Brand names: Ascomp with Codeine (combination), Cheratussin AC (combination), Codar GF (combination)
Drug class: Opiate Agonists
VA class: CN101
Chemical name: (5α,6α)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-methyl-morphan-6-ol phosphate
Molecular formula: C₁₈H₂₁NO₃•H₃PO₄•½H₂O
CAS number: 41444-62-6

Medically reviewed by Drugs.com on Mar 20, 2023. Written by ASHP.

Introduction

Opiate agonist; phenanthrene derivative.

Uses for Codeine

Pain

Symptomatic relief of mild to moderately severe pain that is not relieved by a nonopiate analgesic.

Combinations of codeine and aspirin or acetaminophen may produce additive analgesic effects because of differing mechanisms of action.

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated. Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain. Optimize concomitant use of other appropriate therapies. (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose). (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Cough

Symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.

Not indicated for management of cough in patients <18 years of age. (See Pediatric Use under Cautions.)

Codeine Dosage and Administration

General

Managing Opiate Therapy for Acute Pain

• Optimize concomitant use of other appropriate therapies.

• When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. (See Respiratory Depression under Cautions.)

• When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days). Do not prescribe larger quantities for use in case pain continues longer than expected; instead, reevaluate patient if severe acute pain does not remit.

• For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.

• Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.

• Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery. When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.

Managing Opiate Therapy for Chronic Noncancer Pain

• Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.

• Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction; establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.

• Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.

• Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.

• Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage. Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.

• Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase and reevaluate on ongoing basis (e.g., at least every 3 months ) throughout therapy. Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies. Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment). If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.

• When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks. Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.

• Higher dosages require particular caution, including more frequent and intensive monitoring or referral to specialist. Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, OUD).

• CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥330 mg of codeine daily) for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily. Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended) or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).

• Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.

• Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion. Offer or arrange treatment for patients with OUD.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. (See Respiratory Depression under Cautions.)

Administration

Oral Administration

Administer orally.

Dosage

Available as codeine phosphate and codeine sulfate; dosage expressed in terms of the salt.

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

When switching patients receiving chronic opiate therapy from one opiate analgesic to another, generally reduce the calculated equianalgesic dosage of the new opiate agonist by about 25–50% to avoid inadvertent overdosage. This calculation does not apply when switching to methadone; consult specific recommendations for methadone dosage.

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy. (See Specific Drugs under Interactions.)

Pediatric Patients

Pain

Oral

3 mg/kg or 100 mg/m² daily in 6 divided doses. Alternatively, 0.5 mg/kg or 15 mg/m² every 4–6 hours. (See Pediatric Use under Cautions.)

Adults

Cough

Oral

10–20 mg every 4–6 hours.

Pain

Oral

30 mg every 4 hours as needed; usual dosage range is 15–60 mg every 4 hours as needed.

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component. Nonopiate analgesics are available in various fixed ratios with codeine and also are available in many other prescription and OTC preparations; ensure that therapy is not duplicated and that nonopiate dosage does not exceed maximum recommended dosages.

Individualize initial dosage, taking into account 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.

Prescribing Limits

Adults

Cough

Oral

Maximum 120 mg daily.

Pain

Oral

Maximum 360 mg daily.

For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).

CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥330 mg of codeine daily) for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify their decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).

Special Populations

Geriatric Patients

Reduce dosage in older patients.

Cautions for Codeine

Contraindications

• Known hypersensitivity to codeine or any ingredient in the formulation.

• In children <12 years of age for the management of pain or cough and cold. (See Pediatric Use under Cautions.)

• In children <18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy.

• Known or suspected paralytic ileus.

Warnings/Precautions

Warnings

Respiratory Depression

Possible dose-related respiratory depression (occurs infrequently with oral antitussive doses).

Potential for increased viscosity of bronchial secretions and suppression of cough reflex, with subsequent respiratory insufficiency, in patients with asthma or pulmonary emphysema who indiscriminately use antitussives.

Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including codeine.

Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose) or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opiate analgesic, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.

Concurrent use with other CNS depressants may potentiate CNS depression and result in profound sedation, respiratory depression, coma, or death. (See Specific Drugs under Interactions.)

Abuse Potential

Possible tolerance, psychologic dependence, and physical dependence following prolonged administration. Abuse potential similar to that of morphine.

Pharmacogenomics

Ultrarapid metabolizers of CYP2D6 substrates are likely to have higher than expected serum concentrations of morphine, the active metabolite of codeine. (See Elimination under Pharmacokinetics.) FDA states codeine should not be used in such patients.

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including codeine, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Avoid concomitant use of CNS depressants with codeine antitussives; reserve concomitant use with codeine-containing analgesics for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opiate improved symptoms.

Sulfite Sensitivity

Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

General Precautions

Increased Intracranial Pressure or Head Trauma

Potential for increased respiratory depressant effects and elevation of CSF pressure in patients with increased intracranial pressure, head trauma, or other intracranial lesions.

Adverse effects of opiates may obscure the existence, extent, or course of intracranial pathology.

Acute Abdominal Conditions

Administration may complicate assessment of patients with acute abdominal conditions.

Postoperative Patients

Suppression of cough reflex following thoracotomy or laparotomy may lead to postoperative retention of secretions; cautious use recommended.

Debilitated and Special Risk Patients

Use with caution in debilitated patients and in those with hypothyroidism, Addison’s disease, and prostatic hypertrophy or urethral stricture.

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.

Fixed-combination Preparations

When used in fixed combination with other drug(s), consider the cautions, precautions, and contraindications associated with the other drug(s).

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk; use not recommended. Risk of opiate toxicity in nursing infants, especially if mother is an ultrarapid metabolizer of CYP2D6 substrates.

Opiate toxicity resulting in neonatal death reported in the nursing infant of a woman receiving codeine; woman was an ultrarapid metabolizer of codeine. (See Metabolism and see Special Populations under Pharmacokinetics.) Somnolence also reported more frequently in nursing infants exposed to acetaminophen/codeine compared with nursing infants exposed to acetaminophen alone; some mothers were ultrarapid metabolizers of CYP2D6 substrates.

If infant is exposed to codeine through breast milk, caregiver should monitor closely for manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia) and seek immediate medical treatment for the infant if such manifestations occur.

Pediatric Use

Manufacturers state safety and efficacy of single-entity codeine preparations for the management of mild to moderately severe pain not established in pediatric patients <18 years of age.

Use as an analgesic contraindicated in children <12 years of age. Use as analgesic also contraindicated in pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. FDA states that use for 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.

Do not use antitussive agents containing opiates, including codeine, in pediatric patients <18 years of age; FDA states that risks of respiratory depression, misuse, abuse, addiction, overdosage, and death outweigh the potential benefit. Use of codeine as an antitussive contraindicated in children <12 years of age. (Warning against antitussive use in pediatric patients <18 years of age and contraindication to antitussive use in children <12 years of age are required in labeling of prescription codeine-containing cough and cold preparations; FDA is considering additional regulatory action for codeine-containing cough and cold preparations available without prescription in some states. )

Serious adverse events, including deaths, reported in pediatric patients <18 years of age, mostly in those <12 years of age; pediatric patients who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates are at increased risk. (See Boxed Warning and see Elimination under Pharmacokinetics.) If codeine is used for analgesia in pediatric patients 12–18 years of age, caregivers should monitor closely for manifestations of opiate toxicity and seek immediate medical treatment for the child if such manifestations occur.

Geriatric Use

Use with caution. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with severe hepatic impairment.

Renal Impairment

Use with caution in patients with severe renal impairment.

Common Adverse Effects

When used for pain relief (particularly in ambulatory patients not experiencing severe pain): lightheadedness, dizziness, sedation, nausea, vomiting, sweating.

When used at antitussive doses: nausea, vomiting, constipation (with repeated doses), dizziness, sedation, palpitation, pruritus.

Interactions for Codeine

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs. May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.

If serotonin syndrome is suspected, discontinue codeine, other opiate therapy, and/or any concurrently administered serotonergic agents.

Specific Drugs

Codeine Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.

Onset

Onset occurs in 15–30 minutes. Peak analgesic effects occur within 2 hours; peak antitussive effects within 1–4 hours.

Duration

Analgesic effects persist for 4–6 hours. Antitussive effects may persist for 4 hours.

Distribution

Extent

Rapidly distributed into various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Distributed into milk. Readily crosses the placenta.

Protein Binding

Not bound to plasma proteins.

Elimination

Metabolism

Metabolized in liver, principally by CYP3A4 and to a lesser extent (10%) by CYP2D6 to O-demethylated morphine, the active metabolite.

Metabolism of codeine influenced by CYP2D6 polymorphism; genetic differences in drug metabolism affect drug response. Individuals may be described as poor, extensive, or ultrarapid metabolizers of CYP2D6 substrates.

Elimination Route

Excreted mainly in urine with negligible amounts of codeine and its metabolites found in feces.

Half-life

About 2.5–3 hours.

Special Populations

Pharmacogenomics: Individuals who carry the genotype associated with ultrarapid metabolism of CYP2D6 substrates (approximately 1–7% of Caucasians, 10–30% of Ethiopians and Saudi Arabians) convert codeine to morphine more rapidly and completely than other individuals; ultrarapid metabolizers are likely to have higher than expected serum concentrations of morphine.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at <40°C (preferably 15–30°C).

Solution

Tight, light-resistant containers at <40°C (preferably 15–30°C). Protect from freezing.

Actions

• Principal pharmacologic effects are on CNS and intestines.

• Mild analgesic effect. Acts at several sites within the CNS involving several systems of neurotransmitters to produce analgesia; precise mechanism of action not fully elucidated.

• Suppresses cough reflex by direct effect on cough center in medulla of brain.

• Exerts drying effect on respiratory tract mucosa and increases viscosity of bronchial secretions.

• Antitussive activity is less than that of morphine (on a weight basis).

Advice to Patients

• Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.

• Risk of respiratory depression following overdosage. Advise patients of the benefits of naloxone following opiate overdose and of their options for obtaining the drug.

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly. Avoid concomitant use of CNS depressants with codeine antitussives; also avoid concomitant use with codeine analgesics unless use is supervised by clinician. Importance of informing patients that codeine should not be combined with alcohol.

• Potential risk of serotonin syndrome with concurrent use of codeine and other serotonergic agents. Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.

• Potential risk of adrenal insufficiency. Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as alcohol consumption and any concomitant diseases. Importance of limiting alcohol intake.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Risk of morphine toxicity in nursing infants of women taking codeine, especially if the woman is an ultrarapid metabolizer of the drug. Importance of not taking codeine while nursing. Advise patients to immediately seek medical attention if symptoms of opiate overdosage (e.g., sedation, difficulty breathing, hypotonia, poor feeding) develop in nursing infants exposed to codeine.

• Risk of morphine toxicity in children, especially those who are obese, have respiratory diseases, or have evidence of ultrarapid metabolism of codeine. Importance of not giving codeine to children <12 years of age for management of pain or to pediatric patients <18 years of age for cough and cold or for pain relief following tonsillectomy and/or adenoidectomy. Importance of monitoring children receiving codeine for clinical manifestations of morphine toxicity (e.g., slow, shallow, difficult, or noisy breathing; confusion; unusual sleepiness) and seeking immediate medical attention for the child if symptoms develop.

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use. Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.

• Importance of advising patients of other important precautionary information. (See Cautions.)

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.

Subject to control under the Federal Controlled Substances Act of 1970.

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

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

Codeine phosphate is also commercially available in combination with other antihistamines, decongestants, and expectorants.

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

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

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