Tylenol 3 is one of the most commonly used medications for acute pain and is often used after minor surgical or dental procedures. Some patients complain that Tylenol 3 does not work for them, while others experience extreme nausea, dizziness and other symptoms of delirium. These side effects can be so severe that sometimes individuals prefer to suffer from the pain rather than deal with the side effects. Unfortunately, when Tylenol 3 does not work, physicians tend to prescribe stronger opioid medications like Oxycontin and Percocet, but often times those do not help either. Below, we explain why Tylenol 3 does not work for over 25% of patients, and which pain relievers, also called analgesics, can be more safe and effective for those people.

Why Tylenol 3 doesn’t work for some patients

Tylenol is a brand name for acetaminophen and the 3 in Tylenol 3 stands for 30mg of codeine, which is the component responsible for the extra ‘kick’.  Codeine is an opioid related drug, a common component of many cough syrups, and is a moderately effective pain reliever. There are other less common formulations available such as Tylenol 2, which contains a 20mg of codeine, and Tylenol 4 with 40mg. A person’s response to codeine depends on one’s ability to convert codeine in to morphine. This transformation of codeine to morphine in the liver is the critical step, as codeine by itself is not effective at relieving pain.

A liver enzyme called CYP2D6 does the job of changing codeine to morphine, but some individuals do not process (or metabolize) codeine well. Approximately 10% of Caucasians are poor codeine metabolizers, and the rate is higher in other ethnic groups, particularly in Asians. Poor metabolizers do not benefit from Tylenol 3, as their bodies cannot convert it to morphine. Even worse, these people also do not respond to stronger opioid-based analgesics including tramadol, hydrocodone, Oxycontin (oxycodone) and Percocet (acetaminophen and oxycodone) for the same reason – they simply cannot convert opioids into more active chemicals.

Since many physicians do not know the underlying cause for this issue, they may increase the dose of the same medication or try switching to other analgesics, with no improvements.  Pillcheck follows guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC) which recommends avoiding the use of codeine, tramadol and oxycodone in people who are Poor CYP2D6 metabolizers.  People with reduced CYP2D6 activity, called Intermediate Metabolizers, require higher doses of codeine, tramadol or oxycodone to achieve adequate pain control.

Codeine-induced delirium is another problem that affects some individuals taking Tylenol 3. Rapid elation, followed by blurry vision, slurry speech and impaired movement, and breath suppression may occur when patients metabolize codeine to morphine faster than usual. Such individuals, called ultrafast metabolizers, report stronger but short lasting pain relief on Tylenol 3. Genetic factors related to the CYP2D6 gene leads to enhanced metabolism of codeine, as well as tramadol, Oxycodone and Percocet, making these individuals more sensitive to all opioids. Ultrafast metabolizers are at much higher risk of an accidental drug overdose, especially if they are given a higher drug dose.

The risk of accidental overdose in Ultrafast Metabolizers is the main reason why the US Food and Drug Administration banned the use of Tylenol 3, codeine-containing cough syrups and tramadol for children under 12 years of age, and breastfeeding women. Women who are breastfeeding while taking Tylenol 3 or codeine may produce a high concentration of morphine in their milk, leading to an accidental overdose in babies – the risk is increased substantially for Ultrafast metabolizers.

Unfortunately, due to limitations on the use of codeine, some physicians prescribe tramadol or oxycodone to children after tonsillectomy and other surgeries not realizing the risks of using even more potent opioids, and how they are metabolized. For patients with chronic pain who are poor and ultrafast codeine metabolizers, antiepileptic medications could be a better and safer choice. For acute pain management the Oxford Table of Analgesic Efficacy shows that ketorolac, high doses of ibuprofen (600mg), and celecoxib are more effective for pain control than Tylenol 6 (60mg codeine) and oxycodone. People with chronic arthritis can use celecoxib and naproxen, but these drugs are not useful for chronic neuropathic pain.

Uncontrolled acute pain increases the risk of developing chronic pain. Even a simple root canal treatment can lead to devastating chronic pain. For some patients, antiepileptic medications like carbamazepine, gabapentin and pregabalin have been shown to be more effective in controlling chronic pain than Tylenol 3, Oxycontin or Percocet.  Other therapeutic options for chronic pain include tricyclic antidepressants (TCAs) and another type of antidepressant called SNRIs. However, these drugs are also metabolized by the same liver enzyme CYP2D6 and so present the same sort of problems for Ultrafast and Intermediate metabolizers.

How can you know what medication is right and safe for you and your loved ones?

The answer is very easy – genetic testing for CYP2D6 gene variations and other liver enzymes can tell you what type of metabolizer you are for most commonly prescribed medications. The ideal time to get tested is before surgery or other procedures that will require strong painkillers so that you can avoid the risk of serious side effects or treatment failure. However, many people wait until it is too late – get tested today and share your results with your healthcare professional so you can have piece of mind!

A Pharmacogenetic (PGx) Test, such as Pillcheck™, can help you know in advance whether or not you are at risk for adverse side effects or may not benefit from specific medications due to an inherited altered drug metabolism. A study published in early 2019  shows that pharmacogenetics-guided therapy selection for patients with chronic pain improved pain control. Pillcheck results can help your doctor to find the optimal pain management treatment for you.

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CPIC® Guideline for Codeine and CYP2D6

https://cpicpgx.org/content/guideline/publication/codeine/2014/24458010.pdf

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