Are you a Tylenol or Advil person? Alleviating pain through genetics

Some people are convinced that Advil works much better for their pain than Tylenol, or the other way around. Is it all in their heads, or the result of advertising and brand loyalty? Part of the answer may lie in their genes. Just as genetics affect eye colour, they also affect how the liver breaks down many medications. Small differences in DNA can change how strongly and how long Advil (ibuprofen) and other anti-inflammatory painkillers act, and how likely they are to cause side effects with long-term use.

How genes affect Advil and other NSAIDs

Advil (ibuprofen) belongs to the nonsteroidal anti-inflammatory drugs (NSAIDs), along with celecoxib (Celebrex), naproxen (Aleve), meloxicam, diclofenac and others. Ibuprofen and many other NSAIDs are cleared from the body mainly by the liver enzyme CYP2C9. About one in three people of European descent carries at least one gene variant that lowers CYP2C9 activity. These people are called intermediate or poor metabolizers.

Intermediate and poor metabolizers clear these NSAIDs more slowly, so the same dose leads to higher drug levels in the blood that last longer. Some people may notice stronger or longer pain relief, but the main concern is safety: higher levels increase the risk of stomach bleeding, high blood pressure, kidney problems and heart complications, especially with long-term use. Studies have linked reduced CYP2C9 activity with a higher risk of NSAID-related stomach and intestinal bleeding.

The CPIC 2020 guideline for CYP2C9 and NSAIDs recommends:

• Celecoxib, ibuprofen, flurbiprofen and lornoxicam: usual starting dose for normal metabolizers. Some intermediate metabolizers should start at the lowest dose. Poor metabolizers should start at 25% to 50% of the lowest dose or use another drug.
• Meloxicam: some intermediate metabolizers should start at half the lowest dose or use another drug, and poor metabolizers should use another drug.
• Piroxicam and tenoxicam: these stay in the body for a very long time, so intermediate and poor metabolizers should use another drug.

Naproxen (Aleve), diclofenac and aspirin are not significantly affected by CYP2C9 genes, and the guideline makes no genetic dose recommendations for them.

How Tylenol is processed

Tylenol (acetaminophen, also called paracetamol) is not an NSAID and works differently. It relieves pain and fever but has little effect on inflammation. Most of it is processed by the liver through pathways that attach sugar or sulfate groups to it (glucuronidation and sulfation), not by CYP2C9. A small part is converted by the enzyme CYP2E1 into a toxic by-product, which the liver normally neutralizes right away.

Researchers have found variations in genes such as CYP2E1 and UGT2B15 that change how acetaminophen is processed, but the evidence is not strong enough for clinical use. There is no pharmacogenetic guideline for acetaminophen, and genetic testing is not used to choose its dose. Differences in how well Tylenol works from person to person are more likely due to the type of pain, since it does not reduce inflammation, than to genes.

Tylenol or Advil: safety with long-term use and other drugs

Tylenol is often preferred for people with heart disease, kidney disease, a history of stomach ulcers, or who take blood thinners such as warfarin (Coumadin), because NSAIDs increase the risk of bleeding and heart and kidney problems. Even so, regular use of acetaminophen can raise the effect of warfarin, so people on warfarin should check with their health care provider.

The main risk with Tylenol is liver damage from too much acetaminophen. In Canada, adults should not take more than 4,000 mg a day from all sources, including cold and flu products that also contain acetaminophen. The risk of liver damage is higher in people who drink three or more alcoholic drinks a day, who are fasting or malnourished, or who take some drugs such as isoniazid for tuberculosis. Regular heavy drinking increases CYP2E1 activity and depletes the liver's natural protection, so more of the toxic by-product builds up.

NSAIDs such as Advil and celecoxib are better for inflammatory pain, but long-term use increases the risk of stomach bleeding, high blood pressure, kidney problems and heart complications. Celecoxib is gentler on the stomach than ibuprofen and naproxen. Because CYP2C9 clears celecoxib and ibuprofen, people who get unusually strong or long relief from these drugs may also be at higher risk of side effects. If you take an NSAID regularly, a pharmacogenetic test can show whether your dose or drug choice should change.

Aspirin and other NSAIDs can trigger asthma attacks in some people with asthma and nasal polyps, a condition called aspirin-exacerbated respiratory disease. This reaction is not related to drug metabolism genes. Ask your health care provider which pain reliever is safe for you if you have asthma.

Medical cannabis is also being studied for chronic pain. Your ability to metabolize drugs also affects the risk of cannabis side effects and drug interactions.

Pharmacogenetic testing options

Instead of guessing whether Advil or Tylenol is the better option, you can get a DNA test to learn how you metabolize pain medications. Gene variations also affect how people respond to codeine, tramadol, amitriptyline, venlafaxine and many other medications used for pain. Pharmacogenetic tests such as Pillcheck show your drug-metabolism profile, including CYP2C9. With Pillcheck results, your prescriber can choose safer and more effective pain medications for you and reduce the risks of long-term pain treatment. For a broader overview, read Why don't painkillers work for everyone?

Public health care programs such as OHIP, ODB, PharmaCare and MSP in B.C. do not pay for pharmacogenetic tests. However, many private health insurers help cover the cost.

Frequently asked questions

Why does Advil work better for me than Tylenol?

Advil reduces inflammation and Tylenol does not, so Advil often works better for inflammatory pain. Genes can also play a role: people with low CYP2C9 activity clear ibuprofen more slowly, which keeps drug levels higher for longer.

Which gene affects Advil (ibuprofen)?

CYP2C9. Intermediate and poor metabolizers may need a lower starting dose of ibuprofen, celecoxib and meloxicam, or a different drug, according to CPIC guidelines.

Do genes affect Tylenol (acetaminophen)?

Some gene variations change how acetaminophen is processed, but there are no genetic dosing guidelines for it. Alcohol use, fasting, liver disease and total daily dose matter much more for its safety.

Is Tylenol safer than Advil?

It depends on the person. Tylenol is easier on the stomach, heart and kidneys, but too much can damage the liver. Advil is better for inflammation but carries more risk of bleeding and heart and kidney problems with long-term use.

References

Theken KN, Lee CR, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther. 2020;108(2):191-200.

Mazaleuskaya LL, Sangkuhl K, Thorn CF, et al. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015;25(8):416-426.

Thareja G, et al. Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study. Metabolites. 2022;12(6):496.

Santos EA, et al. Relationship of anti-tuberculosis drug-induced liver injury and genetic polymorphisms in CYP2E1 and GST. Braz J Infect Dis. 2019.

Figueiras A, et al. CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case–control study. Pharmacogenet Genomics. 2016;26(2):66-73.

Allelic variation of CYP2C9 is associated with NSAID-related gastroduodenal bleeding. Nat Rev Gastroenterol Hepatol. 2007;4:591-592.

Bousman CA, et al. Encountering Pharmacogenetic Test Results in the Psychiatric Clinic. Can J Psychiatry. 2022;67(2):95-100.