Codeine (Analgesic) (Monograph)

Drug class: Opiate Agonists
VA class: CN101
CAS number: 41444-62-6

Medically reviewed by Drugs.com on Apr 19, 2023. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for codeine to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of codeine and consists of the following: medication guide and elements to assure safe use. See https://www.accessdata.fda.gov/scripts/cder/rems/.

FDA drug safety communication (4/13/2023): As part of its ongoing efforts to address the nation’s opioid crisis, FDA is requiring several updates to the prescribing information of opioid pain medicines. The changes are being made to provide additional guidance for safe use of these drugs while also recognizing the important benefits when used appropriately. The changes apply to both immediate-release (IR) and extended-release/long-acting preparations (ER/LA).
Updates to the IR opioids state that these drugs should not be used for an extended period unless the pain remains severe enough to require an opioid pain medicine and alternative treatment options are insufficient, and that many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
Updates to the ER/LA opioids recommend that these drugs be reserved for severe and persistent pain requiring an extended period of treatment with a daily opioid pain medicine and for which alternative treatment options are inadequate.
A new warning is being added about opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid pain medicines. This includes information describing the symptoms that differentiate OIH from opioid tolerance and withdrawal.
Information in the boxed warning for all IR and ER/LA opioid pain medicines will be updated and reordered to elevate the importance of warnings concerning life-threatening respiratory depression, and risks associated with using opioid pain medicines in conjunction with benzodiazepines or other medicines that depress the central nervous system (CNS).
Other changes will also be required in various other sections of the prescribing information to educate clinicians, patients, and caregivers about the risks of these drugs.

Introduction

Codeine is a phenanthrene-derivative opiate agonist.

Uses for Codeine (Analgesic)

Codeine is a mild analgesic used in the relief of mild to moderately severe pain that is not relieved by a nonopiate analgesic. Because of differing mechanisms of action, codeine and aspirin or acetaminophen in combination probably produce additive analgesic effects. Combinations containing codeine, aspirin, and caffeine are effective but produce no more analgesia than a combination of aspirin and codeine.

For use of codeine as an antitussive agent, see 48:08.

Codeine (Analgesic) Dosage and Administration

Administration

Codeine sulfate and codeine phosphate are administered orally.

Dosage

Codeine salts should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient. Reduced dosage is indicated in poor-risk patients and in very old patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.

When opiate analgesics are administered in fixed combination with nonopiate analgesics, the opiate dosage may be limited by the nonopiate component. Because commercially available preparations contain codeine and nonopiate analgesics in various fixed ratios and because these nonopiate analgesics also are available in many other prescription and OTC preparations, care should be taken to ensure that therapy is not duplicated and that dosage of the nonopiate drug does not exceed maximum recommended dosages.

The initial dosage must be individualized, taking into account the patient’s prior opiate use; concurrent drug therapy; degree of opiate tolerance; medical condition; type and severity of pain; and risk factors for addiction, abuse, and misuse.

For the relief of mild to moderate pain in adults, the usual oral dosage of codeine phosphate or codeine sulfate is 30 mg every 4 hours as necessary; the usual dose range is 15–60 mg. Adult dosage should not exceed 360 mg daily.

Children may receive 3 mg/kg or 100 mg/m² daily in 6 divided doses. Alternatively, children may be given 0.5 mg/kg or 15 mg/m² every 4–6 hours. (See Cautions: Pediatric Precautions.)

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days). When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 330 mg or more of codeine phosphate or codeine sulfate daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.

Cautions for Codeine (Analgesic)

Precautions and Contraindications

Codeine shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed.

Codeine is contraindicated in children younger than 12 years of age for the management of pain and in pediatric patients younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy. In addition, FDA states that use of codeine for the management of pain is not recommended in pediatric patients 12–18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function. (See Cautions: Pediatric Precautions.)

Individuals who are ultrarapid metabolizers of cytochrome P-450 (CYP) 2D6 substrates are likely to have higher than expected serum concentrations of morphine, the active metabolite of codeine; therefore, FDA states that codeine should not be used in such patients. (See Pharmacokinetics: Pharmacogenomics.)

FDA also states that use of codeine is not recommended in nursing women, especially those who have evidence of ultrarapid metabolism of CYP2D6 substrates. Serious adverse events (e.g., excessive sedation, difficulty nursing, respiratory depression), including death, have been reported in nursing infants exposed to codeine. One case of opiate toxicity resulting in neonatal death has been reported in the nursing infant of a woman receiving codeine; genetic testing of the woman indicated that she was an ultrarapid metabolizer of codeine. (See Pharmacokinetics: Pharmacogenomics.) Higher than expected concentrations of morphine were found in breast milk and in the blood of the infant. Somnolence also has been reported more frequently in nursing infants whose mothers received codeine in combination with acetaminophen compared with those whose mothers received acetaminophen alone; evidence of ultrarapid metabolism of CYP2D6 substrates was identified in some of these women. Concentrations of morphine in breast milk are low and dose dependent in women who are normal metabolizers of codeine. Although not routinely used in clinical practice, FDA-approved tests (e.g., AmpliChip CYP450 Test) are available to identify an individual’s CYP2D6 genotype. However, testing alone may not adequately predict the risk of adverse reactions. Infants exposed to codeine through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia). If such manifestations occur, caregivers should seek immediate medical treatment for the infant.

When preparations containing codeine in fixed combination with other drugs are administered, the cautions, precautions, and contraindications applicable to each ingredient must be considered.

Pediatric Precautions

Pediatric patients receiving codeine for the management of pain, especially those who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates, are at increased risk of respiratory depression. Serious adverse events, including deaths, have been reported during postmarketing experience in pediatric patients receiving codeine. Between January 1969 and May 2015, the FDA Adverse Event Reporting System (AERS) received 64 reports of respiratory depression, including 24 reports of death, worldwide that were associated with codeine use in pediatric patients younger than 18 years of age; in all 10 of the reports that provided information about CYP2D6 metabolizer status, the patients were ultrarapid or extensive metabolizers of CYP2D6 substrates. (See Pharmacokinetics: Pharmacogenomics.) Most of the cases of respiratory depression, including most of the deaths, occurred in children younger than 12 years of age. Respiratory depression may occur despite serum concentrations of codeine or morphine being within the therapeutic range; one patient who had concentrations within the therapeutic range died following use of codeine for management of pain after tonsillectomy and adenoidectomy.

To minimize the risk of serious adverse events in pediatric patients, FDA states that codeine-containing preparations must not be used for the management of pain in children younger than 12 years of age or for the management of postoperative pain following tonsillectomy and/or adenoidectomy in pediatric patients younger than 18 years of age, and that use of codeine for the management of pain is not recommended in pediatric patients 12–18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function (because of potentially greater susceptibility to the respiratory depressant effects of the drug). If codeine is used for the management of pain in pediatric patients 12–18 years of age, caregivers should closely monitor the child for clinical manifestations of opiate toxicity (e.g., shallow, difficult, or noisy breathing; confusion; unusual sleepiness) and seek immediate medical treatment for the child if such manifestations occur.

Serious adverse events, including deaths, also have been reported in children receiving codeine for relief of symptoms of upper respiratory tract infection.

Pharmacology

Equianalgesic parenteral doses of codeine phosphate and morphine sulfate have produced similar degrees of respiratory depression. Codeine has good antitussive activity, although on a weight basis antitussive activity of codeine is less than that of morphine.

Codeine (Analgesic) Pharmacokinetics

Codeine and its salts are well absorbed following oral administration. Following oral administration, onset of action occurs in 15–30 minutes and analgesia is maintained for 4–6 hours. Codeine is distributed into milk. Codeine is metabolized mainly in the liver where it undergoes O-demethylation (by cytochrome P-450 [CYP] isoenzyme 2D6), N-demethylation (by CYP3A4), and partial conjugation with glucuronic acid; the drug is excreted mainly in urine as norcodeine and free and conjugated morphine. Negligible amounts of codeine and its metabolites are found in feces.

Codeine is metabolized by the CYP microsomal enzyme system, principally by CYP3A4, and to a lesser extent by CYP2D6 (debrisoquine hydroxylase). Although the CYP2D6 isoenzyme accounts for only 10% of the metabolism of codeine, it plays an essential role in converting the drug to its active O-demethylated metabolite, morphine.

Pharmacogenomics: Metabolism of certain drugs, including codeine, is influenced by CYP2D6 polymorphism. Individuals who lack functional alleles of the CYP2D6 gene are described as poor metabolizers, those with 1 or 2 functional alleles are described as extensive metabolizers, and those who carry a duplicate or amplified gene are described as ultrarapid metabolizers. Genetically determined differences in drug metabolism can affect an individual’s response to a drug or risk of having an adverse event. Individuals who are poor metabolizers experience no analgesic effects of codeine; individuals who are ultrarapid metabolizers are likely to have higher than expected serum concentrations of morphine.

Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin. Approximately 1–7% of Caucasians and 10–30% of Ethiopians and Saudi Arabians carry the genotype associated with ultrarapid metabolism of CYP2D6 substrates.

Chemistry and Stability

Chemistry

Codeine is a phenanthrene-derivative opiate agonist. Codeine occurs as colorless or white crystals or as a white, crystalline powder; the drug is slightly soluble in water and freely soluble in alcohol. Codeine phosphate occurs as fine, white, needle-shaped crystals or as a white, crystalline powder and is freely soluble in water and slightly soluble in alcohol. Codeine sulfate occurs as white crystals, usually needle-like, or as a white, crystalline powder and is soluble in water and very slightly soluble in alcohol.

Stability

Codeine sulfate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40°C, preferably between 15–30°C.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Codeine preparations are subject to control under the Federal Controlled Substances Act of 1970.

Codeine Phosphate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Crystal
Bulk	Powder

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Acetaminophen and Codeine Phosphate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	120 mg/5 mL Acetaminophen and Codeine Phosphate 12 mg/5 mL*	Acetaminophen and Codeine Phosphate Oral Solution ( C-V )
	Tablets	300 mg Acetaminophen and Codeine Phosphate 15 mg*	Acetaminophen and Codeine Phosphate Tablets ( C-III )
		300 mg Acetaminophen and Codeine Phosphate 30 mg*	Acetaminophen and Codeine Phosphate Tablets ( C-III )
			Tylenol with Codeine No. 3 (C-III)	Janssen
		300 mg Acetaminophen and Codeine Phosphate 60 mg*	Acetaminophen and Codeine Phosphate Tablets ( C-III )
			Tylenol with Codeine No. 4 (C-III)	Janssen

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Other Codeine Phosphate Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	30 mg with Acetaminophen 300 mg, Butalbital 50 mg, and Caffeine 40 mg*	Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules ( C-III )
			Fioricet with Codeine (C-III)	Actavis
		30 mg with Acetaminophen 325 mg, Butalbital 50 mg, and Caffeine 40 mg*	Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules ( C-III )
		30 mg with Aspirin 325 mg, Butalbital 50 mg, and Caffeine 40 mg*	Ascomp with Codeine (C-III)	Nexgen
			Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules ( C-III )
			Fiorinal with Codeine ( C-III )	Allergan
	Tablets	16 mg with Aspirin 325 mg and Carisoprodol 200 mg*	Carisoprodol, Aspirin, and Codeine Phosphate Tablets (C-III)
			Soma Compound with Codeine (C-III)	Meda