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Codeine


Pronunciation

 (KOE deen)


Synonyms

 Codeine Phosphate; Codeine Sulfate; Methylmorphine


Generic Available

 Yes


Canadian Brand Names

 Codeine Contin®


Use

 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)


Lactation

 Enters breast milk/use caution (AAP rates "compatible")


Contraindications

 Hypersensitivity to codeine or any component of the formulation; pregnancy (prolonged use or high doses at term)


Warnings/Precautions

 An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients. Doses should be titrated to pain relief/prevention.

Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (morphine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone); respiratory diseases including asthma, emphysema, COPD, or severe liver or renal insufficiency; some preparations contain sulfites which may cause allergic reactions; tolerance or drug dependence may result from extended use

Not recommended for use for cough control in patients with a productive cough; not recommended as an antitussive for children <2 years of age; the elderly may be particularly susceptible to the CNS depressant and confusion as well as constipating effects of narcotics

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


Adverse Reactions

Frequency not defined: Increased AST, ALT

>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: Decreased urination, ureteral spasm

Hepatic: Increased LFTs

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


Overdosage/Toxicology

 Symptoms of overdose include CNS and respiratory depression, GI cramping, and constipation. Naloxone, 2 mg I.V. with repeat administration as necessary up to a total of 10 mg, can also be used to reverse toxic effects of the opiate.


Drug Interactions

 Substrate of CYP2D6 (major), 3A4 (minor); Inhibits CYP2D6 (weak)

CYP2D6 inhibitors: May decrease the effects of codeine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Decreased effect with cigarette smoking

Increased toxicity: CNS depressants, phenothiazines, TCAs, other narcotic analgesics, guanabenz, MAO inhibitors, neuromuscular blockers


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid or limit ethanol (may increase CNS depression). Watch for sedation.

Herb/Nutraceutical: St John's wort may decrease codeine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).


Stability

 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


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.


Monitoring Parameters

 Pain relief, respiratory and mental status, blood pressure, heart rate


Reference Range

 Therapeutic: Not established; Toxic: >1.1 mcg/mL


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. If you are breast-feeding, take medication immediately after breast-feeding or 3-4 hours prior to next feeding.


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


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


Oncology: Vesicant

 No


Dosage Forms

Injection, as phosphate: 15 mg/mL (2 mL); 30 mg/mL (2 mL) [contains sodium metabisulfite]

Solution, oral, as phosphate: 15 mg/5 mL (5 mL, 500 mL) [strawberry flavor]

Tablet, controlled release (Codeine Contin®) [not available in U.S.]: 50 mg, 100 mg, 150 mg, 200 mg

Tablet, as phosphate: 30 mg, 60 mg

Tablet, as sulfate: 15 mg, 30 mg, 60 mg


References

Cardan E, "Fatal Case of Codeine Poisoning," Lancet , 1981, 1(8233):1313.

Carr DB, Jacox AK, Chapman RC, et al, "Acute Pain Management," Guideline Technical Report, No. 1. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR Publication No. 95-0034. February 1995.

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.

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," 4th ed, Glenview, IL: American Pain Society, 1999.

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.


International Brand Names

 Actacode® (AU); Antitussivum B&uuml;rger® (DE); Bisoltus® (ES); Bromocodeina® (CY, EG, JO, KW, LB, MA, MT, SY); Bromophar® (BE); Bronchicum® (DE); Bronchodine® (BE); Bronchosedal Codeine® (BE); Codant® (IE); Codedrill® (FR); Codeina Fosfat-EEL® (RO); Codeina Fosfat® (RO); Codeina Fosforica® (RO); Codeina® (RO); Codeine Contin® (CA); Codeine Linctus® (GB); Codeine Phosphate® (AU, CY, NZ, RO); Codeine Phosphate® [inj.] (AU); Codeini phosphatis® (HR, SI, YU); Codein Knoll® (CH); Codein Kwizda® (AT); Codeinsaft von ct® (DE); Codein Slovakofarma® (CZ); Codeintropfen Ribbeck® (DE); Codeintropfen von ct® (DE); Codeinum phosphoricum Berlin-Chemie® (DE); Codeinum Phosphoricum® (PL); Codeisan® (ES); Codeisan Jarabe® (ES); Codelin® (RO); Codenfan® (FR); Codical® (IL); Codicaps® (DE); Codicompren® (DE); Codinex® (IE); codi OPT® (DE); Codipertussin® (AT, DE); Codipront mono® (DE, LU); Codol® (PT); Dicton® (LU); Eulyptan® (BE); Farmacod® (RO); Fludan Codeina® (ES); Fosfat de Codeina® (RO); Galcodine® (GB); Glottyl® (BE, LU); Histaverin® (ES); Kaodene® (GB); Kodein Dak® (DK); Kodein fosfat® (YU); Kodein® (NO); Kodein Recip® (SE); Kodein SAD® (DK); Lennon Codeine® (ZA); Makatussin® (CH); Neo-Codion® [Sirup] (DE, RU); Optipect® (DE); Padéryl® (FR); Perduretas Codeina® (ES); Pulmocodeina® (EC); Rekod® (IL); Titretta® (DE); Toseina® (ES); Toularynx® (BE); Tricodein® (CY, EG, JO, KW, LB); Tricodein Solco® (AT, CH); Tryasol® (DE); Tussamag® (RO); Tussimag Codein-Tropfen® (AT); Tussoret® (DE)


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