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Codeine (Codeine Sulfate) - Description and Clinical Pharmacology



Chemically, codeine sulfate is morphinan-6-ol,7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl- (5α,6α)-, sulfate (2:1) (salt), trihydrate. Codeine sulfate trihydrate is a fine, white, crystalline powder which is soluble in water and insoluble in chloroform and ether. Its empirical formula is (C18H21NO3)2 • H2SO4 • 3H2O and its molecular weight is 750.85 g/mol.

Its structure is as follows:

Each 5 mL of oral solution contains 30 mg of codeine sulfate, USP and the following inactive ingredients: sorbitol, glycerin, ascorbic acid, citric acid, disodium edetate, sucralose, sodium benzoate, FD&C Yellow No. 6, FD&C Red No. 40, Orange Flavor XBF-709818, and water. The pH of the oral solution is 3.3.


Mechanism of Action

Codeine is an opioid agonist, related to morphine, but with less potent analgesic properties. Codeine is selective for the mu receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

Effects of the Central Nervous System (CNS): The principal therapeutic action of codeine is analgesia. Although the precise mechanism of the analgesic action is unknown, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression and perception of analgesic effects. Other CNS effects of codeine include anxiolysis, euphoria, and feelings of relaxation. Codeine causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. Codeine and other related opioids depress the cough reflex by direct effect on the cough center in the medulla. Codeine may also cause miosis.

Effects on the Gastrointestinal Tract and on Other Smooth Muscle: Gastric, biliary and pancreatic secretions may be decreased by codeine. Codeine also causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result may be constipation. Codeine can cause a marked increase in biliary tract pressure as a result of the spasm of the sphincter of Oddi. Codeine may also cause spasms of the sphincter of the urinary bladder.

Effects on the Cardiovasclar System: In therapeutic doses, codeine does not usually exert major effects on the cardiovascular system. Codeine produces peripheral vasodilation which may result in orthostatic hypotension and fainting. Release of histamine can occur, which may play a role in opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.

Endocrine System: Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagons in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Immune System: Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.


Codeine plasma concentrations do not correlate with codeine brain concentrations or relief of pain.

The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid use, age and general medical condition. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.


Absorption: Codeine, when administered as codeine sulfate, is absorbed from the gastrointestinal tract with maximum plasma concentration occurring 60 minutes post administration.

Food Effects: When 60 mg codeine sulfate was administered 30 minutes after ingesting a high fat/high calorie meal, there was no significant change in the rate and extent of absorption of codeine.

Steady-state: Administration of 15 mg codeine sulfate every four hours for 5 days resulted in steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine- 6-glucuronide (M6G) within 48 hours.

Distribution: Codeine has been reported to have an apparent volume of distribution of approximately 3-6 L/kg, indicating extensive distribution of the drug into tissues. Codeine has low plasma protein binding with about 7-25% of codeine bound to plasma proteins.

Metabolism: About 70-80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G, about 60%) and via O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDPglucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine (about 5-10%) and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine- 6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

Elimination: Approximately 90% of the total dose of codeine is excreted through the kidneys, of which approximately 10% is unchanged codeine. Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours.


Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Two year carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine (approximately 5 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) for two years.

Mutagenesis: Codeine was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.

Impairment of Fertility: No animal studies were conducted to evaluate the effect of codeine on male or female fertility.

Reproduction and Developmental Toxicology

Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits.

A study in hamsters administered 150 mg/kg twice daily of codeine (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) reported the development of cranial malformations (i.e., meningoencephalocele) in several fetuses examined; as well as the observation of increases in the percentage of resorptions per litter examined. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, doses of 73-360 mg/kg level (oral; approximately 2-8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis), in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/m2 basis) reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) of codeine during organogenesis.

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