II. Indications

  1. Opioid Analgesic
    1. Low efficacy and potential for significant adverse effects
  2. Cough Suppressant (Antitussive)
    1. Often abused (other agents are preferred)

III. Contraindications

  1. Breastfeeding women
  2. All children under age 12 years old
  3. Children ages 12 to 18 years old with additional risks
    1. Tonsillectomy or adenoidectomy
    2. Obesity
    3. Sleep Apnea
  4. References
    1. FDA Drug Safety Communication (4-20-2017)
      1. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm

IV. Preparations: Codeine 30 with Acetaminophen 300 tablets

  1. Dose: 1-2 tablets orally every 4-6 hours
  2. Avoid due to low efficacy and increased toxicity risk

V. Preparations: Acetaminophen with Codeine Elixir (not recommended)

  1. Risk of Opioid induced respiratory depression and other Overdose adverse effects (especially in children)
    1. Deaths in children have occurred with codeine Analgesics following Tonsillectomy and adenoidectomy
    2. Resulted in FDA black box warning in 2013
    3. (2013) Presc Lett 20(4): 21
    4. FDA Drug Safety Communication
      1. http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm
  2. Components
    1. Acetaminophen (120 mg/5ml Elixir)
    2. Codeine (12 mg/5ml Elixir)
  3. Dosing
    1. Age 3 to 6 years: 5 ml/dose every 4 hours prn
    2. Age 7 to 12 years: 10 ml/dose every 4 hours prn

VI. Efficacy

  1. Acetaminophen is a safe and effective Analgesic
  2. Codeine is no more effective than standard NSAIDs
    1. Naprosyn is as effective in post-operative pain
    2. Ouellette (1986) Curr Ther Res 39(5):839 [PubMed]
    3. Busquets (1988) Curr Ther Res 43(2):311 [PubMed]
  3. Codeine offers no significant benefit to Tylenol
    1. Zhang (1996) J Clin Pharm Ther 21(4):261 [PubMed]
  4. Adding Codeine to Tylenol increases adverse effects
    1. Jochimsem (1978) J Am Geriatr Soc 26(11):521 [PubMed]
  5. Codeine 60 mg equivalent to Aspirin 650 mg

VII. Precautions

  1. Weak Analgesic, with abuse potential and risk of death in ultrarapid CYP2D6 metabolizers
    1. Other agents are preferred: NSAIDs, Acetaminophen, short acting Morphine, Hydrocodone, Oxycodone
  2. Non-responders to Codeine: 10% of patients
    1. Lack endogenous enzyme to convert to Morphine
  3. Risk of Opioid induced respiratory depression and other Overdose adverse effects (especially in children)
    1. Associated with CYP2D6 ultrarapid metabolization (fast metabolizers) found in 5-30% (depending on ethnicity)
    2. Deaths in children have occurred with codeine Analgesics following Tonsillectomy and adenoidectomy
    3. Deaths likely related to ultrarapid metabolizers with underlying airway disorders (e.g. Sleep Apnea)
    4. Resulted in FDA black box warning in 2013
    5. AAP recommends no use of Codeine products under age 18 years old
    6. FDA Drug Safety Communication
      1. http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm

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Related Studies

Cost: Medications

codeine (on 2/23/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
CODEINE SULFATE 15 MG TABLET Generic $0.69 each
CODEINE SULFATE 30 MG TABLET Generic $0.68 each
CODEINE-GUAIFEN 10-100 MG/5 ML Generic OTC $0.02 per ml

Ontology: Codeine (C0009214)

Definition (NCI) A naturally occurring phenanthrene alkaloid and opioid agonist with analgesic, antidiarrheal and antitussive activities. Codeine mimics the actions of endogenous opioids by binding to the opioid receptors at many sites within the central nervous system (CNS). Stimulation of mu-subtype opioid receptors results in a decrease in the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline; in addition, the codeine metabolite morphine induces opening of G-protein-coupled inwardly rectifying potassium (GIRK) channels and blocks the opening of N-type voltage-gated calcium channels, resulting in hyperpolarization and reduced neuronal excitability. Stimulation of gut mu-subtype opioid receptors results in a reduction in intestinal motility and delayed intestinal transit times. Antitussive activity is mediated through codeine's action on the cough center in the medulla.
Definition (MSH) An opioid analgesic related to MORPHINE but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough.
Definition (CSP) opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects; also acts centrally to suppress cough.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D003061
SnomedCT 387494007, 85990009
LNC LP16093-4, MTHU004289
English N Methylmorphine, N-Methylmorphine, Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5alpha,6alpha)-, codeine (medication), methylmorphine, narcotics codeine, Codeine, Codeine [Chemical/Ingredient], codeine products, CODEINE, codeine, Methyl morphine, Methylmorphine, Codeine (product), Codeine (substance)
Swedish Kodein
Czech kodein
Finnish Kodeiini
Russian KODEIN, КОДЕИН
Japanese コデイン, 燐酸コデイン, メチルモルフィン, リン酸コデイン
Italian N-metilmorfina, Codeina
Croatian KODEIN
French N-Méthylmorphine, Codéine
Polish Metylomorfina, Kodeina
Spanish codeína (producto), codeína (sustancia), codeína, metilmorfina, Codeína
German Codein, Kodein
Portuguese Codeína

Ontology: Tylenol with Codeine (C0724034)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
English Tylenol with Codeine, codeine tylenol, tylenol with codeine, tylenol codeine

Ontology: Tylenol with Codeine #3 (C0876202)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
English tylenol 3 with codeine, tylenol with codeine #3, 3 codeine tylenol, Tylenol with Codeine #3

Ontology: Acetaminophen / Codeine (C2351132)

Definition (NCI) A synthetic p-aminophenol derivative combined with codeine, with anti-inflammatory and analgesic activites. Acetaminophen with codeine is used against inflammatory conditions, fever, and pain. Codeine is an opium alkaloid with analgesic properties. Acetaminophen appears to inhibit prostaglandin biosynthesis in the central nervous system and less in peripheral tissues.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C526278
SnomedCT 412556009, 346608002, 404870006
LNC LP36597-0, MTHU019762
English ACETAMINOPHEN/CODEINE, Paracetamol +codeine, Paracetamol +codiene, codeine phosphate + acetaminophen, codeine phosphate + acetaminophen (medication), narcotics acetaminophen + codeine, acetaminophen + codeine (medication), acetaminophen + codeine, acetaminophen-codeine, Acetaminophen-Codeine Phosphate, acetaminophen/codeine, co-codamol, acetaminophen - codeine, acetaminophen, codeine drug combination, cocodamol, Acetaminophen / Codeine, codeine acetaminophen phosphate, acetaminophen + codeine phosphate, acetaminophen codeine, co codamol, codeine paracetamol, acetaminophen codeine phosphate, paracetamol codeine phosphate, codeine acetaminophen, paracetamol codeine, Paracetamol + codeine phosphate, Acetaminophen + codeine phosphate (product), Acetaminophen + codeine phosphate, Co-codamol (product), Acetaminophen+Codeine, Acetaminophen #3, Acetaminophen/Codeine, Co-codamol (substance), Acetaminophen + codeine, Acetaminophen + codeine (product), Acetaminophen with Codeine, Paracetamol + codeine, Co-codamol
Spanish acetaminofeno + fosfato de codeína, paracetamol+codeína, paracetamol+codeína (producto), acetaminofeno + fosfato de codeína (producto), paracetamol + codeína (producto), paracetamol + codeína