Can you take codeine with antidepressants?

Can You Take Codeine (Rikodeine) with Antidepressants?

Yes, codeine can generally be taken with most antidepressants, but there are critical exceptions and dose-limiting interactions that require careful attention, particularly with SSRIs that inhibit CYP2D6 and all MAOIs which are absolutely contraindicated.

Absolute Contraindications

MAOIs (Monoamine Oxidase Inhibitors)

• Codeine is contraindicated with MAOIs due to the risk of serotonin syndrome and hypertensive crisis 1
• This includes phenelzine, tranylcypromine, selegiline, isocarboxazid, and linezolid 1
• Tramadol specifically should not be combined with MAOIs, and codeine carries similar risks as an opioid 2, 1
• A minimum 2-week washout period is required when switching between MAOIs and other medications (5 weeks for fluoxetine) 1

Major Interactions: CYP2D6 Inhibition

SSRIs with Strong CYP2D6 Inhibition

Codeine requires CYP2D6 metabolism to convert into morphine for analgesic effect, so strong CYP2D6 inhibitors will significantly reduce or eliminate codeine's pain relief 3, 4

The rank order of CYP2D6 inhibition potency is 4:

• Paroxetine (strongest inhibitor)
• Fluoxetine (strong inhibitor, with long-acting metabolite norfluoxetine)
• Sertraline (moderate inhibitor)
• Fluvoxamine (minimal CYP2D6 inhibition)
• Venlafaxine (minimal CYP2D6 inhibition)

Clinical Consequences

• Paroxetine and fluoxetine produce approximately 3-4 fold increases in plasma concentrations of CYP2D6 substrates 4
• Concomitant prescription of codeine with moderate-to-strong CYP2D6 inhibitor antidepressants leads to inadequate analgesia 3
• Fluoxetine's metabolite norfluoxetine has a long half-life causing significant elevation of drug interactions for approximately 3 weeks after discontinuation 4

Safer Antidepressant Options with Codeine

Minimal Interaction Risk

• Escitalopram: Has minimal effects on CYP450 enzymes and lower propensity for drug interactions 5, 6
• Fluvoxamine: Shows minimal in vivo pharmacokinetic interaction with CYP2D6 substrates 4
• Venlafaxine: Minimal CYP2D6 inhibition 4
• Mirtazapine: Low risk for pharmacokinetic interactions 6
• Agomelatine: Favorable drug interaction profile 6

Moderate Caution Required

• Sertraline (50 mg/day): Produces only modest (approximately 30%) elevation in CYP2D6 substrate concentrations, considerably less than paroxetine or fluoxetine 4
• Duloxetine: Moderate CYP2D6 inhibitor, may reduce codeine efficacy 6
• Bupropion: Moderate CYP2D6 inhibitor, may reduce codeine efficacy 6

Additional Safety Considerations

Serotonin Syndrome Risk

• While rare, there are case reports of fatal intoxication with SSRI and codeine coingestion 7
• Monitor for serotonin syndrome symptoms when combining any antidepressant with opioids 8
• Most serious drug interactions with antidepressants involve CNS-active drugs 8

Tramadol-Specific Warnings

• Tramadol should be used with caution in patients taking antidepressants due to increased seizure risk and serotonin syndrome 2
• Tramadol should not be combined with SSRIs, SNRIs, or tricyclic antidepressants that affect serotonin metabolism 2

Clinical Recommendations

If a patient requires both codeine and an antidepressant 3:

1. Avoid MAOIs entirely - choose alternative antidepressant 1
2. Avoid paroxetine and fluoxetine - they will render codeine ineffective 3, 4
3. Prefer escitalopram, mirtazapine, or venlafaxine - minimal CYP2D6 interaction 5, 6, 4
4. If using sertraline, expect reduced but not eliminated codeine efficacy 4
5. Consider alternative analgesics if strong CYP2D6 inhibitor is necessary for depression management 3

Common Pitfall

The most common error is prescribing codeine to patients on paroxetine or fluoxetine without recognizing that the codeine will provide inadequate pain relief, leading to unnecessary dose escalation or patient suffering 3. A prevalence study found 0.44% of patients received this problematic combination 3.