Have you or anyone in your family experienced complications from medical anesthesia? Overall, estimated rates of perioperative complications from anesthesia are between 3% to 16% dependant on a variety of factors. Anesthetic complications can range from short-term, temporary side effects such as nausea or vomiting to, in rare cases, more severe or long-term effects such as an unexplained fever or even failing to wake up within the expected timeframe. Here, we explain how genetic variations cause these complications and how to assess your risk.

Why does this matter to you and your doctor?

Some people may experience what is known as “Delayed Emergence” when recovering from anesthesia, meaning they fail to wake up after the medication is discontinued. While the severe form of this complication is rare (1 in 3,200-5,000), the milder form, slower recovery, can affect up to 4% of surgery patients.

Malignant hyperthermia is another rare condition (1 in 30,000-100,000) triggered by commonly used inhaled anesthetics, leading to high body temperature, muscle rigidity, spasms, and an accelerated and irregular heartbeat that can be life-threatening. In such cases, rapid administration of dantrolene (a muscle relaxant) and cooling with ice packs are necessary.

While these conditions are rare, affected families require exceptional caution with surgical procedures. Knowing whether you carry genetic risks to anesthesia drugs can be lifesaving. Even if you don’t have a family history of anesthetic complications, pharmacogenetic testing can inform you of how your body processes other medications used during surgery, including painkillers and anti-nausea drugs, helping you to avoid unpleasant complications.

Pharmacogenetics – the science of medication response.

The term “pharmacogenetics” was first coined by Werner Kalow in the 1950s when he identified a genetic variant of the pseudocholinesterase enzyme, now called butyrylcholinesterase, which is encoded by the BCHE gene. Butyrylcholinesterase breaks down certain muscle relaxants (succinylcholine, mivacurium) used during surgery. Low butyrylcholinesterase levels can also be caused by liver disease, malnutrition, pregnancy or certain medications.

Reduced-function BCHE variants (A, F1, F2, H, J, K, and S) are rare, but certain ethnic groups have a higher prevalence of pseudocholinesterase deficiency. Males of European descent, Jews of Iranian descent, and some Native Alaskan tribes are disproportionally affected. People who carry one copy of the low-activity allele have roughly a 30% increase in the duration of muscle paralysis (i.e., neuromuscular blockade) after standard succinylcholine dosing. This presents as a slightly longer post-surgery recovery (1-2 hours). However, people with two copies of a low or no-function allele can be “knocked out” for over 8 hours, staying on a mechanical ventilator much longer.

People with BCHE deficiency can also exhibit a stronger response to local anesthetics (e.g., procaine, tetracaine) and, interestingly, greater sensitivity to certain agricultural pesticides. Cocaine consumption can lead to sudden cardiac death. People with known BCHE deficiency should wear Medical Alert bracelets to alert doctors and paramedics to this condition and avoid the administration of high-risk medications. Family members should also be tested for mutations in the BCHE gene.

What causes malignant hyperthermia?

People with genetic variations in the RYR1 and CACNA1S genes, which regulate calcium storage and transport in muscle, have abnormal responses to certain anesthetics and muscle relaxants. Although a rare genetic variant in these genes does not cause a muscle disease, some people may experience muscle weakness or develop a high fever and muscle spasms after overheating or strenuous activity. The main trouble, however, is when they are exposed to halogenated anesthetic gases (desflurane, enflurane, halothane, isoflurane, methoxyflurane or sevoflurane) or muscle relaxant succinylcholine.

These exposures can be quite dangerous, so if you have such a variant, it is important to warn your doctors, and especially your anesthesiologists, if a general surgical procedure is planned. Other anesthetics should be used. Propofol and ketamine are potentially much safer options.

Red flags: Should you consider genetic testing before anesthesia?

Primary warning signs to consider in your family history are if anyone in your family has previously had a severe reaction to anesthesia, had a critical complication during surgery (such as fever, muscle spasms or a slow recovery from anesthesia), or had a muscle disorder.
It is also highly recommended to get tested if you have had a prolonged recovery from anesthesia, unexplained muscle weakness or cramping after surgery, have a muscle condition, or have unexplained muscle problems. Clinical guidelines recommend genetic testing for individuals at risk of anesthesia-related complications.

Genetic testing before anesthesia assesses genetic variations in the BCHE, RYR1, and CACNA1S genes, which can help to avoid serious complications. There are more than 100 different mutations in the RYR1 gene alone, so sequencing of the target genes, high-coverage exome sequencing, or whole-genome sequencing can identify super-rare variations. More common ones can be captured by high-sensitivity genotyping. Pillcheck uses the GDA-PGx array, which is one of the few high-sensitivity genotyping platforms that supports reporting of multiple rare variations in these genes.

Are there alternatives to gas anesthesia?

Propofol and midazolam are other options for people who cannot tolerate gas anesthetics. However, other genetic variations can affect the depth of sedation and recovery duration for these medications, as well. Pillcheck reports variants in the CYP2B6 gene that affect propofol clearance (the required dose to achieve adequate anesthetic depth) and the speed of recovery. Polymorphisms in CYP3A4 and CYP3A5 influence the response to midazolam. People who have a faster metabolism of these drugs might experience insufficient sedation. Pillcheck insights could help to avoid this and other unpleasant complications.

Pharmacogenetic tests, including Pillcheck, can also reveal how your body processes opioid painkillers (tramadol, codeine, oxycodone), NSAIDs (ibuprofen, celecoxib), and various nausea drugs, so your doctors will be able to optimize your medications and reduce the risk of pain and other side effects.

If you had an “allergy” type reaction, or hypersensitivity to morphine, radiocontrast dyes, antibiotic or anticonvulsant medication that caused severe skin problems, you might be interested in learning more about these conditions here.

Summary:

• General anesthesia can pose significant risks for people with specific genetic variants.
• If you or anyone in your family had a poor experience with anesthesia during surgery, you should consider testing for the BCHE, RYR1, and CACNA1S genes.
• Genetic testing before surgery can help to assess whether you have a high-risk variant and guide your doctors to alternative and safer medications.
• This knowledge can be lifesaving for you and your family members.

References:

Kalow W. Perspectives in pharmacogenetics. Arch Pathol Lab Med. 2001 Jan;125(1):77-80.

Nguyen JQ at al., Hereditary Pseudocholinesterase Deficiency and Succinylcholine: Historical Perspective, Therapeutic Implications, and Future Considerations Pharmacotherapy. 2025 Sep;45(9):600-620.

Reinaldo Trujillo and William P. West. Pseudocholinesterase Deficiency StatPearls Bookshelf ID: NBK541032 PMID: 31082076.

Hopkins PM et al., Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists. Anaesthesia. 2021 May;76(5):655-664

Rossi D et al., Identification of novel potentially causative RYR1 variants in individuals with malignant hyperthermia susceptibility Neuromuscul Disord. 2025 Nov 25;58:106296.

Mikstacki A et al., The impact of genetic factors on response to anaesthetics Adv Med Sci. 2013;58(1):9-14. doi: 10.2478/v10039-012-0065-z.

Bernardo MM Why the Same Anesthetic Fails Sometimes Medscape News Europe March 6, 2026

Gottschalk A, Van Aken H, Zenz M, Standl T. Is anesthesia dangerous? Dtsch Arztebl Int. 2011 Jul;108(27):469-74. doi: 10.3238/arztebl.2011.0469. Epub 2011 Jul 8. PMID: 21814522; PMCID: PMC3147285.