Tylenol 3 Side Effects: Why Codeine Doesn’t Work for Everyone
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Tylenol 3 is one of the most commonly used medications for short-term pain, often after minor surgery or dental procedures. Some people find that it does not work for them, while others get strong side effects such as nausea, dizziness, drowsiness or confusion. These side effects can be bad enough that some people would rather put up with the pain. When Tylenol 3 does not work, stronger opioids are often prescribed, but they do not always help either. Below we explain why your genes can change how Tylenol 3 works, and which pain relievers may be safer and more effective for you.
Why Tylenol 3 doesn't work for some people
Tylenol is a brand name for acetaminophen. According to the Canadian product monograph, each Tylenol with Codeine No. 3 tablet contains 300 mg of acetaminophen, 15 mg of caffeine and 30 mg of codeine, an opioid that adds extra pain relief. Tylenol No. 2 contains 15 mg of codeine, and Tylenol No. 4 contains 60 mg. Codeine itself does little to relieve pain. It works only after the liver converts it into morphine.
This conversion is done by a liver enzyme called CYP2D6, and genetic differences in CYP2D6 change how much morphine your body makes:
- Poor metabolizers make very little morphine from codeine, so Tylenol 3 gives them little or no pain relief.
- Intermediate metabolizers make less morphine than usual and may get weaker pain relief.
- Ultrarapid metabolizers turn codeine into morphine faster and in larger amounts, so even normal doses can cause dangerous side effects such as extreme sleepiness, confusion and slow or shallow breathing. The product monograph estimates that 1 to 10% of Caucasians, 3% of African Americans, 0.5 to 1% of Chinese, Japanese and Hispanic people, and 16 to 28% of North Africans, Ethiopians and Arabs are ultrarapid metabolizers.
The same applies to tramadol, another opioid that CYP2D6 converts into a stronger form. In a Mayo Clinic study, people who were CYP2D6 poor or ultrarapid metabolizers were 2.7 times more likely to have poor pain control or side effects with codeine, tramadol, oxycodone or hydrocodone. The researchers estimated that about 39% of people have one of these two metabolizer types.
What do the guidelines recommend?
The 2021 guideline from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends:
| CYP2D6 metabolizer type | Codeine (Tylenol 3) and tramadol |
|---|---|
| Ultrarapid | Do not use, because of the risk of serious toxicity. Use a non-opioid pain reliever or an opioid not affected by CYP2D6. |
| Normal | Usual dose. |
| Intermediate | Usual dose, with close monitoring. Switch to another pain reliever if it does not work well. |
| Poor | Avoid, because it is unlikely to work. Use a non-opioid pain reliever or an opioid not affected by CYP2D6. |
For hydrocodone, CPIC recommends the usual dose for poor and intermediate metabolizers, with a switch if there is no response. For oxycodone (found in Percocet and OxyContin) and methadone, the evidence is too mixed for a gene-based recommendation. Your prescriber chooses the pain reliever and dose with you.
Who should not take Tylenol 3
The Canadian product monograph says that Tylenol with Codeine must not be used by:
- CYP2D6 ultrarapid metabolizers, because of the risk of life-threatening breathing problems
- women who are breastfeeding, or during labour and delivery, because codeine passes into breast milk and can cause life-threatening breathing problems in the baby
- children under 12
- anyone under 18 after tonsil or adenoid surgery for sleep apnea
It is also not recommended for teenagers aged 12 to 17, and it should be used only when other pain relievers are not enough. Some children have since been prescribed tramadol instead, which carries its own risks.
Drug interactions can change how Tylenol 3 works
Other medications can change how Tylenol 3 works, or make it more dangerous, and they can add to the effects of your genes:
- Medications that block CYP2D6: some antidepressants, such as paroxetine and fluoxetine, and other drugs such as quinidine and methadone, block the enzyme that turns codeine into morphine. This can reduce pain relief. CPIC advises treating people who take strong CYP2D6 blockers as if they were poor metabolizers, even if their genes are normal.
- Alcohol, benzodiazepines and other sedating drugs: taken with codeine, they can cause profound sleepiness, slowed breathing, coma and death. The product monograph advises avoiding alcohol and using these combinations only when there is no alternative.
- Other serotonin-affecting drugs: codeine should be used with caution with medications such as certain antidepressants, tramadol, triptans and lithium, because of the risk of serotonin syndrome.
Learn more about how antidepressants can stop opioid pain relievers from working in Pain and depression drugs not working? Always tell your pharmacist about every medication and supplement you take.
Safer options for pain relief
For short-term pain, such as after dental work or minor surgery, the Oxford League Table of Analgesic Efficacy shows that ibuprofen (400 to 600 mg), ketorolac and celecoxib relieve pain better than acetaminophen with 60 mg of codeine or oxycodone. Learn more in Are you a Tylenol or Advil person?
Poorly controlled short-term pain can increase the risk of chronic pain. For chronic nerve pain, medications such as carbamazepine, gabapentin and pregabalin often work better than opioids. Tricyclic antidepressants and SNRIs such as duloxetine are other options. Tricyclics are also affected by CYP2D6, so your genetic results can help guide their dose. Celecoxib and naproxen can help with arthritis pain but not with nerve pain. Learn more in Why don't painkillers work for everyone?
Should you stop or change your pain medication?
Not on your own. If Tylenol 3 or another opioid is not working or causes side effects, talk to your doctor or pharmacist before stopping or changing the dose. Seek urgent care for extreme sleepiness, confusion or slow or shallow breathing.
How can you find out which pain medication suits you?
A pharmacogenetic test for CYP2D6 and other liver enzymes shows what type of metabolizer you are for many common medications. The best time to be tested is before surgery or a procedure that may need strong pain relief, so you and your care team can plan ahead.
In a 2019 clinical trial, people with chronic pain who were CYP2D6 intermediate or poor metabolizers had better pain control when their pain medications were chosen using their CYP2D6 results. A pharmacogenetic test such as Pillcheck can help your doctor find the most effective and safest pain treatment for you.
Frequently asked questions
Why doesn't Tylenol 3 work for me?
Codeine has to be converted into morphine by the CYP2D6 enzyme. If you are a CYP2D6 poor metabolizer, your body makes very little morphine, so Tylenol 3 gives little or no pain relief.
Is Tylenol 3 dangerous for some people?
Yes. CYP2D6 ultrarapid metabolizers can make too much morphine from codeine, even at normal doses, which can cause extreme sleepiness and slow breathing. Guidelines recommend that they avoid codeine and tramadol.
Can children or breastfeeding mothers take Tylenol 3?
No. In Canada, Tylenol with Codeine must not be used by children under 12, by anyone under 18 after tonsil or adenoid surgery for sleep apnea, or by women who are breastfeeding. It is also not recommended for teenagers aged 12 to 17.
Can my other medications affect Tylenol 3?
Yes. Antidepressants such as paroxetine and fluoxetine can block CYP2D6 and reduce pain relief, and alcohol, benzodiazepines and other sedating drugs can make codeine dangerous. Ask your pharmacist to check your medications.
What can I take instead of Tylenol 3?
For short-term pain, ibuprofen, ketorolac and celecoxib often work better. For chronic nerve pain, medications such as gabapentin or pregabalin may help. Ask your doctor or pharmacist which option suits you.
Does my CYP2D6 result affect oxycodone (Percocet)?
The evidence is mixed, and current guidelines do not give gene-based dose adjustments for oxycodone.
References
Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. 2021;110(4):888-896.
St Sauver JL, Olson JE, Roger VL, et al. CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications. Pharmgenomics Pers Med. 2017;10:217-227.
Smith DM, Weitzel KW, Elsey AR, et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genet Med. 2019;21(8):1842-1850.
Rodieux F, Vutskits L, Posfay-Barbe KM, et al. When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children. Front Pharmacol. 2018;9:148.
Parikh JM, et al. An update on the safety of prescribing opioids in pediatrics. Expert Opin Drug Saf. 2019;18(2):127-143.
Ruano G, Kost JA. Fundamental Considerations for Genetically-Guided Pain Management with Opioids Based on CYP2D6 and OPRM1 Polymorphisms. Pain Physician. 2018;21(6):E611-E621.
Janssen Inc. TYLENOL® with Codeine No. 2 and No. 3 Product Monograph. Health Canada Drug Product Database. Revised November 20, 2018.
