Anesthesia and Genetics: Why It Affects People Differently

You are about to go into surgery. The anesthesiologist asks about drug allergies, previous surgeries, and whether you have eaten in the last 8 hours. What they almost never ask about is your genetics. Yet your genetic makeup can determine whether post-op pain medication works, whether anti-nausea drugs are effective, how quickly you metabolize anesthetic agents, and whether you are at risk for rare but life-threatening reactions.

This is not a theoretical concern. A widely cited review found that postoperative pain is not adequately managed in more than 80% of patients in the U.S., attributing this to factors including the type of surgery, the intervention used, and time elapsed since the procedure. Knowing your metabolizer status before surgery — not after, when you are already in pain — is one of the most actionable applications of pharmacogenomic testing.

Genetics and Post-Operative Pain Management

The most clinically significant drug-gene interactions in surgical settings involve opioid prodrugs — pain medications that require CYP2D6 activation to work. The three most commonly affected are:

• Codeine: Requires CYP2D6 to convert to morphine. If you are a poor metabolizer, codeine provides essentially zero opioid-type pain relief. If you are an ultrarapid metabolizer, standard doses can produce dangerously high morphine levels. For a full explanation: why codeine does not work for some people.
• Tramadol: Same mechanism — CYP2D6 converts it to O-desmethyltramadol (M1). Same problem for poor and ultrarapid metabolizers. See: why tramadol is not working.
• Hydrocodone: Partially activated by CYP2D6 to hydromorphone. The impact is less dramatic than codeine or tramadol, but poor metabolizers may still experience reduced efficacy.

If you are a CYP2D6 poor metabolizer (up to about 5% of people, depending on population) and your post-surgical pain protocol relies on codeine or tramadol, you may be left in significant, avoidable pain. This is not a minor inconvenience — inadequate post-operative pain control is associated with delayed recovery, increased complications, chronic pain development, and longer hospital stays.

Anti-Nausea Medications

Post-operative nausea and vomiting (PONV) affects 20 to 30% of surgical patients and up to 80% of high-risk patients. The most commonly used anti-nausea medication in surgical settings is ondansetron (Zofran).

Ondansetron is metabolized by CYP2D6. In CYP2D6 ultrarapid metabolizers, the drug may be cleared so quickly that therapeutic levels are not maintained — meaning the anti-nausea medication does not work. CPIC notes that ultrarapid metabolizers may require an alternative antiemetic (such as granisetron, which is not CYP2D6-dependent).

This creates a compounding problem for ultrarapid metabolizers in surgical settings: not only might their opioid prodrugs produce excess active metabolite (risking respiratory depression), but their anti-nausea medication may also fail — leaving them both over-sedated and nauseated.

Malignant Hyperthermia

Malignant hyperthermia (MH) is a rare but potentially fatal reaction to certain inhaled anesthetics (sevoflurane, desflurane, isoflurane) and the muscle relaxant succinylcholine. It is caused by variants in the RYR1 gene (and less commonly CACNA1S), which affect calcium release in skeletal muscle.

MH occurs in approximately 1 in 5,000 to 100,000 anesthesia administrations. When it does occur, it produces rapidly rising body temperature, muscle rigidity, metabolic acidosis, and can be fatal without immediate treatment with dantrolene.

Important limitation: Consumer DNA tests (23andMe, AncestryDNA) do not adequately test for malignant hyperthermia variants. RYR1 has hundreds of reported variants associated with malignant hyperthermia susceptibility, and only a subset have been formally reviewed and classified as pathogenic or likely pathogenic by expert curation panels — consumer genotyping arrays cover very few of them, pathogenic or otherwise. If you have a family history of MH or unexplained death during anesthesia, clinical genetic testing (sequencing, not genotyping) is required. Always inform your anesthesiologist of any family history.

NSAIDs and CYP2C9

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for post-operative pain management, either alone or in combination with opioids. Celecoxib (Celebrex) is particularly relevant because it has specific CPIC guidance based on CYP2C9 metabolizer status.

CYP2C9 poor metabolizers have significantly reduced clearance of celecoxib, leading to higher blood levels and increased risk of cardiovascular and gastrointestinal adverse events. CPIC recommends initiating celecoxib at 25 to 50% of the standard dose in poor metabolizers, or selecting an alternative NSAID.

CYP2C9 is the same enzyme involved in warfarin metabolism — another medication commonly relevant in surgical settings. If you are a CYP2C9 poor metabolizer, both your NSAID dosing and your warfarin dosing (if applicable) require adjustment.

The Case for Pre-Surgical Pharmacogenomic Testing

The argument for knowing your pharmacogenomic profile before surgery is straightforward: surgery is a controlled, planned event (in most cases), and the medications used are predictable. You know in advance that pain management, anti-nausea drugs, and potentially blood thinners will be involved. This makes surgery an ideal scenario for pre-emptive PGx testing.

Specifically, pre-surgical PGx testing can:

• Identify CYP2D6 status to determine whether codeine, tramadol, and ondansetron will work as expected — this one requires clinical-grade testing with copy-number analysis, because CYP2D6 phenotype depends on gene deletions and duplications a consumer genotyping array cannot detect
• Identify CYP2C9 status for NSAID and warfarin dosing
• Give you a clear metabolizer-status overview that your surgeon and anesthesiologist can reference during the procedure and post-operative care
• Avoid the common scenario where a patient receives codeine post-op, gets no pain relief, and then spends 12 to 24 hours in avoidable distress while the care team figures out why

For a more detailed discussion of why PGx testing before surgery makes clinical sense: pharmacogenomics before surgery.

How to Get Tested Before Surgery

If you have an upcoming surgery, timing matters. Here is what to consider:

• If you already have 23andMe or AncestryDNA data: Upload to DecodeMyBio and get your Pain & Anesthesia results in minutes. Results include CYP2C9, OPRM1, COMT, and BDNF — the surgical pain-management genes an array can support. They do not include CYP2D6: rather than guess, we tell you the truth that CYP2D6 needs a specialized caller a consumer array does not provide. If your post-op plan depends on codeine or tramadol, that specific question needs clinical-grade testing.
• If you do not have consumer DNA data: A 23andMe or AncestryDNA kit takes 2 to 4 weeks for results, so plan ahead. Clinical PGx testing through your hospital may be faster but significantly more expensive.
• Timeline: Ideally, have your PGx results available at your pre-operative appointment — typically 1 to 2 weeks before surgery. This gives your surgical team time to review and adjust the pain management plan if needed.

For more on testing options and practicalities: at-home pharmacogenomic testing.

What to Bring to Your Surgeon

If you have pharmacogenomic results, bring them to your pre-operative appointment. Specifically:

• Your Decode results: They lay out your metabolizer phenotypes, affected medications, and CPIC-based recommendations in a clear format that does not require your surgeon to interpret raw genetic data.
• Metabolizer status for key genes: CYP2C9 (NSAIDs, warfarin), OPRM1 (opioid dosing), and any other relevant genes from your results. If you also had clinical-grade testing, bring your CYP2D6 result — a consumer raw-data analysis cannot supply one, since the deletions and duplications that define CYP2D6 status are not detectable on a genotyping array.
• A brief explanation: Not all surgical teams are familiar with consumer PGx reports. A simple statement like “My genetic results show reduced CYP2C9 activity, so I may need NSAID doses adjusted” is usually sufficient to start the conversation.

For guidance on reading and interpreting your results: understanding your Decode results.