API: Codeine

What Is Codeine and How Does It Work?

Codeine, also known as 3-methylmorphine, is a phenanthrene derivative with analgesic, narcotic, and antitussive properties that works as an opioid receptor agonist.1 It selectively activates the mu opioid receptor in the central nervous system, which leads to the inhibition of nerve signals that transmit pain.2 Codeine can be converted to morphine, another opioid agonist, by the cytochrome P450 enzyme CYP2D6 in the liver, which increases its analgesic effects because morphine binds to the mu opioid receptor with greater affinity than codeine. Codeine also works as an anti-diarrheal by acting on opioid receptors in the smooth muscles of the intestines to prevent peristaltic contractions.3 The antitussive effects of codeine are mediated by its ability to suppress the cough reflex by decreasing activity in the medullary cough center.4


  • Pain: Codeine provides effective relief for mild to moderate pain. It is often combined with other pain relievers, such as acetaminophen, in order to treat more severe pain.
  • Cough: Codeine works as an antitussive by suppressing the cough reflex.
  • Diarrhea: Codeine can be taken alone or in combination with acetaminophen in order to provide short-term relief for severe cases of diarrhea.

Side Effects and Drug Interactions

Common side effects of codeine include:

  • Drowsiness
  • Dizziness
  • Shortness of breath
  • Constipation
  • Nausea
  • Vomiting
  • Sweating
  • Itching or rash

Patients should contact a doctor immediately if they experience serious side effects, such as shallow breathing, irregular heartbeat, fainting, confusion, extreme mood swings, seizure, severe drowsiness, or urinary retention.5 It is also important to note that codeine can be habit-forming if it is used regularly for extended periods of time. Patients should always follow a doctor’s instructions when starting or stopping codeine treatment.6

There are several classes of drugs that interact with codeine7:

  • Central Nervous System (CNS) Depressants: When codeine is taken alongside other CNS depressants, the effects are additive, which can lead to respiratory depression, hypotension, severe sedation, or even coma. Patients should therefore exercise caution when taking codeine alongside other opioid drugs, antihistamines, antipsychotics, or anti-anxiety drugs. Most doctors recommend that patients avoid alcohol while taking codeine.
  • Mixed Agonist/Antagonist Opioid Analgesics: Pure opioid analgesics like codeine should not be taken in combination with mixed antagonist/antagonist analgesics such as pentazocine, nalbuphine, and butorphanol. Doing so can suppress the drug’s analgesic effects and cause the patient to experience withdrawal symptoms.
  • Anticholinergics: Taking anticholinergic drugs alongside codeine can lead to urinary retention or severe constipation.
  • Antidepressants: MAO inhibitors and tricyclic antidepressants can increase the effects of codeine. Codeine should not be taken within 14 days of taking MAO inhibitors.

Latest News and Research

Codeine was discovered in 1832 by French chemist Pierre Robiquet. Codeine is found in the latex of opium that is prepared from unripe pods of the opium poppy. It can also be synthesized from morphine or from coal tar.8 Codeine was initially used primarily in cough syrup, but today, it is more commonly prescribed for pain. It is the most widely used opioid drug in the world and is considered to be safest opioid analgesic.9 Codeine is also included on the WHO Model List of Essential Medicines for a basic health system.

Because of its potential for abuse leading to addiction, codeine is classified as a Schedule II Controlled Substance in the United States. In April 2015, the European Medicines Agency (EMA) announced that codeine should not be used to treat cough in children under 12, citing safety concerns about serious respiratory side effects. The EMA also recommended against using it to treat adolescents from 12 to 18 years who have respiratory problems such as asthma. In July 2015, the FDA announced that it would also evaluate the safety of using codeine-containing cough medicine for children under 18, but the results of the investigation have not yet been released.10

Codeine is an increasingly popular recreational drug and there is a growing black market for codeine-containing cough syrup.11 The prescription cough syrup Promethazine Codeine is mixed with Sprite and Jolly Rancher candies to create “lean,” a drink that originated in Houston, Texas.

Buying Guide

Many compound pharmacists prefer to treat pain with NSAIDs such as Diclofenac Sodium, Flurbiprofen, Ketoprofen, Meloxicam, and Piroxicam, which can be more effective than codeine and do not put patients at risk of opioid addiction. For diarrhea, many pharmacists prefer Loperamide, which can safely be used to treat both acute and chronic diarrhea. Please find more information about our Bulk APIs here.

Show 11 footnotes

  1. “Codeine,” 2016, https://pubchem.ncbi.nlm.nih.gov/compound/codeine
  2. “Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior,” December 2011, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698859/
  3. “Codeine Phosphate Tablets,” February 16, 2015, http://www.netdoctor.co.uk/medicines/aches-and-pains/a6438/codeine-phosphate-tablets/
  4. “Codeine Sulfate,” May 26, 2011, http://www.rxlist.com/codeine-sulfate-drug/clinical-pharmacology.htm
  5. “Codeine Sulfate Side Effects Center,” June 9, 2015, http://www.rxlist.com/codeine-sulfate-side-effects-drug-center.htm
  6. “Codeine,” March 22, 2016, https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682065.html
  7. “Interactions,” May 26, 2011, http://www.rxlist.com/codeine-sulfate-drug/side-effects-interactions.htm
  8. “History of Codeine,” 2016, http://www.codeine.com/about/history-of-codeine.html
  9. “History of Codeine,” 2016, http://www.narconon.org/drug-information/codeine-history.html
  10. “FDA Drug Safety Communication: FDA evaluating the potential risks of using codeine cough-and-cold medicines in children,” July 1, 2015, http://www.fda.gov/Drugs/DrugSafety/ucm453125.htm
  11. “Inside Florida’s Codeine Black Market,” July 6, 2016, http://www.vice.com/read/purple-drank-florida-lean-codeine-dirty-sprite-black-market