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Codeine and Acetaminophen: how safe and clinically effective are they?


This summary is based on the Rapid Response Report developed by the Canadian Agency for Drugs and Technologies in Health: Codeine and Acetaminophen for Pain Relief: A Review of the Clinical Efficacy and Safety

Full Report (PDF)



Pain has been defined as “an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage.” Pain can be classified as being either acute or chronic. The distinction between acute and chronic pain is usually based on a subjective interval of time since pain onset, the two most commonly used intervals being months and 6 months since onset. Acute pain may be caused by various events as surgery, dental work, bone fractures and burns and cuts. Common types of chronic pain are lower back pain, cancer related pain, arthritis pain, neurogenic pain and psychogenic pain.

Pain can be treated by both pharmacological and non-pharmacological means. Major categories of medications for treatment of pain include non-opioid analgesics, opioids, alpha-2 adrenergric agonists, antidepressants, antiepileptic drugs, muscle relaxants, N-methyl-d-aspartate (NMDS) receptor agonists and topical analgesic agents.

Codeine is an opioid used to treat mild to moderately severe pain.7 Codeine can be habit forming and can cause serious side effects such as slow heart rate, weak pulse, confusion, hallucinations, seizure and problems with urination.

Less severe side effects include dizziness, nausea, vomiting, stomach pain, constipation, sweating and mild rash.

The most commonly used over the counter oral non-opioid analgesic is acetaminophen. Acetaminophen is commonly used for the treatment of knee or hip osteoarthritis. The safety of long-term use of acetaminophen has been questioned. The use of acetaminophen has is the most common cause of acute liver failure in the United States.

Acetaminophen and codeine combination products are used to relieve mild to moderate pain. Acetaminophen/codeine products work in certain areas of the brain and nervous system to decrease pain. The combination of acetaminophen/codeine may provide better pain relief than either medicine alone. The combination drug can have similar side effects as the individual medications.

Research Questions

  1. What is the clinical efficacy of codeine for chronic pain relief?
  2. What is the clinical efficacy of codeine in combination with acetaminophen for chronic pain relief?
  3. What is the clinical evidence on patient safety associated with different doses of codeine?
  4. What is the clinical evidence on patient safety associated with different doses of acetaminophen?
  5. What is the clinical evidence on patient safety associated with different doses of codeine/acetaminophen combination products?

Key Message

  • Based on this review, both codeine and acetaminophen/codeine provide better chronic pain relief than placebo. Chronic use of acetaminophen at doses higher than 2000 mg per day may be associated with increased risk of gastrointestinal events, liver toxicity, and renal dysfunction or failure.
  • This review found evidence of increased risk of adverse events for patients treated with codeine or acetaminophen/codeine combination products compared to placebo. 
  • Acetaminophen/codeine treatment for post-operative pain was found to be associated with a higher risk of adverse events compared to placebo.
  • No evidence was found on relative safety of different doses of either codeine or acetaminophen/codeine combination products.


Do you need further information on this topic? Do you have any comments or suggestions? Email us at oasisdiscussions@cda-adc.ca

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  1. JCDA Oasis July 10, 2013

    Dr. John B.

    In regards to a combination of 600 mg ibuprofen and 1000 mg acetaminophen, I’ve read that this is more effective than codeine with acetaminophen.

    Is this true? My concern is: is there potential toxicity and or liver damage at such high doses even though the patient is taking this combination for a short-term period (a few days)?

    Is there potential toxicity and or liver damage at such high doses?

    What is the maximum amount of days a healthy person can be on the ibuprofen/acetaminophen combination?


    1. Name July 11, 2013

      Acetaminophen and Ibuprofen are cleared through different locations in the body, acetaminophen clearing through the liver, Ibuprofen through the kidney. I use this combo on a regular basis and find my patients respond more favourably then they do to T3’s. From my experience, it works much better as relieving pain for my patients.

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