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Medication Safety Issues
Sound-alike/look-alike issues:
Codeine may be confused with Cardene®, Cophene®, Cordran®, iodine, Lodine®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(KOE deen)
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of mild-to-moderate pain; antitussive in lower doses; dextromethorphan has equivalent antitussive activity but has much lower toxicity in accidental overdose
Use: Dental
Treatment of postoperative pain
Restrictions
C-II
Pregnancy Risk Factor
C/D (prolonged use or high doses at term)
Pregnancy Considerations
Animal reproduction studies have not been conducted. Neonatal abstinence syndrome (NAS) has been observed in the newborn following maternal use of codeine during pregnancy. Symptoms of opiate withdrawal may include excessive crying, diarrhea, fever, hyperreflexia, irritability, tremors, or vomiting. Perinatal stroke has also been reported.
Lactation
Enters breast milk/use caution (AAP rates “compatible”)
Breast-Feeding Considerations
Codeine and its metabolite (morphine) are found in breast milk and can be detected in the serum of nursing infants. The relative dose to a nursing infant has been calculated to be ~1% of the weight-adjusted maternal dose. Higher levels of morphine may be found in the breast milk of lactating mothers who are “ultra-rapid metabolizers” of codeine; patients with two or more copies of the variant CYP2D6*2 allele may have extensive conversion to morphine and thus increased opioid-mediated effects. In one case, excessively high serum concentrations of morphine were reported in a breastfed infant following maternal use of acetaminophen with codeine. The mother was later found to be an “ultra-rapid metabolizer” of codeine; symptoms in the infant included feeding difficulty and lethargy, followed by death. Because exposure to the nursing infant is generally low, the AAP considers codeine to be “usually compatible with breast-feeding”. However, caution should be used since most persons are not aware if they have the genotype resulting in “ultra-rapid metabolizer” status. When codeine is used in breast-feeding women, it is recommended to use the lowest dose for the shortest duration of time and observe the infant for increased sleepiness, difficulty in feeding or breathing, or limpness.
Contraindications
Hypersensitivity to codeine or any component of the formulation; pregnancy (prolonged use or high doses at term)
Warnings/Precautions
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction; acute pancreatitis may cause constriction of sphincter of Oddi.
• CNS depression/coma: Use with caution in patients with CNS depression or coma.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Renal impairment: Use with caution in patients with severe renal impairment.
• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• CYP2D6 “ultra-rapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects.
• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose.
• Pediatrics: Safety and efficacy have not been established for antitussive use in children <2 years of age.
Dosage form specific issues:
• Sulfites: Some preparations contain sulfites which may cause allergic reactions.
Other warnings/precautions:
• Cough control: Not recommended for use for cough control in patients with a productive cough.
• I.V. administration: Not approved for I.V. administration (although this route has been used clinically). If given intravenously, must be given slowly and the patient should be lying down. Rapid intravenous administration of narcotics may increase the incidence of serious adverse effects, in part due to limited opportunity to assess response prior to administration of the full dose. Access to respiratory support should be immediately available.
• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.
Adverse Reactions
Frequency not defined: AST/ALT increased
>10%:
Central nervous system: Drowsiness
Gastrointestinal: Constipation
1% to 10%:
Cardiovascular: Tachycardia or bradycardia, hypotension
Central nervous system: Dizziness, lightheadedness, false feeling of well being, malaise, headache, restlessness, paradoxical CNS stimulation, confusion
Dermatologic: Rash, urticaria
Gastrointestinal: Xerostomia, anorexia, nausea, vomiting
Genitourinary: Urination decreased, ureteral spasm
Hepatic: LFTs increased
Local: Burning at injection site
Neuromuscular & skeletal: Weakness
Ocular: Blurred vision
Respiratory: Dyspnea
Miscellaneous: Histamine release
<1%: Convulsions, hallucinations, mental depression, nightmares, insomnia, paralytic ileus, biliary spasm, stomach cramps, muscle rigidity, trembling
Metabolism/Transport Effects
Substrate of CYP2D6 (major), 3A4 (minor); Inhibits CYP2D6 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy
Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk D: Consider therapy modification
Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy
Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol (may increase CNS depression).
Herb/Nutraceutical: St John's wort may decrease codeine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Store injection between 15°C to 30°C; avoid freezing. Do not use if injection is discolored or contains a precipitate. Protect injection from light.
Compatibility
Compatibility in syringe: Compatible: Glycopyrrolate, hydroxyzine.
Mechanism of Action
Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough supression by direct central action in the medulla; produces generalized CNS depression
Pharmacodynamics/Kinetics
Onset of action: Oral: 0.5-1 hour; I.M.: 10-30 minutes
Peak effect: Oral: 1-1.5 hours; I.M.: 0.5-1 hour
Duration: 4-6 hours
Absorption: Oral: Adequate
Distribution: Crosses placenta; enters breast milk
Protein binding: 7%
Metabolism: Hepatic to morphine (active)
Half-life elimination: 2.5-3.5 hours
Excretion: Urine (3% to 16% as unchanged drug, norcodeine, and free and conjugated morphine)
Dosage
Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention. Doses >1.5 mg/kg body weight are not recommended.
Analgesic:
Children: Oral, I.M., SubQ: 0.5-1 mg/kg/dose every 4-6 hours as needed; maximum: 60 mg/dose
Adults:
Oral: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: 15-120 mg every 4-6 hours as needed
Oral, controlled release formulation (Codeine Contin®, not available in U.S.): 50-300 mg every 12 hours. Note: A patient's codeine requirement should be established using prompt release formulations; conversion to long acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
I.M., SubQ: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: 15-120 mg every 4-6 hours as needed; more frequent dosing may be needed
Antitussive: Oral (for nonproductive cough):
Children: 1-1.5 mg/kg/day in divided doses every 4-6 hours as needed: Alternative dose according to age:
2-6 years: 2.5-5 mg every 4-6 hours as needed; maximum: 30 mg/day
6-12 years: 5-10 mg every 4-6 hours as needed; maximum: 60 mg/day
Adults: 10-20 mg/dose every 4-6 hours as needed; maximum: 120 mg/day
Dosing adjustment in renal impairment:
Clcr 10-50 mL/minute: Administer 75% of dose
Clcr <10 mL/minute: Administer 50% of dose
Dosing adjustment in hepatic impairment: Probably necessary in hepatic insufficiency
Dental Usual Dosing
Postoperative pain: Adults: Oral: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: 15-120 mg every 4-6 hours as needed
Administration: I.V. Detail
pH: 3-6 (codeine phosphate)
Monitoring Parameters
Pain relief, respiratory and mental status, blood pressure, heart rate
Reference Range
Therapeutic: Not established; Toxic: >1.1 mcg/mL
Test Interactions
Some quinolones may produce a false-positive urine screening result for opiates using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opiate screens by more specific methods should be considered.
Patient Education
If self-administered, use exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially sedatives, tranquilizers, antihistamines, or pain medications) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause dizziness, drowsiness, confusion, agitation, impaired coordination, or blurred vision (use caution when driving, climbing stairs, or changing position - rising from sitting or lying to standing, or when engaging in tasks requiring alertness until response to drug is known); nausea or vomiting, or loss of appetite (frequent mouth care, small frequent meals, sucking lozenges, or chewing gum may help); or constipation (increased exercise, fluids, fruit, or fiber may help; if unresolved, consult prescriber about use of stool softeners). Report confusion, insomnia, excessive nervousness, excessive sedation or drowsiness, or shakiness; acute GI upset; respiratory difficulty or shortness of breath; facial flushing, rapid heartbeat, or palpitations; urinary difficulty; unusual muscle weakness; or vision changes. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if you are breast-feeding.
Geriatric Considerations
The elderly may be particularly susceptible to CNS depression and confusion as well as the constipating effects of narcotics.
Anesthesia and Critical Care Concerns/Other Considerations
The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) recommend against using codeine because of its lack of potency, histamine release (may cause hypotension), potential accumulation of active metabolites. The guidelines recommend fentanyl in patients who need immediate pain relief because of its rapid onset of action; fentanyl or hydromorphone is preferred in patients who are hypotensive or have renal dysfunction. Morphine or hydromorphone is recommended for intermittent, scheduled therapy. Both have a longer duration of action requiring less frequent administration.
Cardiovascular Considerations
Codeine may cause constipation which may be problematic in patients with unstable angina, and patients after myocardial infarction. The hemodynamic responses to valsalva-like maneuvers due to straining may have adverse cardiovascular consequences in patients with critical coronary artery disease.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported (see Dental Comment)
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
It is recommended that codeine not be used as the sole entity for analgesia because of moderate efficacy along with relatively high incidence of nausea, sedation, and constipation. In addition, codeine has some narcotic addiction liability. Codeine in combination with acetaminophen or aspirin is recommended. Maximum effective analgesic dose of codeine is 60 mg (1 grain). Beyond 60 mg increases respiratory depression only. Sodium thiosulfate is an effective chemical antidote for codeine poisoning.
Mental Health: Effects on Mental Status
Drowsiness is common; may cause euphoria, confusion, insomnia, hallucinations, or depression
Mental Health: Effects on Psychiatric Treatment
Concurrent use with psychotropics may produce additive toxicity; concurrent use with fluoxetine or paroxetine may result in loss of pain control
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for possible additive or adverse interactions. Monitor for effectiveness of pain relief, for signs of overdose, vital signs and CNS status, and adverse reactions at beginning of therapy and at regular intervals with long-term use. May cause physical and/or psychological dependence. For inpatients, implement safety measures. Assess knowledge/teach patient appropriate use (if self-administered). Teach patient to monitor for adverse reactions, adverse reactions to report, and appropriate interventions to reduce side effects.
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Injection, as phosphate: 15 mg/mL (2 mL); 30 mg/mL (2 mL) [contains sodium metabisulfite]
Powder, for prescription compounding: 10 g, 25 g
Tablet, as phosphate: 30 mg, 60 mg
Tablet, as sulfate: 15 mg, 30 mg, 60 mg
Tablet, controlled release (Codeine Contin®) [CAN]: 50 mg, 100 mg, 150 mg, 200 mg [not available in U.S.]
References
Cardan E, “Fatal Case of Codeine Poisoning,” Lancet, 1981, 1(8233):1313.
de Groot AC and Conemans J, “Allergic Urticarial Rash From Oral Codeine,” Contact Dermatitis, 1986, 14(4):209-14.
Desjardins PJ, Cooper SA, Gallegos TL, et al, “The Relative Analgesic Efficacy of Propiram Fumarate, Codeine, Aspirin, and Placebo in Postimpaction Dental Pain,” J Clin Pharmacol, 1984, 24(1):35-42.
“Drugs for Pain,” Med Lett Drugs Ther, 2000, 42(1085):73-8.
Ferrell BA, “Pain Management in Elderly People,” J Am Geriatr Soc, 1991, 39(1):64-73.
Forbes JA, Keller CK, Smith JW, et al, “Analgesic Effect of Naproxen Sodium, Codeine, a Naproxen-Codeine Combination and Aspirin on the Postoperative Pain of Oral Surgery,” Pharmacotherapy, 1986, 6(5):211-8.
Ivey HH and Kattwinkel J, “Danger of Actifed-C,” Pediatrics, 1976, 57(1):164-5.
Jacobi J, Fraser GL, Coursin DB, et al, “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult,” Crit Care Med, 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.
Kaiko RF, Wallenstein SL, Rogers AG, et al, “Narcotics in the Elderly,” Med Clin North Am, 1982, 66(5):1079-89.
Khan K and Chang J, “Neonatal Abstinence Syndrome Due to Codeine,” Arch Dis Child Fetal Neonatal Ed, 1997; 76(1): F59-60.
Koren G, Caims J, Chitayat D, et al, “Pharmacogenetics of Morphine Poisoning in a Breastfed Neonate of a Codeine-Prescribed Mother,” Lancet, 2006, 368(9536):704.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
“Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain,” 5th ed, Glenview, IL: American Pain Society, 2003.
Reynolds EW, Riel-Romero RM, and Bada HS, “Neonatal Abstinence Syndrome and Cerebral Infarction Following Maternal Codeine Use During Pregnancy,” Clin Pediatr, 2007, 46(7):639-45.
Spigset O and Hagg S, “Analgesics and Breast-Feeding: Safety Considerations,” Paediatr Drugs, 2000, 2(3):223-38.
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, “Public Health Advisory: Use of Codeine by Some Breastfeeding Mothers May Lead to Life-Threatening Side Effects in Nursing Babies.” available at http://www.fda.gov/cder/drug/advisory/codeine.htm
Wilkins D, Rollins DE, Seaman J, et al, “Quantitative Determination of Codeine and Its Major Metabolites in Human Hair by Gas Chromatography - Positive Ion Chemical Ionization Mass Spectrometry: A Clinical Application,” J Anal Toxicol, 1995, 19(5):269-74.
Zacher JL and Givone DM, “False-Positive Urine Opiate Screening Associated With Fluoroquinolone Use,” Ann Pharmacother, 2004, 38:1525-28.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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