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Acetaminophen/codeine: 7 things you should know

Medically reviewed by Carmen Pope, BPharm. Last updated on April 5, 2023.

1. How it works

  • Acetaminophen/codeine is a combination of two different pain-relieving medicines (acetaminophen and codeine) with two different mechanisms of action.
  • Experts aren't sure exactly how acetaminophen works but suspect it blocks a specific type of cyclo-oxygenase (COX) enzyme, located mainly in the brain.
  • Codeine weakly binds to a specific opioid receptor, known as the mu-opioid receptor, but with much less affinity than morphine, which means its analgesic (pain-relieving effects) are much less.
  • Acetaminophen/codeine belongs to the group of medicines known as combination narcotic analgesics.

2. Upsides

  • May be used to treat mild-to-moderate pain that is unrelieved by nonopioid analgesics.
  • The combination of acetaminophen and codeine is more effective than taking either drug alone.
  • Some people find taking fixed-dose combination tablets easier to take than taking two different medicines.
  • Acetaminophen/codeine is a generic medicine and it is also available under the brand name Tylenol With Codeine.

3. Downsides

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

  • Drowsiness or dizziness may impair reaction skills and affect a person's ability to drive or operate machinery (codeine component). Avoid alcohol.
  • Codeine also slows down the motility of the gastrointestinal tract. This can lead to symptoms such as nausea, vomiting, constipation, and abdominal pain. Laxatives may be required.
  • Codeine is habit-forming and potentially abusable. The combination of acetaminophen and codeine should only be used short-term at the lowest effective dose when other nonopioid analgesics are not effective. Tolerance can also develop to codeine's analgesic effect (tolerance means that the same dosage no longer provides adequate pain relief). Legitimate supplies of products containing codeine may be sought out by drug seekers.
  • The codeine component of acetaminophen/codeine may also affect blood pressure, manifesting as dizziness when standing; and stimulate histamine release, which may cause symptoms such as flushing, itchiness, sweating, or red eyes.
  • Abrupt discontinuation of any codeine-containing medication in a person who has become physically dependent on it may lead to a withdrawal syndrome and symptoms such as restlessness, pupil dilation, watery eyes and a runny nose, sweating, muscle aches, insomnia, irritability, and gastrointestinal complaints. Babies born to mothers who are physically dependent on codeine will also be physically dependent.
  • Marked differences may exist in the analgesic effect provided by the combination of acetaminophen and codeine due to genetic variations in the CYP 2D6 liver enzyme responsible for metabolizing codeine into morphine. Consider alternative analgesics if acetaminophen/codeine is not having the desired pain-relieving effect.
  • Rarely, serious, life-threatening, breathing problems may occur attributable to the codeine component. The risk is greater with higher dosages of acetaminophen/codeine, in people with pre-existing respiratory disease, in seniors or the frail, or in those taking other medications that cause respiratory depression (such as benzodiazepines). Children under the age of 12 should never be given medication containing codeine, and those aged 12 to 18 should not be given codeine-containing medication if they have other risk factors for respiratory depression.
  • Rarely, acetaminophen has been associated with liver failure, especially at dosages greater than 4000mg/day.
  • The codeine component of acetaminophen/codeine may interact with several medications that are metabolized through the same liver enzymes CYP3A4 or CYP2D6. Profound sedation, breathing difficulties, and other adverse effects may result if benzodiazepines or similar drugs are given at the same time as codeine.
  • Interaction or overdosage may also cause serotonin syndrome. Symptoms include mental status changes such as agitation, hallucinations, coma, or delirium; a fast heart rate; dizziness; flushing; muscle tremor or rigidity; and stomach symptoms (including nausea, vomiting, and diarrhea).
  • Long-term use of codeine also affects the endocrine system, which may cause symptoms such as sexual dysfunction, an absence of periods, or infertility.
  • May not be suitable for some people including children of any age who have undergone a tonsillectomy or adenoidectomy, people with pre-existing respiratory depression or respiratory disease, with seizure disorders or a head injury, people with gastrointestinal obstruction, or recent use of monoamine oxidase inhibitors.
  • Products containing opioids such as codeine are required by the FDA to have a REMS (Risk Evaluation and Mitigation Strategy) associated with them and healthcare providers are encouraged to complete a REMS-compliant education program, counsel patients or their caregivers with every prescription on the safe use, storage, disposal, and serious risks associated with these products, explain to patients the importance of reading the medication guide, and improve patient, household, and community safety.
  • Keep out of reach of children because accidental ingestion may result in a fatal overdose of acetaminophen/codeine. Babies who have been exposed to acetaminophen/codeine in the womb may experience neonatal opioid withdrawal syndrome when born. Monitor and treat accordingly.
  • Acetaminophen/codeine is a Schedule III controlled substance.

Note: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. View complete list of side effects

4. Bottom Line

Acetaminophen/codeine may be used to treat mild-to-moderate pain that is unrelieved by nonopioid analgesics. However, the codeine component of this combination medicine is addictive and may cause constipation, and there is a wide variation in the way different individuals metabolize it, which can lead to either ineffectiveness or excessive side effects.

5. Tips

  • May be taken with or without food. Do not take more acetaminophen/codeine than you have been prescribed. Acetaminophen/codeine should be used short-term only. Long-term use may lead to addiction and dependence. Acetaminophen/codeine may need to be discontinued slowly depending on the duration of use. Talk to your doctor about a tapering schedule.
  • May cause sedation and affect your ability to drive or operate machinery. Do not drive or perform other hazardous tasks if acetaminophen/codeine affects you in this way.
  • Avoid alcohol while taking the combination of acetaminophen and codeine. Alcohol can contribute to the sedative effects of codeine and also increase the risk of respiratory depression.
  • Acetaminophen/codeine may make you feel dizzy when getting up from a lying down or sitting position to standing. Always get up slowly, but talk with your doctor if this dizziness results in a fall.
  • Acetaminophen/codeine may cause constipation which can be relieved with laxatives. Talk to your doctor if you experience any troublesome side effects.
  • Seek urgent medical advice if you experience any excessive sedation, breathing difficulties, wheezing, rash, itching, or facial swelling. Call emergency services if you suspect somebody has overdosed on acetaminophen/codeine (pinpoint pupils may be indicative of overdosage).
  • Tell your doctor if you think you have become addicted to this combination drug or if the usual dosage does not appear to be working.
  • Avoid taking extra acetaminophen while taking acetaminophen/codeine. Be especially cautious when taking cough and cold remedies in addition to acetaminophen/codeine. Some of these may also contain acetaminophen. Always check with your doctor or pharmacist that the products you buy over-the-counter are compatible with acetaminophen/codeine.
  • Do not use during pregnancy and breastfeeding unless specifically recommended by your doctor.
  • Keep this medicine in a safe place and out of the reach of children and pets. Accidental ingestion can result in a fatal overdose of acetaminophen/codeine, especially in children, and acetaminophen is toxic to dogs and cats. Never give any medication containing codeine to children under the age of 12.

6. Response and effectiveness

  • The analgesic effect of codeine reaches a peak in about two hours and the effects last for between four to six hours. Peak analgesic effects of acetaminophen are reached within 30 to 60 minutes of oral administration and last for three to four hours.
  • About 70-80% of a dose of codeine is metabolized by the liver into several metabolites, some active and some inactive. One of these active metabolites is morphine. About 5-10% of codeine is metabolized into morphine by the hepatic enzyme, CYP2D6. Experts believe some of the analgesic properties of codeine are due to it being converted into morphine. Note that up to 10% of Caucasians, 6% of Mexican-Americans, and 5% of African-Americans are poor metabolizers at CYP2D6 and are unlikely to metabolize codeine into morphine. 30% of Ethiopians, 20% of Saudis, 10% of Portuguese and Greeks, and 4% of North Americans are ultra-rapid metabolizers at CYP 2D6 and may experience excessive side effects, such as extreme sleepiness, confusion, and shallow breathing, even with normal dosages of acetaminophen/codeine.

7. Interactions

Medicines that interact with acetaminophen/codeine may either decrease its effect, affect how long it works, increase side effects, or have less of an effect when taken with acetaminophen/codeine. An interaction between two medications does not always mean that you must stop taking one of the medications; however, sometimes it does. Speak to your doctor about how drug interactions should be managed.

Common medications that may interact with acetaminophen/codeine include:

  • antibiotics, such as erythromycin
  • antidepressants, such as tricyclic antidepressants (eg, amitriptyline), monoamine oxidase inhibitors (eg, isocarboxazid, phenelzine, and tranylcypromine), or SSRIs (eg, fluoxetine, sertraline)
  • antifungal agents, such as itraconazole and ketoconazole
  • anticonvulsants, such as carbamazepine, lamotrigine, phenytoin, phenobarbital, or primidone
  • antimigraine agents such as sumatriptan
  • antipsychotics (such as butyrophenones, phenothiazines, or thioxanthenes) and atypical antipsychotics (eg, olanzapine, quetiapine, ziprasidone)
  • any medication that may cause drowsiness, such as amphetamines, benzodiazepines (eg, diazepam, lorazepam), first-generation antihistamines (such as doxylamine or promethazine), metoclopramide, or opioids (such as hydrocodone, morphine)
  • buprenorphine
  • HIV medications such as ritonavir
  • muscle relaxants, such as cyclobenzaprine
  • naltrexone
  • other medications that are CYP3A4 or CYP2D6 inhibitors or inducers
  • pentazocine
  • rifampin.

Avoid drinking alcohol or taking illegal or recreational drugs while taking acetaminophen/codeine.

Note that this list is not all-inclusive and includes only common medications that may interact with acetaminophen/codeine. You should refer to the prescribing information for acetaminophen/codeine for a complete list of interactions.


Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use acetaminophen/codeine only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2023 Revision date: April 5, 2023.