REMS: FDA approved a REMS for codeine-containing preparations to ensure that the benefits outweigh the risks. 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 the FDA REMS page ([Web]). |
Codeine is a phenanthrene-derivative opiate agonist.106, 122
Codeine is used for the management of mild to moderate pain when treatment with an opioid is appropriate and for which alternative treatments are inadequate.122 Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve use for patients in whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products) have not been or are not expected to be tolerated or have not provided or are not expected to provide adequate analgesia.122
Codeine is commercially available as a single-entity tablet preparation as the sulfate salt,130 and also available as the phosphate salt in various combinations with acetaminophen, aspirin, butalbital (a barbiturate) and/or caffeine for the treatment of mild to moderate pain.115, 116, 130, 131 The fixed combination of butalbital, acetaminophen, caffeine, and codeine phosphate and the fixed combination of butalbital, aspirin, caffeine, and codeine phosphate are FDA-labeled for the management of tension (or muscle contraction) headache, when other non-opioid analgesics and alternative treatments are inadequate; because of the risks of addiction, abuse, and misuse with opioids and butalbital, reserve use of these combination preparations for patients in whom alternative treatment options (e.g., non-opioid, non-barbiturate analgesics) have not been tolerated or are not expected to be tolerated or have not provided or are not expected to provide adequate analgesia.115, 116 Combining analgesic drugs with different mechanisms of action such as a nonsteroidal anti-inflammatory agent (NSAIA) or acetaminophen with an opioid can produce synergistic analgesic effects while allowing reduced doses of the individual drugs and thus, reduce the potential for adverse effects.161
Codeine, alone or in fixed-combination preparations, should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and alternative treatment options continue to be inadequate.115, 116, 122, 130, 131
Pain needs to be appropriately and effectively treated, regardless of whether opioids are part of the treatment regimen.760 Treatment should be individualized, patient-centered, and include multimodal approaches.760 Opioids can be essential in the management of pain but are associated with considerable potential harm, including opioid use disorder and overdose.760 Therefore, safer and more effective treatments should be considered prior to initiating opioid therapy.760 There are multiple nonpharmacologic treatments (e.g., exercise, physical therapy, psychological therapies) and nonopioid drugs (e.g., serotonin and norepinephrine reuptake inhibitors [SNRIs], gabapentinoids, NSAIAs) that have been shown to be at least as effective as opioids for many types of common pain conditions.760 These nonopioid treatments are generally preferred to opioids in most situations.760 If opioids are used, clinicians should carefully evaluate the risk of opioid-related harms and work with the patient to incorporate appropriate risk mitigation strategies into the treatment plan, including offering naloxone.760
The Centers for Disease Control and Prevention (CDC) clinical guideline for prescribing opioids for pain provides recommendations for the management of acute (duration <1 month), subacute (duration 1-3 months), and chronic pain (duration >3 months) in adults in the outpatient setting.760 The CDC guideline addresses the following areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use.760
Other clinical practice guidelines provide recommendations for the management of specific types of pain including postoperative pain, cancer-related pain, sickle-cell pain, and pain associated with palliative care; although specific recommendations for the management of opioid therapy vary across the guidelines, common elements include risk mitigation strategies, careful dosage titration, and consideration of risks and benefits.410, 414, 415, 422, 423, 430, 431, 432, 433, 434, 758, 759
Codeine is used in combination with expectorants, antihistamines, and decongestants for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold.132, 133, 710 FDA states that these products are no longer indicated for use in children younger than 18 years of age due to the risks of codeine-containing prescription cough and cold preparations outweighing their benefits in this age group.710 Codeine may be available in over-the-counter (OTC) combination cough preparations in some states in the US; such preparations are subject to dispensing regulations.123, 134, 135, 710
Dispensing and Administration Precautions
Codeine-containing preparations are administered orally.115, 116, 122, 130, 131, 132, 133
Codeine sulfate is commercially available as a single-entity tablet preparation.130 Codeine phosphate is commercially available in the following fixed-combination preparations for oral use: codeine/acetaminophen, promethazine/codeine, promethazine/phenylephrine/codeine, butalbital/acetaminophen/caffeine/codeine, and butalbital/aspirin/caffeine/codeine.115, 116, 130, 131, 132, 133 See the full prescribing information for additional information on these combination preparations.115, 116, 130, 131, 132, 133 Codeine also may be commercially available in over-the-counter (OTC) preparations in combination with antihistamines, expectorants, or decongestants.123, 134, 135 See the FDA Orange Book and the manufacturer's Drug Facts for additional information.
Codeine sulfate tablets should be stored at 20-25°C (excursions permitted between 15-30°C) in a secure location; protect from moisture.122
Dosage of codeine sulfate and codeine phosphate is expressed in terms of the salt.115, 116, 130, 131, 132, 133
For the management of pain, codeine should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.122 The initial dosage must be individualized, considering previous therapies and response, type and severity of pain, and risk factors for addiction, abuse, and misuse.122
For the relief of mild to moderate pain in adults, the manufacturer of codeine sulfate tablets recommends an initial oral dosage of 15-60 mg every 4 hours as needed; dosage should be titrated based on individual patient response to a dosage that provides adequate analgesia and minimizes adverse reactions.122 If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dosage.122 Adult doses higher than 60 mg provide no additional analgesic efficacy and are associated with an increased risk of adverse effects.122 The maximum 24-hour dose is 360 mg.122
If the fixed-combination codeine preparation with butalbital, caffeine, and acetaminophen or the fixed-combination codeine preparation with butalbital, caffeine, and aspirin is used for the relief of headache pain in adults, 1 or 2 capsules (each capsule containing 30 mg of codeine phosphate) as needed is recommended initially; the total daily dose should not exceed 6 capsules.115, 116
Conversion from other Opioids to Codeine Sulfate Tablets
Because of inter-patient variability in the potency of opioid drugs and formulations, a conservative approach is advised when determining the total daily dosage of codeine sulfate when converting from therapy with other opioids.122 It is safer to underestimate a patient's 24-hour tablet dosage than to overestimate and manage an adverse reaction due to overdose.122
Codeine preparations should be given in the lowest effective dose and shortest duration that is consistent with individual patient treatment goals.132, 133
The usual oral antitussive dosage of codeine phosphate (in combination with promethazine and/or phenylephrine) in adults is 10 mg every 4-6 hours as needed, not to exceed 60 mg daily.132, 133
In patients with hepatic impairment, initiate treatment with a lower than normal dosage of codeine or with longer dosing intervals and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.122
In patients with renal impairment, initiate treatment with a lower than normal dosage of codeine or with longer dosing intervals and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.122
In general, select dosage with caution in geriatric patients, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.122 Titrate dosage of codeine slowly in geriatric patients and frequently re-evaluate the patient for CNS and respiratory depression.122
Pharmacogenomic Considerations in Dosing
The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed dosing guidelines for codeine based on a patient's cytochrome P-450 (CYP) 2D6 phenotype.136 (See Pharmacogenomic Considerations under Cautions.)
For CYP2D6 normal metabolizers, CPIC recommends the age- or weight-specific dosage provided in the product labeling.136
For CYP2D6 intermediate metabolizers, CPIC recommends the age- or weight-specific dosage provided in the product labeling; however, these patients should be monitored closely for suboptimal response and offered an alternative analgesic if warranted.136
For CYP2D6 poor metabolizers, CPIC recommends that codeine be avoided due to the risk of suboptimal or no analgesic efficacy.136
For CYP2D6 ultra-rapid metabolizers, CPIC recommends that codeine be avoided because of the risk of increased toxicity.136
Codeine preparations are controlled substances (schedule II, III, or V depending on the preparation) and expose users to the risks of addiction, abuse, and misuse.115, 116, 122, 130, 131, 132, 133 A boxed warning regarding this risk has been included in the prescribing information for all codeine preparations.115, 116, 122, 130, 131, 132, 133 Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed codeine.115, 116, 122, 130, 131 Addiction can occur at recommended dosages and if the drug is misused or abused.115, 116, 122, 130, 131, 132, 133
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing codeine-containing preparations and monitor regularly for the development of these behaviors or conditions during therapy.115, 116, 122, 130, 131, 132, 133 Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).115, 116, 122, 130, 131, 132, 133 The potential for these risks should not, however, prevent the proper management of pain in any given patient.115, 116, 122, 130, 131, 132, 133 Patients at increased risk may be prescribed opioid agonists such as codeine but use in such patients necessitates intensive counseling about the risks and proper use of the drug along with frequent reevaluation for signs of addiction, abuse, and misuse.115, 116, 122, 130, 131, 132, 133 Consider prescribing naloxone for the emergency treatment of opioid overdose.115, 116, 122, 130, 131, 132, 133
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.115, 116, 122, 130, 131, 132, 133 Consider these risks when prescribing or dispensing codeine.115, 116, 122, 130, 131, 132, 133 Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug.115, 116, 122, 130, 131, 132, 133 Contact a local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion.115, 116, 122, 130, 131, 132, 133
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.115, 116, 122, 130, 131, 132, 133 A boxed warning about this risk has been included in the prescribing information for all codeine preparations.115, 116, 122, 130, 131, 132, 133 Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.115, 116, 122, 130, 131, 132, 133 Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status.115, 116, 122, 130, 131, 132, 133 Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.115, 116, 122, 130, 131, 132, 133
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of codeine, the risk is greatest during the initiation of therapy or following a dosage increase.115, 116, 122, 130, 131, 132, 133
To reduce the risk of respiratory depression, proper dosing and titration of codeine are essential.115, 116, 122, 130, 131, 132, 133 Overestimating the dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.115, 116, 122, 130, 131, 132, 133
Accidental ingestion of even one dose of codeine, especially by children, can result in respiratory depression and death due to an overdose of morphine.115, 116, 122, 130, 131, 132, 133 Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical assistance immediately in the event of a known or suspected overdose.115, 116, 122, 130, 131, 132, 133
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia.115, 116, 122, 130, 131 Opioid use increases the risk of CSA in a dose-dependent fashion.115, 116, 122, 130, 131, 132, 133 In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.115, 116, 122, 130, 131, 132, 133
Discuss the availability of naloxone for the emergency treatment of opioid overdose.115, 116, 122, 130, 131, 132, 133 Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose.115, 116, 122, 130, 131, 132, 133 The presence of risk factors for overdose should not prevent the proper management of pain in any given patient.115, 116, 122, 130, 131, 132, 133 Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.115, 116, 122, 130, 131, 132, 133
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from concomitant use of codeine with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).115, 116, 122, 130, 131, 132, 133 A boxed warning regarding this risk has been included in the prescribing information for codeine preparations.115, 116, 122, 130, 131, 132, 133 Because of these risks, reserve concomitant prescribing of these drugs for patients in whom alternative treatment options are inadequate.115, 116, 122, 130, 131, 132, 133
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.115, 116, 122, 130, 131, 132, 133 Because of similar pharmacological properties, it is reasonable to expect similar risk with concomitant use of other CNS depressant drugs with opioid analgesics.115, 116, 122, 130, 131, 132, 133
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use.115, 116, 122, 130, 131, 132, 133 In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant, and titrate based on clinical response.115, 116, 122, 130, 131, 132, 133 Similarly, if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dosage of the opioid analgesic, and titrate based on clinical response.115, 116, 122, 130, 131, 132, 133 If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.115, 116, 122, 130, 131, 132, 133
Advise both patients and caregivers about the risks of respiratory depression and sedation when codeine is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).115, 116, 122, 130, 131, 132, 133 Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.115, 116, 122, 130, 131, 132, 133 Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.115, 116, 122, 130, 131, 132, 133
Use of codeine for an extended period during pregnancy can result in withdrawal in the neonate.115, 116, 122, 130, 131, 132, 133 A boxed warning regarding this risk has been included in the prescribing information for codeine preparations.115, 116, 122, 130, 131, 132, 133 Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.115, 116, 122, 130, 131, 132, 133 Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.115, 116, 122, 130, 131, 132, 133 Advise pregnant women using opioids for an extended period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.115, 116, 122, 130, 131, 132, 133
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children receiving codeine-containing medications who were found to have a genetic polymorphism for ultrarapid metabolism of codeine or other risk factors; a boxed warning regarding this risk has been included in the prescribing information for codeine preparations.115, 116, 122, 130, 131 Most of the reported cases occurred following use of codeine for pain management after tonsillectomy and/or adenoidectomy procedures; many of the children had evidence of being ultrarapid metabolizers of codeine due to a cytochrome P-450 (CYP) 2D6 polymorphism.115, 116, 122, 130, 131 Ultrarapid metabolizers of CYP2D6 convert codeine to potentially dangerously high levels of morphine, the active form of codeine, thus increasing the risk of life-threatening or fatal respiratory depression.705 Codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.115, 116, 122, 130, 131 Avoid use of codeine-containing preparations in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.115, 116, 122, 130, 131
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
The effects of concomitant use or discontinuation of cytochrome P-450 (3A4) inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with codeine are complex.115, 116, 122, 130, 131, 132, 133 A boxed warning regarding this risk has been included in the prescribing information for codeine preparations.115, 116, 122, 130, 131, 132, 133 Such concomitant use requires careful consideration of the effects on codeine (the parent drug) and morphine (the active metabolite).115, 116, 122, 130, 131, 132, 133
Concomitant use of codeine with all CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a CYP3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in increased codeine plasma concentrations; this can increase metabolism via CYP2D6, resulting in higher morphine concentrations potentially causing fatal respiratory depression.115, 116, 122, 130, 131, 132, 133 Concomitant use of codeine with all CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels.115, 116, 122, 130, 131, 132, 133 This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.115, 116, 122, 130, 131, 132, 133 Regularly evaluate patients receiving concomitant therapy with codeine and any CYP3A4 inhibitor or inducer for signs and symptoms of opioid toxicity and opioid withdrawal.115, 116, 122, 130, 131, 132, 133 If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of codeine until stable drug effects are achieved.115, 116, 122, 130, 131, 132, 133 Regularly evaluate patients for respiratory depression and sedation.115, 116, 122, 130, 131, 132, 133 If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing dosage of codeine until stable drug effects are achieved.115, 116, 122, 130, 131, 132, 133 Regularly evaluate patients for signs of opioid withdrawal.115, 116, 122, 130, 131, 132, 133
Concomitant use of codeine with all CYP2D6 inhibitors (e.g., amiodarone, quinidine) may result in increased codeine plasma concentrations and decreased plasma concentrations of the active morphine metabolite; this may result in reduced analgesic efficacy symptoms or opioid withdrawal.115, 116, 122, 130, 131, 132, 133 Discontinuation of a concomitantly used CYP2D6 inhibitor may result in decreased codeine plasma concentrations and increased plasma concentrations of the active morphine metabolite; this could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.115, 116, 122, 130, 131, 132, 133 If codeine is used concomitantly with a CYP2D6 inhibitor, monitor patients for signs and symptoms of opioid toxicity and withdrawal.115, 116, 122, 130, 131, 132, 133 Regularly evaluate the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the dosage of codeine.115, 116, 122, 130, 131, 132, 133 After discontinuing use of a CYP2D6 inhibitor, consider reducing the dosage of codeine and regularly evaluate the patient for signs and symptoms of respiratory depression or sedation.115, 116, 122, 130, 131, 132, 133
Risk of Accidental Overdose and Death due to Medication Error
Dosing errors can result in accidental overdose and death.130, 132, 133 A boxed warning regarding this risk has been included in the prescribing information for oral solutions of codeine.130, 132, 133 Ensure accuracy when prescribing, dispensing, and administering oral solutions containing codeine.130, 132, 133
Instruct patients and caregivers on how to measure and administer the correct dose of oral solutions containing codeine.130, 132, 133 Instruct patients and caregivers to always use an accurate measuring device when administering the oral solution to ensure that the dose is measured and administered accurately.130, 132, 133
Other Warnings and Precautions
Opioid-Induced Hyperalgesia and Allodynia
Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain; however, this condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.115, 116, 122, 130, 131, 132, 133 Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).115, 116, 122, 130, 131, 132, 133 Evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior should be ruled out to suggest a diagnosis of OIH based on these symptoms.
Cases of OIH have been reported, both with short- and long-term use of opioid analgesics.115, 116, 122, 130, 131, 132, 133 Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.115, 116, 122, 130, 131, 132, 133 There is evidence suggesting a strong biologic plausibility between opioid analgesics, OIH, and allodynia.115, 116, 122, 130, 131, 132, 133 If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or safely switch the patient to a different opioid drug.115, 116, 122, 130, 131, 132, 133
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of codeine in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.115, 116, 122, 130, 131, 132, 133
Patients with significant chronic obstructive pulmonary disease (COPD) or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages.115, 116, 122, 130, 131, 132, 133 Life-threatening respiratory depression is also more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or clearance compared to younger, healthier patients.115, 116, 122, 130, 131, 132, 133
Regularly evaluate or monitor patients, particularly when initiating and titrating codeine and when codeine is given concomitantly with other drugs that depress respiration.115, 116, 122, 130, 131, 132, 133 Alternatively, consider the use of non-opioid analgesics in these patients.115, 116, 122, 130, 131, 132, 133
Interaction with Monoamine Oxidase Inhibitors
Monoamine oxidase (MAO) inhibitors may potentiate the effects of morphine, including respiratory depression, coma, and confusion.115, 116, 122, 130, 131, 132, 133
Do not use in patients taking MAO inhibitors or within 14 days of stopping such treatment.115, 116, 122, 130, 131, 132, 133
Cases of adrenal insufficiency reported with opioid use, generally after 1 month of use.115, 116, 122, 130, 131, 132, 133 Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.115, 116, 122, 130, 131, 132, 133
If adrenal insufficiency is suspected, confirm the diagnosis as soon as possible.115, 116, 122, 130, 131, 132, 133 If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.115, 116, 122, 130, 131, 132, 133 Wean the patient from the opioid to allow adrenal function to recover and continue corticosteroid treatment until recovery.115, 116, 122, 130, 131, 132, 133 Some cases report no recurrence of adrenal insufficiency when initiating different opioids after recovery.115, 116, 122, 130, 131, 132, 133 The current evidence does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.115, 116, 122, 130, 131, 132, 133
Codeine may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.115, 116, 122, 130, 131, 132, 133 There is increased risk in patients whose ability to maintain blood pressure has already been compromised by reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines, general anesthetics).115, 116, 122, 130, 131, 132, 133 Regularly evaluate patients for signs of hypotension after initiating or titrating the dosage of codeine.115, 116, 122, 130, 131, 132, 133
In patients with circulatory shock, codeine may cause vasodilation that can further reduce cardiac output and BP; avoid the use of codeine in such patients.115, 116, 122, 130, 131, 132, 133
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), codeine may reduce respiratory drive; resultant CO2 retention can further increase intracranial pressure.115, 116, 122, 130, 131, 132, 133 Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy.115, 116, 122, 130, 131, 132, 133
Opioids may also obscure the clinical course in a patient with head injuries.115, 116, 122, 130, 131, 132, 133 Avoid the use of codeine in patients with impaired consciousness or coma.115, 116, 122, 130, 131, 132, 133
Risks in Patients with GI Conditions
Codeine is contraindicated in patients with GI obstruction, including paralytic ileus, as the drug may cause spasm of the sphincter of Oddi.115, 116, 122, 130, 131, 132, 133 Opioids may cause increases in serum amylase.115, 116, 122, 130, 131, 132, 133
Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.115, 116, 122, 130, 131, 132, 133
Codeine may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures.115, 116, 122, 130, 131, 132, 133 Regularly evaluate patients with a history of seizure disorders for worsened seizure control during codeine therapy.115, 116, 122, 130, 131, 132, 133
Do not abruptly discontinue codeine in a patient physically dependent on opioids, but rather gradually taper dosage.115, 116, 122, 130, 131, 132, 133 Rapid tapering in a physically dependent patient may lead to withdrawal symptoms and return of pain.
Avoid the use of mixed agonists/antagonists (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonists (e.g., buprenorphine) in patients receiving a full opioid agonist analgesic, including codeine.115, 116, 122, 130, 131, 132, 133 In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.115, 116, 122, 130, 131, 132, 133
Risks of Driving and Operating Machinery
Codeine may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.115, 116, 122, 130, 131, 132, 133
Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of morphine and know how they will react to the medication.115, 116, 122, 130, 131, 132, 133
When preparations containing codeine in fixed combination with other drugs (e.g., acetaminophen, aspirin, butalbital, caffeine, promethazine, phenylephrine) are administered, the cautions, precautions, and contraindications applicable to each drug must be considered.115, 116, 130, 131, 132, 133
Available data with codeine are insufficient to inform a drug-associated risk of major birth defects and miscarriage.115, 116, 122, 130, 131, 132, 133 In animal studies, embryolethal and fetotoxic effects were observed in animals administered codeine during the period of organogenesis.115, 116, 122, 130, 131, 132, 133
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.115, 116, 122, 130, 131, 132, 133 An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.115, 116, 122, 130, 131, 132, 133 Codeine is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.115, 116, 122, 130, 131, 132, 133 Opioid analgesics, including codeine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.115, 116, 122, 130, 131, 132, 133 However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor.115, 116, 122, 130, 131, 132, 133 Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression.115, 116, 122, 130, 131, 132, 133
Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.115, 116, 122, 130, 131, 132, 133 Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.115, 116, 122, 130, 131, 132, 133 Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.115, 116, 122, 130, 131, 132, 133
Breastfeeding is not recommended during treatment with codeine, especially in patients who have evidence of ultrarapid metabolism of CYP2D6 substrates.122 Serious adverse events (e.g., excessive sedation, difficulty nursing, respiratory depression), including death, have been reported in nursing infants exposed to codeine.122 At least one case of opioid 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.107, 705 Higher than expected concentrations of morphine were found in breast milk and in the blood of the infant.107, 705 Somnolence 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.705 Concentrations of morphine in breast milk are low and dose-dependent in women who are normal metabolizers of codeine.705 FDA-approved tests (e.g., AmpliChip® CYP450 Test) are available to identify an individual's CYP2D6 genotype.111 Infants exposed to codeine through breast milk should be monitored closely for clinical manifestations of opioid toxicity (e.g., sedation, difficulty breastfeeding or breathing, hypotonia).122 Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic or breastfeeding is stopped.132, 133
Females and Males of Reproductive Potential
Use of opioids for extended periods may cause reduced fertility in females and males of reproductive potential; it is not known whether these effects on fertility are reversible.115, 116, 122, 130, 131, 132, 133
Safety and effectiveness of codeine have not been established in pediatric patients.122 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.705 Serious adverse events, including deaths, have been reported during postmarketing experience in pediatric patients receiving codeine.122, 125, 126, 127, 128, 129, 705 Between January 1969 and May 2015, the FDA Adverse Event Reporting System (FAERS) 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.705 Ten of the 64 reports provided information about CYP2D6 metabolizer status.705 Seven of these patients were ultrarapid or extensive metabolizers of CYP2D6 substrates; 5 of which reported death.705 Most of the cases of respiratory depression, including most of the deaths, occurred in children younger than 12 years of age.705 Respiratory depression may occur despite therapeutic serum concentrations of codeine or morphine; 1 patient who had concentrations within the therapeutic range died following use of codeine for management of pain after tonsillectomy and adenoidectomy.705
Codeine-containing preparations are contraindicated in children younger than 12 years of age and contraindicated for postoperative pain management following tonsillectomy and/or adenoidectomy in pediatric patients younger than 18 years of age.122 Avoid the use of codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of the drug unless the benefits outweigh the risks.122 Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.122
Geriatric patients may have increased sensitivity to codeine.115, 116, 122, 130, 131, 132, 133 In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.115, 116, 122, 130, 131, 132, 133 Respiratory depression is the main risk for geriatric patients treated with opioids and has occurred after large initial doses in patients who were not opioid-tolerant or when opioids were co-administered with other drugs that depress respiration.115, 116, 122, 130, 131, 132, 133 Titrate the dosage of codeine slowly in geriatric patients and frequently re-evaluate for signs of CNS and respiratory depression.115, 116, 122, 130, 131, 132, 133
Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.115, 116, 122, 130, 131, 132, 133 Elderly patients are more likely to have decreased renal function; dosing should be selected with care and renal function should be regularly evaluated.115, 116, 122, 130, 131, 132, 133
The pharmacokinetics of codeine in patients with hepatic impairment are not known.115, 116, 122, 130, 131, 132, 133 Initiate treatment in these patients with a lower than usual dosage or with longer dosing intervals, and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.115, 116, 122, 130, 131, 132, 133
The pharmacokinetics of codeine may be altered in patients with renal failure.115, 116, 122, 130, 131, 132, 133 Initiate treatment in these patients with a lower than usual dosage or with longer dosing intervals, and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.115, 116, 122, 130, 131, 132, 133
Pharmacogenomic Considerations
Genetic variations in CYP2D6 , OPRM1 (the gene coding the mu opioid receptor mu1), and COMT (the enzyme responsible for the methylconjugation of catecholamines) can influence the clinical effect or adverse effects of some opioid analgesics.136 The Clinical Pharmacogenetics Implementation Consortium (CPIC) developed guidelines for selected opioid analgesics based on these genotypes.136
Codeine is metabolized by CYP2D6 and there is substantial evidence demonstrating that clinical efficacy and toxicity of the drug can be influenced by CYP2D6 polymorphism.108, 109, 110, 112, 114 Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin.107, 108, 109, 110, 114 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.108, 109, 110, 112 Individuals who lack functional alleles of the CYP2D6 gene are described as poor metabolizers.108, 109, 110, 114 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.108, 109, 110, 114 Individuals who are CYP2D6 poor metabolizers have greatly reduced morphine formation resulting in no analgesic effects of codeine.107, 109, 110, 136 Individuals who are CYP2D6 intermediate metabolizers have reduced morphine formation, and those who are ultrarapid metabolizers have higher than expected concentrations of morphine because of more rapid and complete conversion of codeine to morphine, resulting in a greater likelihood of toxicity.107, 109, 110, 136
The CPIC guidelines provide recommendations for codeine based on CYP2D6 phenotype.136 For individuals who are CYP2D6 normal metabolizers, the recommended age- or weight-specific dosage provided in the product labeling is recommended.136 For CYP2D6 intermediate metabolizers, the recommended age- or weight-specific dosing provided in the product labeling also is recommended; however, these patients should be monitored closely for a suboptimal response and offered an alternative analgesic if warranted.136 For CYP2D6 poor metabolizers, CPIC recommends that codeine be avoided due to the risk of suboptimal or absent analgesic effect.136 Codeine should be avoided in individuals who are CYP2D6 ultrarapid metabolizers because of the risk of increased toxicity.136
The CPIC guidelines state that there is insufficient evidence to support any therapeutic recommendations for dosing opioids based on either OPRM1 or COMT at this time.136
The most common adverse reactions reported with codeine sulfate tablets include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating.122
Codeine is metabolized by cytochrome P-450 (CYP) 2D6 to its active metabolite, morphine.122 Codeine is also metabolized by CYP3A4 to an inactive metabolite.122
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
CYP3A4 inhibitors (e.g., macrolide antibiotics [e.g., erythromycin], azole antifungals [e.g., ketoconazole], protease inhibitors [e.g., ritonavir]): may increase plasma codeine concentrations, subsequently increasing metabolism by CYP2D6, resulting in higher morphine concentrations; this can potentially increase the risk of fatal respiratory depression, particularly when the inhibitor is added after a stable dosage of codeine is achieved.122 After discontinuing a CYP3A4 inhibitor, codeine and morphine concentrations may decline, resulting in decreased opioid efficacy or withdrawal symptoms in patients who have developed physical dependence to codeine.122 If concomitant use of a CYP3A4 inhibitor is necessary, consider dosage reduction of codeine until stable drug effects are achieved and monitor the patient for respiratory depression and sedation.122 If a CYP3A4 inhibitor is discontinued, consider increasing the dosage of codeine until stable drug effects are achieved and monitor the patient for signs of opioid withdrawal.122
CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin): may decrease plasma codeine concentrations, subsequently decreasing metabolism by CYP2D6 resulting in lower morphine concentrations; this can potentially cause loss of analgesic efficacy or withdrawal effects in patients who have developed physical dependence.122 After discontinuing a CYP3A4 inducer, codeine and morphine concentrations may increase, resulting in increased adverse effects such as respiratory depression.122 If concomitant use of a CYP3A4 inducer is necessary, consider dosage increase of codeine as needed and monitor patients for reduced efficacy and signs of opioid withdrawal.122 If a CYP3A4 inducer is discontinued, consider decreasing the dosage of codeine and monitor the patient for respiratory depression and sedation.122
CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, quinidine): may increase plasma concentrations of codeine but decrease plasma concentrations of the active morphine metabolite, which can result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when the inhibitor is added after a stable dosage of codeine is achieved.122 If a CYP2D6 inhibitor is discontinued, codeine plasma concentrations will decrease but the active morphine metabolite will increase, potentially causing increased adverse effects including respiratory depression.122 If concomitant use of codeine and a CYP2D6 inhibitor is necessary, consider increasing the dosage of codeine as needed and regularly monitor patients for reduced efficacy or signs of opioid withdrawal.122 If a CYP2D6 inhibitor is discontinued, consider reducing the dosage of codeine and evaluate patients frequently for respiratory depression.122
Concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.122 Evaluate patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with anticholinergic drugs.122
Benzodiazepines and other CNS Depressants
Concomitant use of opioid agonists and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioid agonists, alcohol) can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.122 Concomitant use of opioid analgesics and other CNS depressants for the management of pain should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used.122
Opioids such as codeine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.122 Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.122
Drugs Associated with Serotonin Syndrome
Serotonin syndrome has occurred in patients receiving opioid agonists in conjunction with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 5-HT3 receptor antagonists, certain muscle relaxants (e.g., cyclobenzaprine, metaxalone), other serotonin modulators (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid and methylene blue).122
If concomitant use is warranted, regularly evaluate the patient, particularly during treatment initiation and dose adjustments.122 Discontinue use of codeine if serotonin syndrome is suspected.122
MAO interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).122 Use of codeine is not recommended in patients taking MAO inhibitors or within 14 days of stopping such treatment.122
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist and partial agonist opioid analgesics such as butorphanol, nalbuphine, pentazocine, and buprenorphine may reduce the analgesic effect of codeine and/or precipitate withdrawal symptoms.122 Avoid concomitant use.122
Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression.122 Because respiratory depression may be greater than otherwise expected, decrease the dosage of codeine and/or the muscle relaxant as necessary.122 Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose.122
Codeine is an opioid agonist that is relatively selective for the mu-opioid receptor but has a much weaker affinity than morphine.122 The analgesic properties of codeine may be secondary to its conversion to morphine, although the exact mechanism of analgesic action remains unknown.122
Codeine and its salts are well absorbed following oral administration with peak plasma concentrations occurring 60 minutes after administration.116, 122 When codeine sulfate was administered orally with food (30 minutes after ingesting a high fat/high calorie meal), there was no significant change in the rate and extent of absorption.122 Codeine is widely distributed into tissues.122 Protein binding is low (about 7-25%).122 Codeine is metabolized mainly in the liver where it undergoes O -demethylation by cytochrome P-450 (CYP) isoenzyme 2D6 to the active metabolite morphine, N -demethylation by CYP3A4 to norcodeine, and conjugation with glucuronic acid to codeine-6-glucuronide.110, 136 Morphine and norcodeine are further metabolized via conjugation with glucuronic acid.122 Codeine is excreted mainly (approximately 90%) in the urine as metabolites (only about 10% of unchanged codeine).110, 122 The plasma half-life of codeine and its metabolites is approximately 3 hours.122
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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 1970.115, 116, 122, 130, 131, 132, 133
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 15 mg* | Codeine Sulfate Tablets (C-II) | |
30 mg* | Codeine Sulfate Tablets (C-II) | |||
60 mg* | Codeine Sulfate Tablets (C-II) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | Acetaminophen 120 mg/5 mL and Codeine Phosphate 12 mg/5 mL* | Acetaminophen and Codeine Phosphate Oral Solution (C-V) | |
Tablets | Acetaminophen 300 mg and Codeine Phosphate 15 mg* | Acetaminophen and Codeine Phosphate Tablets (C-III) | ||
Acetaminophen 300 mg and Codeine Phosphate 30 mg* | Acetaminophen and Codeine Phosphate Tablets (C-III) | |||
Acetaminophen 300 mg and Codeine Phosphate 60 mg* | Acetaminophen and Codeine Phosphate Tablets (C-III) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | Promethazine Hydrochloride 6.25 mg/5 mL and Codeine Phosphate 10 mg/5 mL* | Promethazine Hydrochloride and Codeine Phosphate Oral Solution (C-V) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | Promethazine Hydrochloride 6.25 mg/5 mL , Phenylephrine Hydrochloride 5 mg/5 mL , and Codeine Phosphate 10 mg/5 mL* | Promethazine Hydrochloride, Phenylephrine Hydrochloride, and Codeine Phosphate Oral Solution (C-V) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | Butalbital 50 mg, Acetaminophen 300 mg, Caffeine 40 mg, and Codeine Phosphate 30 mg* | Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (C-III) | |
Fioricet® with Codeine (C-III) | Actavis | |||
Butalbital 50 mg, Acetaminophen 325 mg, Caffeine 40 mg, and Codeine Phosphate 30 mg* | Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (C-III) | |||
Butalbital 50 mg, Aspirin 325 mg, Caffeine 40 mg, and Codeine Phosphate 30 mg* | Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules (C-III) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions October 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
106. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008 Mar;11(2 Suppl):S133-53. PMID: 18443637.
107. Koren G, Cairns J, Chitayat D et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet . 2006; 368:704. [PubMed 16920476]
108. Kirchheiner J, Schmidt H, Tzvetkov M et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J . 2007; 7:257-65. [PubMed 16819548]
109. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet . 2000; 356:1667-71. [PubMed 11089838]
110. Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med . 2004; 351:2827-31. [PubMed 15625333]
111. Roche Molecular Systems, Inc. AmpliChip CYP450 Test for in vitro diagnostic use. Branchburg, NJ; 2007 July.
112. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant-an ultra-rapid metabolizer. Paediatr Anaesth . 2007; 17:684-7. [PubMed 17564651]
114. Weinshilboum R. Inheritance and drug response. N Engl J Med . 2003; 348:529-37. [PubMed 12571261]
115. Actavis Pharma. Fioricet® with codeine (butalbital, acetaminophen, caffeine, and codeine capsule) prescribing information. Parsipanny, NJ; 2021 Mar.
116. Amneal Pharmaceuticals. Butalbital, aspirin, caffeine, and codeine phosphate capsule prescribing information. Bridgewater, NJ; 2024 Jan.
122. Hikma Pharmaceuticals. Codeine sulfate tablets prescribing information. Berkeley Heights, NJ; 2023 Dec.
123. Method Pharmaceuticals. Codeine phosphate and guaifenesin solution. Fort Worth, TX; 2023 Dec.
125. Kelly LE, Rieder M, van den Anker J et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics . 2012; 129:e1343-7. [PubMed 22492761]
126. Ciszkowski C, Madadi P, Phillips MS et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med . 2009; 361:827-8. [PubMed 19692698]
127. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatr Anaesth . 2007; 17:684-7. [PubMed 17564651]
128. Yellon RF, Kenna MA, Cladis FP et al. What is the best non-codeine postadenotonsillectomy pain management for children?. Laryngoscope . 2014; :. [PubMed 24867607]
129. Prows CA, Zhang X, Huth MM et al. Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study. Laryngoscope . 2014; 124:1242-50. [PubMed 24122716]
130. PAI Holdings. Acetaminophen and codeine phosphate oral solution prescribing information. Greenville, SC; 2023 Oct.
131. SpecGx LLC. Acetaminophen and codeine phosphate tablets prescribing information. Webster Groves, MO; 2017 Aug.
132. Akorn. Promethazine hydrochloride and codeine phosphate oral solution prescribing information. Gurnee, IL; 2022 Nov.
133. Amneal Pharmaceuticals. Promethazine hydrochloride, phenylephrine hydrochloride, and codeine phosphate oral solution prescribing information. Branchburg, NJ; 2024 Jan.
134. U.S. Food and Drug Administration Over-the-Counter (OTC) Monograph M012: Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-theCounter Human Use (Posted October 14, 2022). [Web]
135. Code of Federal Regulations Title 21 Chapter II Part 1306 Controlled Substances Listed in Schedules III, IV, and V (last amended 7/17/2025). From website. [Web]
136. Crews KR, Monte AA, Huddart R et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. 2021 Oct;110(4):888-896. doi: 10.1002/cpt.2149. Epub 2021 Feb 9. PMID: 33387367; PMCID: PMC8249478.
161. Raffa RB. Pharmacology of oral combination analgesics: rational therapy for pain. J Clin Pharm Ther. 2001; 26:257-64
410. Nuckols TK, Anderson L, Popescu I et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med . 2014; 160:38-47. [PubMed 24217469]
414. Chou R, Cruciani RA, Fiellin DA et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain . 2014; 15:321-37. [PubMed 24685458]
415. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician . 2012; 15(3 Suppl):S67-116.
422. American Academy of Pain Medicine (AAPM). Use of opioids for the treatment of chronic pain. A statement from the American Academy of Pain Medicine. From AAPM website. 2013 Feb. [Web]
423. Franklin GM, American Academy of Neurology. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology . 2014; 83:1277-84. [PubMed 25267983]
430. Chou R, Gordon DB, de Leon-Casasola OA et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain . 2016; 17:131-57. [PubMed 26827847]
431. Washington State Agency Medical Directors' Group (AMDG). Interagency guideline on prescribing opioids for pain, 3rd ed. From Washington State AMDG website. 2015 Jun. [Web]
432. Hegmann KT, Weiss MS, Bowden K et al. ACOEM practice guidelines: opioids for treatment of acute, subacute, chronic, and postoperative pain. J Occup Environ Med . 2014; 56:e143-59.
433. Cantrill SV, Brown MD, Carlisle RJ et al. Clinical policy: critical issues in the prescribing of opioids for adult patients in the emergency department. Ann Emerg Med . 2012; 60:499-525. [PubMed 23010181]
434. Thorson D, Biewen P, Bonte B et al, for Institute for Clinical Systems Improvement (ICSI). Acute pain assessment and opioid prescribing protocol. From ICSI website. 2014 Jan. [Web]
705. Food and Drug Administration. Drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring, MD; 2017 Apr 20. From FDA website. [Web]
710. US Food and Drug Administration. Drug safety communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. Silver Spring, MD; 2018 Jan 11. From FDA website. [Web]
758. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Advances. 2020; 4:2656-2701.
759. Paice JA, Kohlke K, Barton D, et al. Use of opioids for adults with pain from cancer or cancer treatment: ASCO Guideline. J Clin Oncol. 2022; 41:914-930.
760. Dowell D, Ragan KR, Jones CM et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain —United States, 2022. MMWR. 2022; 71:1-95.
762. Opioid analgesic REMS. Initial approval 2012 Jul; revised 2021 Apr 9. Available from FDA website. Accessed 2024 Mar 15. [Web]
772. Institute for Safe Medication Practices (ISMP). ISMP list of high-alert medications in acute care settings. ISMP; 2024.