Anaes · Anaesthetic adjuncts
Tramadol and codeine
Also known as Weak WHO step-2 opioids · CYP2D6-dependent opioids · Tramadol — dual-action analgesic · Codeine — prodrug of morphine
Tramadol and codeine are weak WHO step-2 opioids whose analgesic efficacy depends critically on CYP2D6 metabolism. Tramadol is a dual-action agent: a weak mu agonist in its own right and a serotonin and noradrenaline reuptake inhibitor, whose main opioid effect comes from the CYP2D6 metabolite O-desmethyltramadol (M1). Codeine is a prodrug with very low intrinsic mu affinity, converted by CYP2D6 to morphine. CYP2D6 pharmacogenomic variability determines analgesic response: poor metabolisers get little analgesia while ultra-rapid metabolisers risk opioid toxicity. Tramadol carries a serotonin-syndrome and seizure risk; codeine is contraindicated in breastfeeding and in children post-tonsillectomy. Built on the tramadol clinical-pharmacology review (Grond 2004), the CPIC CYP2D6-opioid prescribing guideline (Crews 2021), the codeine-via-breast-milk review (Rieder 2026), the tramadol serotonin-syndrome case (Zhao 2026), the tramadol singultus case (Jha 2026), the tramadol/paracetamol study (Cipolloni 2026), and the neonatal tramadol study (Rechichi 2026).
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Red flags
- Codeine is CONTRAINDICATED in breastfeeding mothers who are CYP2D6 ultra-rapid metabolisers — they produce morphine in breast milk causing neonatal respiratory depression and death.
- Codeine is CONTRAINDICATED in children for post-tonsillectomy or post-adenoidectomy pain (obstructive sleep apnea) — fatal respiratory depression in ultra-rapid metaboliser children.
- Tramadol carries a SEROTONIN SYNDROME risk when combined with SSRIs, MAOIs, tricyclics, or linezolid (serotonin reuptake inhibition) — avoid these combinations.
- Tramadol LOWERS THE SEIZURE THRESHOLD — avoid in epilepsy and in patients on other seizure-threshold-lowering drugs.
- Both drugs show CYP2D6-dependent pharmacogenomic variability: poor metabolisers get inadequate analgesia; ultra-rapid metabolisers risk opioid toxicity.
Meet the patient
A breastfeeding mother asks for codeine for perineal pain after an episiotomy. The easy answer is yes — and it is the wrong one. Codeine use during breastfeeding is rarely but seriously associated with adverse effects driven by genetic polymorphisms of its metabolism, and clinicians are warned to treat the infant of a breastfeeding mother on codeine as at risk.[1] Regulatory guidance in most formularies goes further and contraindicates the combination outright — confirm local protocol.
The question every tramadol and codeine decision rests on is whether you remember that a label dose is a genetic lottery ticket. Poor metabolisers get no analgesia; ultra-rapid metabolisers get toxicity — the CPIC guideline gives genotype-based prescribing recommendations for both drugs. State the hard stops confidently, and choose a predictable alternative when the genetics are unknown.[1][7]
References7ShowHide
- [1]Rieder M, et al. Codeine toxicity via breast Milk: Can this occur and implications for opiate therapy in children Br J Clin Pharmacol, 2026.PMID 42324075
- [2]Zhao H, et al. Serotonin syndrome associated with concomitant tramadol and linezolid therapy: a case report and literature review Front Pharmacol, 2026.PMID 42292818
- [3]Jha AN, et al. Tramadol-Induced Persistent Singultus: A Case Report on Diagnosis, Mechanism, and Management Clin Case Rep, 2026.PMID 42311778
- [4]Cipolloni V, et al. Short- and Mid-Term Outcomes of Fixed-Dose Tramadol/Paracetamol in Early-Stage Symptomatic Knee Osteoarthritis: A Single-Center Retrospective Observational Extension Study Life (Basel), 2026.PMID 42355490
- [5]Rechichi J, et al. Use of Tramadol in Pain Management of Neonates with Epidermolysis Bullosa: A Single-Center Experience Children (Basel), 2026.PMID 42353915
- [6]Grond S, et al. Clinical pharmacology of tramadol Clin Pharmacokinet, 2004.PMID 15509185
- [7]Crews KR, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy Clin Pharmacol Ther, 2021.PMID 33387367