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codeine

Opiate analgesic. Antitussive. DEA-controlled substance: class 2. Indications: 1) treatment of mild to moderate acute pain-related syndromes* - less effective for chronic pain than morphine or oxycodone [7] - headache [10] 2) cough - not recommended for children with cough due to upper respiratory tract infection [11]* 3) treatment of diarrhea * not recommended for treatment of cough or pain in children [12] Contraindications: Caution: 1) patients with respiratory disorders including: a) asthma b) COPD 2) severe hepatic insufficiency 3) severe renal insufficiency 4) breastfeeding [14] 5) children: opioids are not recommended in children [13,14] Dosage: 1) 0.5 mg/kg up to 15-60 mg PO/IM g4-6 hours. 2) no increase in pain management > 200 mg/day, but increased adverse effects 3) cough 15 mg PO every 4-6 hours PRN 4) opiate activity: 130 mg codeine PO = 30 mg morphine PO Tabs: (codeine sulfate) 15, 30, 60 mg. Tabs: (codeine phosphate) 30, 60 mg. Injection: (codeine phosphate) 30 & 60 mg/mL (1 mL). Pharmacokinetics: 1) well absorbed orally 2) onset of action 15-30 minutes 3) peak action : 60-90 minutes 4) duration of action is 4-6 hours 5) metabolized by liver by cyt P450 2D6, excreted by kidney 6) partially metabolized to morphine & norcodeine - genetic variations can lead to excessive morphine levels [13] 7) codeine itself has little analgesic effect 8) 1/2life 3 hours Adverse effects: 1) common (> 10%) - CNS stimulation, loss of smell & taste, chronic rhinitis, nasal congestion 2) less common (1-10%) - skin rash, hives, histamine release, burning at injection site, shortness of breath, decreased urination, ureteral spasm, blurred vision, dizziness, lightheadedness, false sense of well being, restlessness, paradoxical CNS stimulation, confusion, malaise, weakness, headache, anorexia, nausea/vomiting, hypotension, tachycardia or bradycardia 3) uncommon (< 1%) - convulsions, hallucinations, depression, muscle rigidity, paralytic ileus, trembling, biliary spasm, stomach cramps, nightmares, insomnia 4) other [3] - respiratory depression: dose & tolerance-dependent - drowsiness - tolerance - dependence: physical & psychological - constipation - increased risk of cardiovascular events relative to hydrocodone after 180 days of exposure [7] - increased risk of all-cause mortality after 180 days of exposure [7] - deaths reported in children, aged 2 to 5 years, given typical doses of morphine; apparently, the chidren were "ultra-rapid metabolizers" resulting in rapid & excessive levels of morphine in the circulation [9]; a boxed warning Drug interactions: 1) benzodiazepines, barbiturates & alcohol can increase CNS depressant effects 2) naloxone is a direct opiate antagonist 3) tricyclic antidepressants may potentiate adverse effects of codeine 4) any pharmaceutical agent that inhibits cyt P450 2D6 can increase codeine levels Laboratory: 1) specimen: a) serum; stable for 9 months at -20 degrees C b) urine; stable for 9 months at -20 degrees C 2) methods: a) serum: GLC, GC-MS, RIA, EIA, HPLC b) urine: FPIA 3) CYP2D6 genotyping may be indicated 4) Labs with Loincs - codeine in specimen - codeine in gastric fluid - codeine in hair - codeine in meconium - codeine in saliva - codeine in serum/plasma/blood - codeine in blood - codeine in serum/plasma - codeine free in serum/plasma - codeine in stool - codeine free in stool - codeine in urine Mechanism of action: 1) alters perception of pain at the level of the spinal cord & higher levels of the CNS 2) alters emotional response to pain 3) cough suppressant effects are due to direct action on the cough centers of the medulla Notes: - codeine is available in over-the counter cough medicines in 28 states [13]

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)

General

amine antitussive agent morphinan opiate opioid receptor agonist (narcotic)

Properties

SIZE: MW = 308 G/M MISC-INFO: elimination route LIVER MP 122-124 C {[C18} C18 H21 N O3 1/2life 2.5-3 HOURS therapeutic-range 10-100 NG/ML toxic-range >200 NG/ML protein-binding 7-25% pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. Merck Index 11th ed #8116
  2. Research Biochemicals International 1993-94 catalog
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  6. Prescriber's Letter 13(7): 2006 Codeine and breastfeeding Detail-Document#: 220706 (subscription needed) http://www.prescribersletter.com
  7. Solomon DH et al. The comparative safety of opioids for nonmalignant pain in older adults. Arch Intern Med 2010 Dec 13/27; 170:1979. PMID: 21149754 - Becker WC, O'Connor PG. The safety of opioid analgesics in the elderly: New data raise new concerns: Comment on "The Comparative Safety of Opioids for Nonmalignant Pain in Older Adults". Arch Intern Med 2010; 170(22):1986-1988. PMID: 21149755 - Papaleontiou M, Henderson CR, Turner BJ, et al. Outcomes associated with opioid use in the treatment of chronic noncancer pain in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 2010; 58(7):1353-1369. Epub 2010 Jun 1. PMID: 20533971
  8. Prescriber's Letter 19(6): 2012 Codeine Safety in Kids Detail-Document#: 280608 (subscription needed) http://www.prescribersletter.com
  9. FDA MedWatch, August 15, 2012 Codeine Use in Certain Children After Tonsillectomy and/or Adenoidectomy: Drug Safety Communication - Risk of Rare, But Life-Threatening Adverse Events or Death http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm315627.htm
  10. Deprecated Reference
  11. Kaiser SV et al National Patterns of Codeine Prescriptions for Children in the Emergency Department. Pediatrics. April 21, 2014 PMID: 24753533 http://pediatrics.aappublications.org/content/early/2014/04/16/peds.2013-3171.full.pdf+html - Woolf AD and Greco C Why Can't We Retire Codeine? Pediatrics. April 21, 2014 PMID: 24753529 http://pediatrics.aappublications.org/content/early/2014/04/16/peds.2013-4057.full.pdf+html
  12. FDA Briefing Document. Joint Pulmonary - Allergy Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Meeting. December 10, 2015 http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM475975.pdf - 2015 Meeting Materials, Pulmonary-Allergy Drugs Advisory Committee http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/ucm433815.htm
  13. Tobias JD, Green TP, Cote CJ SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE, COMMITTEE ON DRUGS. Codeine: Time To Say "No" Pediatrics Sep 2016, e20151648 PMID: 27647717
  14. FDA Safety Alert. 04/20/2017 Codeine and Tramadol Medicines: Drug Safety Communication - Restricting Use in Children, Recommending Against Use in Breastfeeding Women. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm554029.htm

Component-of

acetaminophen/aspirin/caffeine/codeine/salicylamide acetaminophen/aspirin/codeine acetaminophen/butalbital/caffeine/codeine (Fioricet with Codeine) acetaminophen/chlorpheniramine/codeine acetaminophen/chlorpheniramine/codeine/phenylephrine acetaminophen/codeine (Tylenol with Codeine) acetaminophen/codeine/guaifenesin/phenylephrine acetaminophen/codeine/guaifenesin/pseudoephedrine acetaminophen/codeine/magnesium salicylate/phenyltoloxamine acetaminophen/codeine/salicylate aspirin/butalbital/caffeine/codeine (Fiorinal with Codeine) aspirin/carisoprodol/codeine (Soma Compound with Codeine) aspirin/codeine (Empirin with Codeine) aspirin/codeine/phosphate bromodiphenhydramine/codeine brompheniramine/codeine brompheniramine/codeine/guaifenesin brompheniramine/codeine/phenylephrine brompheniramine/codeine/phenylpropanolamine brompheniramine/codeine/pseudoephedrine caffeine/codeine/pheniramine/phenylephrine/salicylate calcium iodide/codeine chlorcyclizine/codeine chlorcyclizine/codeine/phenylephrine chlorcyclizine/codeine/pseudoephedrine chlorpheniramine/codeine chlorpheniramine/codeine/phenylephrine chlorpheniramine/codeine/phenylephrine/potassium iodide chlorpheniramine/codeine/pseudoephedrine (Dihistine DH, Novahistine DH) codeine/dexbrompheniramine/pseudoephedrine codeine/dexchlorpheniramine/phenylephrine codeine/dexchlorpheniramine/phenylephrine/phosphate codeine/diethylcarbamazine/guaifenesin/pseudoephedrine codeine/diphenhydramine/phenylephrine codeine/diphenhydramine/phenylephrine/phosphate codeine/guaifenesin (Robitussin AC) codeine/guaifenesin/phenylephrine codeine/guaifenesin/phenylephrine/phosphate codeine/guaifenesin/phosphate codeine/guaifenesin/phosphate/pseudoephedrine codeine/guaifenesin/promethazine codeine/guaifenesin/pseudoephedrine (Robitussin DAC) codeine/phenylephrine codeine/phenylephrine/phosphate codeine/phenylephrine/phosphate/promethazine codeine/phenylephrine/phosphate/pyrilamine codeine/phenylephrine/promethazine (Phenergan with phenylephrine & codeine) codeine/phenylephrine/pyrilamine codeine/phenylephrine/triprolidine codeine/phosphate/promethazine codeine/phosphate/pseudoephedrine codeine/phosphate/pseudoephedrine/pyrilamine codeine/phosphate/pseudoephedrine/triprolidine codeine/promethazine (Phenergan with codeine) codeine/pseudoephedrine codeine/pseudoephedrine/pyrilamine codeine/pseudoephedrine/triprolidine (Actifed with codeine) codeine/pyrilamine