Clinical area · Pain and anaesthesia

How can a painkiller at the right dose become lethal?

Codeine on its own is inactive; pain relief comes from the morphine CYP2D6 produces. If the enzyme is ultrarapid, the same dose can become toxic levels of morphine; if it is poor, the pain is not relieved.

Prepared by the BIODECODE science team · Last updated: October 2026 · Based on CPIC, DPWG, FDA and peer-reviewed publications

In brief

  • Codeine and tramadol are painkillers taken in inactive form and activated by the CYP2D6 enzyme. Pain relief comes from the morphine and similar substances that the enzyme produces.
  • In someone with ultrarapid CYP2D6, the same dose can turn into dangerous amounts of morphine; with poor CYP2D6, the pain is not relieved. The FDA therefore restricted use in children in 2013 and 2017.
  • In anaesthesia, variants in the RYR1 and CACNA1S genes can cause a life-threatening reaction called malignant hyperthermia. Known in advance, a safe anaesthetic can be chosen.

Key concepts

Opioid

A group of strong painkillers with morphine-like effects. Codeine and tramadol belong to this group.

Respiratory depression

Slowed, shallow breathing caused by high morphine levels. It is the most dangerous side effect of opioids.

Malignant hyperthermia

An emergency in which certain anaesthetic gases or the muscle relaxant succinylcholine trigger uncontrolled muscle contraction and a rapidly rising temperature.

Pseudocholinesterase deficiency

Slow breakdown of succinylcholine due to the BCHE gene, so muscle paralysis lasts longer than expected after surgery.

How does codeine work?

  1. Codeine is taken inactive

    Codeine itself has only a weak effect; the real pain relief comes from the morphine it is converted to.

  2. CYP2D6 converts codeine to morphine

    The liver enzyme CYP2D6 turns part of the codeine into morphine. How much depends on the enzyme's speed.

  3. The outcome depends on enzyme speed

    At normal speed, pain is controlled. In ultrarapid metabolizers morphine rises too high; in poor metabolizers too little is made.

What does a CYP2D6 result mean for codeine?

Metabolizer typeWhat happens?General guideline recommendation*
UltrarapidMorphine forms quickly and in excess; risk of respiratory depression.Avoid codeine; choose a painkiller other than tramadol.
NormalExpected morphine level.Standard use.
IntermediateLess morphine may form.Standard use; an alternative if the effect is inadequate.
PoorVery little morphine forms; pain is not relieved.Avoid codeine; choose a painkiller other than tramadol.

* CPIC guideline for CYP2D6 and opioids. A similar mechanism applies to tramadol.

Who is it relevant for?

  • Patients whose pain management is being planned before surgery
  • People who did not get the expected effect from codeine or tramadol, or had severe side effects
  • People with a family history of unexpected reactions during anaesthesia
  • Breastfeeding mothers: if the mother is an ultrarapid metabolizer, the baby's risk of morphine effects may increase

Your physician decides whether the test is right for you.

Evidence

  • 2013

    FDA added a boxed warning and contraindication for codeine in children after tonsillectomy and adenoidectomy

    FDA Drug Safety Communication, 20 February 2013
  • 2017

    FDA contraindicated codeine and tramadol in children under 12

    FDA
  • Both ends

    CPIC recommends an alternative analgesic to codeine in both ultrarapid and poor metabolizers

    CPIC guideline
  • MH

    RYR1 and CACNA1S variants determine malignant hyperthermia risk with volatile anaesthetics and succinylcholine

    CPIC guideline

Related genes and drugs

GeneRoleRelated drugsSource
CYP2D6Enzyme that converts codeine and tramadol to their active formsCodeine, tramadol, ondansetronCPIC
CYP2C9Enzyme that processes many non-steroidal anti-inflammatory drugs (NSAIDs)Celecoxib, ibuprofen, meloxicamCPIC
RYR1 · CACNA1SGenes for calcium channels in muscle cells; linked to malignant hyperthermiaSevoflurane, desflurane, isoflurane, succinylcholineCPIC
BCHEGene for the enzyme that breaks down succinylcholine and mivacuriumSuccinylcholine, mivacuriumFDA / literature

What you will see in the BIODECODE report

  • Activity score

    CYP2D6 activity score and phenotype, copy number included.

  • Alternative scenario

    When phase cannot be resolved, the most likely diplotype and an alternative scenario are reported together.

  • Changed verdicts

    Drugs whose decision would change under the alternative scenario are listed one by one.

  • Anaesthesia

    Malignant hyperthermia susceptibility is assessed separately for RYR1 and CACNA1S.

Sample report (PDF)

Good to know

  • CYP2D6 is the most complex gene in pharmacogenomics. Copy-number changes and hybrid alleles are assessed with limited resolution from short-read data; confirmatory testing is advised when needed.
  • Drugs that suppress CYP2D6, such as some antidepressants, can reduce codeine's effect regardless of genotype.
  • For a person at risk of malignant hyperthermia, it is essential that the anaesthesia team knows before surgery.

Frequently asked questions

Should I be tested before surgery?

That is for your anaesthetist and surgeon to decide. If anyone in your family had an unexpected reaction during anaesthesia, be sure to mention it.

I take a codeine-containing medicine; should I stop?

No, do not stop it or change its dose on your own. Discuss your concerns with your physician.

Can I give my child a codeine cough syrup?

The FDA has contraindicated codeine in children under 12. Every medicine decision for a child should be made with a physician.

References

  1. US Food and Drug Administration (FDA). Safety communication on codeine use, boxed warning and contraindication. 20 February 2013.
  2. US Food and Drug Administration (FDA). Contraindication of codeine and tramadol in children under 12. 2017.
  3. Crews KR et al. CPIC guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther. 2021.
  4. Gonsalves SG et al. CPIC guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin Pharmacol Ther. 2019.
  5. Theken KN et al. CPIC guideline for CYP2C9 and nonsteroidal anti-inflammatory drugs. Clin Pharmacol Ther. 2020.

This page is for information only; diagnosis and treatment decisions belong to your physician. Never stop or change a medicine on your own.

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