Updated September 21, 2023

Some people are convinced that Advil is much more effective at relieving their pain than Tylenol, or vice versa. Is it all in their heads? Could they be under the influence of effective advertising or brand loyalty? More likely, the secret to this phenomenon lies hidden within your genes. Just as genetics can affect your eye colour, genetics also affect how you respond to medications by determining the level of certain drug-metabolizing enzymes in your liver. Small differences in people’s DNA can cause them to respond very differently to Advil (ibuprofen), Tylenol (acetaminophen), and many other painkillers. A person’s genetic profile can play a role in which painkiller brand they reach for at the drug store. It can also seriously affect long-term side effects and interactions with other medications.

How genetics affect pain relief

Metabolism of Advil

There is a straightforward explanation of why Advil is the preferred option for some. Advil is metabolized by the CYP2C9 liver enzyme. People with genetically low CYP2C9 activity, known as Intermediate or Poor metabolizers, clear Advil and other NSAIDs (Nonsteroidal anti-inflammatory drugs) much slower than average. Therefore, while taking the same amount of Advil, the drug concentration in their blood is higher, leading to better pain relief. However, long-term treatment with ibuprofen and similar NSAIDs may pose a significant risk of gastrointestinal bleeding and other side effects in people with reduced CYP2C9 activity.

Metabolism of Tylenol

Tylenol is metabolized by a different liver enzyme called CYP2E1. People who are CYP2C9-poor metabolizers have an average response to acetaminophen. People with reduced CYP2E1 activity have reduced acetaminophen clearance and get a more robust response to this drug. Although several genetic variations in the CYP2E1 and UGT2B15 genes have been identified, pharmacogenetic testing for this enzyme is not yet used due to limited clinical evidence.

Implications for long-term use and interactions with other drugs

Tylenol might be the preferred pain control option for people with heart disease who are taking blood thinners such as warfarin (Coumadin), valproic acid, and similar antiepileptic medications. Acetaminophen has lower interactions with these drugs compared with NSAIDs. However, alcohol, anti-tuberculosis drugs and some oncological medicines block CYP2E1 activity and reduce the elimination of acetaminophen. Concurrent use of Tylenol with these drugs, alcohol, or excessive acetaminophen dose can lead to potentially fatal drug-induced liver failure.

Long-term use of Tylenol can also increase the risk of stomach ulcers. Celecoxib (Celebrex) has a lower impact on the stomach than Tylenol and Advil. The CYP2C9 enzyme clears celecoxib, Advil, Aleve (naproxen) and all other NSAIDs. Ironically, people who get better pain relief with these drugs might be at higher risk of GI bleeding and heart complications due to excessive drug concentration in the blood. If Advil works best for you, you should take a pharmacogenetic test to assess if it is safe for long-term use. Clinical pharmacogenetic guidelines indicate that people with reduced CYP2C9 activity should take the lowest possible dose to manage chronic pain and avoid NSAIDs with long half-lives, such as piroxicam and tenoxicam.

Aspirin, acetaminophen and NSAIDs can also exacerbate asthma in people predisposed to this condition and have reduced drug metabolism.

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

Pharmacogenetic testing options

Instead of wondering whether Advil or Tylenol is the best option, consider getting a DNA test to assess your drug metabolism.  Variations in drug metabolic genes also affect response to codeine, tramadol, oxycodone, venlafaxine, duloxetine and many other painkillers. Pharmacogenetic tests such as Pillcheck provide critical insights into your drug-metabolic profile. With Pillcheck results, your physician can select safer and more effective pain medications for you and reduce the risks associated with long-term pain treatment.

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

References:

Santos EA et al., Relationship of anti-tuberculosis drug-induced liver injury and genetic polymorphisms in CYP2E1 and GST. Braz J Infect Dis. 2019 Nov 4. pii: S1413-8670(19)30445-3.

Sinclairabc JF, et al., Short-term Treatment with Alcohols Causes Hepatic Steatosis and Enhances Acetaminophen Hepatotoxicity in Cyp2e1(-/-) Mice Toxicology and Applied Pharmacology Volume 168, Issue 2, 15 October 2000, Pages 114-122.

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.

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

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

Allelic variation of CYP2C9 is associated with NSAID-related gastroduodenal bleeding. Nat Rev Gastroenterol Hepatol 4, 591–592 (2007).

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