directly compared to hydrocodone and codeine in 177 patients, tramadol showed no superior analgesic efficacy but produced significantly more adverse effects 4

Mechanism and Metabolism

• Tramadol has dual action: weak mu-opioid receptor agonist plus norepinephrine and serotonin reuptake inhibition 1, 5
• The (+)-enantiomer and its M1 metabolite provide opioid effects, while the (-)-enantiomer inhibits norepinephrine reuptake 5, 6
• Analgesic efficacy is highly dependent on CYP2D6 metabolism to the active M1 metabolite, making it ineffective in poor metabolizers 1, 2

Dosing Parameters

• Maximum daily dose: 400 mg for immediate-release or 300 mg for extended-release formulations 1
• Titration over 10 days (50 mg increments every 3 days up to 200 mg daily) results in fewer discontinuations due to dizziness than rapid titration 3
• Reduced doses required for patients ≥75 years and those with hepatic or renal dysfunction 1, 2

Critical Safety Concerns

• Seizure risk: Tramadol lowers seizure threshold, particularly at doses exceeding 400 mg daily 4, 1, 7
• Serotonin syndrome: Absolute contraindication with MAOIs; use extreme caution with SSRIs, tricyclic antidepressants, and other serotonergic medications 4, 1, 7
• Common adverse effects: Dizziness, nausea, vomiting, constipation, vertigo, anorexia, and asthenia occur more frequently than with other opioids 4, 1
• Cognitive effects: May cause cognitive impairment, particularly in elderly patients 1
• Cardiovascular interactions: When combined with sympathomimetics like pseudoephedrine, risk of hypertension and ischemic events increases 7

When Tramadol Fails

• If more than four breakthrough doses per day are needed, escalate directly to strong opioids (morphine) rather than increasing tramadol beyond maximum recommended doses 1
• Do not delay transition to WHO step 3 opioids when tramadol provides inadequate analgesia 1

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Codeine: Prodrug with Unpredictable Efficacy

Codeine should be used with caution as a WHO level 2 analgesic for moderate pain, always combined with non-opioid analgesics, but its efficacy is limited by genetic variability in metabolism and a ceiling effect. 4

Efficacy and Clinical Position

• Codeine is classified as a WHO level 2 "weak" opioid for moderate pain (NRS 5-7) 4
• Typically used in combination products with acetaminophen, aspirin, or NSAIDs, with maximum doses of 240 mg codeine plus 4000 mg acetaminophen daily 4
• Meta-analysis data show no significant difference in effectiveness between non-opioid analgesics alone versus combinations with weak opioids like codeine 4
• The effectiveness of codeine and other step 2 opioids has a time limit of 30-40 days for most cancer patients 4, 1

Metabolism and Genetic Variability

• Codeine is a prodrug with little to no analgesic effect until metabolized to morphine via CYP2D6 2
• Ineffective in poor metabolizers (approximately 7-10% of Caucasians) who cannot convert codeine to morphine 2
• Potentially toxic in ultrarapid metabolizers who produce excessive morphine 2
• This genetic variability makes codeine's analgesic response highly unpredictable 2

Adverse Effects

• Constipation: Must always be anticipated and prophylactically managed with combination stool softener and stimulant laxative 4, 1
• Typical opioid side effects including nausea, sedation, and respiratory depression (though generally less severe than strong opioids) 4

Drug Interactions

• Dextropropoxyphene (when combined with codeine) should not be used with carbamazepine due to increased carbamazepine plasma concentrations 4

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Comparative Considerations: Tramadol vs. Codeine

• Neither tramadol nor codeine demonstrates clear superiority over the other in head-to-head comparisons 4
• Tramadol produces more adverse effects (vomiting, dizziness, weakness) than codeine in comparative trials 4
• Both have ceiling effects limiting dose escalation 4
• Both are subject to genetic variability in metabolism affecting efficacy 1, 2

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The Controversy of WHO Step 2

Many experts now advocate for early use of low-dose strong opioids (morphine) instead of weak opioids for moderate pain, though definitive evidence is lacking. 4

Arguments Against Step 2 Opioids

• Meta-analysis found no significant difference between non-opioid analgesics alone versus combinations with weak opioids 4
• Available studies do not demonstrate clear effectiveness differences between WHO step 1 and step 2 drugs 4
• Effectiveness typically limited to 30-40 days before escalation to step 3 becomes necessary 4, 1
• Ceiling effects prevent dose escalation to achieve better analgesia 4

Current Guideline Recommendations

• For mild to moderate pain, weak opioids (codeine, tramadol, dihydrocodeine) should be given in combination with non-opioid analgesics 4
• As an alternative, low doses of strong opioids combined with non-opioid analgesics should be considered 4
• For moderate to severe cancer pain, oral morphine remains the first-choice opioid 4
• An RCT is urgently needed to definitively address the role of WHO step 2 opioids 4

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Practical Algorithm for Clinical Decision-Making

1. Mild pain (NRS 1-4): Start with non-opioid analgesics (acetaminophen, NSAIDs) 4

2. Moderate pain (NRS 5-7):

   • Consider low-dose strong opioids (morphine, oxycodone) combined with non-opioid analgesics as preferred option 4
   • If using weak opioids, choose based on patient factors:
     • Avoid tramadol if: Patient takes SSRIs, MAOIs, or other serotonergic drugs; history of seizures; age ≥75 years without dose adjustment; renal/hepatic impairment 4, 1, 7
     • Avoid codeine if: Known CYP2D6 poor or ultrarapid metabolizer 2
   • Always combine with non-opioid analgesics 4
   • Always prescribe prophylactic laxatives 4, 1

3. If inadequate response after 30-40 days or requiring >4 breakthrough doses daily: Escalate directly to WHO step 3 strong opioids (oral morphine) 4, 1

4. Moderate to severe pain (NRS ≥7): Start directly with oral morphine, bypassing step 2 entirely 4