Pharmacology.
Codeine is 3-methoxymorphine, a phenanthrene opioid with very low affinity for opioid receptors. Its analgesic activity appears to result from conversion to morphine. Poor metabolizers of debrisoquine/sparteine (approximately 7% of the Caucasian population) cannot convert appreciable amounts of codeine to morphine or obtain analgesia from codeine but are still subject to the same adverse effects.
Administration and Adult Dosage.
PO, SC, or IM for analgesia 15-60 mg q 4-6 hr.
PO or SC for antitussive action 10-20 mg q 4-6 hr, to a maximum of 120 mg/day. IV not recommended.
Special Populations.
Pediatric Dosage. PO, SC, or IM for analgesia (_1 yr) 0.5 mg/kg q 4-6 hr. PO for antitussive action (2-6 yr) 2.5-5 mg q 4-6 hr, to a maximum of 30 mg/day; (7-12 yr) 5-10 mg q 4-6 hr, to a maximum of 60mg/day; (>12 yr) same as adult dosage.
Geriatric Dosage. Same as adult dosage.
Other Conditions. Reduce initial dosage in debilitated patients or those with hypoxia or hypercapnia.
Dosage Forms.
Tab 15, 30, 60 mg; Inj 15, 30, 60 mg/mL; Oral Liquid 2, 2.4, 3mg/mL in various combinations. Formulated as phosphate or sulfate salt.
Patient Instructions.
This drug can cause drowsiness. Until the extent of this effect is known, use caution when driving, operating machinery, or performing other tasks requiring mental alertness. Avoid excessive concurrent use of alcohol and other drugs that cause drowsiness. Prolonged use of this drug can cause constipation, and concurrent use of a stool-softening or stimulant laxative may be helpful.
For moderate to severe pain (pain rating >5 on a 0-10 scale), you must take doses at regular intervals around the clock to anticipate and prevent pain. When the drug is taken at the correct interval and pain relief does not last for this period, use additional “rescue” doses of a short-acting drug to maintain pain relief. When more than 4 rescue doses are used in a day, contact the prescriber for a dosage increase.
Addiction does not occur when these drugs are used for legitimate painful conditions. Dependence, a condition in which the body may go through withdrawal when the drug is stopped suddenly, can occur with prolonged usage but can be managed by slowly decreasing the dosage when the drug is no longer needed.
Missed Doses. If you miss a dose, take it as soon as you remember. If it is about time for the next dose, take that dose only. Do not double the dose or take extra. Take subsequent doses at the same interval previously established for pain relief.
Pharmacokinetics.
Onset and Duration. PO, SC onset 15-30 min; IM peak analgesia 0.5-1 hr; duration (all routes) 4-6 hr.
Fate. Systemic availability averages 40% but with a wide range (12-84%), reflecting large variability in hepatic enzyme activity. A single PO 15 mg dose produces serum levels of 26-33 μg/L (82-104 nmol/L) in 2 hr and 13-22 μg/L (41-69 nmol/L) in 5 hr. The drug is 7% plasma protein bound. Vd is 2.6 ± 0.3L/kg; Cl is 0.66 ± 0.12 L/hr/kg. Metabolized in the liver to codeine-6-glucuronide, N-demethylated to norcodeine, and O-demethylated to morphine by genetic polymorphic CYP2D6. Codeine-6-glucuronide is the major metabolite, and norcodeine and morphine are minor metabolites, each accounting for approximately 10% of the dose. Accumulation of morphine occurs with repeated administration, resulting in a morphine:codeine AUC ratio of 0.29:1. Variation in the reported rates of codeine conversion to morphine may be related to the assays used, with much higher concentrations of morphine reported with radioimmunoassays than with HPLC or GC-MS. Primarily urinary excretion of inactive forms; 3-16% is excreted unchanged in urine.
t1⁄2. 2.9 ± 0.7 hr.
Adverse Reactions.
Sedation, dizziness, nausea, vomiting, constipation, and respiratory depression occur frequently. Dose-related signs of intoxication are miosis, drowsiness, decreased rate and depth of respiration, bradycardia, and hypotension. Dose-related adverse reactions in children are somnolence, ataxia, miosis, and vomiting at 3-5 mg/kg/day and respiratory depression at >5 mg/kg/day. Because hepatic glucuronidation is incomplete in infants, they are at particular risk for dose-related adverse effects.
Precautions.
Because it can cause severe hypotension, do not administer codeine phosphate IV.
Drug Interactions.
Potent CYP2D6 inhibitors (eg, quinidine, fluoxetine) can abolish the conversion to morphine and the pharmacologic effects of codeine.
Notes.
Codeine is no more effective than placebo in suppressing nighttime cough in children. The American Academy of Pediatrics recommends that parents be educated about the lack of proven antitussive effects and the potential risks of codeine-containing products because overdosage has been reported.
